Study of Ibrutinib Combined With Venetoclax in Subjects With Mantle Cell Lymphoma (MCL)

Phase 3 Study of Ibrutinib in Combination With Venetoclax in Subjects With Mantle Cell Lymphoma

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03112174

Acronym

SYMPATICO

Enrollment

366

Registered

2017-04-13

Start date

2017-06-19

Completion date

2024-06-27

Last updated

2025-07-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Mantle-Cell Lymphoma

Keywords

PCYC, MCL, Non-Hodgkin's Lymphoma, NHL, ibrutinib, venetoclax, Pharmacyclics

Brief summary

This Phase 3 multinational, randomized, double-blind study is designed to compare the efficacy and safety of the combination of ibrutinib and venetoclax vs. ibrutinib and placebo in subjects with MCL.

Interventions

DRUGIbrutinib

Administered orally once daily

DRUGVenetoclax

Administered orally once daily

DRUGPlacebo Oral tablet to match Venetoclax

Administered orally once daily

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Relapsed/Refractory Arm Inclusion Criteria: * Pathologically confirmed MCL (in tumor tissue), with documentation of either overexpression of cyclin D1 in association with other relevant markers (eg, CD19, CD20, PAX5, CD5) or evidence of t(11;14) as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR). * At least 1 measurable site of disease on cross-sectional imaging (CT). * At least 1, but no more than 5, prior treatment regimens for MCL. * Failure to achieve at least partial response (PR) with, or documented disease progression after, the most recent treatment regimen. * Subjects must have adequate fresh or paraffin embedded tissue. * Adequate hematologic, hepatic and renal function. * Eastern Cooperative Oncology Group (ECOG) performance status (PS) of \<= 2.

Exclusion criteria

* History or current evidence of central nervous system lymphoma. * Concurrent enrollment in another therapeutic investigational study or prior therapy with ibrutinib or other BTK inhibitors. * Prior treatment with venetoclax or other BCL2 inhibitors. * Anticancer therapy including chemotherapy, radiotherapy, small molecule and investigational agents \<= 21 days prior to receiving the first dose of study drug. * Treatment with any of the following within 7 days prior to the first dose of study drug: moderate to strong cytochrome P450 3A (CYP3A) inhibitors or strong CYP3A inducers. Treatment Naïve Arm Inclusion Criteria: * Pathologically confirmed treatment-naive MCL (tumor tissue), with documentation of either overexpression of cyclin D1 in association with other relevant markers (eg, CD19, CD20, PAX5, CD5) or evidence of t(11;14), as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR). * Men and women ≥18 years of age with a TP53 mutation. * At least 1 measurable site of disease by CT. * Must have adequate fresh or paraffin-embedded tissue. * Eastern Cooperative Oncology Group (ECOG) performance status score 0 to \<= 2. * Adequate hematologic, hepatic, and renal function.

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Tumor Lysis Syndrome (TLS) Events (Safety Run-in)	After at least 3 months of treatment, with an overall median treatment duration of 20.0 months	TLS events are defined as follows: * Clinical TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) with the following exceptions: * For the purpose of TLS assessment during the Safety Run-in Period, only those increases in serum creatinine \> 1.0 mg/dL from pre-treatment baseline will be considered clinical TLS. * In participants with renal dysfunction at baseline (CrCl \< 60 mL/min), clinical TLS is defined as the presence of laboratory TLS plus either seizures, cardiac dysrhythmia, or death. * Laboratory TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) for laboratory TLS, that does not resolve within 72 hours despite protocol required management.
Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	After at least 3 months of treatment, with an overall median treatment duration of 20.0 months	DLT: any Grade (Gr) 3 or higher non-TLS adverse event (AE) at least possibly related to study drug occurring during the DLT assessment period with the following clarifications: Non-Hematologic DLTs: Gr ≥3 nausea, vomiting or diarrhea uncontrolled despite maximum medical supportive care and persisting \>5 days; Gr 3 fatigue persisting \>7 days; Gr 3 infection is not a DLT, however an infection with lifethreatening consequences or requiring urgent intervention (Gr 4) was considered a DLT; Treatment delay of any study drug \>7 days for toxicity. Hematologic DLTs: Gr 3 neutropenia is not a DLT, however, Gr 4 neutropenia (ANC \<500/mm\^3) lasting for \> 7 days is a DLT; Gr 3 or 4 neutropenia complicated by fever ≥38.5°C or infection; Gr 4 thrombocytopenia (\<25,000/mm\^3) that persists for \> 7 days; Gr 3 or 4 thrombocytopenia associated with Gr 2 or greater bleeding; Gr 3 anemia is not a DLT, however, Gr 4 anemia is a DLT; Treatment delay of any study drug \>7 days for hematologic toxicity.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 20.0 months	AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with treatment. The investigator assesses the relationship of each event to the use of study. Serious adverse event (SAE): an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug. Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).
Progression-free Survival (PFS) (Randomization Phase)	For an overall median time on study of 61.34 months	PFS is defined as the time from the date of randomization to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.
Complete Response (CR) Rate (Treatment-Naive Arm)	For an overall median time on study of 40.51 months	CR rate is defined as the percentage of participants with a CR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).

