Trial Outcomes & Findings for A Study of MabThera Added to Bendamustine or Chlorambucil in Patients With Chronic Lymphocytic Leukemia (MaBLe) (NCT NCT01056510)

Last Updated: 2015-06-25

Results Overview

The definition of confirmed CR required all of the following criteria as assessed at least 2 months after completion of therapy: peripheral blood lymphocytes less than (\<) 4 times 10\^9 cells per liter (cells/L); absence of significant lymphadenopathy, hepatomegaly, or splenomegaly due to chronic lymphocytic leukemia (CLL) involvement; absence of constitutional symptoms; normal complete blood count (CBC) without need for transfusion or exogenous growth factors, as exhibited by neutrophils at least (\>/=) 1.5 times 10\^9 cells/L, platelets greater than (\>) 100 times 10\^9 cells/L, and hemoglobin \> 11.0 grams per deciliter (g/dL); normocellular bone marrow (BM) aspirate with \< 30 percent (%) lymphocytes; absence of lymphoid nodules; and BM biopsy without CLL activity. The percentage of participants achieving confirmed CR was calculated as the number of participants meeting the above criteria divided by the number of participants analyzed, multiplied by 100.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

357 participants

Primary outcome timeframe

At least 2 months after completion of therapy (up to 32 weeks)

Results posted on

2015-06-25

Participant Flow

Screening examination was performed within 28 days before randomization. Participants who fulfilled all the inclusion and none of the exclusion criteria were randomized to one of the two treatment groups.

Participant milestones

Participant milestones
Measure	Rituximab + Bendamustine Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received intravenous (IV) rituximab 375 milligrams per square meter (mg/m\^2) on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced progressive disease (PD).	Rituximab + Chlorambucil Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered orally (PO) at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until complete response (CR) was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Overall Study STARTED	178	179
Overall Study COMPLETED	124	115
Overall Study NOT COMPLETED	54	64

Reasons for withdrawal

Reasons for withdrawal
Measure	Rituximab + Bendamustine Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received intravenous (IV) rituximab 375 milligrams per square meter (mg/m\^2) on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced progressive disease (PD).	Rituximab + Chlorambucil Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered orally (PO) at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until complete response (CR) was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Overall Study Dropout Before Start of Treatment	1	1
Overall Study Withdrawal by Subject	4	2
Overall Study Death	29	34
Overall Study Noncompliance	1	3
Overall Study Physician Decision	4	5
Overall Study Lost to Follow-up	5	6
Overall Study Other	10	12
Overall Study Missing	0	1

Baseline Characteristics

A Study of MabThera Added to Bendamustine or Chlorambucil in Patients With Chronic Lymphocytic Leukemia (MaBLe)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rituximab + Bendamustine n=178 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=179 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Total n=357 Participants Total of all reporting groups
Age, Continuous	70.6 years STANDARD_DEVIATION 9.87 • n=93 Participants	70.1 years STANDARD_DEVIATION 9.88 • n=4 Participants	70.3 years STANDARD_DEVIATION 9.87 • n=27 Participants
Sex: Female, Male Female	73 Participants n=93 Participants	61 Participants n=4 Participants	134 Participants n=27 Participants
Sex: Female, Male Male	105 Participants n=93 Participants	118 Participants n=4 Participants	223 Participants n=27 Participants

PRIMARY outcome

Timeframe: At least 2 months after completion of therapy (up to 32 weeks)

Population: ITT Population (First-Line Subpopulation): A subset of participants requiring a first-line regimen for CLL.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=121 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=120 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Percentage of Participants Achieving Confirmed Complete Response (CR) According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Guidelines in the First-Line Subpopulation After 6 Cycles of Therapy Confirmed CR with biopsy	24 percentage of participants	9.2 percentage of participants
Percentage of Participants Achieving Confirmed Complete Response (CR) According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Guidelines in the First-Line Subpopulation After 6 Cycles of Therapy CR without biopsy	2.5 percentage of participants	5.8 percentage of participants
Percentage of Participants Achieving Confirmed Complete Response (CR) According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 Guidelines in the First-Line Subpopulation After 6 Cycles of Therapy No confirmed CR	73.6 percentage of participants	85 percentage of participants

