Protocol Index	

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OP RESEARCH PRO00032606 LOXO-BTK-20022 ARM A SHAH	

Types:      Research Oncology Treatment
Synonyms:  VENETOCLAX, PIRTOBRUTINIB, RITUXIMAB

Cycle 1	Repeat 1 time	Cycle length: 35 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Line Flush
  	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Nursing Orders
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mEq/L; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 19	Interval: --	Occurrences: --	Comments:	Dose Modification for Rituximab: Patients at high risk for infusion related reactions with rituximab may, at the Investigator's discretion, receive the initial dose of rituximab split over 2 consecutive days (refer to Table 1). No other dose modifications are allowed for rituximab. Refer to the rituximab local label (or label for the approved biosimilar that is being used) for administration of  rituximab (US prescribing information is provided as a reference: Venetoclax USPI; Rituximab USPI; Rituximab biosimilars: Riabni USPI; Ruxience USPI; Truxima USPI). Rituximab should be  administered according to local institutional standards with appropriate premedications (refer to Section 6.1.1).
o If rituximab is discontinued, patients can continue to receive venetoclax and/or pirtobrutinib as outlined in this protocol depending on the treatment arm to which the patient is assigned.
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Nursing Orders
  	ONC NURSING COMMUNICATION 20	Interval: --	Occurrences: --	Comments:	Patient reported outcomes to be completed In clinic prior to first dose of study drug (C1D1).
		  	ONC NURSING COMMUNICATION 22	Interval: --	Occurrences: --	Comments:	All PRO assessments MUST be completed electronically. Refer to Section 8.12.1 for more details. 
o EORTC QLQ-C30; 
o EORTC IL 58 (CLL/SLL Symptoms Supplement); 
o EQ-5D-5L;
o PGIS
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	SODIUM LEVEL	Interval: --	Occurrences: --		  	POTASSIUM LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	CHLORIDE LEVEL	Interval: --	Occurrences: --		  	GLUCOSE LEVEL	Interval: --	Occurrences: --		  	CREATININE LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	PROTEIN, TOTAL	Interval: --	Occurrences: --		  	ALBUMIN LEVEL	Interval: --	Occurrences: --		  	TOTAL BILIRUBIN	Interval: --	Occurrences: --		  	ALT (SGPT)	Interval: --	Occurrences: --		  	AST (SGOT)	Interval: --	Occurrences: --		  	LDH	Interval: --	Occurrences: --		  	CALCIUM LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	MAGNESIUM LEVEL	Interval: --	Occurrences: --		  	PHOSPHORUS LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	URIC ACID LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 6	Interval: --	Occurrences: --	Comments:	o CRC to schedule Saliva collection for germline DNA (optional) as clinically indicated. 
o Collect only if patient has consented to collection and testing; refer to Laboratory Manual for details.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Rituximab Pre-Medications
  	acetaminophen (TYLENOL) tablet 650 mg	Dose: 650 mg	Route: oral	once for 1 dose	Start: S			Instructions:	Give 30 minutes before rituximab infusion.		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	once for 1 dose	Start: S			Instructions:	Give 30 minutes before rituximab infusion.		  	sodium chloride 0.9 % infusion 500 mL	Dose: 500 mL	Route: intravenous	continuous	Start: S					Chemotherapy
◉	riTUXimab-abbs (TRUXIMA) 375 mg/m2 in sodium chloride 0.9% INITIAL INFUSION RATE IVPB	Dose: 375 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion at rate of 50 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), then increase infusion rate by 50 mg/hour every 30 minutes, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ABBS 10 MG/ML INTRAVENOUS SOLUTION	Medications	375 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	RiTUXimab (PF) (RITUXAN) 375 mg/m2 in sodium chloride 0.9% INITIAL INFUSION RATE IVPB	Dose: 375 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion at rate of 50 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), then increase infusion rate by 50 mg/hour every 30 minutes, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB 10 MG/ML CONCENTRATE,INTRAVENOUS	Medications	375 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	rituximab-pvvr (PF) (RUXIENCE) 375 mg/m2 in sodium chloride 0.9% INITIAL INFUSION RATE IVPB	Dose: 375 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion at rate of 50 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), then increase infusion rate by 50 mg/hour every 30 minutes, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-PVVR 10 MG/ML INTRAVENOUS SOLUTION	Medications	375 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	rituximab-arrx (RIABNI) 375 mg/m2 in sodium chloride 0.9% INITIAL INFUSION RATE IVPB	Dose: 375 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion at rate of 50 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), then increase infusion rate by 50 mg/hour every 30 minutes, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ARRX 10 MG/ML INTRAVENOUS SOLUTION	Medications	375 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes				Rituximab Instructions
  	VITAL SIGNS - T/P/R/BP PER UNIT PROTOCOL	Interval: --	Occurrences: --	Comments:	1) During Rituximab infusion:
-Vitals every 15 minutes during 1st hour of infusion, THEN
-Every 30 minutes for 1 hour, THEN
-Every hour until end of infusion
-Call MD if SBP less than 90, pulse less than 60 or greater than 120, temperature greater than 38.5 degrees C
		  	ONC NURSING COMMUNICATION 26	Interval: --	Occurrences: --	Comments:	2) Infuse antibody via pump
3) If any of the following occurs: FEVER (T greater than 38.5 degrees C), RIGORS, HYPOTENSION (30mm Hg decrease from baseline), and / or MUCOSAL CONGESTION / EDEMA, HOLD infusion until improvement of symptoms (When symptoms improve, resume infusion at HALF the previous rate)

			Rituximab Infusion Reaction Orders
  	meperidine (DEMEROL) injection 25 mg	Dose: 25 mg	Route: intravenous	once PRN	Start: S				  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	once PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	once PRN					  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	once PRN	Start: S					Rituximab Additional Orders
  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: intramuscular	once PRN	Start: S					Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only – itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Fexofenadine 180 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 – MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms – shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Fexofenadine 180 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	fexofenadine (ALLEGRA) tablet 180 mg	Dose: 180 mg	Route: oral	PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
			Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 2	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Line Flush
  	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Nursing Orders
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mEq/L; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 19	Interval: --	Occurrences: --	Comments:	Dose Modification for Rituximab: Patients at high risk for infusion related reactions with rituximab may, at the Investigator's discretion, receive the initial dose of rituximab split over 2 consecutive days (refer to Table 1). No other dose modifications are allowed for rituximab. Refer to the rituximab local label (or label for the approved biosimilar that is being used) for administration of  rituximab (US prescribing information is provided as a reference: Venetoclax USPI; Rituximab USPI; Rituximab biosimilars: Riabni USPI; Ruxience USPI; Truxima USPI). Rituximab should be  administered according to local institutional standards with appropriate premedications (refer to Section 6.1.1).
o If rituximab is discontinued, patients can continue to receive venetoclax and/or pirtobrutinib as outlined in this protocol depending on the treatment arm to which the patient is assigned.
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Nursing Orders
  	ONC NURSING COMMUNICATION 22	Interval: --	Occurrences: --	Comments:	All PRO assessments MUST be completed electronically. Refer to Section 8.12.1 for more details. 
o EORTC QLQ-C30; 
o EORTC IL 58 (CLL/SLL Symptoms Supplement); 
o EQ-5D-5L
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	SODIUM LEVEL	Interval: --	Occurrences: --		  	POTASSIUM LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	CHLORIDE LEVEL	Interval: --	Occurrences: --		  	GLUCOSE LEVEL	Interval: --	Occurrences: --		  	CREATININE LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	PROTEIN, TOTAL	Interval: --	Occurrences: --		  	ALBUMIN LEVEL	Interval: --	Occurrences: --		  	TOTAL BILIRUBIN	Interval: --	Occurrences: --		  	ALT (SGPT)	Interval: --	Occurrences: --		  	AST (SGOT)	Interval: --	Occurrences: --		  	LDH	Interval: --	Occurrences: --		  	CALCIUM LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	MAGNESIUM LEVEL	Interval: --	Occurrences: --		  	PHOSPHORUS LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	URIC ACID LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --	Comments:	Pre-dose samples only; refer to Section 8.8 and Laboratory Manual for details
o Cycle 2-3: PK draws for pirtobrutinib (LOXO-305) only. 
o Cycle 4-6: PK draws for pirtobrutinib (LOXO-305) AND venetoclax (samples can be drawn at the same time). 
o Samples should be drawn within 2 hours prior to the venetoclax and/or pirtobrutinib (LOXO-305) dose.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Rituximab Pre-Medications
  	acetaminophen (TYLENOL) tablet 650 mg	Dose: 650 mg	Route: oral	once for 1 dose	Start: S			Instructions:	Give 30 minutes before rituximab infusion.		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	once for 1 dose	Start: S			Instructions:	Give 30 minutes before rituximab infusion.		  	sodium chloride 0.9 % infusion 500 mL	Dose: 500 mL	Route: intravenous	continuous	Start: S					Pharmacy Consult
  	PHARMACY CONSULT TO SCREEN FOR RAPID RITUXIMAB INFUSION	Interval: --	Occurrences: --			Chemotherapy
◉	riTUXimab-abbs (TRUXIMA) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ABBS 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	RiTUXimab (PF) (RITUXAN) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB 10 MG/ML CONCENTRATE,INTRAVENOUS	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	rituximab-pvvr (PF) (RUXIENCE) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-PVVR 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	rituximab-arrx (RIABNI) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ARRX 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	riTUXimab-abbs (TRUXIMA) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ABBS 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	RiTUXimab (PF) (RITUXAN) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	RAPID INFUSION RATE:  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.

