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

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.

Time frame: 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.

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.

Time frame: 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); 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, 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.

Time frame: 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); only participants with a tumor response of CR, CRi, PR, or nPR were considered in the analysis.

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.

Time frame: 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)

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.

Time frame: 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.

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.

Time frame: 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 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.

Time frame: 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 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.

Time frame: 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.

Time frame: 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.

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.

Time frame: 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.

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.

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

Time frame: 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, 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.

Time frame: 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.

Time frame: 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 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.

Time frame: 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 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.

Time frame: 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); only participants with a tumor response of CR, CRi, PR, or nPR 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.

Time frame: 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); 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 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.

Time frame: 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 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.

Time frame: 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.

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.

Time frame: 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)