MURANO: 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)

Sponsor
Hoffmann-La Roche (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT02005471
Collaborator
AbbVie (Industry)
389
Enrollment
111
Locations
4
Arms
99.4
Anticipated Duration (Months)
3.5
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or DiseaseIntervention/TreatmentPhase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
389 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Phase III, Open-Label, Randomized Study in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT-199) Plus Rituximab Compared With Bendamustine Plus Rituximab
Actual Study Start Date :
Mar 17, 2014
Actual Primary Completion Date :
May 8, 2017
Anticipated Study Completion Date :
Jun 30, 2022

Arms and Interventions

ArmIntervention/Treatment
Active Comparator: Bendamustine + Rituximab

Participants will receive bendamustine 70 milligrams per meter squared (mg/m^2) via intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 followed by 500 mg/m^2 on Day 1 of Cycles 2-6.

Drug: Bendamustine
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.

Drug: Rituximab
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.

Experimental: Venetoclax + Rituximab

Participants will be initially placed on a venetoclax 5 weeks ramp-up period, and will receive an initial dose of 20 milligrams (mg) via tablet orally once daily (QD). Then the dose will be incremented weekly up to a maximum dose of 400 mg. Participants will then continue receiving venetoclax 400 mg QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards, as directed by the investigator, in combination with rituximab 375 mg/m^2 via IV infusion on Day 1 of Cycle 1 followed by 500 mg/m^2 on Day 1 of Cycles 2-6.

Drug: Venetoclax
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.
Other Names:
  • GDC-0199, ABT-199
  • Drug: Rituximab
    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.

    Experimental: Bendamustine + Rituximab Crossover Substudy

    Participants entering the Crossover Substudy will have a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, Participants will receive 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants will continue to take their daily dose of venetoclax during the rituximab cycles. Participants who have not progressed following the completion of the 6 cycles will continue to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 Crossover Day 1 of the Substudy.

    Drug: Venetoclax
    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.
    Other Names:
  • GDC-0199, ABT-199
  • Drug: Rituximab
    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.

    Experimental: Venetoclax + Rituximab Re-Treatment

    Participants entering the Re-Treatment Substudy will have a 5-week venetoclax dose ramp-up period to reach the target dose of 400 mg QD. Following the venetoclax ramp-up period, Participants will receive 6 cycles of rituximab consisting of a single infusion on the first day of each 28-day cycle. Participants will continue to take their daily dose of venetoclax during the rituximab cycles. Participants who have not progressed following the completion of the 6 cycles will continue to receive venetoclax monotherapy until disease progression or for a maximum of 2 years from Cycle 1 Re-Treatment Day 1 of the Substudy.

    Drug: Venetoclax
    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.
    Other Names:
  • GDC-0199, ABT-199
  • Drug: Rituximab
    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.

    Outcome Measures

    Primary Outcome Measures

    1. Percentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death [Baseline up to PD or death from any cause, whichever occurred first (up to approximately 3 years)]

      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.

    2. Progression-Free Survival (PFS) as Assessed by the Investigator Using Standard iwCLL Guidelines [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]

      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.

    Secondary Outcome Measures

    1. Percentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]

      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.

    2. PFS as Assessed by the IRC Using Standard iwCLL Guidelines [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]

      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.

    3. 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 [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]

      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.

    4. PFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]

      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.

    5. 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 [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]

      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.

    6. PFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test [Baseline up to PD or death, whichever occurred first (up to approximately 3 years)]

      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.

    7. 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 [Baseline up to last follow-up visit (FUV) (maximum up to data cut-off date, overall approximately 3 years)]

      Response was assessed by the investigator 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.

    8. Percentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines [Baseline up to last FUV (maximum up to data cut-off date, overall approximately 3 years)]

      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.

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

      Response was assessed by the investigator 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.

    10. 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 [EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days]

      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.

    11. Percentage of Participants Who Died [Baseline up to last FUV (maximum up to Data Cut-off date, overall approximately 3 years)]

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

    12. Overall Survival (OS) [Baseline up to last FUV (maximum up to Data Cut-off date, overall approximately 3 years)]

      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.

    13. 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 [Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (maximum up to Data Cut-off date, overall approximately 3 years)]

      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.

    14. Event-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines [Baseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (maximum up to Data Cut-off date, overall approximately 3 years)]

      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.

    15. 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 [From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 3 years)]

      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.

    16. Duration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines [From time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 3 years)]

      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.

    17. Percentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator [Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 3 years)]

      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.

    18. Time to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator [Baseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 3 years)]

      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.

    19. Percentage of Participants With Minimal Residual Disease (MRD) Negativity at the EoCTR Visit [EoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days]

      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 at the EoCTR visit was reported. The 95% CI was computed using Pearson-Clopper method.

    20. Plasma Venetoclax Concentrations [Pre-dose (0 hour, anytime before venetoclax administeration) and 4 hours post-dose on D1 of Cycles 1 and 4; Cycle length = 28 days]

    21. Change From Baseline in Lymphocyte Subset Counts at Specified Time Points [Baseline, C4D14-28, Study Treatment Completion/Early Withdrawal (STC/EW, up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and at FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days]

    22. Change From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores [Baseline, Days 1, 8, and 15 of Cycles 1, 2, and 3; Cycle length = 28 days]

      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).

    23. 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 [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]

      The EORTC QLQ-C30 is a validated self-report measure consisting of 30 questions incorporated into five functional scales (Physical, Role, Cognitive, Emotional, and Social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), 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'). Functional scales score and global health status/global QoL scale score are reported. Scores were averaged, transformed to 0-100 scale; where higher score for functional scales = poor level of functioning and higher score for global health status/global QoL = better HRQoL.