Reaction grades:

Grade 3 Reaction: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates).

Grade 4 Reaction: Life-threatening consequences; urgent intervention indicated (e.g., vasopressors or ventilator support).	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB 10 MG/ML CONCENTRATE,INTRAVENOUS	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	rituximab-pvvr (PF) (RUXIENCE) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-PVVR 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	rituximab-arrx (RIABNI) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ARRX 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes				Rituximab Instructions
  	VITAL SIGNS - T/P/R/BP PER UNIT PROTOCOL	Interval: --	Occurrences: --	Comments:	1) During Rituximab infusion:
-Vitals every 15 minutes during 1st hour of infusion, THEN
-Every 30 minutes for 1 hour, THEN
-Every hour until end of infusion
-Call MD if SBP less than 90, pulse less than 60 or greater than 120, temperature greater than 38.5 degrees C
		  	ONC NURSING COMMUNICATION 26	Interval: --	Occurrences: --	Comments:	2) Infuse antibody via pump
3) If any of the following occurs: FEVER (T greater than 38.5 degrees C), RIGORS, HYPOTENSION (30mm Hg decrease from baseline), and / or MUCOSAL CONGESTION / EDEMA, HOLD infusion until improvement of symptoms (When symptoms improve, resume infusion at HALF the previous rate)

			Rituximab Infusion Reaction Orders
  	meperidine (DEMEROL) injection 25 mg	Dose: 25 mg	Route: intravenous	once PRN	Start: S				  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	once PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	once PRN					  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	once PRN	Start: S					Rituximab Additional Orders
  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: intramuscular	once PRN	Start: S					Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only – itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Fexofenadine 180 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 – MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms – shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Fexofenadine 180 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	fexofenadine (ALLEGRA) tablet 180 mg	Dose: 180 mg	Route: oral	PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
			Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 3	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Line Flush
  	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Nursing Orders
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mEq/L; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 19	Interval: --	Occurrences: --	Comments:	Dose Modification for Rituximab: Patients at high risk for infusion related reactions with rituximab may, at the Investigator's discretion, receive the initial dose of rituximab split over 2 consecutive days (refer to Table 1). No other dose modifications are allowed for rituximab. Refer to the rituximab local label (or label for the approved biosimilar that is being used) for administration of  rituximab (US prescribing information is provided as a reference: Venetoclax USPI; Rituximab USPI; Rituximab biosimilars: Riabni USPI; Ruxience USPI; Truxima USPI). Rituximab should be  administered according to local institutional standards with appropriate premedications (refer to Section 6.1.1).
o If rituximab is discontinued, patients can continue to receive venetoclax and/or pirtobrutinib as outlined in this protocol depending on the treatment arm to which the patient is assigned.
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	SODIUM LEVEL	Interval: --	Occurrences: --		  	POTASSIUM LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	CHLORIDE LEVEL	Interval: --	Occurrences: --		  	GLUCOSE LEVEL	Interval: --	Occurrences: --		  	CREATININE LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	PROTEIN, TOTAL	Interval: --	Occurrences: --		  	ALBUMIN LEVEL	Interval: --	Occurrences: --		  	TOTAL BILIRUBIN	Interval: --	Occurrences: --		  	ALT (SGPT)	Interval: --	Occurrences: --		  	AST (SGOT)	Interval: --	Occurrences: --		  	LDH	Interval: --	Occurrences: --		  	CALCIUM LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	MAGNESIUM LEVEL	Interval: --	Occurrences: --		  	PHOSPHORUS LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	URIC ACID LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --	Comments:	Pre-dose samples only; refer to Section 8.8 and Laboratory Manual for details
o Cycle 2-3: PK draws for pirtobrutinib (LOXO-305) only. 
o Cycle 4-6: PK draws for pirtobrutinib (LOXO-305) AND venetoclax (samples can be drawn at the same time). 
o Samples should be drawn within 2 hours prior to the venetoclax and/or pirtobrutinib (LOXO-305) dose.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Rituximab Pre-Medications
  	acetaminophen (TYLENOL) tablet 650 mg	Dose: 650 mg	Route: oral	once for 1 dose	Start: S			Instructions:	Give 30 minutes before rituximab infusion.		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	once for 1 dose	Start: S			Instructions:	Give 30 minutes before rituximab infusion.		  	sodium chloride 0.9 % infusion 500 mL	Dose: 500 mL	Route: intravenous	continuous	Start: S					Pharmacy Consult
  	PHARMACY CONSULT TO SCREEN FOR RAPID RITUXIMAB INFUSION	Interval: --	Occurrences: --			Chemotherapy
◉	riTUXimab-abbs (TRUXIMA) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ABBS 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	RiTUXimab (PF) (RITUXAN) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB 10 MG/ML CONCENTRATE,INTRAVENOUS	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	rituximab-pvvr (PF) (RUXIENCE) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-PVVR 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	rituximab-arrx (RIABNI) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ARRX 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	riTUXimab-abbs (TRUXIMA) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ABBS 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	RiTUXimab (PF) (RITUXAN) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	RAPID INFUSION RATE:  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.

Reaction grades:

Grade 3 Reaction: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates).