Secondary

Measure	Time frame	Description
Overall Response Rate (ORR) (Randomization Phase and Treatment-Naive Arm)	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)	ORR is defined as the percentage of participants with CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).
MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive Arm)	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)	MRD-negative remission rate is defined as the percentage of participants with undetectable MRD at documented CR in participants who were MRD positive at screening as assessed by flow cytometry in bone marrow and/or peripheral blood, with requirement of confirmation of MRD negativity in the subsequent peripheral blood 12 weeks later.
Overall Survival (OS) (Randomization Phase and Treatment-Naive Arm)	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)	OS is defined as the time from the date of randomization (Randomization Phase) or the first dose of study treatment (Treatment-Naïve arm) to death from any cause.
Duration of Response (DOR) (Randomization Phase and Treatment-Naive Arm)	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)	DOR is defined as the time frame for participants who achieve an overall response as the time from the first occurrence of response (CR or PR according to the Revised Response Criteria for Malignant Lymphoma \[Cheson 2014\]) to disease progression or death, whichever occurs first.
Time to Next Treatment (TTNT) (Randomization Phase and Treatment-Naive Arm)	For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)	TTNT is defined as the duration from the date of randomization (Randomization Phase) or date of first dose of study treatment (Treatment-Naive Arm) to the start date of any anti-lymphoma treatment subsequent to study treatment. Post-treatment stem cell transplantation, chimeric antigen receptor (CAR) T-cell therapy, or other cellular therapies were not considered subsequent anti-cancer treatments for participants responding to the study treatment (CR or PR).
Number of Participants With TEAEs (Randomization Phase)	From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 19.5 months	AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with treatment. The investigator assesses the relationship of each event to the use of study. Serious adverse event (SAE): an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug. Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).
Number of Participants With TLS TEAEs (Randomization Phase)	From first dose of study drug until the end of treatment + 7 days, with an overall median treatment duration 19.5 months	Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug (SD). Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).
Steady-State Pharmacokinetics (PK) of Ibrutinib: Maximum Observed Plasma Concentration (Cmax) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Ibrutinib: Time to Cmax (Tmax) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Ibrutinib: Area Under the Concentration-Time Curve From Time Zero to the Time of the Last Measurable Concentration (AUClast) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Ibrutinib: Terminal Elimination Half-Life (t1/2,Term) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Overall Survival (OS) (Safety Run-in)	For an overall median time on study of 74.78 months	OS is defined as the time from the date of the first dose of study treatment to death from any cause.
Steady-State PK of Ibrutinib: Area Under the Concentration-Time Curve From 0-24 Hours (AUC0-24) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Ibrutinib: Terminal Elimination Rate Constant (λz) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Ibrutinib: Apparent Total Clearance at Steady State (CLss/F) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Venetoclax: Cmax (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Venetoclax: AUC0-24 (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Venetoclax: Time to Cmax (Tmax) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Steady-State PK of Venetoclax: CLss/F (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Time to Worsening in Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Subscale of the Health-related Quality of Life (Randomization Phase)	For an overall median time on study of 61.34 months (Randomization Phase)	The FACT-Lym lymphoma-specific additional concerns subscale responses to all items are rated on a 5-point scale ranging from 0 not at all to 4 very much. The lymphoma subscale includes 15 items and scores range from 0 to 60, with higher scores representing better functional status and well-being. A 5-point change in the Lym subscale was selected as a conservative estimate of clinically meaningful deterioration in lymphoma symptoms.
Duration of CR (Treatment-Naive Arm)	For an overall median time on study of 40.51 months	Duration of CR, defined for subjects who achieve CR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014) as the time from the first occurrence of CR to disease progression or death, whichever occurs first.
Progression-free Survival (PFS) (Treatment-Naive Arm)	For an overall median time on study of 40.51 months	PFS is defined as the time from the date of the first dose of study treatment to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.
Steady-State PK of Ibrutinib: Time of Last Measurable Concentration (Tlast) (Randomization Phase)	Week 6, Day 1: Predose, at Dose, 1 hour (± 15 minutes [min]), 2 hours (± 15 min), 4 hours (± 30 min), 6 hours (± 30 min), 8 hours (± 1 hour), 24 hours post-dose	Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.
Progression-free Survival (PFS) (Safety Run-in)	For an overall median time on study of 74.78 months	PFS is defined as the time from the date of the first dose of study treatment to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.
Duration of Response (DOR) (Safety Run-in)	For an overall median time on study of 74.78 months	DOR is defined for participants who achieve an overall response as the time from the first occurrence of response (CR or PR according to the Revised Response Criteria for Malignant Lymphoma \[Cheson 2014\]) to disease progression or death, whichever occurs first.
Overall Response Rate (ORR) (Safety Run-in)	For an overall median time on study of 74.78 months	ORR is defined as the percentage of participants with CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).
Percentage of Participants With a Complete Response (CR) (Randomization Phase)	For an overall median time on study of 61.34 months	Complete response rate (CR) based on the best overall response per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).