SECONDARY outcome

Timeframe: At least 2 months after completion of therapy (up to 32 weeks)

Population: ITT Population

The definition of confirmed CR required all of the following criteria as assessed at least 2 months after completion of therapy: peripheral blood lymphocytes \< 4 times 10\^9 cells/L; absence of significant lymphadenopathy, hepatomegaly, or splenomegaly due to CLL involvement; absence of constitutional symptoms; normal CBC without need for transfusion or exogenous growth factors, as exhibited by neutrophils \>/= 1.5 times 10\^9 cells/L, platelets \> 100 times 10\^9 cells/L, and hemoglobin \> 11.0 g/dL; normocellular BM aspirate with \< 30% lymphocytes; absence of lymphoid nodules; and BM biopsy without CLL activity. The percentage of participants achieving confirmed CR was calculated as the number of participants meeting the above criteria divided by the number of participants analyzed, multiplied by 100.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=178 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=179 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Percentage of Participants Achieving Confirmed CR According to IWCLL 2008 Guidelines in the Pooled Population After 6 Cycles of Therapy Confirmed CR with biopsy	21.3 percentage of participants	6.7 percentage of participants
Percentage of Participants Achieving Confirmed CR According to IWCLL 2008 Guidelines in the Pooled Population After 6 Cycles of Therapy CR without biopsy	2.8 percentage of participants	4.5 percentage of participants
Percentage of Participants Achieving Confirmed CR According to IWCLL 2008 Guidelines in the Pooled Population After 6 Cycles of Therapy No confirmed CR	75.8 percentage of participants	88.8 percentage of participants

SECONDARY outcome

Timeframe: At least 2 months after completion of therapy (up to 32 weeks)

Population: ITT Population (Second-Line Subpopulation): A subset of participants requiring a second-line regimen for CLL.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=57 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=59 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Percentage of Participants Achieving Confirmed CR According to IWCLL 2008 Guidelines in the Second-Line Subpopulation After 6 Cycles of Therapy Confirmed CR with biopsy	15.8 percentage of participants	1.7 percentage of participants
Percentage of Participants Achieving Confirmed CR According to IWCLL 2008 Guidelines in the Second-Line Subpopulation After 6 Cycles of Therapy CR without biopsy	3.5 percentage of participants	1.7 percentage of participants
Percentage of Participants Achieving Confirmed CR According to IWCLL 2008 Guidelines in the Second-Line Subpopulation After 6 Cycles of Therapy No confirmed CR	80.7 percentage of participants	96.6 percentage of participants

SECONDARY outcome

Timeframe: After 3 and 6 treatment cycles and from Baseline to the end-of-treatment (EOT) visit, completed within 10 days before cutoff for data collection

Population: ITT Population (First-Line Subpopulation)

The criteria for CR are identified in previous outcome measure(s). Those fulfilling CR criteria but who have persistent anemia, thrombocytopenia, or neutropenia were considered CRi. The definition of PR required that the following be documented for minimum 2 months: \>/= 50% decrease in peripheral blood lymphocytes from Baseline; reduction in lymphadenopathy; \>/= 50% reduction in spleen or liver enlargement; and CBC with one of the following without need for transfusion or exogenous growth factors: polymorphonuclear leukocytes \>/= 1.5 times 10\^9 cells/L, platelets \> 100 times 10\^9 cells/L or \>/= 50% improvement from Baseline, or hemoglobin \> 11.0 g/dL or \>/= 50% improvement from Baseline. Participants with lymphoid nodules who otherwise met CR criteria were considered nPR. The percentage of participants achieving each level of response was calculated as the number of participants meeting the above criteria divided by the number of participants analyzed, multiplied by 100.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=121 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=120 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Percentage of Participants Achieving a Best Overall Response of CR, CR With Incomplete Marrow Recovery (CRi), Partial Response (PR), or Nodular PR (nPR) in the First-Line Subpopulation After 6 cycles	75.2 percentage of participants Interval 66.5 to 82.6	79.2 percentage of participants Interval 70.8 to 86.0
Percentage of Participants Achieving a Best Overall Response of CR, CR With Incomplete Marrow Recovery (CRi), Partial Response (PR), or Nodular PR (nPR) in the First-Line Subpopulation At the EOT visit	90.9 percentage of participants Interval 84.3 to 95.4	85.8 percentage of participants Interval 78.3 to 91.5
Percentage of Participants Achieving a Best Overall Response of CR, CR With Incomplete Marrow Recovery (CRi), Partial Response (PR), or Nodular PR (nPR) in the First-Line Subpopulation After 3 cycles	78.5 percentage of participants Interval 70.1 to 85.5	80.0 percentage of participants Interval 71.7 to 86.7