Grade 4 Reaction: Life-threatening consequences; urgent intervention indicated (e.g., vasopressors or ventilator support).	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB 10 MG/ML CONCENTRATE,INTRAVENOUS	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	rituximab-pvvr (PF) (RUXIENCE) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-PVVR 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	rituximab-arrx (RIABNI) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ARRX 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes				Rituximab Instructions
  	VITAL SIGNS - T/P/R/BP PER UNIT PROTOCOL	Interval: --	Occurrences: --	Comments:	1) During Rituximab infusion:
-Vitals every 15 minutes during 1st hour of infusion, THEN
-Every 30 minutes for 1 hour, THEN
-Every hour until end of infusion
-Call MD if SBP less than 90, pulse less than 60 or greater than 120, temperature greater than 38.5 degrees C
		  	ONC NURSING COMMUNICATION 26	Interval: --	Occurrences: --	Comments:	2) Infuse antibody via pump
3) If any of the following occurs: FEVER (T greater than 38.5 degrees C), RIGORS, HYPOTENSION (30mm Hg decrease from baseline), and / or MUCOSAL CONGESTION / EDEMA, HOLD infusion until improvement of symptoms (When symptoms improve, resume infusion at HALF the previous rate)

			Rituximab Infusion Reaction Orders
  	meperidine (DEMEROL) injection 25 mg	Dose: 25 mg	Route: intravenous	once PRN	Start: S				  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	once PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	once PRN					  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	once PRN	Start: S					Rituximab Additional Orders
  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: intramuscular	once PRN	Start: S					Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only – itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Fexofenadine 180 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 – MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms – shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Fexofenadine 180 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	fexofenadine (ALLEGRA) tablet 180 mg	Dose: 180 mg	Route: oral	PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
			Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 4	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Line Flush
  	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Nursing Orders
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mEq/L; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 19	Interval: --	Occurrences: --	Comments:	Dose Modification for Rituximab: Patients at high risk for infusion related reactions with rituximab may, at the Investigator's discretion, receive the initial dose of rituximab split over 2 consecutive days (refer to Table 1). No other dose modifications are allowed for rituximab. Refer to the rituximab local label (or label for the approved biosimilar that is being used) for administration of  rituximab (US prescribing information is provided as a reference: Venetoclax USPI; Rituximab USPI; Rituximab biosimilars: Riabni USPI; Ruxience USPI; Truxima USPI). Rituximab should be  administered according to local institutional standards with appropriate premedications (refer to Section 6.1.1).
o If rituximab is discontinued, patients can continue to receive venetoclax and/or pirtobrutinib as outlined in this protocol depending on the treatment arm to which the patient is assigned.
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Provider Communication
  	ONC PROVIDER COMMUNICATION	Interval: --	Occurrences: --	Comments:	TLS Risk as clinically indicated. CRC and treatment team to order if necessary
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	SODIUM LEVEL	Interval: --	Occurrences: --		  	POTASSIUM LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	CHLORIDE LEVEL	Interval: --	Occurrences: --		  	GLUCOSE LEVEL	Interval: --	Occurrences: --		  	CREATININE LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	PROTEIN, TOTAL	Interval: --	Occurrences: --		  	ALBUMIN LEVEL	Interval: --	Occurrences: --		  	TOTAL BILIRUBIN	Interval: --	Occurrences: --		  	ALT (SGPT)	Interval: --	Occurrences: --		  	AST (SGOT)	Interval: --	Occurrences: --		  	LDH	Interval: --	Occurrences: --		  	CALCIUM LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	MAGNESIUM LEVEL	Interval: --	Occurrences: --		  	PHOSPHORUS LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	URIC ACID LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Imaging
☑	CT SOFT TISSUE NECK W CONTRAST	Interval: --	Occurrences: --	Comments:	o Up to 14 days prior to C4D1. 
o CT scan with IV contrast agent is the preferred method of assessment with scans of neck, chest, abdomen and pelvis. However, MRI is acceptable if CT scan with contrast agent is contraindicated
		☑	CT CHEST W CONTRAST ABDOMEN W CONTRAST PELVIS W CONTRAST	Interval: --	Occurrences: --	Comments:	o Up to 14 days prior to C4D1. 
o CT scan with IV contrast agent is the preferred method of assessment with scans of neck, chest, abdomen and pelvis. However, MRI is acceptable if CT scan with contrast agent is contraindicated
		☐	MRI NECK SOFT TISSUE ONLY WO CONTRAST	Interval: --	Occurrences: --	Comments:	Up to 14 days prior to C4D1.
		☐	MRI CHEST WO CONTRAST	Interval: --	Occurrences: --	Comments:	Up to 14 days prior to C4D1.
		☐	MRI ABDOMEN WO CONTRAST	Interval: --	Occurrences: --	Comments:	Up to 14 days prior to C4D1.
		☐	MRI PELVIS WO CONTRAST	Interval: --	Occurrences: --	Comments:	Up to 14 days prior to C4D1.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --	Comments:	Pre-dose samples only; refer to Section 8.8 and Laboratory Manual for details
o Cycle 2-3: PK draws for pirtobrutinib (LOXO-305) only. 
o Cycle 4-6: PK draws for pirtobrutinib (LOXO-305) AND venetoclax (samples can be drawn at the same time). 
o Samples should be drawn within 2 hours prior to the venetoclax and/or pirtobrutinib (LOXO-305) dose.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Rituximab Pre-Medications
  	acetaminophen (TYLENOL) tablet 650 mg	Dose: 650 mg	Route: oral	once for 1 dose	Start: S			Instructions:	Give 30 minutes before rituximab infusion.		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	once for 1 dose	Start: S			Instructions:	Give 30 minutes before rituximab infusion.		  	sodium chloride 0.9 % infusion 500 mL	Dose: 500 mL	Route: intravenous	continuous	Start: S					Pharmacy Consult
  	PHARMACY CONSULT TO SCREEN FOR RAPID RITUXIMAB INFUSION	Interval: --	Occurrences: --			Chemotherapy
◉	riTUXimab-abbs (TRUXIMA) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ABBS 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	RiTUXimab (PF) (RITUXAN) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB 10 MG/ML CONCENTRATE,INTRAVENOUS	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	rituximab-pvvr (PF) (RUXIENCE) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-PVVR 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	rituximab-arrx (RIABNI) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ARRX 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	riTUXimab-abbs (TRUXIMA) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ABBS 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	RiTUXimab (PF) (RITUXAN) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	RAPID INFUSION RATE:  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.

Reaction grades:

Grade 3 Reaction: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates).

Grade 4 Reaction: Life-threatening consequences; urgent intervention indicated (e.g., vasopressors or ventilator support).	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB 10 MG/ML CONCENTRATE,INTRAVENOUS	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	rituximab-pvvr (PF) (RUXIENCE) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-PVVR 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	rituximab-arrx (RIABNI) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ARRX 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes				Rituximab Instructions
  	VITAL SIGNS - T/P/R/BP PER UNIT PROTOCOL	Interval: --	Occurrences: --	Comments:	1) During Rituximab infusion:
-Vitals every 15 minutes during 1st hour of infusion, THEN
-Every 30 minutes for 1 hour, THEN
-Every hour until end of infusion
-Call MD if SBP less than 90, pulse less than 60 or greater than 120, temperature greater than 38.5 degrees C
		  	ONC NURSING COMMUNICATION 26	Interval: --	Occurrences: --	Comments:	2) Infuse antibody via pump
3) If any of the following occurs: FEVER (T greater than 38.5 degrees C), RIGORS, HYPOTENSION (30mm Hg decrease from baseline), and / or MUCOSAL CONGESTION / EDEMA, HOLD infusion until improvement of symptoms (When symptoms improve, resume infusion at HALF the previous rate)

