A Study to Assess the Efficacy of Rituximab (MabThera) in First Line Treatment of Chronic Lymphocytic Leukemia (CLL)

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00545714
• Collaborator: (none)
• Enrollment: 86
• Locations: 33
• Arm: 1
• Actual Duration (Months): 101.9
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This single arm study will assess the efficacy and safety of rituximab in combination with fludarabine and cyclophosphamide, followed by rituximab maintenance therapy, as first line treatment of participants with CLL.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Lymphocytic, Chronic, B-Cell	Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Rituximab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 86 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Multicentre, Non-Randomised, Open-Label Phase II Study to Evaluate the Efficacy and Safety of Induction Treatment With Rituximab, Fludarabine, Cyclophosphamide, Followed by Rituximab Maintenance Therapy (R-Fc-Rm) in the First Line Treatment of Chronic Lymphocytic Leukaemia
• Actual Study Start Date: Nov 21, 2007
• Actual Primary Completion Date: May 20, 2016
• Actual Study Completion Date: May 20, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Rituximab + Fludarabine + Cyclophosphamide Participants will receive 6 cycles (cycle length = 28 days) of treatment with rituximab (375 milligrams per square meter [mg/m^2] as intravenous [IV] infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6); fludarabine (25 mg/m^2 on Days 1-3) and cyclophosphamide (250 mg/m^2 on Days 1-3). Participants with a partial or complete response and appropriate neutrophil conditions will receive maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6.

Drug: Cyclophosphamide; Cyclophosphamide 250 mg/m^2 as IV infusion will be administered on Days 1-3 of first six 28-day cycles.; Drug: Fludarabine; Fludarabine 25 mg/m^2 as IV infusion will be administered on Days 1-3 of first six 28-day cycles.; Drug: Rituximab; Rituximab 375 mg/m^2 as IV infusion will be administered on Day 0 of Cycle 1; 500 mg/m^2 as IV infusion will be administered on Day 1 of Cycle 2-6; and 375 mg/m^2 as IV infusion every 2 months from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6.; Other Names: MabThera, Rituxan

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With CR Achieved After the Rituximab, Fludarabine, and Cyclophosphamide Regimen [Month 9]

   CR was defined as no adenopathies (ADPs) and visceromegalies (VSMs) in physical examination (PE); no general symptoms (Sx); lymphocytes (Lymph) in peripheral blood less than (<) 4000 per cubic millimeter (mm^3); normalization of peripheral blood parameters: neutrophils (Neut) greater than (>) 1500/mm^3, platelets (Plt) >100,000/mm^3, hemoglobin (Hb) >11 grams per deciliter (g/dL) without transfusion; normocellular bone marrow (BM) with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules.

Secondary Outcome Measures

1. Percentage of Participants With Clinical Response of CR or PR as Assessed by Multiparameter Flow Cytometry [Post-Induction Phase (IP): at 6 months; during Maintenance Phase (MP): at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up (FU): at Follow-Up Months 6, 12, 18, 24, 30, 36]

   CR was defined as no ADPs and VSMs in PE; no general Sx; Lymph in peripheral blood <4000/mm^3; normalization of peripheral blood parameters: Neut >1500/mm^3, Plt >100,000/mm^3, Hb >11 g/dL without transfusion; normocellular BM with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules. PR was defined as decrease >50% in Lymph in peripheral blood; reduction in ADPs >50% in total sum of up to 6 ADPs or in the baseline ADP of largest diameter (LD), no new ADP or enlargement of a prior ADP; >50% decrease in VSM; Neut >1500/mm^3 or >50% increase from Baseline; Plt >100,000/mm^3 or >50% increase from Baseline; Hb >11.0 g/dL or >50% increase from Baseline value without transfusion. Participants who met all CR criteria but had persistent anemia or thrombocytopenia were considered as PR.

2. Percentage of Participants With Clinical Response of CR or PR Among Participants With Negative Minimal Residual Disease (MRD) as Assessed by Multiparameter Flow Cytometry [Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 36]

   CR: no ADPs and VSMs in PE; no general Sx; Lymph in peripheral blood <4000/mm^3; normalization of peripheral blood parameters: Neut >1500/mm^3, Plt >100,000/mm^3, Hb >11 g/dL without transfusion; normocellular BM with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules. PR: decrease >50% in Lymph in peripheral blood; reduction in ADPs >50% in total sum of up to 6 ADPs or in the baseline ADP of largest diameter (LD), no new ADP or enlargement of a prior ADP; >50% decrease in VSM; Neut >1500/mm^3 or >50% increase from Baseline; Plt >100,000/mm^3 or >50% increase from Baseline; Hb >11.0 g/dL or >50% increase from Baseline value without transfusion. Participants who met all CR criteria but had persistent anemia or thrombocytopenia were considered as PR. Negative MRD: Lymph <0.01% of all white blood cells (WBCs) in blood or BM after two consecutive measurements. Analysis performed only in blood during the Maintenance Phase and Follow-Up.