Countries

Australia, Belgium, Canada, Czechia, France, Germany, Greece, Hungary, Italy, Netherlands, Poland, South Korea, Spain, Turkey (Türkiye), Ukraine, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
Safety Run-in: Increased TLS Risk at Baseline Participants with an increased risk of tumor lysis syndrome (TLS) enrolled into the open-label Safety Run-in Period received concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramped up to a target dose of 400 mg once daily over a 5-week period.	15
Safety Run-in: Low TLS Risk at Baseline Participants with an low risk of TLS enrolled into the open-label Safety Run-in Period received concurrent ibrutinib at 560 mg once daily and venetoclax starting at 20 mg, and gradually ramped up to a target dose of 400 mg once daily over a 5-week period.	6
Randomization Phase: Ibrutinb + Venetoclax Participants were randomized to ibrutinib 560 mg and venetoclax (starting at 20 mg, and gradually ramped up to a target dose of 400 mg) for approximately 104 weeks, followed by ibrutinib monotherapy until disease progression (PD), unacceptable toxicity or withdrawal of consent. Venetoclax was discontinued after 104 weeks of treatment, regardless of response assessment.	134
Randomization Phase: Ibrutinib + Placebo Participants were randomized to ibrutinib 560 mg and placebo for approximately 104 weeks, followed by ibrutinib monotherapy until PD, unacceptable toxicity or withdrawal of consent. Placebo was discontinued after 104 weeks of treatment, regardless of response assessment.	133
Treatment-naive Open-label Arm Participants were treated with ibrutinib 560 mg and venetoclax (starting at 20 mg, and gradually ramped up to a target dose of 400 mg).	78
Total	366

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004
Overall Study	Death	8	3	67	73	18
Overall Study	Lost to Follow-up	1	1	2	3	2
Overall Study	Other, Not Specified	1	0	1	2	0
Overall Study	Withdrawal by Subject	3	0	11	9	7