			Rituximab Infusion Reaction Orders
  	meperidine (DEMEROL) injection 25 mg	Dose: 25 mg	Route: intravenous	once PRN	Start: S				  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	once PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	once PRN					  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	once PRN	Start: S					Rituximab Additional Orders
  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: intramuscular	once PRN	Start: S					Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only – itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Fexofenadine 180 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 – MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms – shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Fexofenadine 180 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	fexofenadine (ALLEGRA) tablet 180 mg	Dose: 180 mg	Route: oral	PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
			Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 5	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Line Flush
  	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Nursing Orders
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mEq/L; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 19	Interval: --	Occurrences: --	Comments:	Dose Modification for Rituximab: Patients at high risk for infusion related reactions with rituximab may, at the Investigator's discretion, receive the initial dose of rituximab split over 2 consecutive days (refer to Table 1). No other dose modifications are allowed for rituximab. Refer to the rituximab local label (or label for the approved biosimilar that is being used) for administration of  rituximab (US prescribing information is provided as a reference: Venetoclax USPI; Rituximab USPI; Rituximab biosimilars: Riabni USPI; Ruxience USPI; Truxima USPI). Rituximab should be  administered according to local institutional standards with appropriate premedications (refer to Section 6.1.1).
o If rituximab is discontinued, patients can continue to receive venetoclax and/or pirtobrutinib as outlined in this protocol depending on the treatment arm to which the patient is assigned.
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Nursing Orders
  	ONC NURSING COMMUNICATION 22	Interval: --	Occurrences: --	Comments:	All PRO assessments MUST be completed electronically. Refer to Section 8.12.1 for more details. 
o EORTC QLQ-C30; 
o EORTC IL 58 (CLL/SLL Symptoms Supplement); 
o EQ-5D-5L
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	SODIUM LEVEL	Interval: --	Occurrences: --		  	POTASSIUM LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	CHLORIDE LEVEL	Interval: --	Occurrences: --		  	GLUCOSE LEVEL	Interval: --	Occurrences: --		  	CREATININE LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	PROTEIN, TOTAL	Interval: --	Occurrences: --		  	ALBUMIN LEVEL	Interval: --	Occurrences: --		  	TOTAL BILIRUBIN	Interval: --	Occurrences: --		  	ALT (SGPT)	Interval: --	Occurrences: --		  	AST (SGOT)	Interval: --	Occurrences: --		  	LDH	Interval: --	Occurrences: --		  	CALCIUM LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	MAGNESIUM LEVEL	Interval: --	Occurrences: --		  	PHOSPHORUS LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	URIC ACID LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --	Comments:	Pre-dose samples only; refer to Section 8.8 and Laboratory Manual for details
o Cycle 2-3: PK draws for pirtobrutinib (LOXO-305) only. 
o Cycle 4-6: PK draws for pirtobrutinib (LOXO-305) AND venetoclax (samples can be drawn at the same time). 
o Samples should be drawn within 2 hours prior to the venetoclax and/or pirtobrutinib (LOXO-305) dose.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Rituximab Pre-Medications
  	acetaminophen (TYLENOL) tablet 650 mg	Dose: 650 mg	Route: oral	once for 1 dose	Start: S			Instructions:	Give 30 minutes before rituximab infusion.		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	once for 1 dose	Start: S			Instructions:	Give 30 minutes before rituximab infusion.		  	sodium chloride 0.9 % infusion 500 mL	Dose: 500 mL	Route: intravenous	continuous	Start: S					Pharmacy Consult
  	PHARMACY CONSULT TO SCREEN FOR RAPID RITUXIMAB INFUSION	Interval: --	Occurrences: --			Chemotherapy
◉	riTUXimab-abbs (TRUXIMA) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ABBS 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	RiTUXimab (PF) (RITUXAN) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB 10 MG/ML CONCENTRATE,INTRAVENOUS	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	rituximab-pvvr (PF) (RUXIENCE) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-PVVR 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	rituximab-arrx (RIABNI) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ARRX 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	riTUXimab-abbs (TRUXIMA) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ABBS 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	RiTUXimab (PF) (RITUXAN) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	RAPID INFUSION RATE:  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.

Reaction grades:

Grade 3 Reaction: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates).

Grade 4 Reaction: Life-threatening consequences; urgent intervention indicated (e.g., vasopressors or ventilator support).	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB 10 MG/ML CONCENTRATE,INTRAVENOUS	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	rituximab-pvvr (PF) (RUXIENCE) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-PVVR 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	rituximab-arrx (RIABNI) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ARRX 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes				Rituximab Instructions
  	VITAL SIGNS - T/P/R/BP PER UNIT PROTOCOL	Interval: --	Occurrences: --	Comments:	1) During Rituximab infusion:
-Vitals every 15 minutes during 1st hour of infusion, THEN
-Every 30 minutes for 1 hour, THEN
-Every hour until end of infusion
-Call MD if SBP less than 90, pulse less than 60 or greater than 120, temperature greater than 38.5 degrees C
		  	ONC NURSING COMMUNICATION 26	Interval: --	Occurrences: --	Comments:	2) Infuse antibody via pump
3) If any of the following occurs: FEVER (T greater than 38.5 degrees C), RIGORS, HYPOTENSION (30mm Hg decrease from baseline), and / or MUCOSAL CONGESTION / EDEMA, HOLD infusion until improvement of symptoms (When symptoms improve, resume infusion at HALF the previous rate)

			Rituximab Infusion Reaction Orders
  	meperidine (DEMEROL) injection 25 mg	Dose: 25 mg	Route: intravenous	once PRN	Start: S				  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	once PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	once PRN					  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	once PRN	Start: S					Rituximab Additional Orders
  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: intramuscular	once PRN	Start: S					Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only – itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Fexofenadine 180 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 – MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms – shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Fexofenadine 180 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	fexofenadine (ALLEGRA) tablet 180 mg	Dose: 180 mg	Route: oral	PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
			Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 6	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Appointment Requests
  	INFUSION APPOINTMENT REQUEST	Interval: --	Occurrences: --			Line Flush
  	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN	Start: S					Nursing Orders
  	sodium chloride 0.9 % infusion 250 mL	Dose: 250 mL	Route: intravenous	once @ 30 mL/hr for 1 dose	Start: S			Instructions:	To keep vein open.			Outpatient Electrolyte Replacement Protocol
  	TREATMENT CONDITIONS 39	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Potassium level LESS than 3.5 mEq/L; 
3. Recent pre-infusion labs.   

Dosing is based on lab value.
o Serum potassium less than 3.0mEq/L, give 40mEq KCL IV or PO and contact MD/NP. 
o Serum potassium 3.0 to 3.2mEq/L, give 40mEq KCL IV or PO. 
o Serum potassium 3.3 to 3.4mEq/L, give 20mEq KCL IV or PO. 
o Serum potassium 3.5 mEq/L or greater, do not give potassium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
		  	TREATMENT CONDITIONS 40 	Interval: --	Occurrences: --	Comments:	The protocol applies only if the following is met. 
1. SCr LESS than 1.5; 
2. Magnesium level LESS than 1.6 mEq/L; 
3. Recent pre-infusion labs. 

Dosing is based on lab value. 
o Serum Magnesium less than 1.0 mg/dL, give 2 gram magnesium sulfate IV and contact MD/NP. 
o Serum Magnesium 1.0 to 1.2 mg/dL, give 2 gram magnesium sulfate IV. 
o Serum Magnesium 1.3 to 1.5 mg/dL, give 1 gram magnesium sulfate IV. 
o Serum Magnesium 1.6 mg/dL or greater, do not give magnesium replacement. 