3. Percentage of Participants With CR With Incomplete Bone Marrow Recovery (CRi) [Baseline up to progressive disease (PD) or death due to any cause, whichever occurred first (up to 92 months)]

   Participants with CRi were those who met all CR criteria (including BM examinations) but had persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to chronic lymphocytic leukemia (CLL) but related to drug toxicity. CR: no ADPs and VSMs in PE; no general Sx; Lymph in peripheral blood <4000/mm^3; normalization of peripheral blood parameters: Neut >1500/mm^3, Plt >100,000/mm^3, Hb >11 g/dL without transfusion; normocellular BM with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules.

4. Percentage of Participants Who Died [Baseline up to death due to any cause (up to 92 months)]

5. Overall Survival (OS) [Baseline up to death due to any cause (up to 92 months)]

   OS was defined as time from treatment start to death of the participant. For all other participants, the last follow-up available was taken as the last control. If the participant had not completed the study, the date of the last visit available was considered. OS was estimated using Kaplan-Meier (KM) methodology.

6. Percentage of Participants With PD or Death [Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months)]

   PD was defined as new ADPs (1.5 centimeters [cm]), hepato-/splenomegaly (HSM), Richter syndrome (RS), or other infiltrated organs; greater than or equal to (>/=) 50% increase in size of Baseline prior ADPs or HSM in participants with PR; Lymph increase >/=50% in peripheral blood with B Lymph >/=5000/mm^3; cytopenia attributable to CLL. Progression of any cytopenia (not related to autoimmune cytopenia) reported as a 2-g/dL decrease in basal Hb, Hb <10 g/dL, >/=50% decrease in basal Plt count, or count <100,000/mm^3 at >/=3 months post-treatment was defined as PD if BM biopsy confirmed infiltration of clonal CLL cells.

7. Progression-Free Survival (PFS) [Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months)]

   PFS was defined as time from start of study treatment to PD or death, whichever occurred first. For other participants, last follow-up available was taken as last control. If participant did not complete study, date of last visit available was considered. PFS was estimated using KM methodology. PD was defined as new ADPs (1.5 cm), HSM, RS, or other infiltrated organs; >/=50% increase in size of Baseline prior ADPs or HSM in participants with PR; Lymph increase >/=50% in peripheral blood with B Lymph >/=5000/mm^3; cytopenia attributable to CLL. Progression of any cytopenia (not related to autoimmune cytopenia) reported as a 2-g/dL decrease in basal Hb, Hb <10 g/dL, >/=50% decrease in basal Plt count, or count <100,000/mm^3 at >/=3 months post-treatment was defined as PD if BM biopsy confirmed infiltration of clonal CLL cells.

8. Treatment-Free Survival (TFS) [Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months)]

   TFS was defined time from start of study treatment until participant received new chemotherapy/immunotherapy because of PD and to reduce the disease with palliative or curative intent. PD was defined as new ADPs (1.5 cm), HSM, RS, or other infiltrated organs; >/=50% increase in size of Baseline prior ADPs or HSM in participants with PR; Lymph increase >/=50% in peripheral blood with B Lymph >/=5000/mm^3; cytopenia attributable to CLL. Progression of any cytopenia (not related to autoimmune cytopenia) reported as a 2-g/dL decrease in basal Hb, Hb <10 g/dL, >/=50% decrease in basal Plt count, or count <100,000/mm^3 at >/=3 months post-treatment was defined as PD if BM biopsy confirmed infiltration of clonal CLL cells.

9. Duration of Response (DOR) [From first CR or PR up to detectable MRD or disease occurrence/PD, whichever occurred first (up to 92 months)]

   DOR: time from CR/PR to MRD/PD. PD: new ADP (1.5 cm), HSM, RS, other infiltrated organs or >/=50% increase size in those with PR; blood Lymph increase >/=50% with B Lymph >/=5000/mm^3; cytopenia due to CLL. Progression of (nonautoimmune) cytopenia: 2-g/dL decrease basal Hb, Hb <10 g/dL, >/=50% decrease basal Plt or <100,000/mm^3 at >/=3 months post-treatment was PD if clonal CLL cell infiltration on BM biopsy. CR: no ADP/VSM in PE; no general Sx; blood Lymph <4000/mm^3; Neut >1500/mm^3; Plt >100,000/mm^3; Hb >11 g/dL (no transfusion); normocellular BM with <30% Lymph; BM aspirate/biopsy with no lymphoid nodule infiltration. PR: >50% decrease blood Lymph; >50% decrease in total sum up to 6 ADPs or baseline ADP of LD, no new/enlargement of prior ADP; >50% decrease VSM; Neut >1500/mm^3 or >50% increase; Plt >100,000/mm^3 or >50% increase; Hb >11.0 g/dL or >50% increase (no transfusion). All CR criteria but persistent anemia or thrombocytopenia was PR. MRD: Lymph >0.01% of blood/BM WBCs.

