A Study to Assess the Effect of Maintenance Treatment With Rituximab Versus No Treatment in Participants With Progressive B-Cell Chronic Lymphocytic Leukemia (CLL)

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00718549
• Collaborator: (none)
• Enrollment: 128
• Locations: 6
• Arms: 3
• Actual Duration (Months): 73.8
• Patients Per Site: 21.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study will assess the effect of maintenance treatment with rituximab in comparison with observation period (no treatment), in participants with progressive B-cell CLL who have had previous first-line induction treatment with rituximab, cladribine and cyclophosphamide (RCC regimen). After 6 months of RCC induction therapy, participants will be randomized either to receive maintenance treatment with rituximab or to receive no treatment (observation only) for 96 weeks. Participants completing maintenance/observation period will be followed-up for approximately 3 years.

Condition or Disease	Intervention/Treatment	Phase
Lymphocytic Leukemia, Chronic	Drug: Cladribine; Drug: Cyclophosphamide; Drug: Rituximab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 128 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open Label Study to Assess the Effect of Maintenance Treatment With Mabthera (Rituximab) Versus No Treatment, After Induction Treatment With Rituximab, Cladribine and Cyclophosphamide (RCC) on Progression-Free Survival in Previously Untreated Patients With Progressive B-Cell Chronic Lymphocytic Leukemia
• Actual Study Start Date: Jul 21, 2009
• Actual Primary Completion Date: Sep 14, 2015
• Actual Study Completion Date: Sep 14, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Induction: Rituximab, Cladribine, Cyclophosphamide Participants will receive rituximab at a dose of 375 milligrams per meter squared (mg/m^2) as intravenous (IV) infusion on Day 1, cladribine at a dose of 0.12 milligrams per kilogram per day (mg/kg/day) as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 minutes on Days 2-4 in Cycle 1. Then, rituximab at a dose of 500 mg/m^2 as IV infusion on Day 1, cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 minutes on Days 2-4 will be administered in Cycles 2-6. Each cycle will be of 28 days in duration.	Drug: Cladribine; Cladribine will be adminiatered at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4 of each 28-day cycle during induction phase.; Drug: Cyclophosphamide; Cyclophosphamide will be administred at a dose of 250 mg/m^2/day as IV infusion over 15-30 minutes on Days 2-4 of each 28-day cycle during induction phase.; Drug: Rituximab; Rituximab will be administered at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 during induction phase. Rituximab will be administered at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle during maintenance phase.; Other Names: MabThera
Experimental: Maintenance Arm: Rituximab Participants with PR or CR after induction phase who will be randomized to maintenance arm will receive rituximab treatment for 8 cycles. Twelve weeks after the last induction cycle, participants will receive rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle until disease progression (up to approximately 96 weeks).	Drug: Rituximab; Rituximab will be administered at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and at a dose of 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 during induction phase. Rituximab will be administered at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle during maintenance phase.; Other Names: MabThera
No Intervention: Observation Arm: No Intervention Participants with PR or CR after induction phase who will be randomized to observation arm will not receive any intervention. Participants will be assessed every 4-weeks for the first 12 weeks and every 12-weeks afterwards up to 96 weeks.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Disease Progression (PD), Relapse, or Death Due to Any Cause Assessed According to the National Cancer Institute (NCI) Revised Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia (CLL) [From randomization to PD, Relapse, or death due to any cause (overall approximately 5 years)]

   PD occurred if any of the following events was observed: appearance of any new lesion, such as enlarged lymph nodes (greater than [>]1.5 centimeters [cm]), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of greater than or equal to (>/=) 50 percent (%) in greatest determined diameter of any previous site; an increase in the previously noted enlargement of the liver or spleen by >/=50%; an increase in the number of blood lymphocytes by >/=50% with B-lymphocytes >/=5000 per microliter (/mcL); transformation to a more aggressive histology; occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL.

2. Progression-Fee Survival (PFS) Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL [From randomization to PD, relapse, or death due to any cause (overall approximately 5 years)]

   PFS was defined as the time from date of randomization to date of PD, relapse, or death due to any cause. Participants alive with no evidence of PD or relapse were censored at date of last clinical examination. PD occurred if any of the following events was observed: appearance of any new lesion, such as enlarged lymph nodes (>1.5 cm), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of >/=50% in greatest determined diameter of any previous site; an increase in the previously noted enlargement of the liver or spleen by >/=50%; an increase in the number of blood lymphocytes by >/=50% with B-lymphocytes >/=5000/mcL; transformation to a more aggressive histology; occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL.

Secondary Outcome Measures

1. Percentage of Participants With CR or PR Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL [8 weeks after the last dose of rituximab during induction treatment (Week 29) and 12 weeks after the end of maintenance treatment or observation phase (Week 129)]

   CR was achieved if participants met all of the following criteria >/= 2 months after last treatment: no lymphadenopathy (Ly)/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, platelets (PL) >100,000/mcL, hemoglobin (Hb) >11.0 grams per deciliter (g/dL), bone marrow (BM) sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly (decrease in lymph node size by >/=50% compared to pre-treatment state, no increase in any lymph node, no new enlarged lymph node); a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline).

2. Percentage of Participants With Minimal Residual Disease (MRD) According to Rawstron Criteria in Participants With CR or PR [8 weeks after the last dose of rituximab during induction treatment (Week 29) and 12 weeks after the end of maintenance treatment or observation phase (Week 129)]

   MRD was defined by the presence of tumor cells in bone marrow, using 4-color flow cytometry of cluster of differentiation (CD)19/CD5/CD20/CD79b. MRD was assessed in participants who achieved CR or PR. CR: if participants met all of the following criteria >/=2 months after last treatment: no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline).

3. PFS Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL According to Clinical and Biochemical Factors [From randomization to PD, relapse, or death due to any cause (overall approximately 5 years)]

   PFS: time from date of randomization to date of PD, relapse, or death from any cause. Participants alive with no evidence of PD or relapse were censored at date of last clinical examination. PD: appearance of any new lesion, such as enlarged lymph nodes (>1.5 cm), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of >/=50% in greatest determined diameter of any previous site; an increase in previously noted enlargement of liver or spleen by >/=50%; an increase in number of blood lymphocytes by >/=50% with B-lymphocytes >/=5000/mcL; transformation to a more aggressive histology; or occurrence of cytopenia attributable to CLL. Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed relationship between clinical markers and clinical outcome (PFS) after study treatment.

