FCR Versus FC Alone in the Treatment of Chronic Lymphocytic Leukemia (CLL) in Relapsed Patients

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00090051
• Collaborator: Biogen (Industry), Genentech, Inc. (Industry)
• Enrollment: 552
• Locations: 106
• Arms: 2
• Actual Duration (Months): 106
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to provide treatment for patients who have chronic lymphocytic leukemia (CLL), and to compare the use of rituximab added to fludarabine+cyclophosphamide (FC) with FC alone, to determine if rituximab lengthens the time a patient remains free of leukemia symptoms.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 552 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label, Multicenter, Randomized, Comparative, Phase III Study to Evaluate the Efficacy and Safety of FCR vs. FC Alone in Previously Treated Patients With CD20 Positive B-cell CLL
• Actual Study Start Date: Jul 31, 2003
• Actual Primary Completion Date: Jul 23, 2008
• Actual Study Completion Date: May 31, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Fludarabine+Cyclophosphamide (FC)	Drug: Fludarabine Phosphate; Intravenous repeating dose; Drug: Cyclophosphamide; Intravenous repeating dose
Experimental: Fludarabine+Cyclophosphamide+Rituximab (FCR)	Drug: Rituximab; Intravenous repeating dose; Drug: Fludarabine Phosphate; Intravenous repeating dose; Drug: Cyclophosphamide; Intravenous repeating dose

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) as Assessed by the Independent Review Committee (IRC) [Mean observation time at time of analysis was approximately 26 months]

   Progression-free survival as assessed by the IRC was defined as the time between randomization and the date of first documented disease progression, relapse after response, or death from any cause, whichever came first. Patients without a PFS event were censored at their last tumor assessment date.

2. Number of Participants With Progression-free Survival (PFS) Events Assessed by the Independent Review Committee (IRC) [Mean observation time at time of analysis was approximately 26 months]

   Progression-free survival as assessed by the IRC was defined as the time between randomization and the date of first documented disease progression, relapse after response, or death from any cause (PFS events), whichever came first. Patients without a PFS event were censored at their last tumor assessment date.

3. Final Analysis: Time to Progression-Free Survival Event [Median observation time was approximately 5 years]

   Time to progression-free survival (PFS) event was defined as the time between randomization and the date of first documented PFS event: disease progression, relapse or death by any cause, whichever came first.

Secondary Outcome Measures

1. Overall Survival (OS) [Mean observation time at time of analysis was approximately 26 months]

   Overall survival was determined from the date of randomization to the date of death irrespective of cause. Patients who had not died at the time of the final analysis (clinical data cut-off) were censored at the date of the last contact.

2. Number of Participants With Overall Survival (OS) Events [Mean observation time at time of analysis was approximately 26 months]

   Overall survival was determined from the date of randomization to the date of death (OS event) irrespective of cause. Patients who had not died at the time of the final analysis (clinical data cut-off) were censored at the date of the last contact.

3. Event-free Survival (EFS) [Mean observation time at time of analysis was approximately 26 months]

   Event free survival was measured from the day of randomization to the date of first documented PD, relapse after response, start of a new treatment or death from any cause. Patients without an EFS event were censored at their last tumor assessment date.

4. Number of Participants With Event-free Survival (EFS) Events [Mean observation time at time of analysis was approximately 26 months]

   Event free survival was measured from the day of randomization to the date of first documented Progressive Disease (PD), relapse after response, start of a new treatment or death from any cause (EFS events). Patients without an EFS event were censored at their last tumor assessment date.

5. Disease-free Survival (DFS) [Mean observation time at time of analysis was approximately 26 months]

   Disease free survival was defined for all patients with a best overall response (BOR) of Complete Response (CR) and measured the time from first documented CR in a sequence of consecutive CRs until documented disease progression, relapse or death from any cause. Patients without a DFS event at the time of the analysis (clinical data cut-off) were censored at their last tumor assessment date.