10. Percentage of Participants With Cluster of Differentiation (CD) 38 Cells >/=30% in Peripheral Blood [Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 30, 36]

    Percentages of participants with CD38 expression by >/=30% of CLL cells during the Induction Phase, Maintenance Phase, and Follow-Up were reported.

11. Percentage of Participants With Genetic Abnormalities [Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months)]

    Percentages of participants with genetic abnormalities (deletion 6q, deletion 11q22-q23, deletion p53, trisomy 12, and deletion 13q14) in the course of the disease during the Induction Phase and Maintenance Phase were reported.

12. Percentage of Participants With Positive and Negative Zeta-Chain-Associated Protein Kinase 70 (ZAP-70) Expression [Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 30, 36]

    Percentages of participants with positive and negative ZAP-70 expression during the Induction Phase, Maintenance Phase, and Follow-Up were reported. Positive ZAP-70 was defined as ZAP-70 expression by >/=20% of CLL cells. Negative ZAP-70 was defined as ZAP-70 expression by <20% of CLL cells.

13. Percentage of Participants With Immunoglobulin Heavy Locus (IgH) Rearrangement [Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 30, 36]

    Percentages of participants with IgH rearrangement during the Induction Phase, Maintenance Phase, and Follow-Up were reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• CLL according to World Health Organization diagnostic criteria

• Active disease

• No previous treatment

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

Exclusion Criteria:

• Transformation to aggressive B-cell malignancy (prolymphocytic leukemia, large-cell lymphoma, Hodgkin's lymphoma)

• Other malignancies except for localized skin cancer

• Continuous systemic corticosteroid treatment

• Known infection with hepatitis B or C

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital De Txagorritxu; Servicio de Hematologia	Vitoria	Alava	Spain	01009
2	Hospital Universitario Puerta del Mar; Servicio de Hematologia	Cádiz	Cadiz	Spain	11009
3	Hospital de Jerez de la Frontera; Servicio de Hematologia	Jerez de La Frontera	Cadiz	Spain	11407
4	Hospital Universitario Marques de Valdecilla; Servicio de Hematologia	Santander	Cantabria	Spain	39008
5	Complejo Hospitalario Universitario A Coruña (CHUAC); Servicio de Hematologia	La Coruna	LA Coruña	Spain	15006
6	Fundacion Hospital de Alcorcon; Servicio de Hematologia	Alcorcon	Madrid	Spain	28922
7	Hosital Universitario de Mostoles;Servicio de Hematologia	Mostoles	Madrid	Spain	28935
8	Hospital Francesc de Borja; Servicio de Hematologia	Gandia	Valencia	Spain	46702
9	Hospital de Sagunto; Servicio de Hematologia	Sagunto	Valencia	Spain	46520
10	Hospital de Basurto; Servicio de Hematologia	Bilbao	Vizcaya	Spain	48013
11	Hospital Universitario Infanta Cristina; Servicio de Hematologia	Badajoz		Spain	06080
12	Hospital Duran i Reynals; Servicio de Hematologia	Barcelona		Spain	08907
13	Hospital San Pedro De Alcantara; Servicio de Hematologia	Caceres		Spain	10003
14	Hospital General de Castellon; Servicio de Hematologia	Castellon		Spain	12004
15	Hospital Universitario Virgen de las Nieves; Servicio de Hematologia	Granada		Spain	18014
16	Hospital General Universitario Gregorio Marañon; Servicio de Hematología	Madrid		Spain	28007
17	Hospital Ramon y Cajal; Servicio de Hematologia	Madrid		Spain	28034
18	Hospital Universitario Clínico San Carlos; Servicio de Hematología	Madrid		Spain	28040
19	Hospital Univ. 12 de Octubre; Servicio de Hematologia	Madrid		Spain	28041
20	Hospital Universitario la Paz; Servicio de Hematologia	Madrid		Spain	28046
21	HOSPITAL DE MADRID NORTE SANCHINARRO- CENTRO INTEGRAL ONCOLOGICO CLARA CAMPAL; Servicio Hematologia	Madrid		Spain	28050
22	Hospital Universitario Puerta de Hierro; Servicio de Hematologia	Madrid		Spain	28222
23	Hospital Universitario Principe de Asturias; Servicio de Hematología	Madrid		Spain	28805
24	Hospital Universitario de Getafe; Servico de Hematologia	Madrid		Spain	28905
25	Hospital Clinico Universitario Virgen de la Victoria; Servicio de Hematologia	Malaga		Spain	29010
26	Hospital General Universitario J.M Morales Meseguer; Servicio de Hematología	Murcia		Spain	30008
27	Hospital Clinico Universitario de Salamanca;Servicio de Hematologia	Salamanca		Spain	37007
28	Hospital General Universitario de Valencia; Servicio de Hematologia	Valencia		Spain	46014
29	Hospital Arnau de Vilanova (Valencia) Servicio de Hematologia	Valencia		Spain	46015
30	Hospital Universitario Dr. Peset; Servicio de Hematologia	Valencia		Spain	46017
31	Hospital Universitario la Fe; Servicio de Hematologia	Valencia		Spain	46026
32	Hospital Clinico Universitario Lozano Blesa; Servicio de Hematologia	Zaragoza		Spain	50009
33	Hospital Universitario Miguel Servet; Servicio Hematologia	Zaragoza		Spain	50009