4. Percentage of Participants With CR or PR Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL According to Clinical and Biochemical Factors at Week 29 [8 weeks after the last dose of rituximab during induction treatment (Week 29)]

   CR was achieved if participants met all of the following criteria >/= 2 months after last treatment: no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed the relationship between clinical markers and clinical outcome (response) after study treatment.

5. Percentage of Participants With CR or PR Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL According to Clinical and Biochemical Factors at Week 129 [12 weeks after the end of maintenance treatment or observation phase (Week 129)]

   CR was achieved if participants met all of the following criteria >/=2 months after last treatment: no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed the relationship between clinical markers and clinical outcome (response) after study treatment.

6. Percentage of Participants With MRD According to Rawstron Criteria in Participants With CR or PR According to Clinical and Biochemical Factors at Week 29 [8 weeks after the last dose of rituximab during induction treatment (Week 29)]

   MRD: the presence of tumor cells in bone marrow, using 4-color flow cytometry of CD19/CD5/CD20/CD79b. MRD was assessed in participants who achieved CR or PR. CR (>/=2 months after last treatment): no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed relationship between clinical markers and MRD after study treatment.

7. Percentage of Participants With MRD According to Rawstron Criteria in Participants With CR or PR According to Clinical and Biochemical Factors at Week 129 [12 weeks after the end of maintenance treatment or observation phase (Week 129)]

   MRD: the presence of tumor cells in bone marrow, using 4-color flow cytometry of CD19/CD5/CD20/CD79b. MRD was assessed in participants who achieved CR or PR. CR (>/=2 months after last treatment): no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed relationship between clinical markers and MRD after study treatment.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Immunologically confirmed diagnosis of B-cell CLL

• Rai stage I-IV disease with evidence of progression

• No previous chemotherapy, radiotherapy, or immunotherapy for B-cell CLL

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

Exclusion Criteria:

• Active secondary malignancy or transformation to aggressive lymphoma

• Medical condition requiring chronic use of oral corticosteroids at a dose of 1 mg/kg or 60 mg/m^2 over 2 weeks

• Prior treatment with interferon, rituximab or another monoclonal antibody, immunosuppressive treatment or radiotherapy before inclusion to the study

• History of other malignancies within 2 years before study entry, except for dequately treated carcinoma in situ of the cervix; basal or squamous cell skin cancer; low grade, early stage localized prostate cancer treated surgically with curative intent; good prognosis ductal carcinoma in situ (DCIS) of the breast treated with lumpectomy alone with curative intent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City Clinical Hospital #9	Minsk		Belarus	220116
2	Medical University, Independent Public Clinical Hospital; Dept. of Hematology, SPSK	Bialystok		Poland	15-276
3	Szpital Uniwersytecki W Krakowie; Klinika Hematologii	Krakow		Poland	31-501
4	Medical University School; Dept. of Haematology	Lodz		Poland	93-510
5	Istytut Hematologii i Transfuzjologii; Hematologia	Warszawa		Poland	02 776
6	Medical Uni of Wroclaw; Hematology	Wroclaw		Poland	50-367

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00718549
• Other Study ID Numbers: ML21283; 2008-001140-39
• First Posted: Jul 18, 2008
• Last Update Posted: Aug 20, 2018
• Last Verified: Nov 1, 2017

• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Cyclophosphamide; Rituximab; Cladribine

Study Results

Participant Flow

Pre-assignment Detail	A total 136 participants were screened, out of which 128 participants were enrolled in this study.

Arm/Group Title	Induction: Rituximab, Cladribine, Cyclophosphamide	Maintenance Arm: Rituximab	Observation Arm: No Intervention
Arm/Group Description	Participants received rituximab at a dose of 375 milligrams per meter squared (mg/m^2) as intravenous (IV) infusion on Day 1, cladribine at a dose of 0.12 milligrams per kilogram per day (mg/kg/day) as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 minutes (min) on Days 2-4 in Cycle 1. Then, rituximab at a dose of 500 mg/m^2 as IV infusion on Day 1, cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 were administered in Cycles 2-6. Each cycle was of 28 days in duration.	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase who were randomized to maintenance arm received rituximab treatment for 8 cycles. Twelve weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle until disease progression (up to approximately 96 weeks).	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase who were randomized to observation arm did not receive any intervention. Participants were assessed every 4-weeks for the first 12 weeks and every 12-weeks afterwards up to 96 weeks.
Period Title: Induction Phase
STARTED	128	0	0
COMPLETED	66	0	0
NOT COMPLETED	62	0	0
Period Title: Induction Phase
STARTED	0	33	33
COMPLETED	0	5	3
NOT COMPLETED	0	28	30

Baseline Characteristics

Arm/Group Title	Induction: Rituximab, Cladribine, Cyclophosphamide
Arm/Group Description	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1, cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 in Cycle 1. Then, rituximab at a dose of 500 mg/m^2 as IV infusion on Day 1, cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 were administered in Cycles 2-6. Each cycle was of 28 days in duration.
Overall Participants	128
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.5 (8.3)
Sex: Female, Male (Count of Participants)
Female	44 34.4%
Male	84 65.6%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Disease Progression (PD), Relapse, or Death Due to Any Cause Assessed According to the National Cancer Institute (NCI) Revised Guidelines for the Diagnosis and Treatment of Chronic Lymphocytic Leukemia (CLL)
Description	PD occurred if any of the following events was observed: appearance of any new lesion, such as enlarged lymph nodes (greater than [>]1.5 centimeters [cm]), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of greater than or equal to (>/=) 50 percent (%) in greatest determined diameter of any previous site; an increase in the previously noted enlargement of the liver or spleen by >/=50%; an increase in the number of blood lymphocytes by >/=50% with B-lymphocytes >/=5000 per microliter (/mcL); transformation to a more aggressive histology; occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL.
Time Frame	From randomization to PD, Relapse, or death due to any cause (overall approximately 5 years)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all participants who received at least one dose of study medication and had at least one post-treatment efficacy measurement available. Here, 'Overall Number of Participants Analyzed' signifies the number of participants evaluable for this outcome measure.

