A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

Phase 3CompletedNCT02005471

Hoffmann-La Roche389 enrolled

Overview

The purpose of this open-label, multicenter, randomized, Phase III study is to evaluate the benefit of venetoclax in combination with rituximab compared with bendamustine in combination with rituximab in participants with relapsed or refractory CLL. Participants will be randomly assigned in 1:1 ratio to receive either venetoclax + rituximab (Arm A) or bendamustine + rituximab (Arm B).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

389

Conditions

Chronic Lymphocytic Leukemia

Interventions

BendamustineDRUG

Bendamustine will be administered at a dose of 70 mg/m\^2 via IV infusion on Days 1 and 2 of each 28-day cycle, for 6 cycles.

VenetoclaxDRUG

Venetoclax will be administered at an initial dose of 20 mg via tablet orally QD, incremented weekly up to a maximum dose of 400 mg during a 5-week ramp-up period. Venetoclax will be continued at 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to disease progression (PD) or 2 years, whichever occurs first. R/C Substudy: venetoclax will be administered for 5-week dose ramp-up period to reach the target dose of 400 mg QD. Venetoclax will continue to be administered during the rituximab cycles until disease progression or for a maximum of 2 years from Cycle 1R/C Day 1 of the R/C Substudy.

RituximabDRUG

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Diagnosis of CLL per diagnostic criteria for relapsed or refractory CLL per the international workshop on chronic lymphocytic leukemia (iwCLL) guidelines * Previously treated with 1-3 lines of therapy (example: completed greater than or equal to \[\>/=\] 2 treatment cycles per therapy), including at least one standard chemotherapy-containing regimen * Participants previously treated with bendamustine only if their duration of response was \>/= 24 months * Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to (\</=) 1 * Adequate bone marrow function * Adequate renal and hepatic function * Participants must use effective birth control throughout study until at least 30 days after study treatment or 1 year after rituximab treatment, whichever is later; female participants must not be pregnant or breast-feeding * For participants with the 17p deletion, previously treated with 1-3 lines of therapy, including at least one prior standard chemotherapy-containing regimen or at least one prior alemtuzumab-containing therapy Inclusion Criteria R/C Substudy: * Participants randomized to Arm A or Arm B with a confirmed disease progression of CLL per iwCLL criteria * Participants who have not received new anti-CLL therapy following disease progression in Arm A or Arm B * Adequate renal and hepatic function per laboratory reference range Exclusion Criteria: * Transformation of CLL to aggressive non-Hodgkin lymphoma or central nervous system (CNS) involvement by CLL * Undergone an allogenic stem cell transplant * A history of significant renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular or hepatic disease * Hepatitis B or C or known human immunodeficiency virus (HIV) positive * Receiving warfarin treatment * Received an anti-CLL monoclonal antibody within 8 weeks prior to the first dose of study drug * Received any anti-cancer or investigational therapy within 28 days prior to the first dose of study drug or has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) of any previous therapy * Received cytochrome P450 3A4 (CYP3A4) inhibitors (such as fluconazole, ketoconazole and clarithromycin) or inducers (such as rifampin, carbamazapine, phenytoin, St. John's Wort) within 7 days prior to the first dose of venetoclax * History of prior venetoclax treatment * Participants with another cancer, history of another cancer considered uncured on in complete remission for \<5 years, or currently under treatment for another suspected cancer except non-melanoma skin cancer or carcinoma in situ of the cervix that has been treated or excised and is considered resolved * Malabsorption syndrome or other condition that precludes enteral route of administration * Other clinically significant uncontrolled condition(s) including, but not limited to, systemic infection (viral, bacterial or fungal) * Vaccination with a live vaccine within 28 days prior to randomization * Consumed grapefruit or grapefruit products, seville oranges (including marmalade containing seville oranges), or star fruit within 3 days prior to the first dose of study treatment * A cardiovascular disability status of New York Heart Association Class \>/=3. Class 3 is defined as cardiac disease in which participants are comfortable at rest but have marked limitation of physical activity due to fatigue, palpitations, dyspnea, or anginal pain * Major surgery within 30 days prior to the first dose of study treatment * A participant who is pregnant or breastfeeding * Known allergy to both xanthine oxidase inhibitors and rasburicase Exclusion Criteria R/C Substudy: * Transformation of CLL to aggressive NHL (e.g., Richter's transformation, prolymphocytic leukemia, or DLBCL) or CNS involvement by CLL * Evidence of other clinically significant uncontrolled condition(s) including, but not limited to, uncontrolled systemic infection (viral, bacterial, or fungal) * Development of other malignancy since enrollment into the study, with the exception of curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix * Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia * History of severe (i.e., requiring permanent discontinuation of prior rituximab therapy) prior allergic or anaphylactic reactions to rituximab * Known HIV positivity * Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen \[HbsAg\] serology) * Positive test results for hepatitis C virus (HCV; HCV antibody serology testing) * Requires the use of warfarin (due to potential drug interactions that may potentially increase the exposure of warfarin) * Has not recovered to less than Grade 2 clinically significant adverse effect(s)/toxicity(ies) of any previous therapy * Received potent CYP3A4 inhibitors (such as fluconazole, ketoconazole, and clarithromycin) within 7 days prior to the first dose of study treatment * Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin, St. John's wort) within 7 days prior to the first dose of study treatment * Consumed grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of study treatment * A cardiovascular disability status of New York Heart Association Class \>/= 3 * A significant history of renal, neurologic, psychiatric, endocrine, metabolic, immunologic, cardiovascular, or hepatic disease that, in the opinion of the investigator, would adversely affect the participants's participation in this study or interpretation of study outcomes * Major surgery within 30 days prior to the first dose of study treatment * A participant who is pregnant or breastfeeding * Malabsorption syndrome or other condition that precludes enteral route of administration * Known allergy to both xanthine oxidase inhibitors and rasburicase * Vaccination with a live vaccine within 28 days prior to randomization