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: NCT00545714
• Other Study ID Numbers: ML21135; 2007-002733-36
• First Posted: Oct 17, 2007
• Last Update Posted: Jan 16, 2019
• Last Verified: Jul 1, 2018

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

Study Results

Participant Flow

Pre-assignment Detail	A total of 86 participants were enrolled in 29 centers in Spain in this two-phase study (Induction Phase and Maintenance Phase).

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) as intravenous (IV) infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a partial response (PR) or complete response (CR) and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Period Title: Induction Phase (6 Months)
STARTED	86
Safety Population	86
Intent-to-Treat (ITT) Population	84
COMPLETED	74
NOT COMPLETED	12
Period Title: Induction Phase (6 Months)
STARTED	74
COMPLETED	42
NOT COMPLETED	32

Baseline Characteristics

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Overall Participants	84
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	57.92 (7.87)
Sex: Female, Male (Count of Participants)
Female	27 32.1%
Male	57 67.9%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With CR Achieved After the Rituximab, Fludarabine, and Cyclophosphamide Regimen
Description	CR was defined as no adenopathies (ADPs) and visceromegalies (VSMs) in physical examination (PE); no general symptoms (Sx); lymphocytes (Lymph) in peripheral blood less than (<) 4000 per cubic millimeter (mm^3); normalization of peripheral blood parameters: neutrophils (Neut) greater than (>) 1500/mm^3, platelets (Plt) >100,000/mm^3, hemoglobin (Hb) >11 grams per deciliter (g/dL) without transfusion; normocellular bone marrow (BM) with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules.
Time Frame	Month 9

Outcome Measure Data

Analysis Population Description

ITT Population included all participants who received at least one dose of study drug and met inclusion/exclusion criteria.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	84
Number (95% Confidence Interval) [Percentage of Participants]	95.2 113.3%

2. Secondary Outcome

Title	Percentage of Participants With Clinical Response of CR or PR as Assessed by Multiparameter Flow Cytometry
Description	CR was defined as no ADPs and VSMs in PE; no general Sx; Lymph in peripheral blood <4000/mm^3; normalization of peripheral blood parameters: Neut >1500/mm^3, Plt >100,000/mm^3, Hb >11 g/dL without transfusion; normocellular BM with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules. PR was defined as decrease >50% in Lymph in peripheral blood; reduction in ADPs >50% in total sum of up to 6 ADPs or in the baseline ADP of largest diameter (LD), no new ADP or enlargement of a prior ADP; >50% decrease in VSM; Neut >1500/mm^3 or >50% increase from Baseline; Plt >100,000/mm^3 or >50% increase from Baseline; Hb >11.0 g/dL or >50% increase from Baseline value without transfusion. Participants who met all CR criteria but had persistent anemia or thrombocytopenia were considered as PR.
Time Frame	Post-Induction Phase (IP): at 6 months; during Maintenance Phase (MP): at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up (FU): at Follow-Up Months 6, 12, 18, 24, 30, 36

Outcome Measure Data

Analysis Population Description

ITT Population. Here, 'Number Analyzed' signifies participants who were evaluable for indicated category.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	84
Post-IP: CR	75.0 89.3%
Post-IP: PR	13.1 15.6%
MP (9 Cycles): CR	89.4 106.4%
MP (9 Cycles): PR	6.4 7.6%
MP (12 Cycles): CR	87.9 104.6%
MP (12 Cycles): PR	6.1 7.3%
MP (15 Cycles): CR	90.9 108.2%
MP (15 Cycles): PR	4.5 5.4%
MP (18 Cycles): CR	88.1 104.9%
MP (18 Cycles): PR	8.5 10.1%
6 Months FU: CR	83.3 99.2%
6 Months FU: PR	0.0 0%
12 Months FU: CR	94.4 112.4%
12 Months FU: PR	0.0 0%
18 Months FU: CR	100.0 119%
18 Months FU: PR	0.0 0%
24 Months FU: CR	93.1 110.8%
24 Months FU: PR	0.0 0%
30 Months FU: CR	100.0 119%
30 Months FU: PR	0.0 0%
36 Months FU: CR	100.0 119%
36 Months FU: PR	0.0 0%