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

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1University of California San Diego Medical CenterLa JollaCaliforniaUnited States92093-5354
    2Henry Ford Health SystemDetroitMichiganUnited States48202
    3Memorial Sloan Kettering Cancer Center; Clinical Trials OfficeNew YorkNew YorkUnited States10021
    4Perlmutter Cancer Center NYU Langone HealthNew YorkNew YorkUnited States10032
    5Huntsman Cancer Institute; University of UtahSalt Lake CityUtahUnited States84112
    6The Canberra HospitalGarranAustralian Capital TerritoryAustralia2065
    7Concord Repatriation General HospitalConcordNew South WalesAustralia2139
    8St George HospitalKogarah, New South WalesNew South WalesAustralia2217
    9Princess Alexandra HospitalWoolloongabbaQueenslandAustralia4102
    10Royal Adelaide HospitalAdelaideSouth AustraliaAustralia5000
    11Flinders Medical CentreBedford ParkSouth AustraliaAustralia5042
    12Royal Hobart HospitalHobartTasmaniaAustralia7000
    13Peter MacCallum Cancer CenterEast MelbourneVictoriaAustralia3002
    14Frankston HospitalFrankstonVictoriaAustralia3199
    15Monash Medical Centre; HaematologyMelbourneVictoriaAustralia3168
    16Slade Health PharmacyMount WaverleyVictoriaAustralia3149
    17Royal Melbourne HospitalParkvilleVictoriaAustralia3050
    18The Perth Blood InstituteNedlandsWestern AustraliaAustralia6009
    19Medizinische Universität InnsbruckInnsbruckAustria6020
    20LKH - Universitätsklinikum der PMU SalzburgSalzburgAustria5020
    21Medizinische Universität WienWienAustria1090
    22Klinik OttakringWienAustria1160
    23ZNA Antwerpen; Department HematologyAntwerpenBelgium2060
    24Cliniques Universitaires Saint-Luc; HematologyBruxellesBelgium1200
    25AZ GroeningeKortrijkBelgium8500
    26UZ Leuven; Department HematologyLeuvenBelgium3000
    27CHU UCL Mont-GodinneMont-godinneBelgium5530
    28AZ Delta (Campus Rumbeke)RoeselareBelgium8800
    29Foothills Medical Centre; Centre Dept of Medical Clinical NeuroscienceCalgaryAlbertaCanadaT2N 2T9
    30Juravinski Cancer ClinicHamiltonOntarioCanadaL8N 3Z5
    31Jewish General HospitalMontrealQuebecCanadaH3T 1E2
    32Saskatoon City Hospital;Saskatchewan Cancer CentreSaskatoonSaskatchewanCanadaS7N 4H4
    33Fakultni nemocnice BrnoBrnoCzechia613 00
    34Fakultni nemocnice Hradec KraloveHradec KraloveCzechia500 05
    35Fakultní nemocnice OlomoucOlomoucCzechia775 20
    36Fakultni nemocnice OstravaOstrava - PorubaCzechia708 52
    37Vseobecna fakultni nemocnice v PrazePraha 2Czechia128 08
    38Fakultni nemocnice Kralovske VinohradyPrahaCzechia100 34
    39Herlev HospitalHerlevDenmark2730
    40RigshospitaletKøbenhavn ØDenmark2100
    41Odense UniversitetshospitalOdense CDenmark5000
    42Sjællands Universitetshospital, RoskildeRoskildeDenmark4000
    43Sygehus Lillebælt, VejleVejleDenmark7100
    44Hôpital MorvanBrestFrance29609
    45Centre Hospitalier Départemental Les OudairiesLa Roche sur YonFrance85025
    46Hopital Claude Huriez - CHU LilleLilleFrance59037
    47Hopital Saint EloiMontpellierFrance34295
    48CHU Nantes - Hôtel Dieu; Service Assistance Medicale à la ProcreationNantesFrance44093
    49Hopital Robert DebreParisFrance75019
    50Centre Hospitalier Lyon SudPierre BeniteFrance69495
    51CHU Poitiers - Hopital La MiletriePoitiersFrance86000
    52CHU de Rennes - Hopital de PontchailloRennesFrance35033
    53Centre Henri BecquerelRouenFrance76038
    54Institut Universitaire du Cancer - Oncopole Toulouse (IUCT-O)ToulouseFrance31059
    55CHU Tours - Hôpital BretonneauToursFrance37044
    56Hôpital de Brabois AdultesVandoeuvre-les-nancyFrance54511
    57Universitätsklinikum "Carl Gustav Carus" der Technischen Universität DresdenDresdenGermany01307
    58Universitaetsklinikum FreiburgFreiburgGermany79106
    59Universitätsklinikum TübingenTuebingenGermany72076
    60Semmelweis EgyetemBudapestHungary1083
    61Orszagos Onkologiai IntezetBudapestHungary1122
    62Debreceni Egyetem Klinikai Központ; Bőrgyógyászati KlinikaDebrecenHungary4012
    63Somogy Megyei Kaposi Mor Oktato KorhazPecsHungary7624
    64Szegedi Tud.Egyetem Szent-Gyorgyi Albert Klin.Kozp.SzegedHungary6720
    65Azienda Ospedaliera Città della Salute e della Scienza di Torino; RadiologyTorinoAbruzzoItaly10126
    66Azienda Ospedaliero Universitaria San MartinoGenovaLiguriaItaly16132
    67Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)BergamoLombardiaItaly24127
    68Ospedale San RaffaeleMilanoLombardiaItaly20132
    69Asst Grande Ospedale Metropolitano Niguarda; SC Farmacia OspedaleMilanoLombardiaItaly20162
    70Azienda Ospedaliero Universitaria Ospedali RiunitiTorrette Di AnconaMarcheItaly60126
    71Istituto Tumori Giovanni Paolo II IRCCS Ospedale Oncologico BariBariPugliaItaly70124
    72Azienda Ospedaliera Universitaria CareggiFirenzeToscanaItaly50141
    73Azienda Ospedaliera Di PadovaPadovaVenetoItaly35128
    74Seoul National University Bundang HospitalSeongnam-siKorea, Republic of13605
    75Severance Hospital, Yonsei University Health SystemSeoulKorea, Republic of03722
    76Konkuk University Medical CenterSeoulKorea, Republic of05030
    77The Catholic University of Korea Seoul St. Mary's HospitalSeoulKorea, Republic of137-701
    78Amsterdam UMC, Locatie VUMC; NeurologyAmsterdamNetherlands1081 HV
    79Amsterdam UMC Location AMCAmsterdamNetherlands1105 AZ
    80Albert Schweitzer Ziekenhuis, Dordwijk; Internal Medicine, Hemato-OncologyDordrechtNetherlands3318 AT
    81Medisch Spectrum TwenteEnschedeNetherlands7512 KZ
    82Leids Universitair Medisch Centrum; CardiologyLeidenNetherlands2333 ZA
    83Erasmus Medisch Centrum Rotterdam; Lokatie Daniel den HoedRotterdamNetherlands3015 GD
    84UMC UtrechtUtrechtNetherlands3508 GA
    85North Shore Hospital; HaematolgyAucklandNew Zealand1309
    86Middlemore HospitalAucklandNew Zealand
    87Christchurch Hospital NZChristchurchNew Zealand8011
    88Baxter HealthcareMount WellingtonNew Zealand1060
    89SP ZOZ Zespol Szpitali Miejskich w ChorzowieChorzowPoland41-500
    90Uniwersyteckie Centrum KliniczneGdanskPoland80-214
    91Wojewódzkie Wielospecjalistyczne Centrum Onkologii i Traumatologii im. M. Kopernika w LodziLodzPoland93-513
    92Szpital Wojewodzki w OpoluOpolePoland45-061
    93MTZ Clinical Research Sp. z o.o.WarszawaPoland02-106
    94Samodzielny Publiczny Szpital Kliniczny nr 1ZabrzePoland44803
    95Kemerovo Regional Clinical HospitalKemerovoRussian Federation650066
    96FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin"MoscowRussian Federation115478
    97BHI of Omsk region Clinical Oncology DispensaryOmskRussian Federation644013
    98SRI of Hematology and TransfusiologySt. PetersburgRussian Federation191024
    99North-West Federal Medical Research Center n.a. V.A. AlmazovSt. PetersburgRussian Federation197341
    100Complejo Hospitalario de NavarraPamplonaNavarraSpain31008
    101Hospital Universitari Vall d'HebronBarcelonaSpain08035
    102Hospital Clinic i Provincial de Barcelona; HematologyBarcelonaSpain08036
    103Hospital Universitario 12 de OctubreMadridSpain28041
    104Hospital Clinico Universitario de SalamancaSalamancaSpain37007
    105Skånes UniversitetssjukhusLundSweden221 85
    106Akademiska SjukhusetUppsalaSweden751 85
    107National Taiwan University HospitalTaipeiTaiwan10002
    108Bristol Haematology and Oncology CentreBristolUnited KingdomBS2 8ED
    109The ChristieManchesterUnited KingdomM20 4BX
    110Southampton General HospitalSouthamptonUnited KingdomSO16 6YD
    111Singleton Hospital; Pharmacy DepartmentSwanseaUnited KingdomSA2 8QA

    Sponsors and Collaborators

    • Hoffmann-La Roche
    • AbbVie

    Investigators

    • Study Director: Clinical Trials, Hoffmann-La Roche

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT02005471
    Other Study ID Numbers:
    • GO28667
    • 2013-002110-12
    First Posted:
    Dec 9, 2013
    Last Update Posted:
    Nov 11, 2021
    Last Verified:
    Nov 1, 2021

    Study Results

    Participant Flow

    Recruitment DetailsA total of 489 participants were screened, out of which, 389 participants were enrolled into the study.
    Pre-assignment Detail
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 milligrams per meter squared (mg/m^2) via intravenous (IV) infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 milligrams (mg) via tablet orally once daily (QD) for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to disease progression (PD) or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Period Title: Overall Study
    STARTED195194
    Treated188194
    COMPLETED00
    NOT COMPLETED195194

    Baseline Characteristics

    Arm/Group TitleBendamustine + RituximabVenetoclax + RituximabTotal
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.Total of all reporting groups
    Overall Participants195194389
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    64.4
    (9.6)
    63.9
    (10.5)
    64.1
    (10.1)
    Sex: Female, Male (Count of Participants)
    Female
    44
    22.6%
    58
    29.9%
    102
    26.2%
    Male
    151
    77.4%
    136
    70.1%
    287
    73.8%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    3
    1.5%
    4
    2.1%
    7
    1.8%
    Not Hispanic or Latino
    186
    95.4%
    186
    95.9%
    372
    95.6%
    Unknown or Not Reported
    6
    3.1%
    4
    2.1%
    10
    2.6%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    4
    2.1%
    6
    3.1%
    10
    2.6%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    2
    1%
    0
    0%
    2
    0.5%
    White
    178
    91.3%
    181
    93.3%
    359
    92.3%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    11
    5.6%
    7
    3.6%
    18
    4.6%