Locations (111)

Outcomes

Primary Outcomes

Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death

Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (greater than \[\>\] 1.5 centimeters \[cm\]); unequivocal progression of non-target lesion; an increase of greater than or equal to (\>/=) 50 percent (%) compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count \>/=5000 per microliter (mcL), or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of \>/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by \>2 grams per deciliter (g/dL) or to less than \[\<\] 10 g/dL. Percentages are rounded off.

Time frame: Baseline up to PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months)

Progression-Free Survival (PFS) as Assessed by the Investigator Using Standard iwCLL Guidelines

PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (\>1.5 cm); unequivocal progression of non-target lesion; increase of \>/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count \>/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of \>/=50% in platelet or neutrophil count, or hemoglobin level by \>2 g/dL or to \<10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% confidence interval (CI) was computed using method of Brookmeyer and Crowley.

Time frame: Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months)

Secondary Outcomes

Data from ClinicalTrials.gov

This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.

Rituximab will be administered at a dose of 375 mg/m\^2 via IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m\^2 on Day 1 of Cycles 2-6. R/C Substudy: Following the venetoclax ramp-up period, rituximab will be administered for 6 cycles consisting of a single infusion on the first day of each 28-day cycle.

University of California San Diego Medical Center

La Jolla, California, United States

Henry Ford Health System

Detroit, Michigan, United States

Memorial Sloan Kettering Cancer Center; Clinical Trials Office

New York, New York, United States

Perlmutter Cancer Center NYU Langone Health

New York, New York, United States

Huntsman Cancer Institute; University of Utah

Salt Lake City, Utah, United States

The Canberra Hospital

Garran, Australian Capital Territory, Australia

Concord Repatriation General Hospital

Concord, New South Wales, Australia

St George Hospital

Kogarah, New South Wales, New South Wales, Australia

Princess Alexandra Hospital

Woolloongabba, Queensland, Australia

Royal Adelaide Hospital

Adelaide, South Australia, Australia

...and 101 more locations

Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines

Assessment of response was performed by the IRC according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (\>1.5 cm); unequivocal progression of non-target lesion; an increase of \>/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count \>/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of \>/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by \>2 g/dL or to \<10 g/dL. No new IRC data was generated post the primary analysis.

Time frame: Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

PFS as Assessed by the IRC Using Standard iwCLL Guidelines

PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the IRC using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (\>1.5 cm); unequivocal progression of non-target lesion; increase of \>/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count \>/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of \>/=50% in platelet or neutrophil count, or hemoglobin level by \>2 g/dL or to \<10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. No new IRC data was generated post the primary analysis.