Arm/Group Title	Maintenance Arm: Rituximab	Observation Arm: No Intervention	All Randomized Participants
Arm/Group Description	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase who were randomized to maintenance arm received rituximab treatment for 8 cycles. Twelve weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle until disease progression (up to approximately 96 weeks).	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase who were randomized to observation arm did not receive any intervention. Participants were assessed every 4-weeks for the first 12 weeks and every 12-weeks afterwards up to 96 weeks.	Participants with PR or CR after induction phase were randomized to observation arm (received no intervention) or to maintenance arm (12 weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle for 8 cycles or until disease progression [up to approximately 96 weeks]).
Measure Participants	33	33	66
Number [percentage of participants]	27.3 21.3%	54.5 NaN	40.9 NaN

2. Primary Outcome

Title	Progression-Fee Survival (PFS) Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL
Description	PFS was defined as the time from date of randomization to date of PD, relapse, or death due to any cause. Participants alive with no evidence of PD or relapse were censored at date of last clinical examination. PD occurred if any of the following events was observed: appearance of any new lesion, such as enlarged lymph nodes (>1.5 cm), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of >/=50% in greatest determined diameter of any previous site; an increase in the previously noted enlargement of the liver or spleen by >/=50%; an increase in the number of blood lymphocytes by >/=50% with B-lymphocytes >/=5000/mcL; transformation to a more aggressive histology; occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL.
Time Frame	From randomization to PD, relapse, or death due to any cause (overall approximately 5 years)

Outcome Measure Data

Analysis Population Description

ITT population. Here, 'Overall Number of Participants Analyzed' signifies the number of participants evaluable for this outcome measure.

Arm/Group Title	Maintenance Arm: Rituximab	Observation Arm: No Intervention	All Randomized Participants
Arm/Group Description	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase who were randomized to maintenance arm received rituximab treatment for 8 cycles. Twelve weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle until disease progression (up to approximately 96 weeks).	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase who were randomized to observation arm did not receive any intervention. Participants were assessed every 4-weeks for the first 12 weeks and every 12-weeks afterwards up to 96 weeks.	Participants with PR or CR after induction phase were randomized to observation arm (received no intervention) or to maintenance arm (12 weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle for 8 cycles or until disease progression [up to approximately 96 weeks]).
Measure Participants	33	33	66
Median (95% Confidence Interval) [years]	NA	2.1	3.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab, Observation Arm: No Intervention
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.028
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab, Observation Arm: No Intervention
	Comments	Univariate comparison
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.033
	Comments
	Method	Cox's proportional hazards regression
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.418
	Confidence Interval	() 95%; 0.187 to 0.933
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab, Observation Arm: No Intervention
	Comments	Multivariate Comparison
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.111
	Comments
	Method	Cox's proportional hazards model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.052
	Confidence Interval	(2-Sided) 95%; 0.001 to 1.972
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With CR or PR Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL
Description	CR was achieved if participants met all of the following criteria >/= 2 months after last treatment: no lymphadenopathy (Ly)/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, platelets (PL) >100,000/mcL, hemoglobin (Hb) >11.0 grams per deciliter (g/dL), bone marrow (BM) sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly (decrease in lymph node size by >/=50% compared to pre-treatment state, no increase in any lymph node, no new enlarged lymph node); a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline).
Time Frame	8 weeks after the last dose of rituximab during induction treatment (Week 29) and 12 weeks after the end of maintenance treatment or observation phase (Week 129)

Outcome Measure Data

Analysis Population Description

ITT 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 Title	Maintenance Arm: Rituximab	Observation Arm: No Intervention	Overall Population
Arm/Group Description	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase who were randomized to maintenance arm received rituximab treatment for 8 cycles. Twelve weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle until disease progression (up to approximately 96 weeks).	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase who were randomized to observation arm did not receive any intervention. Participants were assessed every 4-weeks for the first 12 weeks and every 12-weeks afterwards up to 96 weeks.	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase were randomized to observation arm (received no intervention) or to maintenance arm (12 weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle for 8 cycles or until disease progression [up to approximately 96 weeks]).
Measure Participants	21	18	97
Week 29	73.2 57.2%
Week 129	90.5 70.7%	72.2 NaN	82.1 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab, Observation Arm: No Intervention
	Comments	Week 129: Univariate Comparison
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.155
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.654
	Confidence Interval	(2-Sided) 95%; 0.674 to 28.337
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants With Minimal Residual Disease (MRD) According to Rawstron Criteria in Participants With CR or PR
Description	MRD was defined by the presence of tumor cells in bone marrow, using 4-color flow cytometry of cluster of differentiation (CD)19/CD5/CD20/CD79b. MRD was assessed in participants who achieved CR or PR. CR: if participants met all of the following criteria >/=2 months after last treatment: no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline).
Time Frame	8 weeks after the last dose of rituximab during induction treatment (Week 29) and 12 weeks after the end of maintenance treatment or observation phase (Week 129)

Outcome Measure Data

Analysis Population Description

ITT 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 Title	Maintenance Arm: Rituximab	Observation Arm: No Intervention	All Randomized Participants
Arm/Group Description	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase who were randomized to maintenance arm received rituximab treatment for 8 cycles. Twelve weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle until disease progression (up to approximately 96 weeks).	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase who were randomized to observation arm did not receive any intervention. Participants were assessed every 4-weeks for the first 12 weeks and every 12-weeks afterwards up to 96 weeks.	Participants with PR or CR after induction phase were randomized to observation arm (received no intervention) or to maintenance arm (12 weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle for 8 cycles or until disease progression [up to approximately 96 weeks]).
Measure Participants	14	10	65
Week 29	15.4 12%
Week 129	28.6 22.3%	20.0 NaN	25.0 NaN

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab, Observation Arm: No Intervention
	Comments	Week 129: Univariate comparison
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.634
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.625
	Confidence Interval	(2-Sided) 95%; 0.073 to 4.114
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	PFS Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL According to Clinical and Biochemical Factors
Description	PFS: time from date of randomization to date of PD, relapse, or death from any cause. Participants alive with no evidence of PD or relapse were censored at date of last clinical examination. PD: appearance of any new lesion, such as enlarged lymph nodes (>1.5 cm), splenomegaly, hepatomegaly, or other organ infiltrates; an increase of >/=50% in greatest determined diameter of any previous site; an increase in previously noted enlargement of liver or spleen by >/=50%; an increase in number of blood lymphocytes by >/=50% with B-lymphocytes >/=5000/mcL; transformation to a more aggressive histology; or occurrence of cytopenia attributable to CLL. Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed relationship between clinical markers and clinical outcome (PFS) after study treatment.
Time Frame	From randomization to PD, relapse, or death due to any cause (overall approximately 5 years)

Outcome Measure Data

Analysis Population Description

ITT population. Overall Number of Participants Analyzed: participants evaluable for this outcome; Number Analyzed: participants evaluable for specified category. This outcome was planned to be reported for groups defined by clinical and biochemical factors (i.e. reported categories) among All Randomized Participants only.