    Outcome Measures

    1. Primary Outcome
    TitlePercentage of Participants With PD as Assessed by the Investigator Using Standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) Guidelines or Death
    DescriptionAssessment 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.
    Time FrameBaseline up to PD or death from any cause, whichever occurred first (up to approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Number [percentage of participants]
    58.5
    30%
    16.5
    8.5%
    2. Primary Outcome
    TitleProgression-Free Survival (PFS) as Assessed by the Investigator Using Standard iwCLL Guidelines
    DescriptionPFS 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 FrameBaseline up to PD or death, whichever occurred first (up to approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Median (95% Confidence Interval) [months]
    17.0
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.17
    Confidence Interval (2-Sided) 95%
    0.11 to 0.25
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments Unstratified Analysis
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.17
    Confidence Interval (2-Sided) 95%
    0.12 to 0.26
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    3. Secondary Outcome
    TitlePercentage of Participants With PD or Death as Assessed by the Independent Review Committee (IRC) Using Standard iwCLL Guidelines
    DescriptionAssessment 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.
    Time FrameBaseline up to PD or death, whichever occurred first (up to approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Number [percentage of participants]
    54.4
    27.9%
    18.0
    9.3%
    4. Secondary Outcome
    TitlePFS as Assessed by the IRC Using Standard iwCLL Guidelines
    DescriptionPFS 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.
    Time FrameBaseline up to PD or death, whichever occurred first (up to approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Median (95% Confidence Interval) [months]
    18.1
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.19
    Confidence Interval (2-Sided) 95%
    0.13 to 0.28
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments Unstratified Analysis
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.20
    Confidence Interval (2-Sided) 95%
    0.14 to 0.30
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    5. Secondary Outcome
    TitlePercentage 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
    DescriptionAssessment 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.
    Time FrameBaseline up to PD or death, whichever occurred first (up to approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.
    Arm/Group TitleBendamustine + Rituximab 17p Del. PopulationVenetoclax + Rituximab 17p Del. Population
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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. Only participants with 17p deletion as identified by FISH test were included.Participants were initially placed on a venetoclax ramp-up period of 4 to 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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. Only participants with 17p deletion as identified by FISH test were included.
    Measure Participants4646
    Number [percentage of participants]
    58.7
    30.1%
    15.2
    7.8%
    6. Secondary Outcome
    TitlePFS as Assessed by the Investigator Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test
    DescriptionPFS 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 FrameBaseline up to PD or death, whichever occurred first (up to approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.
    Arm/Group TitleBendamustine + Rituximab 17p Del. PopulationVenetoclax + Rituximab 17p Del. Population
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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. Only participants with 17p deletion as identified by FISH test were included.Participants were initially placed on a venetoclax ramp-up period of 4 to 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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. Only participants with 17p deletion as identified by FISH test were included.
    Measure Participants4646
    Median (95% Confidence Interval) [months]
    15.4
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments Stratified Analysis; Stratification factor: geographic region.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.13
    Confidence Interval (2-Sided) 95%
    0.05 to 0.31
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments Unstratified Analysis
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.13
    Confidence Interval (2-Sided) 95%
    0.05 to 0.29
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    7. Secondary Outcome
    TitlePercentage 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
    DescriptionAssessment 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.
    Time FrameBaseline up to PD or death, whichever occurred first (up to approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.
    Arm/Group TitleBendamustine + Rituximab 17p Del. PopulationVenetoclax + Rituximab 17p Del. Population
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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. Only participants with 17p deletion as identified by FISH test were included.Participants were initially placed on a venetoclax ramp-up period of 4 to 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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. Only participants with 17p deletion as identified by FISH test were included.
    Measure Participants4646
    Number [percentage of participants]
    47.8
    24.5%
    19.6
    10.1%
    8. Secondary Outcome
    TitlePFS as Assessed by the IRC Using Standard iwCLL Guidelines in Participants With 17p Deletion as Identified by FISH Test
    DescriptionPFS 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.
    Time FrameBaseline up to PD or death, whichever occurred first (up to approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population participants with 17p deletion as identified by FISH test.
    Arm/Group TitleBendamustine + Rituximab 17p Del. PopulationVenetoclax + Rituximab 17p Del. Population
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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. Only participants with 17p deletion as identified by FISH test were included.Participants were initially placed on a venetoclax ramp-up period of 4 to 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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. Only participants with 17p deletion as identified by FISH test were included.
    Measure Participants4646
    Median (95% Confidence Interval) [months]
    16.1
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments Stratified Analysis; Stratification factor: geographic region.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.21
    Confidence Interval (2-Sided) 95%
    0.09 to 0.49
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments Unstratified Analysis
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.21
    Confidence Interval (2-Sided) 95%
    0.09 to 0.46
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    9. Secondary Outcome
    TitlePercentage 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
    DescriptionResponse was assessed by the investigator 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 FrameBaseline up to last follow-up visit (FUV) (maximum up to data cut-off date, overall approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population. Participants without post-baseline response assessment were considered as non-responders.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Number (95% Confidence Interval) [percentage of participants]
    67.7
    34.7%
    93.3
    48.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    Method of EstimationEstimation ParameterDifference in Response Rates
    Estimated Value25.61
    Confidence Interval (2-Sided) 95%
    17.88 to 33.33
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 95% CI was computed using Anderson-Hauck method.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterOdds Ratio (OR)
    Estimated Value7.81
    Confidence Interval (2-Sided) 95%
    3.97 to 15.37
    Parameter Dispersion Type:
    Value:
    Estimation CommentsOR was estimated using logistic regression model. The 95% CI was computed using Wald test.
    10. Secondary Outcome
    TitlePercentage of Participants With Best Overall Response of CR, CRi, nPR, or PR as Assessed by the IRC Using iwCLL Guidelines
    DescriptionResponse 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 FrameBaseline up to last FUV (maximum up to data cut-off date, overall approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population. Participants without post-baseline response assessment were considered as non-responders.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Number (95% Confidence Interval) [percentage of participants]
    72.3
    37.1%
    92.3
    47.6%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    Method of EstimationEstimation ParameterDifference in Response Rates
    Estimated Value19.96
    Confidence Interval (2-Sided) 95%
    12.36 to 27.56
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 95% CI was computed using Anderson-Hauck method.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterOdds Ratio (OR)
    Estimated Value4.79
    Confidence Interval (2-Sided) 95%
    2.56 to 8.99
    Parameter Dispersion Type:
    Value:
    Estimation CommentsOR was estimated using logistic regression model. The 95% CI was computed using Wald test.
    11. Secondary Outcome
    TitlePercentage 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
    DescriptionResponse was assessed by the investigator 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 FrameEnd of combination treatment response (EoCTR) visit (8 to 12 weeks after Cycle [C] 6 Day [1]); Cycle length = 28 days