Time frame: Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

Percentage of Participants With PD or Death as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by Fluorescence In-situ Hybridization (FISH) Test

Assessment of response was performed by the investigator according to the iwCLL guidelines. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (\>1.5 cm); unequivocal progression of non-target lesion; an increase of \>/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count \>/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of \>/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by \>2 g/dL or to \<10 g/dL. Percentages are rounded off.

Time frame: Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months)

PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

PFS was defined as the time from randomization until first occurrence of PD/relapse as assessed by the investigator using iwCLL guidelines, or death from any cause, whichever occurred first. PD: occurrence of one of the following: new lesion; new palpable lymph node (\>1.5 cm); unequivocal progression of non-target lesion; increase of \>/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count \>/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of \>/=50% in platelet or neutrophil count, or hemoglobin level by \>2 g/dL or to \<10 g/dL. Participants who had not progressed, relapsed, or died at the time of analysis, were censored on the date of last assessment. In case of no disease assessment after baseline, PFS was censored at the time of randomization+1 day. The median PFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.

Time frame: Baseline up to PD or death, whichever occurred first (up to approximately 8 years 5 months)

Percentage of Participants With PD or Death as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Time frame: Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test

Time frame: Baseline up to PD or death, whichever occurred first (up to approximately 3 years)

Percentage of Participants With Best Overall Response of Complete Response (CR), CR With Incomplete Bone Marrow Recovery (CRi), Nodular Partial Response (nPR), or Partial Response (PR) as Assessed by the Investigator Using iwCLL Guidelines

Response was assessed by investigator according to iwCLL guidelines and was confirmed by repeat assessment \>/=4 weeks after initial documentation. CR: peripheral blood lymphocytes \<4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils \>1500/mcL, platelets \>100000/mcL, hemoglobin \>11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with \<30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: \>/=50% reduction in two of following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and 1 of following: neutrophils \>1500/mcL, platelets \>100000/mcL, hemoglobin \>11.0 g/dL or \>/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. 95% CI was computed using Pearson-Clopper method.Percentages are rounded off.

Time frame: Baseline up to approximately 8 years 5 months

Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines

Response was assessed by IRC according to iwCLL guidelines and was confirmed by repeat assessment \>/=4 weeks after initial documentation. CR: peripheral blood lymphocytes \<4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, constitutional symptoms; neutrophils \>1500/mcL, platelets \>100000/mcL, hemoglobin \>11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with \<30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: \>/=50% reduction in 2 of following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; 1 of following: neutrophils \>1500/mcL, platelets \>100000/mcL, hemoglobin \>11.0 g/dL or \>/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. 95% CI was computed using Pearson-Clopper method.No new IRC data was generated post primary analysis.

Time frame: Baseline up to last FUV (up to approximately 3 years)

Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at End of Combination Treatment Visit as Assessed by the Investigator Using iwCLL Guidelines

Response was assessed by investigator according to iwCLL guidelines and was confirmed by repeat assessment \>/=4 weeks after initial documentation. CR: peripheral blood lymphocytes \<4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils \>1500/mcL, platelets \>100000/mcL, hemoglobin \>11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with \<30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: \>/=50% reduction in 2 of following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and 1 of following: neutrophils \>1500/mcL, platelets \>100000/mcL, hemoglobin \>11.0 g/dL or \>/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. 95% CI was computed using Pearson-Clopper method. Percentages are rounded off.

Time frame: End of combination treatment response (EoCTR) visit (8 to 12 weeks after Cycle [C] 6 Day [1]); Cycle length = 28 days

Percentage of Participants With Overall Response of CR, Cri, nPR, or PR at End of Combination Treatment Visit as Assessed by the IRC Using iwCLL Guidelines

Response was assessed by the IRC according to the iwCLL guidelines and was confirmed by repeat assessment \>/=4 weeks after initial documentation. CR: peripheral blood lymphocytes \<4000/mcL; absence of any new lesion, nodal disease, lymphadenopathy, hepatomegaly, splenomegaly, and constitutional symptoms; neutrophils \>1500/mcL, platelets \>100000/mcL, hemoglobin \>11.0 g/dL without need for transfusion or exogenous growth factors; normocellular bone marrow with \<30% lymphocytes; no lymphoid nodules. CRi: fulfilling all CR criteria but persistent cytopenia. PR: \>/=50% reduction in two of the following: peripheral blood lymphocytes, lymphadenopathy, spleen and/or liver enlargement; and one of the following: neutrophils \>1500/mcL, platelets \>100000/mcL, hemoglobin \>11.0 g/dL or \>/=50% improvement without need for transfusion or exogenous growth factors. nPR: fulfilling all CR criteria but presence of lymphoid nodules. The 95% CI was computed using Pearson-Clopper method.