3. Secondary Outcome

Title	Percentage of Participants With Clinical Response of CR or PR Among Participants With Negative Minimal Residual Disease (MRD) as Assessed by Multiparameter Flow Cytometry
Description	CR: no ADPs and VSMs in PE; no general Sx; Lymph in peripheral blood <4000/mm^3; normalization of peripheral blood parameters: Neut >1500/mm^3, Plt >100,000/mm^3, Hb >11 g/dL without transfusion; normocellular BM with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules. PR: decrease >50% in Lymph in peripheral blood; reduction in ADPs >50% in total sum of up to 6 ADPs or in the baseline ADP of largest diameter (LD), no new ADP or enlargement of a prior ADP; >50% decrease in VSM; Neut >1500/mm^3 or >50% increase from Baseline; Plt >100,000/mm^3 or >50% increase from Baseline; Hb >11.0 g/dL or >50% increase from Baseline value without transfusion. Participants who met all CR criteria but had persistent anemia or thrombocytopenia were considered as PR. Negative MRD: Lymph <0.01% of all white blood cells (WBCs) in blood or BM after two consecutive measurements. Analysis performed only in blood during the Maintenance Phase and Follow-Up.
Time Frame	Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 36

Outcome Measure Data

Analysis Population Description

ITT Population. Only those with negative MRD were included in the analysis. Here, 'Number Analyzed' signifies participants who were evaluable for indicated category.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	60
Post-IP: Blood MRD Negative	100.0 119%
Post-IP: BM MRD Negative	100.0 119%
MP (9 Cycles): Blood MRD Negative	100.0 119%
MP (12 Cycles): Blood MRD Negative	100.0 119%
MP (15 Cycles): Blood MRD Negative	100.0 119%
MP (18 Cycles): Blood MRD Negative	100.0 119%
6 Months FU: Blood MRD Negative	100.0 119%
12 Months FU: Blood MRD Negative	100.0 119%
18 Months FU: Blood MRD Negative	100.0 119%
24 Months FU: Blood MRD Negative	100.0 119%
36 Months FU: Blood MRD Negative	100.0 119%

4. Secondary Outcome

Title	Percentage of Participants With CR With Incomplete Bone Marrow Recovery (CRi)
Description	Participants with CRi were those who met all CR criteria (including BM examinations) but had persistent anemia, thrombocytopenia, or neutropenia apparently unrelated to chronic lymphocytic leukemia (CLL) but related to drug toxicity. CR: no ADPs and VSMs in PE; no general Sx; Lymph in peripheral blood <4000/mm^3; normalization of peripheral blood parameters: Neut >1500/mm^3, Plt >100,000/mm^3, Hb >11 g/dL without transfusion; normocellular BM with <30% Lymph; BM aspirate/biopsy with no evidence of infiltration of lymphoid nodules.
Time Frame	Baseline up to progressive disease (PD) or death due to any cause, whichever occurred first (up to 92 months)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	84
Number [Percentage of Participants]	7.1 8.5%

5. Secondary Outcome

Title	Percentage of Participants Who Died
Time Frame	Baseline up to death due to any cause (up to 92 months)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	86
Number [Percentage of Participants]	23.2 27.6%

6. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as time from treatment start to death of the participant. For all other participants, the last follow-up available was taken as the last control. If the participant had not completed the study, the date of the last visit available was considered. OS was estimated using Kaplan-Meier (KM) methodology.
Time Frame	Baseline up to death due to any cause (up to 92 months)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	84
Median (95% Confidence Interval) [Years]	7.51

7. Secondary Outcome

Title	Percentage of Participants With PD or Death
Description	PD was defined as new ADPs (1.5 centimeters [cm]), hepato-/splenomegaly (HSM), Richter syndrome (RS), or other infiltrated organs; greater than or equal to (>/=) 50% increase in size of Baseline prior ADPs or HSM in participants with PR; Lymph increase >/=50% in peripheral blood with B Lymph >/=5000/mm^3; cytopenia attributable to CLL. Progression of any cytopenia (not related to autoimmune cytopenia) reported as a 2-g/dL decrease in basal Hb, Hb <10 g/dL, >/=50% decrease in basal Plt count, or count <100,000/mm^3 at >/=3 months post-treatment was defined as PD if BM biopsy confirmed infiltration of clonal CLL cells.
Time Frame	Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	84
Number [Percentage of Participants]	39.29 46.8%