Baseline characteristics

Characteristic	Randomization Phase: Ibrutinb + Venetoclax	Randomization Phase: Ibrutinib + Placebo	Safety Run-in: Increased TLS Risk at Baseline	Treatment-naive Open-label Arm	Total	Safety Run-in: Low TLS Risk at Baseline
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	93 Participants	86 Participants	13 Participants	65 Participants	258 Participants	1 Participants
Age, Categorical Between 18 and 65 years	41 Participants	47 Participants	2 Participants	13 Participants	108 Participants	5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants	7 Participants	1 Participants	1 Participants	17 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	112 Participants	110 Participants	11 Participants	72 Participants	310 Participants	5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	14 Participants	16 Participants	3 Participants	5 Participants	39 Participants	1 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	2 Participants	3 Participants	0 Participants	6 Participants	11 Participants	0 Participants
Race (NIH/OMB) Black or African American	1 Participants	1 Participants	0 Participants	1 Participants	3 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	15 Participants	14 Participants	3 Participants	3 Participants	35 Participants	0 Participants
Race (NIH/OMB) White	116 Participants	115 Participants	12 Participants	68 Participants	317 Participants	6 Participants
Sex: Female, Male Female	31 Participants	25 Participants	6 Participants	25 Participants	89 Participants	2 Participants
Sex: Female, Male Male	103 Participants	108 Participants	9 Participants	53 Participants	277 Participants	4 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	8 / 15	3 / 6	70 / 134	78 / 132	20 / 78
other Total, other adverse events	15 / 15	6 / 6	131 / 134	127 / 132	77 / 78
serious Total, serious adverse events	15 / 15	3 / 6	92 / 134	86 / 132	48 / 78

Outcome results

Primary

Complete Response (CR) Rate (Treatment-Naive Arm)

CR rate is defined as the percentage of participants with a CR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).

Time frame: For an overall median time on study of 40.51 months

Population: All Enrolled Treatment-Naïve Participants

Arm	Measure	Value (NUMBER)
Safety Run-in: Increased TLS Risk at Baseline	Complete Response (CR) Rate (Treatment-Naive Arm)	69.2 percentage of participants

Primary

Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)

DLT: any Grade (Gr) 3 or higher non-TLS adverse event (AE) at least possibly related to study drug occurring during the DLT assessment period with the following clarifications: Non-Hematologic DLTs: Gr ≥3 nausea, vomiting or diarrhea uncontrolled despite maximum medical supportive care and persisting \>5 days; Gr 3 fatigue persisting \>7 days; Gr 3 infection is not a DLT, however an infection with lifethreatening consequences or requiring urgent intervention (Gr 4) was considered a DLT; Treatment delay of any study drug \>7 days for toxicity. Hematologic DLTs: Gr 3 neutropenia is not a DLT, however, Gr 4 neutropenia (ANC \<500/mm\^3) lasting for \> 7 days is a DLT; Gr 3 or 4 neutropenia complicated by fever ≥38.5°C or infection; Gr 4 thrombocytopenia (\<25,000/mm\^3) that persists for \> 7 days; Gr 3 or 4 thrombocytopenia associated with Gr 2 or greater bleeding; Gr 3 anemia is not a DLT, however, Gr 4 anemia is a DLT; Treatment delay of any study drug \>7 days for hematologic toxicity.

Time frame: After at least 3 months of treatment, with an overall median treatment duration of 20.0 months

Population: All treated safety run-in participants

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Any TEAE/Any Grade	3 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Any TEAE/ Grade 3+4	3 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Any TEAE/Grade 5	0 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Atrial fibrillation/Any Grade	1 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Atrial fibrillation/Grade 3+4	1 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Atrial fibrillation/Grade 5	0 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Infection/Any Grade	1 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Infection/Grade 3+4	1 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Infection/Grade 5	0 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Neutropenia/Any Grade	1 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Neutropenia/Grade 3+4	1 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Neutropenia/Grade 5	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Neutropenia/Grade 3+4	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Any TEAE/Any Grade	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Infection/Any Grade	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Any TEAE/ Grade 3+4	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Neutropenia/Any Grade	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Any TEAE/Grade 5	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Infection/Grade 3+4	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Atrial fibrillation/Any Grade	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Neutropenia/Grade 5	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Atrial fibrillation/Grade 3+4	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Infection/Grade 5	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Dose Limiting Toxicities (DLT) (Safety Run-in)	Atrial fibrillation/Grade 5	0 Participants

Primary

Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)

AE: any untoward medical occurrence in a participant that does not necessarily have a causal relationship with treatment. The investigator assesses the relationship of each event to the use of study. Serious adverse event (SAE): an event that results in death, is life-threatening, requires or prolongs hospitalization, results in a congenital anomaly, persistent or significant disability/incapacity or is an important medical event that, based on medical judgment, may jeopardize the participant and may require medical or surgical intervention to prevent any of the outcomes listed above. Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug. Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).