Time frame: EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days

Percentage of Participants Who Died

Percentage of participants who died from any cause, during the study, was reported. Percentage is rounded off.

Time frame: Baseline up to approximately 8 years 5 months

Overall Survival (OS)

OS was defined as the time from the date of randomization to the date of death from any cause. Participants alive at the time of the analysis were censored at the date when they were last known to be alive as documented by the investigator. The median OS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.

Time frame: Baseline up to approximately 8 years 5 months

Percentage of Participants With PD/Relapse, Start of a New Anti-Chronic Lymphocytic Leukemia (CLL) Therapy, or Death as Assessed by the Investigator Using iwCLL Guidelines

Percentage of participants with PD/relapse, death from any cause, or start of a new non-protocol-specified anti-CLL therapy as assessed by the investigator, during the study, was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (\>1.5 cm); unequivocal progression of non-target lesion; an increase of \>/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count \>/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of \>/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by \>2 g/dL or to \<10 g/dL. Percentages are rounded off.

Time frame: Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (approximately 8 years 5 months)

Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines

EFS was defined as the time from date of randomization until the date of PD/relapse, start of a new non-protocol-specified anti-CLL therapy, or death from any cause, whichever occurred first, as assessed by the investigator. PD: occurrence of one of the following: new lesion; new palpable lymph node (\>1.5 cm); unequivocal progression of non-target lesion; increase of \>/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count \>/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of \>/=50% in platelet or neutrophil count, or hemoglobin level by \>2 g/dL or to \<10 g/dL. Participants without any of the specified event at the time of analysis were censored at the date of last adequate response assessment. In case of no post-baseline response assessment, participants were censored at the randomization date. The median EFS was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.

Time frame: Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (approximately 8 years 5 months)

Percentage of Participants With PD or Death Among Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the Investigator Using iwCLL Guidelines

Percentage of participants with PD as assessed by the investigator according to the iwCLL guidelines or death from any cause during the study was reported. PD was defined as occurrence of one of the following events: appearance of any new extra nodal lesion; new palpable lymph node (\>1.5 cm); unequivocal progression of non-target lesion; an increase of \>/=50% compared to baseline in splenomegaly, hepatomegaly, number of blood lymphocytes with lymphocyte count \>/=5000/mcL, or in longest diameter of any extra nodal lesion; transformation to a more aggressive histology; decrease of \>/=50% compared to baseline in platelet or neutrophil count; or decrease in hemoglobin level by \>2 g/dL or to \<10 g/dL. CR, CRi, nPR, and PR have been defined in previous outcomes, and are not repeated here due to space constraint. Percentage is rounded off.

Time frame: From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months)

Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines

DOR was defined as the time from first occurrence of a documented response of CR, CRi, nPR, or PR until PD/relapse, as assessed by the investigator according to the iwCLL guidelines, or death from any cause. PD: occurrence of one of the following: new lesion; new palpable lymph node (\>1.5 cm); unequivocal progression of non-target lesion; increase of \>/=50% in splenomegaly, hepatomegaly, blood lymphocytes with count \>/=5000/mcL, longest diameter of any lesion; transformation to more aggressive histology; decrease of \>/=50% in platelet or neutrophil count, or hemoglobin level by \>2 g/dL or to \<10 g/dL. Participants without PD or death after response were censored at the last date of adequate response assessment. The median DOR was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley. CR, CRi, nPR, and PR have been defined in previous outcomes, and are not repeated here due to space constraint.

Time frame: From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 8 years 5 months)

Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator

Percentage of participants with start of new non-protocol-specified anti-CLL therapy, as assessed by the investigator, or death from any cause, during the study, was reported. Percentage is rounded off.

Time frame: Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 8 years 5 months)

Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator

TTNT was defined as the time from randomization until start of new non-protocol-specified anti-CLL treatment or death from any cause. Participants without the event at the time of analysis were censored at the last visit date for this outcome measure analysis. The median TTNT was estimated using Kaplan-Meier method and the 95% CI was computed using method of Brookmeyer and Crowley.