If patient meets criteria, order THERAPY PLAN called "Outpatient Electrolyte Replacement". 
Sign electrolyte replacement order as Per protocol: cosign required.
			Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 19	Interval: --	Occurrences: --	Comments:	Dose Modification for Rituximab: Patients at high risk for infusion related reactions with rituximab may, at the Investigator's discretion, receive the initial dose of rituximab split over 2 consecutive days (refer to Table 1). No other dose modifications are allowed for rituximab. Refer to the rituximab local label (or label for the approved biosimilar that is being used) for administration of  rituximab (US prescribing information is provided as a reference: Venetoclax USPI; Rituximab USPI; Rituximab biosimilars: Riabni USPI; Ruxience USPI; Truxima USPI). Rituximab should be  administered according to local institutional standards with appropriate premedications (refer to Section 6.1.1).
o If rituximab is discontinued, patients can continue to receive venetoclax and/or pirtobrutinib as outlined in this protocol depending on the treatment arm to which the patient is assigned.
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	SODIUM LEVEL	Interval: --	Occurrences: --		  	POTASSIUM LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	CHLORIDE LEVEL	Interval: --	Occurrences: --		  	GLUCOSE LEVEL	Interval: --	Occurrences: --		  	CREATININE LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	PROTEIN, TOTAL	Interval: --	Occurrences: --		  	ALBUMIN LEVEL	Interval: --	Occurrences: --		  	TOTAL BILIRUBIN	Interval: --	Occurrences: --		  	ALT (SGPT)	Interval: --	Occurrences: --		  	AST (SGOT)	Interval: --	Occurrences: --		  	LDH	Interval: --	Occurrences: --		  	CALCIUM LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	MAGNESIUM LEVEL	Interval: --	Occurrences: --		  	PHOSPHORUS LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
		  	URIC ACID LEVEL	Interval: --	Occurrences: --	Comments:	Sample to be drawn for venetoclax TLS monitoring. For start of both 20mg dose and 50mg dose: collected pre-dose, 6-8 hours post-dose, and 24 hours post dose. For remaining dose increases of venetoclax, labs are drawn pre-dose.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --	Comments:	Pre-dose samples only; refer to Section 8.8 and Laboratory Manual for details
o Cycle 2-3: PK draws for pirtobrutinib (LOXO-305) only. 
o Cycle 4-6: PK draws for pirtobrutinib (LOXO-305) AND venetoclax (samples can be drawn at the same time). 
o Samples should be drawn within 2 hours prior to the venetoclax and/or pirtobrutinib (LOXO-305) dose.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Rituximab Pre-Medications
  	acetaminophen (TYLENOL) tablet 650 mg	Dose: 650 mg	Route: oral	once for 1 dose	Start: S			Instructions:	Give 30 minutes before rituximab infusion.		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	once for 1 dose	Start: S			Instructions:	Give 30 minutes before rituximab infusion.		  	sodium chloride 0.9 % infusion 500 mL	Dose: 500 mL	Route: intravenous	continuous	Start: S					Pharmacy Consult
  	PHARMACY CONSULT TO SCREEN FOR RAPID RITUXIMAB INFUSION	Interval: --	Occurrences: --			Chemotherapy
◉	riTUXimab-abbs (TRUXIMA) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ABBS 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	RiTUXimab (PF) (RITUXAN) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB 10 MG/ML CONCENTRATE,INTRAVENOUS	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	rituximab-pvvr (PF) (RUXIENCE) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-PVVR 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	rituximab-arrx (RIABNI) 500 mg/m2 in sodium chloride 0.9% NON-INITIAL INFUSION IVPB	Dose: 500 mg/m2	Route: intravenous	once for 1 dose			Offset: 30 Minutes	Instructions:	Initiate infusion rate at a 100 mg/hour.  In the absence of infusion toxicity (SBP within 20 mmHG of baseline, PULSE between 60 and 120 and TEMP less than 38 degrees C, and no symptoms), increase rate by 100 mg/hour increments at 30 minute intervals, to a maximum rate of 400 mg/hour.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ARRX 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	Base	 	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	Base	 	No	Yes			◯	riTUXimab-abbs (TRUXIMA) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ABBS 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	RiTUXimab (PF) (RITUXAN) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	RAPID INFUSION RATE:  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.

Reaction grades:

Grade 3 Reaction: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates).

Grade 4 Reaction: Life-threatening consequences; urgent intervention indicated (e.g., vasopressors or ventilator support).	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB 10 MG/ML CONCENTRATE,INTRAVENOUS	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	rituximab-pvvr (PF) (RUXIENCE) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-PVVR 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes			◯	rituximab-arrx (RIABNI) 500 mg/m2 in sodium chloride 0.9% 250 mL RAPID INFUSION RATE IVPB	Dose: 500 mg/m2	Route: intravenous	once over 90 Minutes for 1 dose			Offset: 30 Minutes	Instructions:	Do not shake.  Initiate infusion at a rate of 100mL/hour.  After 30 minutes, in the absence of infusion reactions (SBP within 20 mmHg of baseline, PULSE between 60 and 120 and Temp less than 38 degrees C, and no symptoms), increase the infusion rate to 200mL/hour.  This infusion should take 90 minutes to administer.	Ingredients:	Name	Type	Dose	Selected	Adds Vol.	RITUXIMAB-ARRX 10 MG/ML INTRAVENOUS SOLUTION	Medications	500 mg/m2	Main Ingredient	Yes	SODIUM CHLORIDE 0.9 % INTRAVENOUS SOLUTION	QS Base	250 mL	Yes	Yes	DEXTROSE 5 % IN WATER (D5W) INTRAVENOUS SOLUTION	QS Base	 	No	Yes				Rituximab Instructions
  	VITAL SIGNS - T/P/R/BP PER UNIT PROTOCOL	Interval: --	Occurrences: --	Comments:	1) During Rituximab infusion:
-Vitals every 15 minutes during 1st hour of infusion, THEN
-Every 30 minutes for 1 hour, THEN
-Every hour until end of infusion
-Call MD if SBP less than 90, pulse less than 60 or greater than 120, temperature greater than 38.5 degrees C
		  	ONC NURSING COMMUNICATION 26	Interval: --	Occurrences: --	Comments:	2) Infuse antibody via pump
3) If any of the following occurs: FEVER (T greater than 38.5 degrees C), RIGORS, HYPOTENSION (30mm Hg decrease from baseline), and / or MUCOSAL CONGESTION / EDEMA, HOLD infusion until improvement of symptoms (When symptoms improve, resume infusion at HALF the previous rate)