SECONDARY outcome

Timeframe: After 6 treatment cycles and at the confirmation of response assessment at least 12 weeks later (up to 36 weeks)

Population: ITT Population (First-Line Subpopulation)

The criteria for CR, CRi, PR, and nPR are identified in previous outcome measure(s). PD was defined by at least one of the following: the presence of lymphadenopathy; an increase in the previously noted enlargement of the liver or spleen by \>/= 50% or the de novo appearance of hepatomegaly or splenomegaly; an increase in the number of blood lymphocytes by \>/= 50% with \>/= 5000 B-cells per microliter (B-cells/mcL); transformation to a more aggressive histology; or occurrence of cytopenia attributable to CLL. Participants not achieving a CR or PR, and who did not exhibit PD, were considered to have stable disease (SD). The percentage of participants achieving each level of response was calculated as the number of participants meeting the above criteria divided by the number of participants analyzed. The rows below are labeled first by the level of response at the end of 6 cycles (C6), then by level of response at the confirmation assessment.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=121 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=120 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR with biopsy (C6), CR (confirmed)	21.5 percentage of participants	9.2 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR with biopsy (C6), CRi (confirmed)	2.5 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR with biopsy (C6), nPR (confirmed)	1.7 percentage of participants	6.7 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR with biopsy (C6), PR (confirmed)	19.0 percentage of participants	17.5 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR with biopsy (C6), SD (confirmed)	0 percentage of participants	1.7 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR with biopsy (C6), PD (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR with biopsy (C6), Missing (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR without biopsy (C6), CR (confirmed)	2.5 percentage of participants	5.8 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR without biopsy (C6), CRi (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR without biopsy (C6), nPR (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR without biopsy (C6), PR (confirmed)	16.5 percentage of participants	10.0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR without biopsy (C6), SD (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR without biopsy (C6), PD (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation CR without biopsy (C6), Missing (confirmed)	0.8 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation PR (C6), CR (confirmed)	1.7 percentage of participants	4.2 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation PR (C6), CRi (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation PR (C6), nPR (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation PR (C6), PR (confirmed)	8.3 percentage of participants	21.7 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation PR (C6), SD (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation PR (C6), PD (confirmed)	0.8 percentage of participants	2.5 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation PR (C6), Missing (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation SD (C6), CR (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation SD (C6), CRi (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation SD (C6), nPR (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation SD (C6), PR (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation SD (C6), SD (confirmed)	0 percentage of participants	0.8 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation SD (C6), PD (confirmed)	0 percentage of participants	0.8 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation SD (C6), Missing (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation Missing (C6), CR (confirmed)	0.8 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation Missing (C6), CRi (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation Missing (C6), nPR (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation Missing (C6), PR (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation Missing (C6), SD (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation Missing (C6), PD (confirmed)	0 percentage of participants	0 percentage of participants
Percentage of Participants by Disease Response Category in the First-Line Subpopulation Missing (C6), Missing (confirmed)	24.0 percentage of participants	19.2 percentage of participants

SECONDARY outcome

Timeframe: End of Cycles 3 and 6 (both treatment arms), end of Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks as confirmation of response, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years)

Population: ITT Population (First-Line Subpopulation)

The criteria for PD are identified in previous outcome measure(s). The percentage of participants experiencing PD or death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=121 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=120 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Percentage of Participants Experiencing PD or Death in the First-Line Subpopulation	27.3 percentage of participants	46.7 percentage of participants