8. Secondary Outcome

Title	Progression-Free Survival (PFS)
Description	PFS was defined as time from start of study treatment to PD or death, whichever occurred first. For other participants, last follow-up available was taken as last control. If participant did not complete study, date of last visit available was considered. PFS was estimated using KM methodology. PD was defined as new ADPs (1.5 cm), HSM, RS, or other infiltrated organs; >/=50% increase in size of Baseline prior ADPs or HSM in participants with PR; Lymph increase >/=50% in peripheral blood with B Lymph >/=5000/mm^3; cytopenia attributable to CLL. Progression of any cytopenia (not related to autoimmune cytopenia) reported as a 2-g/dL decrease in basal Hb, Hb <10 g/dL, >/=50% decrease in basal Plt count, or count <100,000/mm^3 at >/=3 months post-treatment was defined as PD if BM biopsy confirmed infiltration of clonal CLL cells.
Time Frame	Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	84
Median (95% Confidence Interval) [Years]	6.96

9. Secondary Outcome

Title	Treatment-Free Survival (TFS)
Description	TFS was defined time from start of study treatment until participant received new chemotherapy/immunotherapy because of PD and to reduce the disease with palliative or curative intent. PD was defined as new ADPs (1.5 cm), HSM, RS, or other infiltrated organs; >/=50% increase in size of Baseline prior ADPs or HSM in participants with PR; Lymph increase >/=50% in peripheral blood with B Lymph >/=5000/mm^3; cytopenia attributable to CLL. Progression of any cytopenia (not related to autoimmune cytopenia) reported as a 2-g/dL decrease in basal Hb, Hb <10 g/dL, >/=50% decrease in basal Plt count, or count <100,000/mm^3 at >/=3 months post-treatment was defined as PD if BM biopsy confirmed infiltration of clonal CLL cells.
Time Frame	Baseline up to PD or death due to any cause, whichever occurred first (up to 92 months)

Outcome Measure Data

Analysis Population Description

ITT Population. Only those who received new chemotherapy/immunotherapy, as per definitions for TFS, were included in the analysis.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	27
Median (95% Confidence Interval) [Years]	4.13

10. Secondary Outcome

Title	Duration of Response (DOR)
Description	DOR: time from CR/PR to MRD/PD. PD: new ADP (1.5 cm), HSM, RS, other infiltrated organs or >/=50% increase size in those with PR; blood Lymph increase >/=50% with B Lymph >/=5000/mm^3; cytopenia due to CLL. Progression of (nonautoimmune) cytopenia: 2-g/dL decrease basal Hb, Hb <10 g/dL, >/=50% decrease basal Plt or <100,000/mm^3 at >/=3 months post-treatment was PD if clonal CLL cell infiltration on BM biopsy. CR: no ADP/VSM in PE; no general Sx; blood Lymph <4000/mm^3; Neut >1500/mm^3; Plt >100,000/mm^3; Hb >11 g/dL (no transfusion); normocellular BM with <30% Lymph; BM aspirate/biopsy with no lymphoid nodule infiltration. PR: >50% decrease blood Lymph; >50% decrease in total sum up to 6 ADPs or baseline ADP of LD, no new/enlargement of prior ADP; >50% decrease VSM; Neut >1500/mm^3 or >50% increase; Plt >100,000/mm^3 or >50% increase; Hb >11.0 g/dL or >50% increase (no transfusion). All CR criteria but persistent anemia or thrombocytopenia was PR. MRD: Lymph >0.01% of blood/BM WBCs.
Time Frame	From first CR or PR up to detectable MRD or disease occurrence/PD, whichever occurred first (up to 92 months)

Outcome Measure Data

Analysis Population Description

ITT Population. Only those participants who achieved a clinical response of CR or PR were evaluable for this measure.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	80
Median (95% Confidence Interval) [Years]	NA

11. Secondary Outcome

Title	Percentage of Participants With Cluster of Differentiation (CD) 38 Cells >/=30% in Peripheral Blood
Description	Percentages of participants with CD38 expression by >/=30% of CLL cells during the Induction Phase, Maintenance Phase, and Follow-Up were reported.
Time Frame	Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 30, 36