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population. Participants without post-baseline response assessment were considered as non-responders.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Number (95% Confidence Interval) [percentage of participants]
    62.6
    32.1%
    88.1
    45.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    Method of EstimationEstimation ParameterDifference in Response Rates
    Estimated Value25.58
    Confidence Interval (2-Sided) 95%
    17.13 to 34.03
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 95% CI was computed using Anderson-Hauck method.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterOdds Ratio (OR)
    Estimated Value4.75
    Confidence Interval (2-Sided) 95%
    2.76 to 8.16
    Parameter Dispersion Type:
    Value:
    Estimation CommentsOR was estimated using logistic regression model. The 95% CI was computed using Wald test.
    12. Secondary Outcome
    TitlePercentage 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
    DescriptionResponse 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 FrameEoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population. Participants without post-baseline response assessment were considered as non-responders.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Number (95% Confidence Interval) [percentage of participants]
    62.6
    32.1%
    87.1
    44.9%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodCochran-Mantel-Haenszel
    Comments
    Method of EstimationEstimation ParameterDifference in Response Rates
    Estimated Value24.55
    Confidence Interval (2-Sided) 95%
    16.00 to 33.10
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 95% CI was computed using Anderson-Hauck method.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterOdds Ratio (OR)
    Estimated Value4.59
    Confidence Interval (2-Sided) 95%
    2.68 to 7.85
    Parameter Dispersion Type:
    Value:
    Estimation CommentsOR was estimated using logistic regression model. The 95% CI was computed using Wald test.
    13. Secondary Outcome
    TitlePercentage of Participants Who Died
    DescriptionPercentage of participants who died from any cause, during the study, was reported.
    Time FrameBaseline up to last FUV (maximum up to Data Cut-off date, overall approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Number [percentage of participants]
    13.8
    7.1%
    7.7
    4%
    14. Secondary Outcome
    TitleOverall Survival (OS)
    DescriptionOS 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 FrameBaseline up to last FUV (maximum up to Data Cut-off date, overall approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Median (95% Confidence Interval) [months]
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments
    Type of Statistical Test Superiority
    Comments Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.
    Statistical Test of Hypothesisp-Value0.0186
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.48
    Confidence Interval (2-Sided) 95%
    0.25 to 0.90
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments Unstratified Analysis
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value0.0190
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.48
    Confidence Interval (2-Sided) 95%
    0.25 to 0.90
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    15. Secondary Outcome
    TitlePercentage 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
    DescriptionPercentage 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.
    Time FrameBaseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (maximum up to Data Cut-off date, overall approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Number [percentage of participants]
    60.5
    31%
    17.0
    8.8%
    16. Secondary Outcome
    TitleEvent-Free Survival (EFS) as Assessed by the Investigator Using iwCLL Guidelines
    DescriptionEFS 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 FrameBaseline up to PD/relapse, start of a new anti-CLL therapy, or death from any cause, whichever occurred first (maximum up to Data Cut-off date, overall approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Median (95% Confidence Interval) [months]
    16.4
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.17
    Confidence Interval (2-Sided) 95%
    0.11 to 0.25
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments Unstratified Analysis
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.18
    Confidence Interval (2-Sided) 95%
    0.12 to 0.26
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    17. Secondary Outcome
    TitlePercentage 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
    DescriptionPercentage 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.
    Time FrameFrom time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population participants who had best overall response of CR, CRi, nPR, or PR.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants132181
    Number [percentage of participants]
    53.8
    27.6%
    11.0
    5.7%
    18. Secondary Outcome
    TitleDuration of Responses (DOR) as Assessed by the Investigator Using iwCLL Guidelines
    DescriptionDOR 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 FrameFrom time of achieving best overall response until PD or death from any cause, whichever occurred first (up to approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population participants who had best overall response of CR, CRi, nPR, or PR.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants132181
    Median (95% Confidence Interval) [months]
    19.4
    NA
    19. Secondary Outcome
    TitlePercentage of Participants With Start of New Anti-CLL Treatment or Death as Assessed by the Investigator
    DescriptionPercentage 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.
    Time FrameBaseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Number [percentage of participants]
    42.6
    21.8%
    11.9
    6.1%
    20. Secondary Outcome
    TitleTime to New Anti-CLL Treatment (TTNT) as Assessed by the Investigator
    DescriptionTTNT 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 FrameBaseline up to start of new ani-CLL therapy or death, whichever occurred first (up to approximately 3 years)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Median (95% Confidence Interval) [months]
    26.4
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments Stratified Analysis; Stratification factors: 17p deletion, risk status, geographic region.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.19
    Confidence Interval (2-Sided) 95%
    0.12 to 0.31
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments Unstratified Analysis
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodLog Rank
    Comments
    Method of EstimationEstimation ParameterHazard Ratio (HR)
    Estimated Value0.19
    Confidence Interval (2-Sided) 95%
    0.12 to 0.31
    Parameter Dispersion Type:
    Value:
    Estimation CommentsHazard ratio was estimated by Cox regression model.
    21. Secondary Outcome
    TitlePercentage of Participants With Minimal Residual Disease (MRD) Negativity at the EoCTR Visit
    DescriptionMRD-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 at the EoCTR visit was reported. The 95% CI was computed using Pearson-Clopper method.
    Time FrameEoCTR visit (8 to 12 weeks after C6D1); Cycle length = 28 days

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on ITT population.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants195194
    Number (95% Confidence Interval) [percentage of participants]
    13.3
    6.8%
    62.4
    32.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value<.0001
    Comments
    MethodChi-squared
    Comments
    Method of EstimationEstimation ParameterDifference in MRD Negativity Rates
    Estimated Value49.04
    Confidence Interval (2-Sided) 95%
    40.44 to 57.64
    Parameter Dispersion Type:
    Value:
    Estimation CommentsThe 95% CI was computed using Anderson-Hauck method.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Bendamustine + Rituximab, Venetoclax + Rituximab
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesisp-Value
    Comments
    Method
    Comments
    Method of EstimationEstimation ParameterOdds Ratio (OR)
    Estimated Value10.77
    Confidence Interval (2-Sided) 95%
    6.50 to 17.85
    Parameter Dispersion Type:
    Value:
    Estimation CommentsOR was estimated using logistic regression model. The 95% CI was computed using Wald test.
    22. Secondary Outcome
    TitlePlasma Venetoclax Concentrations
    Description
    Time FramePre-dose (0 hour, anytime before venetoclax administeration) and 4 hours post-dose on D1 of Cycles 1 and 4; Cycle length = 28 days

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on Pharmacokinetic (PK)-Evaluable population, which included all participants in the 'Venetoclax + Rituximab' arm and who received at least one dose of venetoclax with at least one post-dose PK concentration result available. Here 'Number Analyzed' signifies the number of participants evaluable at specified time point.
    Arm/Group TitleVenetoclax + Rituximab
    Arm/Group DescriptionParticipants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants184
    C1D1, Pre-dose
    0.626
    (0.540)
    C1D1, 4 hours Post-Dose
    1.34
    (0.881)
    C4D1, Pre-dose
    0.681
    (0.745)
    C4D1, 4 hours Post-Dose
    1.34
    (0.905)
    23. Secondary Outcome
    TitleChange From Baseline in Lymphocyte Subset Counts at Specified Time Points
    Description
    Time FrameBaseline, C4D14-28, Study Treatment Completion/Early Withdrawal (STC/EW, up to C6D28), EoCTR visit (8 to 12 weeks after C6D1), and at FUVs (every 12 weeks after EoCTR up to 3 years); Cycle length = 28 days

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    24. Secondary Outcome
    TitleChange From Baseline in Monroe Dunaway (MD) Anderson Symptom Inventory (MDASI) Core Symptom Severity, Module Symptom Severity, and Interference Scores
    DescriptionMDASI 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 FrameBaseline, Days 1, 8, and 15 of Cycles 1, 2, and 3; Cycle length = 28 days

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on patient reported outcome (PRO)-evaluable population, which included all participants with baseline and at least one post-baseline PRO assessment. Here, 'Overall Number of Participants Analyzed' = participants evaluable for this outcome measure and 'Number Analyzed' = participants evaluable at specified time point.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants11742
    Baseline; Mean core symptom severity
    1.76
    (1.55)
    1.55
    (1.31)
    Change at C1D1; Mean core symptom severity
    0.00
    (0.00)
    -0.08
    (0.98)
    Change at C1D8; Mean core symptom severity
    0.26
    (1.34)
    -0.30
    (0.84)
    Change at C1D15; Mean core symptom severity
    0.00
    (1.31)
    -0.27
    (0.93)
    Change at C2D1; Mean core symptom severity
    -0.23
    (1.30)
    -0.33
    (0.91)
    Change at C2D8; Mean core symptom severity
    0.17
    (1.59)
    -0.45
    (0.91)
    Change at C2D15; Mean core symptom severity
    -0.13
    (1.53)
    -0.53
    (0.90)
    Change at C3D1; Mean core symptom severity
    -0.26
    (1.60)
    -0.40
    (1.13)
    Change at C3D8; Mean core symptom severity
    -0.13
    (1.63)
    -0.66
    (1.20)
    Change at C3D15; Mean core symptom severity
    -0.42
    (1.52)
    -0.53
    (1.05)
    Baseline; Mean module symptom severity
    1.60
    (1.46)
    1.57
    (1.11)
    Change at C1D1; Mean module symptom severity
    0.00
    (0.00)
    -0.19
    (0.96)
    Change at C1D8; Mean module symptom severity
    -0.22
    (1.40)
    -0.53
    (0.96)
    Change at C1D15; Mean module symptom severity
    -0.43
    (1.51)
    -0.73
    (1.13)
    Change at C2D1; Mean module symptom severity
    -0.49
    (1.46)
    -0.65
    (0.92)
    Change at C2D8; Mean module symptom severity
    -0.46
    (1.63)
    -0.77
    (0.87)
    Change at C2D15; Mean module symptom severity
    -0.69
    (1.47)
    -0.94
    (0.93)
    Change at C3D1; Mean module symptom severity
    -0.65
    (1.48)
    -0.81
    (0.97)
    Change at C3D8; Mean module symptom severity
    -0.51
    (1.58)
    -0.83
    (0.97)
    Change at C3D15; Mean module symptom severity
    -0.83
    (1.51)
    -0.92
    (0.97)
    Baseline; Mean interference
    1.81
    (2.05)
    1.90
    (2.25)
    Change at C1D1; Mean interference
    0.00
    (0.00)
    -0.13
    (1.49)
    Change at C1D8; Mean interference
    0.45
    (1.78)
    -0.29
    (2.14)
    Change at C1D15; Mean interference
    0.36
    (1.85)
    0.01
    (2.04)
    Change at C2D1; Mean interference
    0.01
    (1.73)
    -0.34
    (1.78)
    Change at C2D8; Mean interference
    0.58
    (2.20)
    -0.58
    (1.81)
    Change at C2D15; Mean interference
    0.06
    (1.84)
    -0.64
    (1.59)
    Change at C3D1; Mean interference
    -0.02
    (2.02)
    -0.73
    (2.06)
    Change at C3D8; Mean interference
    0.15
    (1.91)
    -0.82
    (2.09)
    Change at C3D15; Mean interference
    -0.07
    (2.01)
    -0.55
    (2.18)
    25. Secondary Outcome
    TitleChange 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
    DescriptionThe EORTC QLQ-C30 is a validated self-report measure consisting of 30 questions incorporated into five functional scales (Physical, Role, Cognitive, Emotional, and Social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), 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'). Functional scales score and global health status/global QoL scale score are reported. Scores were averaged, transformed to 0-100 scale; where higher score for functional scales = poor level of functioning and higher score for global health status/global QoL = better HRQoL.
    Time FrameBaseline, 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