			Rituximab Infusion Reaction Orders
  	meperidine (DEMEROL) injection 25 mg	Dose: 25 mg	Route: intravenous	once PRN	Start: S				  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	once PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	once PRN					  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	once PRN	Start: S					Rituximab Additional Orders
  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: intramuscular	once PRN	Start: S					Hematology & Oncology Hypersensitivity Reaction Standing Order
  	ONC NURSING COMMUNICATION 82	Interval: --	Occurrences: --	Comments:	Grade 1 - MILD Symptoms (cutaneous and subcutaneous symptoms only – itching, flushing, periorbital edema, rash, or runny nose)
1. Stop the infusion.
2. Place the patient on continuous monitoring.
3. Obtain vital signs.
4. Administer Normal Saline at 50 mL per hour using a new bag and new intravenous tubing.
5. If greater than or equal to 30 minutes since the last dose of Diphenhydramine, administer Diphenhydramine 25 mg intravenous once.
6. If less than 30 minutes since the last dose of Diphenhydramine, administer Fexofenadine 180 mg orally and Famotidine 20 mg intravenous once.
7. Notify the treating physician.
8. If no improvement after 15 minutes, advance level of care to Grade 2 (Moderate) or Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	Grade 2 – MODERATE Symptoms (cardiovascular, respiratory, or gastrointestinal symptoms – shortness of breath, wheezing, nausea, vomiting, dizziness, diaphoresis, throat or chest tightness, abdominal or back pain)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
6. Administer Normal Saline at 150 mL per hour using a new bag and new intravenous tubing.
7. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous), Fexofenadine 180 mg orally and Famotidine 20 mg intravenous once.
8. If no improvement after 15 minutes, advance level of care to Grade 3 (Severe).
9. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	ONC NURSING COMMUNICATION 83	Interval: --	Occurrences: --	Comments:	Grade 3 – SEVERE Symptoms (hypoxia, hypotension, or neurologic compromise – cyanosis or O2 saturation less than 92%, hypotension with systolic blood pressure less than 90 mmHg, confusion, collapse, loss of consciousness, or incontinence)
1. Stop the infusion.
2. Notify the CERT team and treating physician immediately.
3. Place the patient on continuous monitoring.
4. Obtain vital signs.
5. If heart rate is less than 50 or greater than 120, or blood pressure is less than 90/50 mmHg, place patient in reclined or flattened position.
6. Administer Oxygen at 2 L per minute via nasal cannula. Titrate to maintain O2 saturation of greater than or equal to 92%.
7. Administer Normal Saline at 1000 mL intravenous bolus using a new bag and new intravenous tubing.
8. Administer Hydrocortisone 100 mg intravenous (if patient has allergy to Hydrocortisone, please administer Dexamethasone 4 mg intravenous) and Famotidine 20 mg intravenous once.
9. Administer Epinephrine (1:1000) 0.3 mg subcutaneous.
10. Assess vital signs every 15 minutes until resolution of symptoms or otherwise ordered by covering physician.
		  	diphenhydrAMINE (BENADRYL) injection 25 mg	Dose: 25 mg	Route: intravenous	PRN	Start: S				  	fexofenadine (ALLEGRA) tablet 180 mg	Dose: 180 mg	Route: oral	PRN	Start: S				  	famotidine (PEPCID) injection 20 mg	Dose: 20 mg	Route: intravenous	PRN	Start: S				  	hydrocortisone sodium succinate (Solu-CORTEF) injection 100 mg	Dose: 100 mg	Route: intravenous	PRN					  	dexAMETHasone (DECADRON) IV 4 mg	Dose: 4 mg	Route: intravenous	PRN					  	epINEPHrine (ADRENALIN) 1 mg/1 mL injection 0.3 mg	Dose: 0.3 mg	Route: subcutaneous	PRN	Start: S					Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
			Discharge Nursing Orders
  	ONC NURSING COMMUNICATION 76	Interval: --	Occurrences: --	Comments:	Discontinue IV.
			Discharge Nursing Orders
☑	sodium chloride 0.9 % flush 20 mL	Dose: 20 mL	Route: intravenous	PRN					☑	HEParin, porcine (PF) injection 500 Units	Dose: 500 Units	Route: intra-catheter	once PRN	Start: S			Instructions:	Concentration: 100 units/mL. Heparin flush for Implanted Vascular Access Device maintenance.			Discharge Nursing Orders
  	alteplase (CATHFLO) for NON Quinton and NON Hemodialysis Catheters 2 mg	Dose: 2 mg	Route: intra-catheter	once PRN	Start: S			Instructions:	HOLD and notify provider if Platelets LESS than 50.  Instill dose into occluded catheter. Do not force solution into
catheter. After a 30-minute dwell time, assess catheter function by attempting
to aspirate blood. If catheter is functional, aspirate 4 to 5 mL of blood in
patients greater than or equal to 10 kg to remove Cathflo Activase and
residual clots. Gently irrigate the catheter with NS. If catheter remains
nonfunctional, let Cathflo Activase dwell for another 90 minutes (total dwell
time: 120 minutes) and reassess function. If catheter function is not restored,
a second dose may be instilled					
Cycle 7	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 8	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 22	Interval: --	Occurrences: --	Comments:	All PRO assessments MUST be completed electronically. Refer to Section 8.12.1 for more details. 
o EORTC QLQ-C30; 
o EORTC IL 58 (CLL/SLL Symptoms Supplement); 
o EQ-5D-5L
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 9	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 10	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Imaging
☑	CT SOFT TISSUE NECK W CONTRAST	Interval: --	Occurrences: --	Comments:	CT scan with IV contrast agent is the preferred method of assessment with scans of neck, chest, abdomen and pelvis. However, MRI is acceptable if CT scan with contrast agent is contraindicated
		☑	CT CHEST W CONTRAST ABDOMEN W CONTRAST PELVIS W CONTRAST	Interval: --	Occurrences: --	Comments:	CT scan with IV contrast agent is the preferred method of assessment with scans of neck, chest, abdomen and pelvis. However, MRI is acceptable if CT scan with contrast agent is contraindicated
		☐	MRI NECK SOFT TISSUE ONLY WO CONTRAST	Interval: --	Occurrences: --		☐	MRI CHEST WO CONTRAST	Interval: --	Occurrences: --		☐	MRI ABDOMEN WO CONTRAST	Interval: --	Occurrences: --		☐	MRI PELVIS WO CONTRAST	Interval: --	Occurrences: --			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 11	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 22	Interval: --	Occurrences: --	Comments:	All PRO assessments MUST be completed electronically. Refer to Section 8.12.1 for more details. 
o EORTC QLQ-C30; 
o EORTC IL 58 (CLL/SLL Symptoms Supplement); 
o EQ-5D-5L
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 12	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 13	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 14	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 22	Interval: --	Occurrences: --	Comments:	All PRO assessments MUST be completed electronically. Refer to Section 8.12.1 for more details. 
o EORTC QLQ-C30; 
o EORTC IL 58 (CLL/SLL Symptoms Supplement); 
o EQ-5D-5L
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 15	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 16	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Imaging
☑	CT SOFT TISSUE NECK W CONTRAST	Interval: --	Occurrences: --	Comments:	CT scan with IV contrast agent is the preferred method of assessment with scans of neck, chest, abdomen and pelvis. However, MRI is acceptable if CT scan with contrast agent is contraindicated
		☑	CT CHEST W CONTRAST ABDOMEN W CONTRAST PELVIS W CONTRAST	Interval: --	Occurrences: --	Comments:	CT scan with IV contrast agent is the preferred method of assessment with scans of neck, chest, abdomen and pelvis. However, MRI is acceptable if CT scan with contrast agent is contraindicated
		☐	MRI NECK SOFT TISSUE ONLY WO CONTRAST	Interval: --	Occurrences: --		☐	MRI CHEST WO CONTRAST	Interval: --	Occurrences: --		☐	MRI ABDOMEN WO CONTRAST	Interval: --	Occurrences: --		☐	MRI PELVIS WO CONTRAST	Interval: --	Occurrences: --			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 17	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 22	Interval: --	Occurrences: --	Comments:	All PRO assessments MUST be completed electronically. Refer to Section 8.12.1 for more details. 
o EORTC QLQ-C30; 
o EORTC IL 58 (CLL/SLL Symptoms Supplement); 
o EQ-5D-5L
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 18	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 19	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 20	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 22	Interval: --	Occurrences: --	Comments:	All PRO assessments MUST be completed electronically. Refer to Section 8.12.1 for more details. 
o EORTC QLQ-C30; 
o EORTC IL 58 (CLL/SLL Symptoms Supplement); 
o EQ-5D-5L
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 21	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 22	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Imaging
☑	CT SOFT TISSUE NECK W CONTRAST	Interval: --	Occurrences: --	Comments:	CT scan with IV contrast agent is the preferred method of assessment with scans of neck, chest, abdomen and pelvis. However, MRI is acceptable if CT scan with contrast agent is contraindicated
		☑	CT CHEST W CONTRAST ABDOMEN W CONTRAST PELVIS W CONTRAST	Interval: --	Occurrences: --	Comments:	CT scan with IV contrast agent is the preferred method of assessment with scans of neck, chest, abdomen and pelvis. However, MRI is acceptable if CT scan with contrast agent is contraindicated
		☐	MRI NECK SOFT TISSUE ONLY WO CONTRAST	Interval: --	Occurrences: --		☐	MRI CHEST WO CONTRAST	Interval: --	Occurrences: --		☐	MRI ABDOMEN WO CONTRAST	Interval: --	Occurrences: --		☐	MRI PELVIS WO CONTRAST	Interval: --	Occurrences: --			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 23	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 22	Interval: --	Occurrences: --	Comments:	All PRO assessments MUST be completed electronically. Refer to Section 8.12.1 for more details. 
o EORTC QLQ-C30; 
o EORTC IL 58 (CLL/SLL Symptoms Supplement); 
o EQ-5D-5L
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 24	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 25	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 26	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 22	Interval: --	Occurrences: --	Comments:	All PRO assessments MUST be completed electronically. Refer to Section 8.12.1 for more details. 
o EORTC QLQ-C30; 
o EORTC IL 58 (CLL/SLL Symptoms Supplement); 
o EQ-5D-5L
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 27	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
Cycle 28	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Nursing Orders
  	TREATMENT CONDITIONS	Interval: --	Occurrences: --	Comments:	Treatment Conditions/Parameters For Pirtobrutinib (LOXO-305) Administration Days (be as specific as possible): 
Dose hold and/or reduction will be implemented for any patient who experiences a clinically significant hematologic AE (i.e., GREATER than or EQUAL to Grade 3, or GREATER than 1 grade change from baseline if baseline is Grade 2 or above) as assessed by the NCI CTCAE v5.0.  If the pirtobrutinib dose is reduced for apparent treatment-related toxicity, the dose need not be re-escalated, even if there is minimal or no toxicity with the reduced dose. However, if the patient tolerates a reduced dose of pirtobrutinib for GREATER than or EQUAL to 2 weeks then the dose may be re-escalated to the next higher dose level, at the discretion of  the Investigator and with written approval of the Sponsor. Repeat re-escalation, not to exceed the starting dose, may be considered if tolerated as outlined. Such re-escalation may be warranted if the AE that led to the dose reduction was not treatment-related.
		  	TREATMENT CONDITIONS 3	Interval: --	Occurrences: --	Comments:	First occurrence of one of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at original dose level (200 mg QD) 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 10	Interval: --	Occurrences: --	Comments:	Second occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia.  
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (100 mg QD)
aa) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 11	Interval: --	Occurrences: --	Comments:	Third occurrence of any of the following: • Grade 3 or greater nonhematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Hold pirtobrutinib until recovery to Grade 1 or baseline; may restart at one dose level lower (50 mg QD)
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN.
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 12	Interval: --	Occurrences: --	Comments:	Fourth occurrence of any of the following: • Grade 3 or greater non-hematologic toxicity; • Grade 3 neutropenia with fever and/or infection; • Grade 4 neutropenia lasting GREATER than or EQUAL to 7 days; • Grade 3 thrombocytopenia with bleeding; or • Grade 4 thrombocytopenia. 
Discontinue - 
a) For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
b) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Nursing Orders
  	TREATMENT CONDITIONS 13	Interval: --	Occurrences: --	Comments:	Dose Modification for Venetoclax: Refer to the venetoclax local label for the current dose modification and toxicity management guidelines for venetoclax. Recommended Dose Modifications for Toxicitiesa in Patients Receiving Venetoclax.
		  	TREATMENT CONDITIONS 14	Interval: --	Occurrences: --	Comments:	Blood chemistry changes or symptoms suggestive of TLS (see Warnings and Precautions in the Venclexta USPI): 
1. Withhold the next day's dose. If resolved within 24 to 48 hours of last dose, resume at the same dose. 
2. For any blood chemistry changes requiring more than 48 hours to resolve, resume at a reduced dose (see Table 6). 
3. For any events of clinical TLSb resume at a reduced dose following resolution (see Table 6).
		  	TREATMENT CONDITIONS 15	Interval: --	Occurrences: --	Comments:	First occurrence of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Upon resolution to Grade 1 or baseline level, resume venetoclax at the same dose.
		  	TREATMENT CONDITIONS 16	Interval: --	Occurrences: --	Comments:	Second and subsequent occurrences of any of the following: • Grade 3 or 4 non-hematologic toxicities (see Adverse Reactions in the Venclexta USPI); • Grade 3 neutropenia
with infection or feverc; or Grade 4 hematologic toxicities (except lymphopenia) (see Warnings and Precautions in the Venclexta USPI). 
Interrupt venetoclax. Follow dose reduction guidelines in Table 6 when resuming treatment with venetoclax after resolution. A larger dose reduction may occur at the discretion of the physician.
		  	TREATMENT CONDITIONS 17	Interval: --	Occurrences: --	Comments:	Consider discontinuing venetoclax for patients who require dose reductions to less than 100 mg for more than 2 weeks. 
a) Diverse reactions were graded using NCI CTCAE version 4.0 according to the source Venclexta USPI. 
b) Clinical TLS was defined as laboratory TLS with clinical consequences such as acute renal failure, cardiac arrhythmias, or sudden death and/or seizures (see Adverse Reactions in the Venclexta USPI). 
c) Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF), as per ASCO guidelines or institutional standards.
		  	TREATMENT CONDITIONS 18	Interval: --	Occurrences: --	Comments:	Table 6: Dose Modification for Toxicity During Venetoclax Treatment
Dose at Interruption, mg	Restart Dose, mg
400	                                    300
300	                                    200
200	                                    100
100	                                    50
50	                                    20
20	                                    10
			Nursing Orders
  	TREATMENT CONDITIONS 20	Interval: --	Occurrences: --	Comments:	Integrated Dose Modification for Overlapping Toxicities if Both Pirtobrutinib and Venetoclax are Likely Responsible: 
Integrated toxicity management may be required in the event that Grade 3 or 4 toxicity cannot be clearly attributed to either pirtobrutinib or venetoclax, and in such instances, both drugs will be subject to dose modification. Dose modification for hematologic toxicity is summarized in Table 7 and nonhematologic toxicity is summarized in Table 8.
		  	TREATMENT CONDITIONS 21	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 neutropenia, with OR without infection or fever Grade 3 thrombocytopenia. 
First occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Upon resolution to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at same dose. 