Time frame: From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 20.0 months

Population: All treated safety run-in participants

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Discontinuation of Study Drug (I only)	1 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Hold of Study Drug (I or V)	14 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any Ibrutinib (I) Related TEAE	13 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Hold of Study Drug (I Only)	1 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Discontinuation of Study Drug (V only)	1 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Hold of Study Drug (V Only)	0 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE, Grade 3	15 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Hold of Study Drug (Both I and V)	13 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Discontinuation of Study Drug (Both I and V)	4 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TESAE	14 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any I Related TEAE Grade >=3	12 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TESAE, Grade >=3	14 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Reduction of Study Drug (I or V)	7 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TESAE, V Related	9 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any V Related TEAE Grade >=3	13 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TESAE, I Related	10 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Reduction of Study Drug (I Only)	1 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TESAE, V or I Related	10 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Discontinuation of Study Drug (I or V)	6 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Fatal TEAE	1 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Reduction of Study Drug (V Only)	3 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Major Hemorrhage	2 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any Venetoclax (V) Related TEAE	14 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Major Hemorrhage, Grade >=3	2 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Reduction of Study Drug (Both I and V)	3 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Major Hemorrhage, TESAE	2 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE	15 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Major Hemorrhage, TESAE	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE	6 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE, Grade 3	5 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any Venetoclax (V) Related TEAE	6 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any V Related TEAE Grade >=3	4 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any Ibrutinib (I) Related TEAE	5 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any I Related TEAE Grade >=3	4 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Discontinuation of Study Drug (I or V)	2 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Discontinuation of Study Drug (I only)	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Discontinuation of Study Drug (V only)	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Discontinuation of Study Drug (Both I and V)	2 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Reduction of Study Drug (I or V)	4 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Reduction of Study Drug (I Only)	3 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Reduction of Study Drug (V Only)	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Reduction of Study Drug (Both I and V)	1 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Hold of Study Drug (I or V)	4 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Hold of Study Drug (I Only)	1 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Hold of Study Drug (V Only)	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TEAE Leading to Dose Hold of Study Drug (Both I and V)	3 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TESAE	3 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TESAE, Grade >=3	2 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TESAE, V Related	1 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TESAE, I Related	1 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Any TESAE, V or I Related	1 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Fatal TEAE	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Major Hemorrhage	0 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Treatment Emergent Adverse Events (TEAEs) (Safety Run-in)	Major Hemorrhage, Grade >=3	0 Participants

Primary

Number of Participants With Tumor Lysis Syndrome (TLS) Events (Safety Run-in)

TLS events are defined as follows: * Clinical TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) with the following exceptions: * For the purpose of TLS assessment during the Safety Run-in Period, only those increases in serum creatinine \> 1.0 mg/dL from pre-treatment baseline will be considered clinical TLS. * In participants with renal dysfunction at baseline (CrCl \< 60 mL/min), clinical TLS is defined as the presence of laboratory TLS plus either seizures, cardiac dysrhythmia, or death. * Laboratory TLS: any event that meets Howard criteria (N Engl J Med 2011;364:1844-1854) for laboratory TLS, that does not resolve within 72 hours despite protocol required management.

Time frame: After at least 3 months of treatment, with an overall median treatment duration of 20.0 months

Population: All treated safety run-in participants

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With Tumor Lysis Syndrome (TLS) Events (Safety Run-in)	1 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With Tumor Lysis Syndrome (TLS) Events (Safety Run-in)	0 Participants

Primary

Progression-free Survival (PFS) (Randomization Phase)

PFS is defined as the time from the date of randomization to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.