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on PRO-evaluable population. Here, 'Overall Number of Participants Analyzed' signifies the number of participants evaluable for this outcome measure and 'Number Analyzed' signifies the number of participants evaluable at specified time point.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants17769
    Baseline; Physical functioning
    82.59
    (17.46)
    83.77
    (15.27)
    Change at C1D1; Physical functioning
    0.0
    (0.0)
    1.39
    (12.90)
    Change at C2D1; Physical functioning
    0.31
    (15.81)
    2.99
    (12.83)
    Change at C3D1; Physical functioning
    0.22
    (16.43)
    1.46
    (14.76)
    Change at C4D1; Physical functioning
    2.11
    (14.95)
    5.54
    (14.17)
    Change at C5D1; Physical functioning
    2.44
    (18.19)
    4.62
    (15.27)
    Change at C6D1; Physical functioning
    2.25
    (16.82)
    4.51
    (16.59)
    Change at STC/EW; Physical functioning
    1.68
    (18.76)
    4.53
    (16.04)
    Change at EoCTR; Physical functioning
    2.92
    (18.03)
    4.34
    (16.12)
    Change at FUV1; Physical functioning
    2.27
    (18.86)
    3.81
    (16.27)
    Change at FUV2; Physical functioning
    2.40
    (19.21)
    2.75
    (17.17)
    Change at FUV3; Physical functioning
    2.54
    (17.83)
    3.44
    (17.31)
    Change at FUV4; Physical functioning
    4.74
    (20.14)
    0.85
    (21.06)
    Change at FUV5; Physical functioning
    1.90
    (17.68)
    -1.75
    (19.35)
    Change at FUV6; Physical functioning
    -1.41
    (15.34)
    1.33
    (5.58)
    Change at FUV7; Physical functioning
    -3.08
    (11.74)
    0.00
    Change at FUV8; Physical functioning
    -9.33
    (23.38)
    0.00
    Change at FUV9; Physical functioning
    -10.00
    (33.0)
    Baseline; Role functioning
    78.25
    (25.67)
    83.82
    (21.00)
    Change at C1D1; Role functioning
    0.0
    (0.0)
    -1.74
    (23.23)
    Change at C2D1; Role functioning
    -1.26
    (27.45)
    2.49
    (23.07)
    Change at C3D1; Role functioning
    -0.10
    (29.64)
    1.82
    (26.08)
    Change at C4D1; Role functioning
    0.87
    (29.01)
    5.13
    (22.03)
    Change at C5D1; Role functioning
    0.45
    (30.75)
    4.36
    (23.44)
    Change at C6D1; Role functioning
    0.70
    (29.92)
    1.79
    (25.71)
    Change at STC/EW; Role functioning
    -0.41
    (32.91)
    2.60
    (25.58)
    Change at EoCTR; Role functioning
    3.26
    (29.95)
    2.12
    (26.69)
    Change at FUV1; Role functioning
    2.93
    (32.31)
    2.65
    (27.47)
    Change at FUV2; Role functioning
    3.07
    (32.63)
    -1.85
    (31.84)
    Change at FUV3; Role functioning
    5.26
    (31.16)
    1.88
    (28.17)
    Change at FUV4; Role functioning
    5.41
    (33.16)
    -0.35
    (30.39)
    Change at FUV5; Role functioning
    2.34
    (29.79)
    1.75
    (34.20)
    Change at FUV6; Role functioning
    -4.04
    (27.01)
    -13.33
    (32.06)
    Change at FUV7; Role functioning
    2.56
    (29.54)
    -16.67
    Change at FUV8; Role functioning
    0.00
    (23.57)
    16.67
    Change at FUV9; Role functioning
    -16.67
    (23.57)
    Baseline; Emotional functioning
    78.98
    (22.47)
    82.13
    (15.80)
    Change at C1D1; Emotional functioning
    0.0
    (0.0)
    4.35
    (15.17)
    Change at C2D1; Emotional functioning
    2.24
    (20.07)
    5.60
    (14.68)
    Change at C3D1; Emotional functioning
    2.99
    (20.06)
    5.34
    (19.09)
    Change at C4D1; Emotional functioning
    2.61
    (18.35)
    4.19
    (15.45)
    Change at C5D1; Emotional functioning
    1.14
    (18.79)
    3.97
    (17.37)
    Change at C6D1; Emotional functioning
    2.06
    (18.74)
    3.08
    (17.96)
    Change at STC/EW; Emotional functioning
    2.43
    (20.61)
    5.34
    (18.69)
    Change at EoCTR; Emotional functioning
    2.58
    (19.45)
    3.49
    (17.83)
    Change at FUV1; Emotional functioning
    3.49
    (20.91)
    4.37
    (18.50)
    Change at FUV2; Emotional functioning
    4.39
    (20.33)
    0.66
    (21.02)
    Change at FUV3; Emotional functioning
    0.63
    (19.97)
    2.82
    (17.66)
    Change at FUV4; Emotional functioning
    4.82
    (19.73)
    1.95
    (18.41)
    Change at FUV5; Emotional functioning
    3.13
    (17.95)
    2.63
    (20.61)
    Change at FUV6; Emotional functioning
    2.27
    (21.78)
    5.00
    (17.28)
    Change at FUV7; Emotional functioning
    5.77
    (17.48)
    -8.33
    Change at FUV8; Emotional functioning
    3.33
    (28.01)
    0.00
    Change at FUV9; Emotional functioning
    -16.67
    (11.79)
    Baseline; Cognitive functioning
    86.55
    (16.78)
    89.86
    (14.91)
    Change at C1D1; Cognitive functioning
    0.0
    (0.0)
    -1.24
    (14.01)
    Change at C2D1; Cognitive functioning
    -0.19
    (15.34)
    0.25
    (14.06)
    Change at C3D1; Cognitive functioning
    -0.32
    (16.34)
    -1.56
    (17.50)
    Change at C4D1; Cognitive functioning
    -1.54
    (17.41)
    -0.26
    (17.05)
    Change at C5D1; Cognitive functioning
    -1.94
    (18.10)
    -0.26
    (14.28)
    Change at C6D1; Cognitive functioning
    -2.68
    (16.97)
    -0.77
    (15.98)
    Change at STC/EW; Cognitive functioning
    -2.19
    (17.65)
    1.04
    (18.28)
    Change at EoCTR; Cognitive functioning
    -2.23
    (18.11)
    -0.27
    (16.94)
    Change at FUV1; Cognitive functioning
    -2.02
    (17.21)
    -0.26
    (15.98)
    Change at FUV2; Cognitive functioning
    1.32
    (16.16)
    -2.38
    (18.17)
    Change at FUV3; Cognitive functioning
    -1.63
    (14.84)
    -2.96
    (18.24)
    Change at FUV4; Cognitive functioning
    0.44
    (17.63)
    -1.77
    (19.11)
    Change at FUV5; Cognitive functioning
    -1.49
    (15.66)
    -6.14
    (21.67)
    Change at FUV6; Cognitive functioning
    -0.51
    (14.72)
    0.00
    (0.00)
    Change at FUV7; Cognitive functioning
    -1.28
    (14.37)
    0.00
    Change at FUV8; Cognitive functioning
    0.00
    (23.57)
    0.00
    Change at FUV9; Cognitive functioning
    16.67
    (23.57)
    Baseline; Social functioning
    82.48
    (22.06)
    85.51
    (21.18)
    Change at C1D1; Social functioning
    0.0
    (0.0)
    -1.74
    (19.92)
    Change at C2D1; Social functioning
    -2.44
    (21.44)
    0.25
    (18.46)
    Change at C3D1; Social functioning
    -2.32
    (22.61)
    3.65
    (25.45)
    Change at C4D1; Social functioning
    -0.55
    (22.15)
    4.62
    (20.09)
    Change at C5D1; Social functioning
    -5.48
    (26.49)
    2.56
    (20.46)
    Change at C6D1; Social functioning
    -5.13
    (24.80)
    3.85
    (24.61)
    Change at STC/EW; Social functioning
    -4.06
    (27.71)
    1.04
    (19.22)
    Change at EoCTR; Social functioning
    -0.47
    (24.95)
    1.88
    (20.49)
    Change at FUV1; Social functioning
    -1.08
    (26.09)
    1.59
    (24.27)
    Change at FUV2; Social functioning
    0.58
    (24.68)
    1.32
    (27.97)
    Change at FUV3; Social functioning
    -0.91
    (24.00)
    1.88
    (25.98)
    Change at FUV4; Social functioning
    1.97
    (27.35)
    1.06
    (32.12)
    Change at FUV5; Social functioning
    1.79
    (26.72)
    0.00
    (33.79)
    Change at FUV6; Social functioning
    1.52
    (29.27)
    10.00
    (14.91)
    Change at FUV7; Social functioning
    -2.56
    (23.42)
    33.33
    Change at FUV8; Social functioning
    -10.00
    (22.36)
    33.33
    Change at FUV9; Social functioning
    -25.00
    (35.36)
    Baseline; Global health status/QoL
    63.02
    (21.45)
    67.39
    (22.17)
    Change at C1D1; Global health status/QoL
    0.0
    (0.0)
    6.34
    (18.41)
    Change at C2D1; Global health status/QoL
    2.73
    (21.69)
    5.35
    (20.14)
    Change at C3D1; Global health status/QoL
    2.34
    (24.66)
    2.21
    (23.58)
    Change at C4D1; Global health status/QoL
    3.84
    (22.26)
    7.05
    (21.05)
    Change at C5D1; Global health status/QoL
    7.36
    (24.20)
    7.18
    (21.94)
    Change at C6D1; Global health status/QoL
    4.25
    (25.00)
    5.90
    (25.16)
    Change at STC/EW; Global health status/QoL
    4.32
    (26.20)
    6.51
    (23.22)
    Change at EoCTR; Global health status/QoL
    6.10
    (23.65)
    7.66
    (24.11)
    Change at FUV1; Global health status/QoL
    5.91
    (24.57)
    7.01
    (25.01)
    Change at FUV2; Global health status/QoL
    6.94
    (24.81)
    4.50
    (26.51)
    Change at FUV3; Global health status/QoL
    4.80
    (25.30)
    6.32
    (27.36)
    Change at FUV4; Global health status/QoL
    7.35
    (26.77)
    6.38
    (27.60)
    Change at FUV5; Global health status/QoL
    4.46
    (23.89)
    4.39
    (18.08)
    Change at FUV6; Global health status/QoL
    1.01
    (24.00)
    5.00
    (7.45)
    Change at FUV7; Global health status/QoL
    8.33
    (25.69)
    16.67
    Change at FUV8; Global health status/QoL
    6.67
    (16.03)
    8.33
    Change at FUV9; Global health status/QoL
    0.00
    (0.00)
    26. Secondary Outcome
    TitleChange From Baseline in HRQoL as Measured by Quality of Life Questionnaire Associated CLL Module (QLQ-CLL16) Multi-Item Scales Score
    DescriptionThe 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 FrameBaseline, 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