Time frame: Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 8 years 5 months)

Percentage of Participants With Minimal Residual Disease (MRD) Negativity in Peripheral Blood

MRD-negativity was defined as the presence of \<1 malignant B-cell per 10000 normal B-cells in a sample of at least 200000 B-cells, as assessed by the allele specific oligonucleotide polymerase chain reaction (ASO-PCR) and/or flow cytometry technique. Percentage of participants with MRD-negativity was reported. The 95% CI was computed using Pearson-Clopper method. Percentage is rounded off.

Time frame: EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days

Percentage of Participants With MRD Negativity in Bone Marrow

MRD-negativity was defined as the presence of \<1 malignant B-cell per 10000 normal B-cells in a sample of at least 200000 B-cells, as assessed flow cytometry technique. Percentage of participants with MRD-negativity was reported. The 95% CI was computed using Pearson-Clopper method. Percentages are rounded off.

Time frame: EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days

Plasma Venetoclax Concentrations

Time frame: Pre-dose (0 hour, anytime before venetoclax administration) and 4 hours post-dose on D1 of Cycles 1 and 4; Cycle length = 28 days

Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores

MDASI is a 25-item validated questionnaire consisting of 2 parts. Part 1: 19-items divided into 2 scales, Core Symptom Severity (average of Questions 1 to 13; total 13 items: pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, remembering things, lack of appetite, drowsiness, dry mouth, sadness, vomiting, and numbness) and Module Symptom Severity (average of Questions 14 to 19; total 6 items: night sweats, fevers and chills, lymph node swelling, diarrhea, bruising easy or bleeding, and constipation). Part 2: 6-items to assess Interference (symptom distress) (average of Questions 20 to 25; total 6 items: general activity, walking, work, mood, relations with other people, and enjoyment of life). Each item was rated from 0 to 10, with lower scores indicating better outcome. Total score for Core Symptom Severity, Module Symptom Severity, and Interference are reported which range from 0 to 10, with lower scores indicating better health-related quality of life (HRQoL).

Time frame: Baseline, Days 1, 8, and 15 of Cycles 1, 2, and 3; Cycle length = 28 days

Change From Baseline in HRQoL as Measured by European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) Functional Scales Score and Global Health Status/Global Quality-of-Life (QoL) Scale Score

EORTC QLQ-C30 is a validated self-report measure consisting of 30 questions incorporated into 5 functional scales (Physical, Role, Cognitive, Emotional, and Social), 3 symptom scales (fatigue, pain, nausea, and vomiting), a global health status/global QoL scale, and single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea). Most questions used 4-point scale (1='Not at all' to 4='Very much'), while 2 questions used 7-point scale (1='very poor' to 7='Excellent'). Scores were averaged, transformed to 0-100 scale; where higher score for functional scales=poor level of functioning; higher score for global health status/global QoL=better HRQoL.

Time frame: Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days

Change From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score

The EORTC QLQ-CLL16 module is designed for participants with Stage 0 to Stage 4 CLL. It is composed of 16 questions and there are four multi-item scales on Fatigue (2 items), Treatment-related side effects (TRSE, 4 items), Disease-related symptoms (DRS, 4 items), and Infection (4 items); and two single-item scales on social activities and future health worries. Multi-item scales score are reported and the total score for each multi-item scale was transformed to result in a total score range of 0 to 100, where higher score = poor HRQoL.

Time frame: Baseline, D1 of Cycles 1, 2, 3, 4, 5, 6, STC/EW visit (up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

An AE was defined as any untoward medical occurrence in a participant administered with Mircera and which does not necessarily have a causal relationship with Mircera. A Serious Adverse Event (SAE) is any significant hazard, contraindication, side effect that is fatal or life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is medically significant or requires intervention to prevent one or other of the outcomes listed above. AEs were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE, v4.0)

Time frame: From signing of informed consent form up to approximately 8 years 5 months

Number of Participants With Grade 3 or Higher Tumor Lysis Syndrome (TLS) and Infusion-related Reactions (IRRs)

An AE was defined as any untoward medical occurrence in a participant administered with Mircera and which does not necessarily have a causal relationship with Mircera. A SAE is any significant hazard, contraindication, side effect that is fatal or life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is medically significant or requires intervention to prevent one or other of the outcomes listed above. TLS and IRRs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe or medically significant; Grade 4 = Life-threatening; Grade 5 = Death. A higher grade indicates a worse outcome.

Time frame: From signing of informed consent form up to approximately 8 years 5 months