Time frame: For an overall median time on study of 61.34 months

Population: All randomized participants

Arm	Measure	Value (MEDIAN)
Safety Run-in: Increased TLS Risk at Baseline	Progression-free Survival (PFS) (Randomization Phase)	31.9 months
Safety Run-in: Low TLS Risk at Baseline	Progression-free Survival (PFS) (Randomization Phase)	22.1 months

p-value: 0.002495% CI: [0.465, 0.85]Log Rank

Secondary

Duration of CR (Treatment-Naive Arm)

Duration of CR, defined for subjects who achieve CR according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014) as the time from the first occurrence of CR to disease progression or death, whichever occurs first.

Time frame: For an overall median time on study of 40.51 months

Population: All Enrolled Treatment-Naïve Subjects Achieving CR

Arm	Measure	Value (MEDIAN)
Safety Run-in: Increased TLS Risk at Baseline	Duration of CR (Treatment-Naive Arm)	37.1 months

Secondary

Duration of Response (DOR) (Randomization Phase and Treatment-Naive Arm)

DOR is defined as the time frame for participants who achieve an overall response as the time from the first occurrence of response (CR or PR according to the Revised Response Criteria for Malignant Lymphoma \[Cheson 2014\]) to disease progression or death, whichever occurs first.

Time frame: For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)

Population: All randomized participants and all enrolled treatment-naïve participants achieving response (partial response or better)

Arm	Measure	Value (MEDIAN)
Safety Run-in: Increased TLS Risk at Baseline	Duration of Response (DOR) (Randomization Phase and Treatment-Naive Arm)	42.1 months
Safety Run-in: Low TLS Risk at Baseline	Duration of Response (DOR) (Randomization Phase and Treatment-Naive Arm)	27.6 months
Treatment-naive Open-label Arm	Duration of Response (DOR) (Randomization Phase and Treatment-Naive Arm)	37.1 months

Secondary

Duration of Response (DOR) (Safety Run-in)

DOR is defined for participants who achieve an overall response as the time from the first occurrence of response (CR or PR according to the Revised Response Criteria for Malignant Lymphoma \[Cheson 2014\]) to disease progression or death, whichever occurs first.

Time frame: For an overall median time on study of 74.78 months

Population: All Enrolled Safety Run-in Subjects Achieving Response (Partial Response or Better)

Arm	Measure	Value (MEDIAN)
Safety Run-in: Increased TLS Risk at Baseline	Duration of Response (DOR) (Safety Run-in)	44.1 months
Safety Run-in: Low TLS Risk at Baseline	Duration of Response (DOR) (Safety Run-in)	NA months

Secondary

MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive Arm)

MRD-negative remission rate is defined as the percentage of participants with undetectable MRD at documented CR in participants who were MRD positive at screening as assessed by flow cytometry in bone marrow and/or peripheral blood, with requirement of confirmation of MRD negativity in the subsequent peripheral blood 12 weeks later.

Time frame: For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)

Population: All enrolled treatment-naïve participants achieving CR who were evaluable for MRD (those who had positive MRD status at screening). Participants with a given post-screening sample.

Arm	Measure	Group	Value (NUMBER)
Safety Run-in: Increased TLS Risk at Baseline	MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive Arm)	Bone marrow aspirate	61.5 percentage of participants
Safety Run-in: Increased TLS Risk at Baseline	MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive Arm)	Peripheral blood	77.4 percentage of participants
Safety Run-in: Low TLS Risk at Baseline	MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive Arm)	Bone marrow aspirate	28.6 percentage of participants
Safety Run-in: Low TLS Risk at Baseline	MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive Arm)	Peripheral blood	12.5 percentage of participants
Treatment-naive Open-label Arm	MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive Arm)	Bone marrow aspirate	59.1 percentage of participants
Treatment-naive Open-label Arm	MRD-negative Remission Rate in Participants Who Achieve CR Per Investigator Assessment (Randomization Phase and Treatment-Naive Arm)	Peripheral blood	76.5 percentage of participants

Comparison: Bone marrow aspiratep-value: 0.2028Fisher Exact

Comparison: Peripheral bloodp-value: 0.0014Fisher Exact

Secondary

Number of Participants With TEAEs (Randomization Phase)