Arm/Group Title	All Randomized Participants
Arm/Group Description	Participants with PR or CR after induction phase were randomized to observation arm (received no intervention) or to maintenance arm (12 weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle for 8 cycles or until disease progression [up to approximately 96 weeks]).
Measure Participants	66
Age <60 years	3.0
Age >/=60 years	4.0
Sex: Female	4.0
Sex: Male	3.0
Rai Stage: I or II	3.1
Rai Stage: III or IV	3.0
Beta-2-Microglobulin >/= Median Value	1.9
Beta-2-Microglobulin <Median Value	NA
Zeta-Associated Protein (ZAP)-70: Negative	3.0
ZAP-70 Expression: Positive	NA
CD38 Expression: Negative	2.1
CD38 Expression: Positive	2.8
Cytogenetic abnormality 17p: No	3.1
Cytogenetic abnormality 17p: Yes	1.9
Cytogenetic abnormality 13q: No	3.5
Cytogenetic abnormality 13q: Yes	3.0
Cytogenetic abnormality 11q: No	3.5
Cytogenetic abnormality 11q: Yes	2.8
Cytogenetic abnormality 12q: No	2.2
Cytogenetic abnormality 12q: Yes	3.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Multivariate Comparison: Age <60 years versus Age >/=60 years
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.752
	Comments
	Method	Cox's proportional hazards model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.769
	Confidence Interval	(2-Sided) 95%; 0.151 to 3.920
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Multivariate Comparison: Sex: Female versus Male
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.128
	Comments
	Method	Cox's proportional hazards model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.068
	Confidence Interval	(2-Sided) 95%; 0.002 to 2.158
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Multivariate Comparison: Rai Stage: I or II versus Rai Stage: III or IV
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.728
	Comments
	Method	Cox's proportional hazards model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.282
	Confidence Interval	(2-Sided) 95%; 0.022 to 240.864
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Multivariate Comparison: Beta-2-Microglobulin >/= Median Value versus Beta-2-Microglobulin <Median Value
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments
	Method	Cox's proportional hazards model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	26.275
	Confidence Interval	(2-Sided) 95%; 1.036 to 666.708
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Multivariate Comparison: ZAP-70 Expression Negative versus Positive
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.417
	Comments
	Method	Cox's proportional hazards model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.210
	Confidence Interval	(2-Sided) 95%; 0.005 to 9.100
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Multivariate Comparison: CD38 Expression Negative versus Positive
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.134
	Comments
	Method	Cox's proportional hazards model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.197
	Confidence Interval	(2-Sided) 95%; 0.024 to 1.647
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Multivariate Comparison: Cytogenetic abnormality 17p No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.426
	Comments
	Method	Cox's proportional hazards model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	8.373
	Confidence Interval	(2-Sided) 95%; 0.045 to 1568.717
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Multivariate Comparison: Cytogenetic abnormality 13q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.733
	Comments
	Method	Cox's proportional hazards model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.438
	Confidence Interval	(2-Sided) 95%; 0.004 to 50.334
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Multivariate Comparison: Cytogenetic abnormality 11q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.463
	Comments
	Method	Cox's proportional hazards model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.621
	Confidence Interval	(2-Sided) 95%; 0.200 to 34.422
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Multivariate Comparison: Cytogenetic abnormality 12q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.397
	Comments
	Method	Cox's proportional hazards model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.288
	Confidence Interval	(2-Sided) 95%; 0.016 to 5.122
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants With CR or PR Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL According to Clinical and Biochemical Factors at Week 29
Description	CR was achieved if participants met all of the following criteria >/= 2 months after last treatment: no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed the relationship between clinical markers and clinical outcome (response) after study treatment.
Time Frame	8 weeks after the last dose of rituximab during induction treatment (Week 29)

Outcome Measure Data

Analysis Population Description

ITT population. Number Analyzed: participants evaluable for specified category. This outcome was planned to be reported for groups defined by clinical and biochemical factors (i.e. reported categories) among Participants included in Overall IIT population only.