Second and subsequent occurrence: 
a. Hold venetoclax and pirtobrutinib (LOXO-305); 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 22	Interval: --	Occurrences: --	Comments:	Any occurrences of Grade 4 thrombocytopenia and/or symptomatic bleeding. 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 23	Interval: --	Occurrences: --	Comments:	Any occurrences of Blood chemistry changes or symptoms suggestive of TLS. 
a. Withhold the next day's dose of both venetoclax and pirtobrutinib (LOXO-305). If abnormalities are resolved within 24 to 48 hours of last dose, resume both drugs at the same dose. 
b. For blood chemistry changes requiring more than 48 hours to resolve despite appropriate management, resume venetoclax at a reduced dose (Table 6.5) and continue pirtobrutinib (LOXO-305) with no modification. 
c. For any events of clinical TLS, resume venetoclax at a reduced dose (Table 6.5) following resolution; continue pirtobrutinib (LOXO-305) with no dose modification.
		  	TREATMENT CONDITIONS 24	Interval: --	Occurrences: --	Comments:	Grade 3 or 4 non-hematologic toxicity not otherwise specified above. 
First occurrence: Hold venetoclax and pirtobrutinib (LOXO-305). If improvement to Grade = 1 or baseline, resume venetoclax and pirtobrutinib (LOXO-305) at the same dose.  
Second and subsequent occurrences: 
a. Hold venetoclax and pirtobrutinib (LOXO-305). 
b. Resume venetoclax (Table 6.5) and pirtobrutinib (LOXO-305) (Table 6.4) according to respective dose modification tables after resolution.
		  	TREATMENT CONDITIONS 25	Interval: --	Occurrences: --	Comments:	o For patients with abnormal baseline liver function, pirtobrutinib dose interruption and modification recommendations should be implemented if patients experience an increase of GREATER than or EQUAL to 3× baseline AST or ALT or an AST or ALT increase of GREATER than or EQUAL to 2× baseline with concurrent total bilirubin GREATER than or EQUAL to 2× ULN. 
o Patients who have been dose-reduced and who tolerate the new dose level of pirtobrutinib without toxicity for at least 2 weeks may be re-escalated back to the next higher dose level of
drug with written approval of Sponsor.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 10	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For Low tumor burden - All LN LESS than 5 cm AND ALC LESS than 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L); 
o Allopurinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose.
		  	ONC PROVIDER COMMUNICATION 11	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For medium tumor burden - Any LN 5 cm to LESS than 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L. 
o Administer oral hydration (1.5 to 2 L) and consider additional intravenous; 
o Allopruinol; 
o Blood chemistry monitoring (outpatient) 
a. For first dose of 20 mg and 50 mg: Pre-dose, 6 to 8 hours, 24 hours; 
b. For subsequent ramp-up doses: Pre-dose;  
c. For first dose of 20 mg and 50 mg: Consider hospitalization for patients with CrCl LESS than 80 ml/min; see below for monitoring in hospital.
		  	ONC PROVIDER COMMUNICATION 12	Interval: --	Occurrences: --	Comments:	TLS prophylaxis recommendations. 
For hight tumor burden - Any LN GREATER than or EQUAL to 10 cm OR ALC GREATER than or EQUAL to 25 × 10^9/L AND any LN GREATER than or EQUAL to 5 cm. 
o Administer oral hydration (1.5 to 2 L) and intravenous (150 to 200 mL/hour as tolerated); 
o Allopurinol. Consider Rasburicase IF baseline uric acid is elevated;
o Blood chemistry monitoring 
a. (In hospital) For first dose of 20 mg and 50 mg: Pre-dose, 4, 8, 12 and 24 hours; 
b. (Outpatient) For subsequent ramp-up doses: Pre-dose, 6 to 8 hours, 24 hours.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 15	Interval: --	Occurrences: --	Comments:	Physical Exam: The screening physical examination will include, at a minimum, the general appearance of the patient, height (Screening only) and weight, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, extremities, musculoskeletal system, nervous system, and lymphatic system.
		  	ONC NURSING COMMUNICATION 16	Interval: --	Occurrences: --	Comments:	CRC & treatment team to collect ECOG PS
		  	VITAL SIGNS - T/P/R/BP	Interval: --	Occurrences: --	Comments:	Includes Body temperature, SBP, DBP, HR, RR  (after patient has rested in sitting position)
		  	ECG 12-LEAD	Interval: --	Occurrences: --	Comments:	1. Obtain ECGs at specified visits and when patients are symptomatic. Refer to Section 8.4.4
2. ECGs should be collected: 
a. At Screening: triplicate ECG; 
b. C1D1: pre-dose single ECG; 
c. All other timepoints: post-dose single ECG.
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --	Comments:	(IF applicable) Within 24 hours pre-dose: Pregnancy tests should occur monthly during the study treatment and should continue monthly for 30 days from the last dose of pirtobrutinib or venetoclax, or 12 months after the last dose of rituximab whichever is later.
			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Nursing Orders
  	ONC NURSING COMMUNICATION 35	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus rituximab occurs on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), then 
2) infusion of rituximab, followed by observation per site standards.
		  	ONC NURSING COMMUNICATION 36	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax and rituximab drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), 
2) administration of venetoclax, and then 3) infusion of rituximab, followed by observation per site standards. 
		  	ONC NURSING COMMUNICATION 37	Interval: --	Occurrences: --	Comments:	On days when pirtobrutinib (LOXO-305) plus venetoclax drug administration coincides to occur on the same day, the sequence of dosing should be as follows: 
1) administration of pirtobrutinib (LOXO-305), and then 
2) administration of venetoclax.
			Nursing Orders
  	ONC NURSING COMMUNICATION 33	Interval: --	Occurrences: --	Comments:	Administer home Pirtobrutinib and/OR Venetoclax orally as prescribed.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
EOT	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 22	Interval: --	Occurrences: --	Comments:	All PRO assessments MUST be completed electronically. Refer to Section 8.12.1 for more details. 
o EORTC QLQ-C30; 
o EORTC IL 58 (CLL/SLL Symptoms Supplement); 
o EQ-5D-5L
			Nursing Orders
  	ONC NURSING COMMUNICATION 25	Interval: --	Occurrences: --	Comments:	o EORTC IL19 (Physical Function) 
o EORTC IL87 (CLL/SLL Symptom Assessment)  
These instruments will not administered on weeks where the EORTC QLQ-C30 and EORTC IL58 are administered due to overlapping items.
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 8	Interval: --	Occurrences: --	Comments:	CRC to collect Patient Pill Diary: the dosing diary applies to pirtobrutinib and venetoclax only.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
SFU	Repeat 1 time	Cycle length: 28 days	Day 1	Perform every 1 day x1		Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Nursing Orders
  	ONC NURSING COMMUNICATION 22	Interval: --	Occurrences: --	Comments:	All PRO assessments MUST be completed electronically. Refer to Section 8.12.1 for more details. 
o EORTC QLQ-C30; 
o EORTC IL 58 (CLL/SLL Symptoms Supplement); 
o EQ-5D-5L
			Nursing Orders
  	ONC NURSING COMMUNICATION 30	Interval: --	Occurrences: --	Comments:	PGIS
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Nursing Orders
  	ONC NURSING COMMUNICATION 32	Interval: --	Occurrences: --	Comments:	PGIC
o All PRO assessments MUST be completed electronically. 
o Refer to Section 8.12.1 for more details.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --		  	COMPREHENSIVE METABOLIC PANEL	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 2	Interval: --	Occurrences: --	Comments:	CRC and treatment tem to order aPTT and PT (or INR) as clinically indicated.
			Provider Communication
  	ONC PROVIDER COMMUNICATION 3	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order Urinalysis  as clinically indicated. 
o Dipstick analysis is acceptable and should include color, specific gravity, pH, glucose, bilirubin, occult blood, protein, leukocytes, and urobilinogen.  
			Provider Communication
  	ONC PROVIDER COMMUNICATION 4	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirate as clinically indicated or or at time of confirmed Complete Response (CR). 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 9	Interval: --	Occurrences: --	Comments:	CRC to collect 
1. Concomitant Medications. 
2. Adverse events.
					