Time frame: From first dose of study drug until the end of treatment + 30 days, with an overall median treatment duration of 19.5 months

Population: All randomized and treated participants

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Discontinuation of Study Drug (I only)	15 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Hold of Study Drug (I or V)	106 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any Ibrutinib (I) Related TEAE	121 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Hold of Study Drug (I Only)	18 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Discontinuation of Study Drug (V only)	2 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Hold of Study Drug (V Only)	6 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE, Grade 3	113 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Hold of Study Drug (Both I and V)	82 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Discontinuation of Study Drug (Both I and V)	26 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TESAE	88 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any I Related TEAE Grade >=3	83 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TESAE, Grade >=3	76 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Reduction of Study Drug (I or V)	50 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TESAE, V Related	31 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any V Related TEAE Grade >=3	75 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TESAE, I Related	47 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Reduction of Study Drug (I Only)	19 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TESAE, V or I Related	49 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Discontinuation of Study Drug (I or V)	43 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Fatal TEAE	22 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Reduction of Study Drug (V Only)	13 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Major Hemorrhage	13 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any Venetoclax (V) Related TEAE	112 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Major Hemorrhage, Grade >=3	10 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Reduction of Study Drug (Both I and V)	18 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Major Hemorrhage, TESAE	12 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE	134 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Major Hemorrhage, TESAE	6 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE	131 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE, Grade 3	100 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any Venetoclax (V) Related TEAE	104 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any V Related TEAE Grade >=3	46 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any Ibrutinib (I) Related TEAE	114 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any I Related TEAE Grade >=3	58 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Discontinuation of Study Drug (I or V)	48 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Discontinuation of Study Drug (I only)	11 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Discontinuation of Study Drug (V only)	7 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Discontinuation of Study Drug (Both I and V)	30 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Reduction of Study Drug (I or V)	29 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Reduction of Study Drug (I Only)	14 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Reduction of Study Drug (V Only)	7 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Reduction of Study Drug (Both I and V)	8 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Hold of Study Drug (I or V)	99 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Hold of Study Drug (I Only)	18 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Hold of Study Drug (V Only)	4 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TEAE Leading to Dose Hold of Study Drug (Both I and V)	77 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TESAE	80 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TESAE, Grade >=3	73 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TESAE, V Related	25 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TESAE, I Related	37 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Any TESAE, V or I Related	37 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Fatal TEAE	18 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Major Hemorrhage	8 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TEAEs (Randomization Phase)	Major Hemorrhage, Grade >=3	7 Participants

Secondary

Number of Participants With TLS TEAEs (Randomization Phase)

Treatment-emergent adverse events/treatment-emergent serious adverse events (TEAEs/TESAEs): any event that began or worsened in severity on or after the first dose of study drug (SD). Event severity is graded as mild (1), moderate (2), severe (3), life threatening (4), death (5).

Time frame: From first dose of study drug until the end of treatment + 7 days, with an overall median treatment duration 19.5 months

Population: All randomized and treated participants

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TLS TEAEs (Randomization Phase)	Any Grade	7 Participants
Safety Run-in: Increased TLS Risk at Baseline	Number of Participants With TLS TEAEs (Randomization Phase)	Grades 3 and 4	6 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TLS TEAEs (Randomization Phase)	Any Grade	3 Participants
Safety Run-in: Low TLS Risk at Baseline	Number of Participants With TLS TEAEs (Randomization Phase)	Grades 3 and 4	3 Participants

Secondary

Overall Response Rate (ORR) (Randomization Phase and Treatment-Naive Arm)

ORR is defined as the percentage of participants with CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).

Time frame: For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)

Population: All randomized participants and all treatment-naive open-label arm participants.

Arm	Measure	Value (NUMBER)
Safety Run-in: Increased TLS Risk at Baseline	Overall Response Rate (ORR) (Randomization Phase and Treatment-Naive Arm)	82.1 percentage of participants
Safety Run-in: Low TLS Risk at Baseline	Overall Response Rate (ORR) (Randomization Phase and Treatment-Naive Arm)	74.4 percentage of participants
Treatment-naive Open-label Arm	Overall Response Rate (ORR) (Randomization Phase and Treatment-Naive Arm)	94.9 percentage of participants

p-value: 0.127995% CI: [0.973, 1.247]Cochran-Mantel-Haenszel

Secondary

Overall Response Rate (ORR) (Safety Run-in)

ORR is defined as the percentage of participants with CR or PR per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).