Arm/Group Title	Overall Population
Arm/Group Description	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase were randomized to observation arm (received no intervention) or to maintenance arm (12 weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle for 8 cycles or until disease progression [up to approximately 96 weeks]).
Measure Participants	97
Age <60 years	73.3 57.3%
Age >/=60 years	73.0 57%
Sex: Female	80.6 63%
Sex: Male	69.7 54.5%
Rai Stage: I or II	77.5 60.5%
Rai Stage: III or IV	61.5 48%
Beta-2-Microglobulin >/= Median Value	64.6 50.5%
Beta-2-Microglobulin <Median Value	83.0 64.8%
ZAP-70 Expression: Negative	67.1 52.4%
ZAP-70 Expression: Positive	94.7 74%
CD38 Expression: Negative	73.1 57.1%
CD38 Expression: Positive	71.4 55.8%
Cytogenetic abnormality 17p: No	72.8 56.9%
Cytogenetic abnormality 17p: Yes	71.4 55.8%
Cytogenetic abnormality 13q: No	62.9 49.1%
Cytogenetic abnormality 13q: Yes	76.1 59.5%
Cytogenetic abnormality 11q: No	69.5 54.3%
Cytogenetic abnormality 11q: Yes	79.2 61.9%
Cytogenetic abnormality 12q: No	67.6 52.8%
Cytogenetic abnormality 12q: Yes	66.7 52.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Age <60 years versus Age >/=60 years
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.969
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.982
	Confidence Interval	(2-Sided) 95%; 0.393 to 2.531
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Sex: Female versus Male
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.260
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.552
	Confidence Interval	(2-Sided) 95%; 0.183 to 1.488
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Rai Stage: I or II versus Rai Stage: III or IV
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.121
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.465
	Confidence Interval	(2-Sided) 95%; 0.177 to 1.242
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Beta-2-Microglobulin >/= Median Value versus Beta-2-Microglobulin <Median Value
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.045
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.374
	Confidence Interval	(2-Sided) 95%; 0.137 to 0.957
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: ZAP-70 Expression Negative versus Positive
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.040
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	8.809
	Confidence Interval	(2-Sided) 95%; 1.655 to 163.316
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: CD38 Expression Negative versus Positive
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.887
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.921
	Confidence Interval	(2-Sided) 95%; 0.287 to 2.851
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Cytogenetic abnormality 17p No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.936
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.932
	Confidence Interval	(2-Sided) 95%; 0.186 to 6.839
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Cytogenetic abnormality 13q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.199
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.880
	Confidence Interval	(2-Sided) 95%; 0.719 to 5.012
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Cytogenetic abnormality 11q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.375
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.668
	Confidence Interval	(2-Sided) 95%; 0.566 to 5.649
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Cytogenetic abnormality 12q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.961
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.957
	Confidence Interval	(2-Sided) 95%; 0.173 to 7.275
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Participants With CR or PR Assessed According to the NCI Revised Guidelines for the Diagnosis and Treatment of CLL According to Clinical and Biochemical Factors at Week 129
Description	CR was achieved if participants met all of the following criteria >/=2 months after last treatment: no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed the relationship between clinical markers and clinical outcome (response) after study treatment.
Time Frame	12 weeks after the end of maintenance treatment or observation phase (Week 129)

Outcome Measure Data

Analysis Population Description

ITT population. Overall Number of Participants Analyzed: participants evaluable for this outcome; Number Analyzed: participants evaluable for specified category. This outcome was planned to be reported for groups defined by clinical and biochemical factors (i.e. reported categories) among All Randomized Participants only.

Arm/Group Title	All Randomized Participants
Arm/Group Description	Participants with PR or CR after induction phase were randomized to observation arm (received no intervention) or to maintenance arm (12 weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle for 8 cycles or until disease progression [up to approximately 96 weeks]).
Measure Participants	39
Age <60 years	80.8 63.1%
Age >/=60 years	84.6 66.1%
Sex: Female	85.7 67%
Sex: Male	80.0 62.5%
Rai Stage: I or II	80.6 63%
Rai Stage: III or IV	87.5 68.4%
Beta-2-Microglobulin >/= Median Value	76.9 60.1%
Beta-2-Microglobulin <Median Value	84.0 65.6%
ZAP-70 Expression: Negative	83.3 65.1%
ZAP-70 Expression: Positive	83.3 65.1%
CD38 Expression: Negative	77.8 60.8%
CD38 Expression: Positive	75.0 58.6%
Cytogenetic abnormality 17p: No	86.7 67.7%
Cytogenetic abnormality 17p: Yes	50.0 39.1%
Cytogenetic abnormality 13q: No	90.0 70.3%
Cytogenetic abnormality 13q: Yes	76.5 59.8%
Cytogenetic abnormality 11q: No	84.2 65.8%
Cytogenetic abnormality 11q: Yes	80.0 62.5%
Cytogenetic abnormality 12q: No	76.2 59.5%
Cytogenetic abnormality 12q: Yes	100.0 78.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Age <60 years versus Age >/=60 years
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.768
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.310
	Confidence Interval	(2-Sided) 95%; 0.237 to 10.189
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Sex: Female versus Male
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.657
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.667
	Confidence Interval	(2-Sided) 95%; 0.086 to 3.653
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Rai Stage: I or II versus Rai Stage: III or IV
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.655
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.680
	Confidence Interval	(2-Sided) 95%; 0.229 to 34.486
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Beta-2-Microglobulin >/= Median Value versus Beta-2-Microglobulin <Median Value
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.595
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.635
	Confidence Interval	(2-Sided) 95%; 0.117 to 3.730
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: ZAP-70 Expression Negative versus Positive
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.000
	Confidence Interval	(2-Sided) 95%; 0.164 to 8.102
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: CD38 Expression Negative versus Positive
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.882
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.857
	Confidence Interval	(2-Sided) 95%; 0.093 to 6.636
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Cytogenetic abnormality 17p No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.216
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.154
	Confidence Interval	(2-Sided) 95%; 0.005 to 4.405
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Cytogenetic abnormality 13q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.396
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.361
	Confidence Interval	(2-Sided) 95%; 0.017 to 2.971
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Cytogenetic abnormality 11q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.776
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.750
	Confidence Interval	(2-Sided) 95%; 0.103 to 6.572
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Percentage of Participants With MRD According to Rawstron Criteria in Participants With CR or PR According to Clinical and Biochemical Factors at Week 29
Description	MRD: the presence of tumor cells in bone marrow, using 4-color flow cytometry of CD19/CD5/CD20/CD79b. MRD was assessed in participants who achieved CR or PR. CR (>/=2 months after last treatment): no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed relationship between clinical markers and MRD after study treatment.
Time Frame	8 weeks after the last dose of rituximab during induction treatment (Week 29)

Outcome Measure Data

Analysis Population Description

ITT population. Overall Number of Participants Analyzed: participants evaluable for this outcome; Number Analyzed: participants evaluable for specified category. This outcome was planned to be reported for groups defined by clinical and biochemical factors (i.e. reported categories) among All Randomized Participants only.