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on PRO-evaluable population. Here, 'Overall Number of Participants Analyzed' signifies the number of participants evaluable for this outcome measure and 'Number Analyzed' signifies the number of participants evaluable at specified time point.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    Measure Participants17569
    Baseline; TRSE
    14.29
    (13.95)
    9.42
    (8.80)
    Change at C1D1; TRSE
    0.0
    (0.0)
    0.12
    (10.10)
    Change at C2D1; TRSE
    1.62
    (13.82)
    0.62
    (12.76)
    Change at C3D1; TRSE
    -0.26
    (13.76)
    1.98
    (14.72)
    Change at C4D1; TRSE
    -0.49
    (13.97)
    0.52
    (11.87)
    Change at C5D1; TRSE
    -0.51
    (14.57)
    0.64
    (10.02)
    Change at C6D1; TRSE
    0.46
    (15.51)
    -0.13
    (10.04)
    Change at STC/EW; TRSE
    0.81
    (18.11)
    0.13
    (10.76)
    Change at EoCTR; TRSE
    -0.88
    (16.06)
    0.26
    (12.61)
    Change at FUV1; TRSE
    -1.20
    (14.87)
    1.19
    (12.24)
    Change at FUV2; TRSE
    -1.70
    (15.28)
    2.65
    (14.03)
    Change at FUV3; TRSE
    -2.08
    (12.64)
    -0.13
    (13.70)
    Change at FUV4; TRSE
    -1.97
    (12.76)
    2.84
    (15.18)
    Change at FUV5; TRSE
    -2.68
    (11.02)
    1.32
    (10.49)
    Change at FUV6; TRSE
    -1.01
    (12.10)
    -1.67
    (3.73)
    Change at FUV7; TRSE
    2.56
    (22.67)
    -8.33
    Change at FUV8; TRSE
    1.67
    (13.69)
    0.00
    Change at FUV9; TRSE
    8.33
    (11.79)
    Baseline; DRS
    19.57
    (16.81)
    16.95
    (17.37)
    Change at C1D1; DRS
    0.0
    (0.0)
    -2.74
    (16.18)
    Change at C2D1; DRS
    -3.33
    (16.05)
    -4.77
    (16.84)
    Change at C3D1; DRS
    -4.77
    (16.49)
    -3.35
    (17.48)
    Change at C4D1; DRS
    -6.03
    (16.51)
    -5.12
    (17.72)
    Change at C5D1; DRS
    -5.90
    (16.73)
    -4.79
    (17.50)
    Change at C6D1; DRS
    -6.40
    (17.26)
    -5.30
    (16.72)
    Change at STC/EW; DRS
    -5.80
    (18.52)
    -6.51
    (18.45)
    Change at EoCTR; DRS
    -6.57
    (17.21)
    -5.86
    (20.38)
    Change at FUV1; DRS
    -6.55
    (15.73)
    -5.82
    (19.20)
    Change at FUV2; DRS
    -8.63
    (14.39)
    -3.57
    (18.31)
    Change at FUV3; DRS
    -7.37
    (14.88)
    -3.76
    (19.25)
    Change at FUV4; DRS
    -8.55
    (18.56)
    -2.66
    (20.49)
    Change at FUV5; DRS
    -8.33
    (16.13)
    -2.19
    (19.41)
    Change at FUV6; DRS
    -6.31
    (16.01)
    -3.33
    (13.94)
    Change at FUV7; DRS
    -15.38
    (20.08)
    -8.33
    Change at FUV8; DRS
    -10.00
    (16.03)
    -8.33
    Change at FUV9; DRS
    -4.17
    (5.89)
    Baseline; Fatigue
    28.76
    (24.66)
    21.74
    (20.67)
    Change at C1D1; Fatigue
    0.0
    (0.0)
    -2.24
    (20.29)
    Change at C2D1; Fatigue
    -2.55
    (22.86)
    -5.47
    (21.40)
    Change at C3D1; Fatigue
    -2.83
    (25.17)
    -3.17
    (23.73)
    Change at C4D1; Fatigue
    -3.18
    (23.23)
    -4.17
    (22.02)
    Change at C5D1; Fatigue
    -2.38
    (27.52)
    -4.36
    (20.89)
    Change at C6D1; Fatigue
    -2.66
    (26.35)
    -2.31
    (21.42)
    Change at STC/EW; Fatigue
    -3.11
    (28.64)
    -4.69
    (21.30)
    Change at EoCTR; Fatigue
    -6.69
    (26.78)
    -3.97
    (24.27)
    Change at FUV1; Fatigue
    -6.37
    (26.61)
    -4.23
    (22.99)
    Change at FUV2; Fatigue
    -6.64
    (24.55)
    -1.85
    (24.70)
    Change at FUV3; Fatigue
    -5.79
    (23.29)
    -2.42
    (23.73)
    Change at FUV4; Fatigue
    -9.65
    (26.84)
    -0.35
    (25.18)
    Change at FUV5; Fatigue
    -6.55
    (25.56)
    3.51
    (23.95)
    Change at FUV6; Fatigue
    -5.05
    (24.82)
    3.33
    (24.72)
    Change at FUV7; Fatigue
    -10.26
    (30.08)
    -33.33
    Change at FUV8; Fatigue
    -6.67
    (19.00)
    0.00
    Change at FUV9; Fatigue
    -8.33
    (11.79)
    Baseline; Infection
    15.92
    (17.63)
    14.01
    (18.99)
    Change at C1D1; Infection
    0.0
    (0.0)
    -2.24
    (20.03)
    Change at C2D1; Infection
    -0.02
    (19.98)
    -3.61
    (21.72)
    Change at C3D1; Infection
    -1.66
    (19.21)
    -1.32
    (20.48)
    Change at C4D1; Infection
    -1.44
    (22.07)
    -3.13
    (21.28)
    Change at C5D1; Infection
    -1.91
    (24.00)
    -2.56
    (23.47)
    Change at C6D1; Infection
    -1.09
    (20.66)
    -2.95
    (20.54)
    Change at STC/EW; Infection
    -0.12
    (23.28)
    -1.69
    (23.34)
    Change at EoCTR; Infection
    -0.55
    (21.73)
    -3.44
    (25.78)
    Change at FUV1; Infection
    1.08
    (18.77)
    -2.65
    (26.51)
    Change at FUV2; Infection
    0.05
    (23.29)
    -0.53
    (25.74)
    Change at FUV3; Infection
    -1.90
    (16.97)
    -0.54
    (26.48)
    Change at FUV4; Infection
    -4.24
    (16.71)
    0.53
    (25.56)
    Change at FUV5; Infection
    -4.51
    (22.66)
    7.46
    (27.20)
    Change at FUV6; Infection
    -1.60
    (18.90)
    8.33
    (15.59)
    Change at FUV7; Infection
    -0.43
    (21.84)
    -16.67
    Change at FUV8; Infection
    8.89
    (23.36)
    -25.00
    Change at FUV9; Infection
    -2.78
    (3.93)
    27. Post-Hoc Outcome
    TitleEuro QoL 5 Dimension (EQ-5D) Questionnaire Score
    Description
    Time FrameBaseline, 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time FrameBaseline up to Follow-up (maximum up to Data Cut-off date, overall approximately 3 years)
    Adverse Event Reporting Description Analysis was performed on safety evaluable (SE) population, which included all randomized participants who received at least one dose of study treatment (venetoclax, rituximab, or bendamustine), with participants grouped according to the actual treatment received.