Outcome Measure Data

Analysis Population Description

ITT Population. Here, 'Number Analyzed' signifies participants who were evaluable for indicated category.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	84
Post-IP	47.6 56.7%
MP (9 Cycles)	44.4 52.9%
MP (12 Cycles)	45.5 54.2%
MP (15 Cycles)	47.6 56.7%
MP (18 Cycles)	47.4 56.4%
6 Months FU	66.7 79.4%
12 Months FU	45.7 54.4%
18 Months FU	100.0 119%
24 Months FU	41.4 49.3%
30 Months FU	50.0 59.5%
36 Months FU	35.5 42.3%

12. Secondary Outcome

Title	Percentage of Participants With Genetic Abnormalities
Description	Percentages of participants with genetic abnormalities (deletion 6q, deletion 11q22-q23, deletion p53, trisomy 12, and deletion 13q14) in the course of the disease during the Induction Phase and Maintenance Phase were reported.
Time Frame	Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months)

Outcome Measure Data

Analysis Population Description

ITT Population. Here, 'Number Analyzed' signifies participants who were evaluable for indicated category. Designation of 'MP (xC)' refers to number of cycles in Maintenance Phase.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	84
Post-IP: Deletion 6q	3.6 4.3%
Post-IP: Deletion 11q22-q23	26.2 31.2%
Post-IP: Deletion p53	4.8 5.7%
Post-IP: Trisomy 12	15.5 18.5%
Post-IP: Deletion 13q14	50.0 59.5%
MP (9C): Deletion 6q	4.3 5.1%
MP (9C): Deletion 11q22-q23	25.5 30.4%
MP (9C): Deletion p53	0.0 0%
MP (9C): Trisomy 12	17.0 20.2%
MP (9C): Deletion 13q14	55.3 65.8%
MP (12C): Deletion 6q	3.0 3.6%
MP (12C): Deletion 11q22-q23	21.2 25.2%
MP (12C): Deletion p53	0.0 0%
MP (12C): Trisomy 12 (n= 33)	21.2 25.2%
MP (12C): Deletion 13q14	51.5 61.3%
MP (15C): Deletion 6q	4.5 5.4%
MP (15C): Deletion 11q22-q23	31.8 37.9%
MP (15C): Deletion p53	0.0 0%
MP (15C): Trisomy 12	18.2 21.7%
MP (15C): Deletion 13q14	59.1 70.4%
MP (18C): Deletion 6q	3.4 4%
MP (18C): Deletion 11q22-q23	23.7 28.2%
MP (18C): Deletion p53	0.0 0%
MP (18C): Trisomy 12	18.6 22.1%
MP (18C): Deletion 13q14	49.2 58.6%

13. Secondary Outcome

Title	Percentage of Participants With Positive and Negative Zeta-Chain-Associated Protein Kinase 70 (ZAP-70) Expression
Description	Percentages of participants with positive and negative ZAP-70 expression during the Induction Phase, Maintenance Phase, and Follow-Up were reported. Positive ZAP-70 was defined as ZAP-70 expression by >/=20% of CLL cells. Negative ZAP-70 was defined as ZAP-70 expression by <20% of CLL cells.
Time Frame	Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 30, 36

Outcome Measure Data

Analysis Population Description

ITT Population. Here, 'Number Analyzed' signifies participants who were evaluable for indicated category.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	84
Post-IP: Positive	57.3 68.2%
Post-IP: Negative	42.7 50.8%
MP (9 Cycles): Positive	57.5 68.5%
MP (9 Cycles): Negative	42.5 50.6%
MP (12 Cycles): Positive	62.1 73.9%
MP (12 Cycles): Negative	37.9 45.1%
MP (15 Cycles): Positive	57.1 68%
MP (15 Cycles): Negative	42.9 51.1%
MP (18 Cycles): Positive	54.9 65.4%
MP (18 Cycles): Negative	45.1 53.7%
6 Months FU: Positive	63.6 75.7%
6 Months FU: Negative	36.4 43.3%
12 Months FU: Positive	60.0 71.4%
12 Months FU: Negative	40.0 47.6%
18 Months FU: Positive	100.0 119%
18 Months FU: Negative	0.0 0%
24 Months FU: Positive	59.3 70.6%
24 Months FU: Negative	40.7 48.5%
30 Months FU: Positive	100.0 119%
30 Months FU: Negative	0.0 0%
36 Months FU: Positive	57.1 68%
36 Months FU: Negative	42.9 51.1%

14. Secondary Outcome

Title	Percentage of Participants With Immunoglobulin Heavy Locus (IgH) Rearrangement
Description	Percentages of participants with IgH rearrangement during the Induction Phase, Maintenance Phase, and Follow-Up were reported.
Time Frame	Post-Induction Phase: at 6 months; during Maintenance Phase: at Cycles 9, 12, 15, 18 (cycle length = 2 months); during Follow-Up: at Follow-Up Months 6, 12, 18, 24, 30, 36