Arm/Group Title	All Randomized Participants
Arm/Group Description	Participants with PR or CR after induction phase were randomized to either observation arm (received no intervention) or to maintenance arm (received maintenance treatment with rituximab administered at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle for 8 cycles until disease progression for up to approximately 96 weeks).
Measure Participants	65
Age <60 years	87.8 68.6%
Age >/=60 years	79.2 61.9%
Sex: Female	87.5 68.4%
Sex: Male	82.9 64.8%
Rai Stage: I or II	80.4 62.8%
Rai Stage: III or IV	100.0 78.1%
Beta-2-Microglobulin >/= Median Value	93.1 72.7%
Beta-2-Microglobulin <Median Value	77.1 60.2%
ZAP-70 Expression: Negative	82.6 64.5%
ZAP-70 Expression: Positive	100.0 78.1%
CD38 Expression: Negative	83.3 65.1%
CD38 Expression: Positive	95.5 74.6%
Cytogenetic abnormality 17p: No	83.6 65.3%
Cytogenetic abnormality 17p: Yes	100.0 78.1%
Cytogenetic abnormality 13q: No	84.2 65.8%
Cytogenetic abnormality 13q: Yes	81.8 63.9%
Cytogenetic abnormality 11q: No	83.3 65.1%
Cytogenetic abnormality 11q: Yes	84.2 65.8%
Cytogenetic abnormality 12q: No	80.5 62.9%
Cytogenetic abnormality 12q: Yes	75.0 58.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Age <60 years versus Age >/=60 years
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.357
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.528
	Confidence Interval	(2-Sided) 95%; 0.131 to 2.114
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Sex: Female versus Male
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.623
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.694
	Confidence Interval	(2-Sided) 95%; 0.138 to 2.800
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Beta-2-Microglobulin >/= Median Value versus Beta-2-Microglobulin <Median Value
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.097
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.000
	Confidence Interval	(2-Sided) 95%; 0.901 to 28.158
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: CD38 Expression Negative versus Positive
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.233
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	4.200
	Confidence Interval	(2-Sided) 95%; 0.484 to 89.588
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Cytogenetic abnormality 13q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.826
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.844
	Confidence Interval	(2-Sided) 95%; 0.161 to 3.681
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Cytogenetic abnormality 11q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.933
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.067
	Confidence Interval	(2-Sided) 95%; 0.246 to 5.581
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Cytogenetic abnormality 12q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.794
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.727
	Confidence Interval	(2-Sided) 95%; 0.080 to 15.779
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Percentage of Participants With MRD According to Rawstron Criteria in Participants With CR or PR According to Clinical and Biochemical Factors at Week 129
Description	MRD: the presence of tumor cells in bone marrow, using 4-color flow cytometry of CD19/CD5/CD20/CD79b. MRD was assessed in participants who achieved CR or PR. CR (>/=2 months after last treatment): no Ly/ hepatomegaly/ splenomegaly/constitutional symptoms; neutrophils >1500/mcL, PL >100,000/mcL, Hb >11.0 g/dL, BM sample must be normocellular for age with lymphocytes <30% of nucleated cells. PR: a reduction in Ly; a reduction of >/=50% from pre-treatment state in the lymphocytes count, and in enlargement of the spleen or liver; any one of the following: neutrophils >1500/mcL, PL >100,000/mcL (or 50% improvement from baseline), Hb >11.0 g/dL (or 50% improvement from baseline). Rai Stage: staging for CLL, based on lymphocyte, red blood cell and platelet counts and size of lymph nodes, spleen, and liver. Rai Stage I or II are intermediate risk CLL and Rai Stage III or IV are high risk CLL. This outcome measure assessed relationship between clinical markers and MRD after study treatment.
Time Frame	12 weeks after the end of maintenance treatment or observation phase (Week 129)

Outcome Measure Data

Analysis Population Description

ITT population. Overall Number of Participants Analyzed: participants evaluable for this outcome; Number Analyzed: participants evaluable for specified category. This outcome was planned to be reported for groups defined by clinical and biochemical factors (i.e. reported categories) among All Randomized Participants only.