SECONDARY outcome

Population: ITT Population (First-Line Subpopulation)

The criteria for PD are identified in previous outcome measure(s). PFS was defined as the time from the first dose of trial treatment to the first documentation of PD or death, whichever occurred first. PFS was calculated in months as \[first event date minus first dose date plus 1\] divided by 30.44.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=121 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=120 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Progression-Free Survival (PFS) in the First-Line Subpopulation	39.6 months Interval 34.3 to Due to insufficient follow-up among participants assigned to Rituximab + Bendamustine in the first-line subpopulation, a confidence interval upper limit was not reached.	29.9 months Interval 22.4 to 34.4

SECONDARY outcome

Population: ITT Population (First-Line Subpopulation); only participants with a tumor response of CR or CRi during study treatment or within 4 months after the end of treatment were considered in the analysis.

The criteria for CR, CRi, and PD are identified in previous outcome measure(s). The percentage of participants experiencing PD or death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=90 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=77 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Percentage of Participants With Tumor Response of CR or CRi Experiencing PD or Death in the First-Line Subpopulation	17.8 percentage of participants	33.8 percentage of participants

SECONDARY outcome

The criteria for CR, CRi, and PD are identified in previous outcome measure(s). DFS was defined as the time from the first assessment of CR or CRi to the first documentation of PD or death, whichever occurred first. DFS was calculated in months as \[first event date minus first assessment date of CR/CRi plus 1\] divided by 30.44.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=90 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=77 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Disease-Free Survival (DFS) in the First-Line Subpopulation	36.8 months Interval 32.0 to Data for \> 50% of participants were censored, and thus a confidence interval upper limit was not reached.	32.0 months Interval 22.2 to Data for \> 50% of participants were censored, and thus a confidence interval upper limit was not reached.

SECONDARY outcome

Population: ITT Population (First-Line Subpopulation)

The criteria for PD are identified in previous outcome measure(s). The percentage of participants experiencing PD, intake of new (post-trial) leukemia therapy, or death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=121 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=120 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Percentage of Participants Experiencing PD, Documented Intake of New Leukemia Therapy, or Death in the First-Line Subpopulation	29.8 percentage of participants	49.2 percentage of participants

SECONDARY outcome

Population: ITT Population (First-Line Subpopulation)

The criteria for PD and SD are identified in previous outcome measure(s). EFS was defined as the time from the first dose of trial treatment to the first documentation of PD, the beginning of new treatment for any hematologic malignancy, or death from any cause. Those with SD were considered event-free. EFS was calculated in months as \[first event date minus first dose date plus 1\] divided by 30.44.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=121 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=120 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Event-Free Survival (EFS) in the First-Line Subpopulation	39.6 months Interval 34.3 to Data for \> 50% of participants were censored, and thus a confidence interval upper limit was not reached.	29.9 months Interval 21.9 to 34.4

SECONDARY outcome

Timeframe: During Cycles 1 to 6 (both treatment arms), Cycles 7 to 12 (Rituximab + Chlorambucil arm), after an additional 8 weeks, then every 3 months for 1 year, then every 6 months until study cutoff (up to 4.5 years)

Population: ITT Population (First-Line Subpopulation)

The percentage of participants with documented intake of new (post-trial) leukemia therapy was calculated as the number of participants with new therapy divided by the number of participants analyzed, multiplied by 100.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=121 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=120 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Percentage of Participants With Documented Intake of New Leukemia Therapy in the First-Line Subpopulation	9.1 percentage of participants	18.3 percentage of participants

SECONDARY outcome

Population: ITT Population (First-Line Subpopulation)

TNLT was defined as the time from the first dose of trial treatment to the first documentation of any new leukemia treatment. TNLT was calculated in months as \[first new treatment date minus first dose date plus 1\] divided by 30.44.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=121 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=120 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Time to Next Leukemia Treatment (TNLT) in the First-Line Subpopulation	NA months Due to the low number of participants who received new leukemia treatment, the median TNLT could not be calculated. Data for \> 90% of participants were censored.	NA months Due to the low number of participants who received new leukemia treatment, the median TNLT could not be calculated. Data for \> 80% of participants were censored.