    Arm/Group TitleBendamustine + RituximabVenetoclax + Rituximab
    Arm/Group DescriptionParticipants received bendamustine at a dose of 70 mg/m^2 via IV infusion on Days 1 and 2 of each 28-day cycle for 6 cycles, in combination with rituximab 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.Participants were initially placed on a venetoclax ramp-up period of 5 weeks, and received an initial dose of 20 mg via tablet orally QD for initial 1 to 7 days, then venetoclax dose was incremented weekly up to a maximum dose of 400 mg via tablet orally QD. Participants continued receiving venetoclax at a dose of 400 mg via tablet orally QD from Week 6 (Day 1 of Cycle 1 of combination therapy) onwards up to PD or 2 years, whichever occurred first, as directed by the investigator, in combination with rituximab 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.
    All Cause Mortality
    Bendamustine + RituximabVenetoclax + Rituximab
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total27/188 (14.4%) 15/194 (7.7%)
    Serious Adverse Events
    Bendamustine + RituximabVenetoclax + Rituximab
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total81/188 (43.1%) 90/194 (46.4%)
    Blood and lymphatic system disorders
    Anaemia5/188 (2.7%) 3/194 (1.5%)
    Autoimmune haemolytic anaemia3/188 (1.6%) 3/194 (1.5%)
    Disseminated intravascular coagulation0/188 (0%) 1/194 (0.5%)
    Febrile neutropenia16/188 (8.5%) 7/194 (3.6%)
    Immune thrombocytopenic purpura0/188 (0%) 1/194 (0.5%)
    Leukocytosis1/188 (0.5%) 0/194 (0%)
    Neutropenia3/188 (1.6%) 3/194 (1.5%)
    Pancytopenia0/188 (0%) 1/194 (0.5%)
    Thrombocytopenia2/188 (1.1%) 2/194 (1%)
    Cardiac disorders
    Acute myocardial infarction1/188 (0.5%) 0/194 (0%)
    Angina pectoris0/188 (0%) 1/194 (0.5%)
    Atrial fibrillation1/188 (0.5%) 0/194 (0%)
    Cardiac failure0/188 (0%) 1/194 (0.5%)
    Coronary artery disease1/188 (0.5%) 0/194 (0%)
    Myocardial infarction0/188 (0%) 2/194 (1%)
    Ventricular tachycardia0/188 (0%) 1/194 (0.5%)
    Ear and labyrinth disorders
    Deafness0/188 (0%) 1/194 (0.5%)
    Vertigo0/188 (0%) 1/194 (0.5%)
    Eye disorders
    Eye haemorrhage0/188 (0%) 1/194 (0.5%)
    Gastrointestinal disorders
    Abdominal pain0/188 (0%) 1/194 (0.5%)
    Anal fistula1/188 (0.5%) 0/194 (0%)
    Ascites0/188 (0%) 1/194 (0.5%)
    Colitis1/188 (0.5%) 0/194 (0%)
    Crohn's disease0/188 (0%) 1/194 (0.5%)
    Diarrhoea0/188 (0%) 2/194 (1%)
    Dyspepsia0/188 (0%) 1/194 (0.5%)
    Gastrointestinal haemorrhage0/188 (0%) 1/194 (0.5%)
    Nausea1/188 (0.5%) 0/194 (0%)
    Oesophageal obstruction0/188 (0%) 1/194 (0.5%)
    Small intestinal obstruction0/188 (0%) 1/194 (0.5%)
    Vomiting1/188 (0.5%) 1/194 (0.5%)
    General disorders
    Asthenia1/188 (0.5%) 0/194 (0%)
    Hyperpyrexia1/188 (0.5%) 1/194 (0.5%)
    Malaise1/188 (0.5%) 0/194 (0%)
    Pyrexia13/188 (6.9%) 5/194 (2.6%)
    Sudden cardiac death0/188 (0%) 1/194 (0.5%)
    Sudden death1/188 (0.5%) 0/194 (0%)
    Unevaluable event1/188 (0.5%) 0/194 (0%)
    Hepatobiliary disorders
    Bile duct obstruction0/188 (0%) 1/194 (0.5%)
    Infections and infestations
    Abscess neck1/188 (0.5%) 0/194 (0%)
    Appendicitis0/188 (0%) 2/194 (1%)
    Atypical pneumonia1/188 (0.5%) 0/194 (0%)
    Bronchitis2/188 (1.1%) 0/194 (0%)
    Bronchopulmonary aspergillosis1/188 (0.5%) 0/194 (0%)
    Campylobacter gastroenteritis0/188 (0%) 1/194 (0.5%)
    Cellulitis1/188 (0.5%) 0/194 (0%)
    Clostridium difficile colitis1/188 (0.5%) 0/194 (0%)
    Cystitis0/188 (0%) 1/194 (0.5%)
    Diverticulitis0/188 (0%) 1/194 (0.5%)
    Erysipelas0/188 (0%) 1/194 (0.5%)
    Escherichia sepsis1/188 (0.5%) 0/194 (0%)
    Gastroenteritis rotavirus0/188 (0%) 1/194 (0.5%)
    Gastroenteritis viral1/188 (0.5%) 0/194 (0%)
    Haemophilus infection0/188 (0%) 1/194 (0.5%)
    Hepatitis B1/188 (0.5%) 0/194 (0%)
    Herpes simplex otitis externa0/188 (0%) 1/194 (0.5%)
    Herpes zoster0/188 (0%) 1/194 (0.5%)
    Influenza2/188 (1.1%) 3/194 (1.5%)
    Listeria sepsis1/188 (0.5%) 0/194 (0%)
    Localised infection1/188 (0.5%) 0/194 (0%)
    Lung infection0/188 (0%) 3/194 (1.5%)
    Meningitis0/188 (0%) 1/194 (0.5%)
    Moraxella infection0/188 (0%) 1/194 (0.5%)
    Neutropenic sepsis1/188 (0.5%) 0/194 (0%)
    Peritoneal tuberculosis0/188 (0%) 1/194 (0.5%)
    Pharyngitis2/188 (1.1%) 0/194 (0%)
    Pneumococcal bacteraemia1/188 (0.5%) 0/194 (0%)
    Pneumocystis jirovecii pneumonia1/188 (0.5%) 0/194 (0%)
    Pneumonia15/188 (8%) 16/194 (8.2%)
    Pneumonia influenzal0/188 (0%) 1/194 (0.5%)
    Pneumonia legionella1/188 (0.5%) 0/194 (0%)
    Pneumonia streptococcal0/188 (0%) 1/194 (0.5%)
    Respiratory tract infection0/188 (0%) 2/194 (1%)
    Respiratory tract infection fungal0/188 (0%) 1/194 (0.5%)
    Respiratory tract infection viral0/188 (0%) 1/194 (0.5%)
    Rhinovirus infection0/188 (0%) 1/194 (0.5%)
    Scedosporium infection1/188 (0.5%) 0/194 (0%)
    Sepsis4/188 (2.1%) 1/194 (0.5%)
    Septic shock1/188 (0.5%) 0/194 (0%)
    Sinusitis1/188 (0.5%) 2/194 (1%)
    Staphylococcal infection1/188 (0.5%) 0/194 (0%)
    Tooth abscess0/188 (0%) 1/194 (0.5%)
    Upper respiratory tract infection2/188 (1.1%) 3/194 (1.5%)
    Urinary tract infection1/188 (0.5%) 1/194 (0.5%)
    Urinary tract infection pseudomonal0/188 (0%) 1/194 (0.5%)
    Urosepsis1/188 (0.5%) 0/194 (0%)
    Varicella zoster virus infection1/188 (0.5%) 0/194 (0%)
    Viral infection0/188 (0%) 1/194 (0.5%)
    Viral upper respiratory tract infection0/188 (0%) 1/194 (0.5%)
    Lower respiratory tract infection1/188 (0.5%) 0/194 (0%)