Arm/Group Title	All Randomized Participants
Arm/Group Description	Participants with PR or CR after induction phase were randomized to observation arm (received no intervention) or to maintenance arm (12 weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle for 8 cycles or until disease progression [up to approximately 96 weeks]).
Measure Participants	24
Age <60 years	72.2 56.4%
Age >/=60 years	83.3 65.1%
Sex: Female	71.4 55.8%
Sex: Male	76.5 59.8%
Rai Stage: I or II	75.0 58.6%
Rai Stage: III or IV	75.0 58.6%
Beta-2-Microglobulin >/= Median Value	88.9 69.5%
Beta-2-Microglobulin <Median Value	71.4 55.8%
ZAP-70 Expression: Negative	66.7 52.1%
ZAP-70 Expression: Positive	100.0 78.1%
CD38 Expression: Negative	60.0 46.9%
CD38 Expression: Positive	77.8 60.8%
Cytogenetic abnormality 17p: No	76.2 59.5%
Cytogenetic abnormality 17p: Yes	0.0 0%
Cytogenetic abnormality 13q: No	75.0 58.6%
Cytogenetic abnormality 13q: Yes	66.7 52.1%
Cytogenetic abnormality 11q: No	66.7 52.1%
Cytogenetic abnormality 11q: Yes	75.0 58.6%
Cytogenetic abnormality 12q: No	66.7 52.1%
Cytogenetic abnormality 12q: Yes	66.7 52.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Age <60 years versus Age >/=60 years
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.591
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.923
	Confidence Interval	(2-Sided) 95%; 0.225 to 41.751
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Sex: Female versus Male
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.796
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.300
	Confidence Interval	(2-Sided) 95%; 0.147 to 9.222
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Beta-2-Microglobulin >/= Median Value versus Beta-2-Microglobulin <Median Value
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.338
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.200
	Confidence Interval	(2-Sided) 95%; 0.375 to 69.479
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: CD38 Expression Negative versus Positive
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.486
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.333
	Confidence Interval	(2-Sided) 95%; 0.201 to 29.008
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Cytogenetic abnormality 13q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.691
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.667
	Confidence Interval	(2-Sided) 95%; 0.074 to 4.722
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Cytogenetic abnormality 11q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.691
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.500
	Confidence Interval	(2-Sided) 95%; 0.212 to 13.563
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Cytogenetic abnormality 12q No versus Yes
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.000
	Confidence Interval	(2-Sided) 95%; 0.076 to 24.621
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Maintenance Arm: Rituximab
	Comments	Univariate Comparison: Rai Stage: I or II versus Rai Stage: III or IV
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.000
	Confidence Interval	(2-Sided) 95%; 0.099 to 22.791
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From Day 1 to end of study (up to 261 weeks)
Adverse Event Reporting Description	All enrolled participants who received at least one dose of study medication were included in the analysis.
Arm/Group Title	Induction (Excluding Maintenance/ Observation)		Maintenance Arm: Rituximab		Observation Arm: No Intervention		All Participants
Arm/Group Description	Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1, cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 in Cycle 1. Then, rituximab at a dose of 500 mg/m^2 as IV infusion on Day 1, cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 were administered in Cycles 2-6. Each cycle was of 28 days in duration. Only participants who were not randomized to maintenance or observation arm were included.		Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase who were randomized to maintenance arm received rituximab treatment for 8 cycles. Twelve weeks after the last induction cycle, participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of each 12-week cycle until disease progression (up to approximately 96 weeks).		Participants received rituximab at a dose of 375 mg/m^2 as IV infusion on Day 1 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6, along with cladribine at a dose of 0.12 mg/kg/day as IV infusion on Days 2-4, and cyclophosphamide at a dose of 250 mg/m^2/day as IV infusion over 15-30 min on Days 2-4 of each 28-days cycle for 6 cycles during induction phase. Participants with PR or CR after induction phase who were randomized to observation arm did not receive any intervention. Participants were assessed every 4-weeks for the first 12 weeks and every 12-weeks afterwards up to 96 weeks.		All enrolled participants who received at least one dose of study medication were included in the analysis.
All Cause Mortality
	Induction (Excluding Maintenance/ Observation)		Maintenance Arm: Rituximab		Observation Arm: No Intervention		All Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Induction (Excluding Maintenance/ Observation)		Maintenance Arm: Rituximab		Observation Arm: No Intervention		All Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/62 (37.1%)		13/33 (39.4%)		9/33 (27.3%)		45/128 (35.2%)
Blood and lymphatic system disorders
Anaemia	2/62 (3.2%)		0/33 (0%)		0/33 (0%)		2/128 (1.6%)
Aplasia pure red cell	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Febrile neutropenia	4/62 (6.5%)		2/33 (6.1%)		0/33 (0%)		6/128 (4.7%)
Leukopenia	0/62 (0%)		1/33 (3%)		2/33 (6.1%)		3/128 (2.3%)
Neutropenia	1/62 (1.6%)		4/33 (12.1%)		0/33 (0%)		5/128 (3.9%)
Pancytopenia	3/62 (4.8%)		0/33 (0%)		0/33 (0%)		3/128 (2.3%)
Thrombocytopenia	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Cardiac disorders
Atrial fibrillation	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Gastrointestinal disorders
Abdominal pain upper	0/62 (0%)		1/33 (3%)		0/33 (0%)		1/128 (0.8%)
Diarrhoea	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
General disorders
Disease progression	0/62 (0%)		0/33 (0%)		1/33 (3%)		1/128 (0.8%)
Pelvic mass	0/62 (0%)		1/33 (3%)		0/33 (0%)		1/128 (0.8%)
Pyrexia	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Soft tissue inflammation	0/62 (0%)		1/33 (3%)		0/33 (0%)		1/128 (0.8%)
Hepatobiliary disorders
Cholecystitis acute	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Infections and infestations