SECONDARY outcome

Population: ITT Population (First-Line Subpopulation); only participants with a tumor response of CR, CRi, PR, or nPR were considered in the analysis.

The criteria for CR, CRi, PR, nPR, and PD are identified in previous outcome measure(s). The percentage of participants experiencing PD or death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=114 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=107 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Percentage of Participants With Tumor Response of CR, CRi, PR, or nPR Experiencing PD or Death in the First-Line Subpopulation	24.6 percentage of participants	43.9 percentage of participants

SECONDARY outcome

Population: ITT Population (First-Line Subpopulation); only participants with a tumor response of CR, CRi, PR, or nPR were considered in the analysis.

The criteria for CR, CRi, PR, nPR, and PD are identified in previous outcome measure(s). Duration of response was defined as the time from the first assessment of CR, CRi, PR, or nPR to the first documentation of PD or death, whichever occurred first. Duration of response was calculated in months as \[first event date minus first assessment date of CR/CRi/PR/nPR plus 1\] divided by 30.44.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=114 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=107 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Duration of Response in the First-Line Subpopulation	36.8 months Interval 31.0 to Data for \> 75% of participants were censored, and thus a confidence interval upper limit was not reached.	27.7 months Interval 20.8 to 40.9

SECONDARY outcome

Population: ITT Population (First-Line Subpopulation)

The percentage of participants experiencing death was calculated as the number of participants with event divided by the number of participants analyzed, multiplied by 100.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=121 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=120 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Percentage of Participants Experiencing Death in the First-Line Subpopulation	14.9 percentage of participants	15.0 percentage of participants

SECONDARY outcome

Population: ITT Population (First-Line Subpopulation)

OS was defined as the time from recorded diagnosis to death from any cause. OS was calculated in months as \[death date or last-known alive date minus diagnosis date plus 1\] divided by 30.44.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=121 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=120 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Overall Survival (OS) in the First-Line Subpopulation	43.8 months Interval 39.6 to 43.8	NA months Due to insufficient follow-up among participants assigned to Rituximab + Chlorambucil in the first-line subpopulation, the median OS could not be calculated.

SECONDARY outcome

Timeframe: Up to 4 months after the last treatment cycle (up to 40 weeks)

Population: ITT Population (First-Line Subpopulation); only participants with a tumor response of CR, CRi, PR, or nPR during study treatment or within 4 months after the end of treatment were considered in the analysis.

Molecular response was defined as negative minimal residual disease (MRD) during study treatment or within 4 months after the end of treatment. Negative MRD was defined as a proportion of malignant B-cells in normal B-cells \< 0.0001. The percentage of participants achieving molecular response was calculated as the number of participants with negative MRD divided by the number of participants analyzed.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=112 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=106 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Percentage of Participants Achieving Molecular Response in the First-Line Subpopulation Molecular response	57.1 percentage of participants	16.0 percentage of participants
Percentage of Participants Achieving Molecular Response in the First-Line Subpopulation No molecular response	42.9 percentage of participants	84.0 percentage of participants

SECONDARY outcome

Timeframe: After 6 treatment cycles (up to 24 weeks)

Population: ITT Population (First-Line Subpopulation); only participants with available MRD data (MRD-evaluable participants) were included in the analysis.

Negative MRD was defined as a proportion of malignant B-cells in normal B-cells \< 0.0001, and positive MRD was defined as a proportion of malignant B-cells in normal B-cells \>/= 0.0001.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=78 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=78 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Number of Participants With Positive and Negative Outcome for MRD in the First-Line Subpopulation Positive outcome	30 participants	64 participants
Number of Participants With Positive and Negative Outcome for MRD in the First-Line Subpopulation Negative outcome	48 participants	14 participants

SECONDARY outcome

Timeframe: After 6 treatment cycles (up to 24 weeks)

Population: ITT Population (First-Line Subpopulation); only participants with a positive outcome for MRD were included in the analysis.