    Parainfluenzae virus infection1/188 (0.5%) 0/194 (0%)
    Injury, poisoning and procedural complications
    Humerus fracture0/188 (0%) 1/194 (0.5%)
    Infusion related reaction6/188 (3.2%) 1/194 (0.5%)
    Tendon rupture1/188 (0.5%) 0/194 (0%)
    Investigations
    Body temperature increased1/188 (0.5%) 0/194 (0%)
    Metabolism and nutrition disorders
    Decreased appetite0/188 (0%) 1/194 (0.5%)
    Dehydration0/188 (0%) 2/194 (1%)
    Diabetes mellitus0/188 (0%) 1/194 (0.5%)
    Fluid overload0/188 (0%) 1/194 (0.5%)
    Hyperkalaemia0/188 (0%) 2/194 (1%)
    Hyperphosphataemia0/188 (0%) 2/194 (1%)
    Tumour lysis syndrome1/188 (0.5%) 4/194 (2.1%)
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion1/188 (0.5%) 0/194 (0%)
    Musculoskeletal chest pain1/188 (0.5%) 0/194 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia1/188 (0.5%) 0/194 (0%)
    Adenocarcinoma gastric0/188 (0%) 1/194 (0.5%)
    Adenocarcinoma of colon1/188 (0.5%) 0/194 (0%)
    Basal cell carcinoma0/188 (0%) 1/194 (0.5%)
    Colon cancer0/188 (0%) 1/194 (0.5%)
    Colorectal cancer0/188 (0%) 2/194 (1%)
    Lung neoplasm malignant2/188 (1.1%) 0/194 (0%)
    Lymphoma1/188 (0.5%) 0/194 (0%)
    Malignant melanoma0/188 (0%) 1/194 (0.5%)
    Medullary thyroid cancer1/188 (0.5%) 0/194 (0%)
    Metastatic malignant melanoma0/188 (0%) 1/194 (0.5%)
    Myelodysplastic syndrome0/188 (0%) 2/194 (1%)
    Pancreatic carcinoma0/188 (0%) 1/194 (0.5%)
    Prostate cancer1/188 (0.5%) 0/194 (0%)
    Prostatic adenoma0/188 (0%) 1/194 (0.5%)
    Skin cancer0/188 (0%) 1/194 (0.5%)
    Squamous cell carcinoma1/188 (0.5%) 3/194 (1.5%)
    Transitional cell carcinoma1/188 (0.5%) 0/194 (0%)
    Nervous system disorders
    Dizziness0/188 (0%) 1/194 (0.5%)
    Haemorrhagic stroke1/188 (0.5%) 0/194 (0%)
    Lacunar infarction0/188 (0%) 1/194 (0.5%)
    Polyneuropathy1/188 (0.5%) 0/194 (0%)
    Status epilepticus0/188 (0%) 1/194 (0.5%)
    Syncope1/188 (0.5%) 0/194 (0%)
    Renal and urinary disorders
    Acute kidney injury1/188 (0.5%) 1/194 (0.5%)
    Nephrolithiasis0/188 (0%) 1/194 (0.5%)
    Renal impairment1/188 (0.5%) 0/194 (0%)
    Reproductive system and breast disorders
    Cervical dysplasia0/188 (0%) 1/194 (0.5%)
    Uterine haemorrhage0/188 (0%) 1/194 (0.5%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure0/188 (0%) 1/194 (0.5%)
    Bronchiectasis0/188 (0%) 1/194 (0.5%)
    Lung disorder0/188 (0%) 1/194 (0.5%)
    Pulmonary embolism1/188 (0.5%) 1/194 (0.5%)
    Skin and subcutaneous tissue disorders
    Dermatitis allergic1/188 (0.5%) 0/194 (0%)
    Vascular disorders
    Aortic stenosis1/188 (0.5%) 0/194 (0%)
    Deep vein thrombosis1/188 (0.5%) 1/194 (0.5%)
    Embolism1/188 (0.5%) 0/194 (0%)
    Hypotension5/188 (2.7%) 0/194 (0%)
    Other (Not Including Serious) Adverse Events
    Bendamustine + RituximabVenetoclax + Rituximab
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total176/188 (93.6%) 190/194 (97.9%)
    Blood and lymphatic system disorders
    Anaemia40/188 (21.3%) 28/194 (14.4%)
    Neutropenia82/188 (43.6%) 118/194 (60.8%)
    Thrombocytopenia42/188 (22.3%) 24/194 (12.4%)
    Gastrointestinal disorders
    Abdominal pain6/188 (3.2%) 13/194 (6.7%)
    Constipation39/188 (20.7%) 27/194 (13.9%)
    Diarrhoea31/188 (16.5%) 76/194 (39.2%)
    Nausea64/188 (34%) 41/194 (21.1%)
    Vomiting22/188 (11.7%) 15/194 (7.7%)
    General disorders
    Chills16/188 (8.5%) 8/194 (4.1%)
    Fatigue39/188 (20.7%) 34/194 (17.5%)
    Oedema peripheral7/188 (3.7%) 11/194 (5.7%)
    Pyrexia33/188 (17.6%) 27/194 (13.9%)
    Infections and infestations
    Bronchitis13/188 (6.9%) 20/194 (10.3%)
    Conjunctivitis5/188 (2.7%) 10/194 (5.2%)
    Lower respiratory tract infection4/188 (2.1%) 11/194 (5.7%)
    Nasopharyngitis10/188 (5.3%) 22/194 (11.3%)
    Oral herpes12/188 (6.4%) 8/194 (4.1%)
    Pharyngitis1/188 (0.5%) 13/194 (6.7%)
    Pneumonia11/188 (5.9%) 5/194 (2.6%)
    Sinusitis5/188 (2.7%) 17/194 (8.8%)
    Upper respiratory tract infection28/188 (14.9%) 41/194 (21.1%)
    Urinary tract infection7/188 (3.7%) 11/194 (5.7%)
    Injury, poisoning and procedural complications
    Infusion related reaction40/188 (21.3%) 15/194 (7.7%)
    Investigations
    Alanine aminotransferase increased10/188 (5.3%) 9/194 (4.6%)
    Neutrophil count decreased13/188 (6.9%) 11/194 (5.7%)
    Metabolism and nutrition disorders
    Decreased appetite17/188 (9%) 8/194 (4.1%)
    Hyperkalaemia0/188 (0%) 11/194 (5.7%)
    Hypokalaemia7/188 (3.7%) 12/194 (6.2%)
    Musculoskeletal and connective tissue disorders
    Arthralgia10/188 (5.3%) 12/194 (6.2%)
    Back pain11/188 (5.9%) 15/194 (7.7%)
    Muscle spasms11/188 (5.9%) 4/194 (2.1%)
    Nervous system disorders
    Dizziness10/188 (5.3%) 12/194 (6.2%)
    Headache19/188 (10.1%) 21/194 (10.8%)
    Psychiatric disorders
    Insomnia12/188 (6.4%) 21/194 (10.8%)
    Respiratory, thoracic and mediastinal disorders
    Cough31/188 (16.5%) 35/194 (18%)
    Dyspnoea14/188 (7.4%) 11/194 (5.7%)
    Oropharyngeal pain7/188 (3.7%) 10/194 (5.2%)
    Productive cough4/188 (2.1%) 12/194 (6.2%)
    Skin and subcutaneous tissue disorders
    Pruritus8/188 (4.3%) 10/194 (5.2%)
    Rash24/188 (12.8%) 14/194 (7.2%)
    Vascular disorders
    Hypertension7/188 (3.7%) 12/194 (6.2%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

    Results Point of Contact

    Name/TitleMedical Communications
    OrganizationHoffmann-La Roche
    Phone800-821-8590
    Emailgenentech@druginfo.com
    Responsible Party:
    Hoffmann-La Roche
    ClinicalTrials.gov Identifier:
    NCT02005471
    Other Study ID Numbers:
    • GO28667
    • 2013-002110-12
    First Posted:
    Dec 9, 2013
    Last Update Posted:
    Nov 11, 2021
    Last Verified:
    Nov 1, 2021