Appendiceal abscess	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Bacterial sepsis	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Cytomegalovirus infection	2/62 (3.2%)		0/33 (0%)		0/33 (0%)		2/128 (1.6%)
Herpes zoster	2/62 (3.2%)		0/33 (0%)		1/33 (3%)		3/128 (2.3%)
Oral fungal infection	0/62 (0%)		1/33 (3%)		0/33 (0%)		1/128 (0.8%)
Pneumonia	1/62 (1.6%)		1/33 (3%)		2/33 (6.1%)		4/128 (3.1%)
Injury, poisoning and procedural complications
Overdose	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Metabolism and nutrition disorders
Abnormal loss of weight	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Musculoskeletal and connective tissue disorders
Groin abscess	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Myositis	0/62 (0%)		1/33 (3%)		0/33 (0%)		1/128 (0.8%)
Sympathetic posterior cervical syndrome	0/62 (0%)		1/33 (3%)		0/33 (0%)		1/128 (0.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute leukaemia	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Breast cancer recurrent	0/62 (0%)		0/33 (0%)		1/33 (3%)		1/128 (0.8%)
Lip neoplasm malignant stage unspecified	0/62 (0%)		1/33 (3%)		0/33 (0%)		1/128 (0.8%)
Meningioma	0/62 (0%)		1/33 (3%)		0/33 (0%)		1/128 (0.8%)
Richter's syndrome	1/62 (1.6%)		0/33 (0%)		1/33 (3%)		2/128 (1.6%)
Squamous cell carcinoma of skin	0/62 (0%)		0/33 (0%)		1/33 (3%)		1/128 (0.8%)
Uterine cancer	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Nervous system disorders
Haemorrhage intracranial	0/62 (0%)		0/33 (0%)		1/33 (3%)		1/128 (0.8%)
Loss of consciousness	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Renal and urinary disorders
Renal failure	0/62 (0%)		0/33 (0%)		1/33 (3%)		1/128 (0.8%)
Reproductive system and breast disorders
Endometrial hyperplasia	0/62 (0%)		1/33 (3%)		0/33 (0%)		1/128 (0.8%)
Uterine polyp	0/62 (0%)		1/33 (3%)		0/33 (0%)		1/128 (0.8%)
Respiratory, thoracic and mediastinal disorders
Bronchitis	1/62 (1.6%)		0/33 (0%)		1/33 (3%)		2/128 (1.6%)
Pulmonary embolism	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Skin and subcutaneous tissue disorders
Acne varioliformis	0/62 (0%)		0/33 (0%)		1/33 (3%)		1/128 (0.8%)
Cellulitis	1/62 (1.6%)		0/33 (0%)		0/33 (0%)		1/128 (0.8%)
Skin ulcer	0/62 (0%)		1/33 (3%)		0/33 (0%)		1/128 (0.8%)
Toxic epidermal necrolysis	0/62 (0%)		0/33 (0%)		1/33 (3%)		1/128 (0.8%)
Surgical and medical procedures
Heart valve operation	0/62 (0%)		0/33 (0%)		1/33 (3%)		1/128 (0.8%)
Other (Not Including Serious) Adverse Events
	Induction (Excluding Maintenance/ Observation)		Maintenance Arm: Rituximab		Observation Arm: No Intervention		All Participants
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	58/62 (93.5%)		31/33 (93.9%)		32/33 (97%)		121/128 (94.5%)
Blood and lymphatic system disorders
Anaemia	11/62 (17.7%)		1/33 (3%)		3/33 (9.1%)		15/128 (11.7%)
Leukopenia	1/62 (1.6%)		6/33 (18.2%)		6/33 (18.2%)		13/128 (10.2%)
Lymphopenia	0/62 (0%)		3/33 (9.1%)		5/33 (15.2%)		8/128 (6.3%)
Neutropenia	47/62 (75.8%)		26/33 (78.8%)		20/33 (60.6%)		93/128 (72.7%)
Thrombocytopenia	18/62 (29%)		5/33 (15.2%)		5/33 (15.2%)		28/128 (21.9%)
Cardiac disorders
Cardiomegaly	0/62 (0%)		2/33 (6.1%)		0/33 (0%)		2/128 (1.6%)
Endocrine disorders
Goitre	0/62 (0%)		1/33 (3%)		2/33 (6.1%)		3/128 (2.3%)
Gastrointestinal disorders
Abdominal pain	2/62 (3.2%)		0/33 (0%)		2/33 (6.1%)		4/128 (3.1%)
Abdominal pain upper	0/62 (0%)		1/33 (3%)		2/33 (6.1%)		3/128 (2.3%)
Diarrhoea	6/62 (9.7%)		7/33 (21.2%)		3/33 (9.1%)		16/128 (12.5%)
Nausea	7/62 (11.3%)		12/33 (36.4%)		4/33 (12.1%)		23/128 (18%)
Vomiting	4/62 (6.5%)		0/33 (0%)		1/33 (3%)		5/128 (3.9%)
General disorders
Asthenia	3/62 (4.8%)		2/33 (6.1%)		2/33 (6.1%)		7/128 (5.5%)
Chills	8/62 (12.9%)		3/33 (9.1%)		3/33 (9.1%)		14/128 (10.9%)
Influenza like illness	0/62 (0%)		0/33 (0%)		2/33 (6.1%)		2/128 (1.6%)
Pyrexia	11/62 (17.7%)		5/33 (15.2%)		3/33 (9.1%)		19/128 (14.8%)
Hepatobiliary disorders
Hepatomegaly	0/62 (0%)		0/33 (0%)		3/33 (9.1%)		3/128 (2.3%)
Hepatic steatosis	0/62 (0%)		2/33 (6.1%)		2/33 (6.1%)		4/128 (3.1%)
Infections and infestations
Chronic sinusitis	0/62 (0%)		2/33 (6.1%)		0/33 (0%)		2/128 (1.6%)
Oral herpes	2/62 (3.2%)		1/33 (3%)		2/33 (6.1%)		5/128 (3.9%)
Respiratory tract infection	1/62 (1.6%)		2/33 (6.1%)		2/33 (6.1%)		5/128 (3.9%)
Upper respiratory tract infection	4/62 (6.5%)		3/33 (9.1%)		6/33 (18.2%)		13/128 (10.2%)
Urinary tract infection	0/62 (0%)		3/33 (9.1%)		1/33 (3%)		4/128 (3.1%)
Investigations
Blood lactate dehydrogenase increased	1/62 (1.6%)		0/33 (0%)		2/33 (6.1%)		3/128 (2.3%)
Hepatic enzyme increased	0/62 (0%)		2/33 (6.1%)		2/33 (6.1%)		4/128 (3.1%)
Metabolism and nutrition disorders
Diabetes mellitus	0/62 (0%)		2/33 (6.1%)		0/33 (0%)		2/128 (1.6%)
Hyperuricaemia	5/62 (8.1%)		4/33 (12.1%)		2/33 (6.1%)		11/128 (8.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/62 (0%)		2/33 (6.1%)		0/33 (0%)		2/128 (1.6%)
Back pain	0/62 (0%)		2/33 (6.1%)		2/33 (6.1%)		4/128 (3.1%)
Osteoarthritis	0/62 (0%)		2/33 (6.1%)		0/33 (0%)		2/128 (1.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Haemangioma of liver	0/62 (0%)		2/33 (6.1%)		1/33 (3%)		3/128 (2.3%)
Metastasis	0/62 (0%)		3/33 (9.1%)		3/33 (9.1%)		6/128 (4.7%)
Nervous system disorders
Headache	2/62 (3.2%)		2/33 (6.1%)		2/33 (6.1%)		6/128 (4.7%)
Sciatica	1/62 (1.6%)		2/33 (6.1%)		1/33 (3%)		4/128 (3.1%)
Renal and urinary disorders
Nephroptosis	0/62 (0%)		0/33 (0%)		3/33 (9.1%)		3/128 (2.3%)
Renal cyst	0/62 (0%)		2/33 (6.1%)		5/33 (15.2%)		7/128 (5.5%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	0/62 (0%)		2/33 (6.1%)		0/33 (0%)		2/128 (1.6%)
Respiratory, thoracic and mediastinal disorders
Bronchitis	2/62 (3.2%)		3/33 (9.1%)		1/33 (3%)		6/128 (4.7%)
Cough	2/62 (3.2%)		4/33 (12.1%)		0/33 (0%)		6/128 (4.7%)
Emphysema	0/62 (0%)		3/33 (9.1%)		4/33 (12.1%)		7/128 (5.5%)
Oropharyngeal pain	1/62 (1.6%)		2/33 (6.1%)		1/33 (3%)		4/128 (3.1%)
Pulmonary fibrosis	0/62 (0%)		6/33 (18.2%)		2/33 (6.1%)		8/128 (6.3%)
Skin and subcutaneous tissue disorders
Pruritus	0/62 (0%)		3/33 (9.1%)		1/33 (3%)		4/128 (3.1%)
Rash	1/62 (1.6%)		2/33 (6.1%)		1/33 (3%)		4/128 (3.1%)
Rash pruritic	4/62 (6.5%)		1/33 (3%)		1/33 (3%)		6/128 (4.7%)
Vascular disorders
Aortic arteriosclerosis	0/62 (0%)		1/33 (3%)		2/33 (6.1%)		3/128 (2.3%)
Hypertension	2/62 (3.2%)		4/33 (12.1%)		3/33 (9.1%)		9/128 (7%)
Hypotension	3/62 (4.8%)		0/33 (0%)		2/33 (6.1%)		5/128 (3.9%)

Limitations/Caveats

In 2011 the recruitment was stopped due to low enrollment rate, and in 2015 the trial was prematurely discontinued.

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.