The proportion of malignant B-cells in normal B-cells was quantitatively determined, and was calculated as the number of malignant B-cells divided by the number of normal B-cells observed.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=30 Participants Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=64 Participants Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Proportion of Malignant B-cells in Normal B-cells Among Participants With a Positive Outcome for MRD in the First-Line Subpopulation	0.0836 proportion Standard Deviation 0.22739	0.1125 proportion Standard Deviation 0.27662

Adverse Events

Rituximab + Bendamustine

Serious events: 73 serious events

Other events: 165 other events

Deaths: 0 deaths

Rituximab + Chlorambucil

Serious events: 56 serious events

Other events: 159 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Communications

Hoffmann-LaRoche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Rituximab + Bendamustine n=177 participants at risk Participants received a specialized first-line or second-line regimen based upon prior chemotherapy exposure. Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. In those requiring a first-line regimen, bendamustine was administered IV at a dose of 90 mg/m\^2 on Days 1 and 2 of Cycles 1 to 6. In those requiring a second-line regimen, the bendamustine dose was lowered to 70 mg/m\^2. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.	Rituximab + Chlorambucil n=178 participants at risk Participants received IV rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2 to 6. Chlorambucil was administered PO at a dose of 10 mg/m\^2 on Days 1 to 7, beginning with Cycle 1 and continuing for up to 12 cycles or until CR was achieved. Each cycle was 4 weeks in duration. Treatment was discontinued early in participants who experienced PD.
Blood and lymphatic system disorders Neutropenia	54.8% 97/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	48.3% 86/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Blood and lymphatic system disorders Leukopenia	23.7% 42/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	17.4% 31/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Blood and lymphatic system disorders Thrombocytopenia	19.8% 35/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	23.0% 41/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Blood and lymphatic system disorders Anaemia	22.6% 40/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	15.2% 27/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Blood and lymphatic system disorders Lymphopenia	16.9% 30/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	11.8% 21/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Gastrointestinal disorders Nausea	29.9% 53/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	25.8% 46/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Gastrointestinal disorders Diarrhoea	16.4% 29/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	11.2% 20/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Gastrointestinal disorders Constipation	15.3% 27/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	12.4% 22/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Gastrointestinal disorders Vomiting	10.2% 18/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	11.2% 20/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Gastrointestinal disorders Abdominal pain	1.7% 3/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	6.2% 11/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
General disorders Asthenia	16.4% 29/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	19.1% 34/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
General disorders Pyrexia	18.6% 33/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	9.0% 16/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
General disorders Fatigue	9.6% 17/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	10.1% 18/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
General disorders Chills	9.0% 16/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	8.4% 15/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
General disorders Oedema peripheral	5.1% 9/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	5.6% 10/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Skin and subcutaneous tissue disorders Rash	15.8% 28/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	5.1% 9/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Skin and subcutaneous tissue disorders Pruritus	7.9% 14/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	4.5% 8/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Respiratory, thoracic and mediastinal disorders Cough	9.6% 17/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	10.1% 18/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.6% 10/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	6.7% 12/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Investigations Neutrophil count decreased	4.5% 8/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	6.2% 11/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Investigations Weight decreased	7.3% 13/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	2.8% 5/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Nervous system disorders Headache	5.6% 10/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	7.9% 14/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Nervous system disorders Dizziness	4.0% 7/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	6.7% 12/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Infections and infestations Nasopharyngitis	5.6% 10/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	5.1% 9/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Infections and infestations Bronchitis	4.5% 8/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	5.1% 9/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Injury, poisoning and procedural complications Infusion related reaction	6.8% 12/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	10.1% 18/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Metabolism and nutrition disorders Decreased appetite	7.9% 14/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	4.5% 8/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Musculoskeletal and connective tissue disorders Back pain	2.8% 5/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	6.7% 12/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants
Vascular disorders Hypotension	5.1% 9/177 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants	2.8% 5/178 • From Baseline up to 8 weeks after the start of the last treatment cycle (nonserious adverse events [AEs]; up to 56 weeks) or until the EOT visit (serious AEs; up to 4.5 years) Based upon the pooled population including both first-line and second line participants