Outcome Measure Data

Analysis Population Description

ITT Population. Here, 'Number Analyzed' signifies participants who were evaluable for indicated category.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
Measure Participants	84
Post-IP	36.2 43.1%
MP (9 Cycles)	37.1 44.2%
MP (12 Cycles)	20.0 23.8%
MP (15 Cycles)	29.4 35%
MP (18 Cycles)	33.3 39.6%
6 Months FU	100.0 119%
12 Months FU	37.9 45.1%
18 Months FU	50.0 59.5%
24 Months FU	33.3 39.6%
30 Months FU	0.0 0%
36 Months FU	45.8 54.5%

Adverse Events

Time Frame	Baseline through end of Follow-Up (up to 92 months)
Adverse Event Reporting Description	Safety Population included all participants who received at least one dose of study drug.
Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 mg/m^2 as IV infusion on Day 0 of Cycle 1 and 500 mg/m^2 as IV infusion on Day 1 of Cycles 2-6 (cycle length = 28 days); fludarabine 25 mg/m^2 on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 on Days 1-3 of each cycle during the Induction Phase. Participants with a PR or CR and appropriate neutrophil conditions received maintenance treatment with rituximab (375 mg/m^2 as IV infusion every 2 months) from 3 months after Day 1 Cycle 6 up to a total of 18 doses or up to 3 years after Cycle 6 of Induction Phase.
All Cause Mortality
	Rituximab + Fludarabine + Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Rituximab + Fludarabine + Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	35/86 (40.7%)
Blood and lymphatic system disorders
Anaemia	1/86 (1.2%)
Febrile neutropenia	8/86 (9.3%)
Neutropenia	1/86 (1.2%)
Cardiac disorders
Myocardial infarction	1/86 (1.2%)
Gastrointestinal disorders
Crohn's disease	1/86 (1.2%)
Diarrhoea	1/86 (1.2%)
Malabsorption	1/86 (1.2%)
Pancreatitis	1/86 (1.2%)
Vomiting	1/86 (1.2%)
General disorders
Chest pain	1/86 (1.2%)
General physical health deterioration	1/86 (1.2%)
Pyrexia	6/86 (7%)
Hepatobiliary disorders
Cholelithiasis	1/86 (1.2%)
Hepatic mass	1/86 (1.2%)
Immune system disorders
Cytokine release syndrome	1/86 (1.2%)
Infections and infestations
Gastroenteritis	1/86 (1.2%)
Influenza	2/86 (2.3%)
Meningitis	1/86 (1.2%)
Pharyngitis	1/86 (1.2%)
Pneumonia	7/86 (8.1%)
Respiratory tract infection	2/86 (2.3%)
Sinusitis	1/86 (1.2%)
Viral myocarditis	1/86 (1.2%)
Injury, poisoning and procedural complications
Jaw fracture	1/86 (1.2%)
Metabolism and nutrition disorders
Hypercalcaemia	1/86 (1.2%)
Tumour lysis syndrome	1/86 (1.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acoustic neuroma	1/86 (1.2%)
Basal cell carcinoma	1/86 (1.2%)
Bladder neoplasm	1/86 (1.2%)
Nervous system disorders
Cerebral haemorrhage	1/86 (1.2%)
Syncope	1/86 (1.2%)
Renal and urinary disorders
Renal failure	1/86 (1.2%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/86 (1.2%)
Pulmonary sarcoidosis	1/86 (1.2%)
Surgical and medical procedures
Vertebroplasty	1/86 (1.2%)
Vascular disorders
Capillary leak syndrome	1/86 (1.2%)
Other (Not Including Serious) Adverse Events
	Rituximab + Fludarabine + Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	82/86 (95.3%)
Blood and lymphatic system disorders
Leukopenia	15/86 (17.4%)
Lymphopenia	24/86 (27.9%)
Neutropenia	52/86 (60.5%)
Thrombocytopenia	18/86 (20.9%)
Gastrointestinal disorders
Constipation	6/86 (7%)
Diarrhoea	16/86 (18.6%)
Nausea	26/86 (30.2%)
Vomiting	15/86 (17.4%)
General disorders
Asthenia	14/86 (16.3%)
Chills	6/86 (7%)
Pyrexia	31/86 (36%)
Infections and infestations
Nasopharyngitis	27/86 (31.4%)
Pneumonia	7/86 (8.1%)
Respiratory tract infection	14/86 (16.3%)
Upper respiratory tract infection	7/86 (8.1%)
Urinary tract infection	8/86 (9.3%)
Musculoskeletal and connective tissue disorders
Back pain	5/86 (5.8%)
Respiratory, thoracic and mediastinal disorders
Cough	7/86 (8.1%)
Skin and subcutaneous tissue disorders
Rash	5/86 (5.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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