LTFU	Repeat 1 time	Cycle length: 1 day	Day 1	Perform every 1 day x1		Provider Communication
  	ONC PROVIDER COMMUNICATION 13	Interval: --	Occurrences: --	Comments:	Pneumocystis jirovecii pneumonia (PJP) prevention per site standard - During treatment and up to 12 months post treatment.
		  	ONC PROVIDER COMMUNICATION 14	Interval: --	Occurrences: --	Comments:	Herpes virus infection prevention per site standard - During treatment and up to 12 months post treatment.
			Labs
  	CBC WITH PLATELET AND DIFFERENTIAL	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --			Provider Communication
  	ONC PROVIDER COMMUNICATION 5	Interval: --	Occurrences: --	Comments:	o CRC and treatment tem to order bone marrow biopsy and aspirateas clinically indicated. 
o Perform within 8-12 weeks of CR or Cri by scan or peripheral blood assessment. 
o Aspirate and biopsy are both required at Screening and with response assessment only for confirmation of CR or CRi (meeting all CR criteria with persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to CLL). 
o Biopsy should be collected even if unable to collect aspirate due to dry tap.
			Labs
☐	HCG QUALITATIVE, SERUM SCREEN	Interval: --	Occurrences: --		☐	HCG QUANTITATIVE, SERUM	Interval: --	Occurrences: --		☐	HCG QUALITATIVE, URINE SCREEN	Interval: --	Occurrences: --			Labs
  	RESEARCH STUDY SPECIMEN	Interval: --	Occurrences: --