Time frame: For an overall median time on study of 74.78 months

Population: All enrolled Safety Run-in participants

Arm	Measure	Value (NUMBER)
Safety Run-in: Increased TLS Risk at Baseline	Overall Response Rate (ORR) (Safety Run-in)	80.0 percentage of participants
Safety Run-in: Low TLS Risk at Baseline	Overall Response Rate (ORR) (Safety Run-in)	83.3 percentage of participants

Secondary

Overall Survival (OS) (Randomization Phase and Treatment-Naive Arm)

OS is defined as the time from the date of randomization (Randomization Phase) or the first dose of study treatment (Treatment-Naïve arm) to death from any cause.

Time frame: For an overall median time on study of 61.34 months (Randomization Phase) and 40.51 months (Treatment-Naïve arm)

Population: All randomized and all enrolled treatment-naïve participants

Arm	Measure	Value (MEDIAN)
Safety Run-in: Increased TLS Risk at Baseline	Overall Survival (OS) (Randomization Phase and Treatment-Naive Arm)	44.9 months
Safety Run-in: Low TLS Risk at Baseline	Overall Survival (OS) (Randomization Phase and Treatment-Naive Arm)	38.6 months
Treatment-naive Open-label Arm	Overall Survival (OS) (Randomization Phase and Treatment-Naive Arm)	NA months

p-value: 0.266995% CI: [0.602, 1.151]Log Rank

Secondary

Overall Survival (OS) (Safety Run-in)

OS is defined as the time from the date of the first dose of study treatment to death from any cause.

Time frame: For an overall median time on study of 74.78 months

Population: All Enrolled Safety Run-in participants

Arm	Measure	Value (MEDIAN)
Safety Run-in: Increased TLS Risk at Baseline	Overall Survival (OS) (Safety Run-in)	52.3 months
Safety Run-in: Low TLS Risk at Baseline	Overall Survival (OS) (Safety Run-in)	NA months

Secondary

Percentage of Participants With a Complete Response (CR) (Randomization Phase)

Complete response rate (CR) based on the best overall response per investigator assessment according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2014).

Time frame: For an overall median time on study of 61.34 months

Population: All randomized participants

Arm	Measure	Value (NUMBER)
Safety Run-in: Increased TLS Risk at Baseline	Percentage of Participants With a Complete Response (CR) (Randomization Phase)	53.7 percentage of participants
Safety Run-in: Low TLS Risk at Baseline	Percentage of Participants With a Complete Response (CR) (Randomization Phase)	32.3 percentage of participants

p-value: 0.000495% CI: [1.24, 2.218]Cochran-Mantel-Haenszel

Secondary

Progression-free Survival (PFS) (Safety Run-in)

PFS is defined as the time from the date of the first dose of study treatment to the date of disease progression using the Revised Response Criteria for Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs first.

Time frame: For an overall median time on study of 74.78 months

Population: All Enrolled Safety Run-in participants

Arm	Measure	Value (MEDIAN)
Safety Run-in: Increased TLS Risk at Baseline	Progression-free Survival (PFS) (Safety Run-in)	46.9 months
Safety Run-in: Low TLS Risk at Baseline	Progression-free Survival (PFS) (Safety Run-in)	35.0 months

Secondary

Progression-free Survival (PFS) (Treatment-Naive Arm)

Time frame: For an overall median time on study of 40.51 months

Population: All enrolled treatment-naïve participants

Arm	Measure	Value (MEDIAN)
Safety Run-in: Increased TLS Risk at Baseline	Progression-free Survival (PFS) (Treatment-Naive Arm)	40.2 months

Secondary

Steady-State Pharmacokinetics (PK) of Ibrutinib: Maximum Observed Plasma Concentration (Cmax) (Randomization Phase)

Pre-dose concentrations were applied as 24-hour concentrations in order to calculate steady-state PK parameters.