6. Number of Participants With Disease-free Survival (DFS) Events [Mean observation time at time of analysis was approximately 26 months]

   Disease free survival was defined for all patients with a best overall response (BOR) of Complete Response (CR) and measured the time from first documented CR in a sequence of consecutive CRs until documented disease progression, relapse or death from any cause (DFS events). Patients without a DFS event at the time of the analysis (clinical data cut-off) were censored at their last tumor assessment date.

7. Final Analysis: Time to Overall Survival Event [Median observation time was approximately 5 years]

   Overall survival (OS) was determined from the date of randomization to the date of death (OS event) irrespective of cause.

8. Final Analysis: Time to Event-Free Survival Event [Median observation time was approximately 5 years]

   Event free survival (EFS) was defined as the time from the day of randomization to the date of first EFS event: documented disease progression, relapse after response, start of a new treatment or death from any cause.

9. Final Analysis: Percentage of Participants With Complete Response [Median observation time was approximately 5 years]

   Complete response was defined as the disappearance of all signs of cancer in response to treatment.

10. Final Analysis: Time to Disease-Free Survival Event [Median observation time was approximately 5 years]

    Time to disease-free survival (DFS) event was defined as the time from first documented response until the first documented DFS event: disease progression, relapse or death from any cause.

11. Final Analysis: Duration of Response [Median observation time was approximately 5 years]

    Duration of response was defined as the time between the date of the earliest qualifying response and the date of disease progression or death due to any cause.

12. Final Analysis: Time to New Chronic Lymphocytic Leukemia (CLL) Treatment [Median observation time was approximately 5 years]

    Time to new CCL treatment was defined as the time from randomization to the first day of new treatment for CCL or death.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Age ≥18 years

• Established diagnosis of B-cell CLL by NCI Working Group criteria

• ≤1 previous line of chemotherapy

• Expected survival >6 months

• Acceptable hematologic status, liver function, renal function, and pulmonary function

• Negative serum pregnancy test for both pre-menopausal women and for women who are < 2 years after the onset of menopause

• Written informed consent

Exclusion Criteria:

• Prior treatment with interferon, rituximab or other monoclonal antibody

• Prior allogeneic bone marrow transplant (BMT) or autologous BMT or peripheral stem cell transplant (PBSCT) or patients who are considered to be candidates for allogeneic or autologous BMT or PSCT as assessed by their treating physician

• Fertile men or women of childbearing potential not using adequate contraception

• Severe Grade 3 or 4 non-hematological toxicity or prolonged (> 2 weeks) Grade 3 or 4 cytopenia on prior fludarabine or nucleoside analogue regimen

• History of fludarabine-induced or clinically significant autoimmune cytopenia

• History of other malignancies within 2 years prior to study entry, except for adequately 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.

• Medical conditions requiring long term use (> 1 month) of systemic corticosteroids

• Active bacterial, viral, or fungal infection requiring systemic therapy

• Severe cardiac disease

• Seizure disorders requiring anticonvulsant therapy

• Severe chronic obstructive pulmonary disease with hypoxemia

• Uncontrolled diabetes mellitus or hypertension

• Transformation to aggressive B-cell malignancy.

• Known infection with HIV, HCV, or hepatitis B

• Treatment with any other investigational agent, or participation in another clinical trial within 30 days prior to entering this study

• Known hypersensitivity or anaphylactic reactions to murine antibodies or proteins

• Any co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Uab Comprehensive Cancer Center	Birmingham	Alabama	United States	35294-3300
2	Pacific Coast Hematology/Oncology Medical Group	Fountain Valley	California	United States	92708
3	California Cancer Center Woodward Park; Community Medical Centers	Fresno	California	United States	93720
4	Rush-Presbyterian St. Luke'S Medical Center	Chicago	Illinois	United States	60612
5	Duke University Medical Center	Durham	North Carolina	United States	27710
6	Milton S. Hershey Medical Center; Penn State Cancer Inst.	Hershey	Pennsylvania	United States	17033
7	Concord Repatriation General Hospital; Haematology	Sydney	New South Wales	Australia	2139
8	Mater Hospital; Division of Cancer Services	Brisbane	Queensland	Australia	4101
9	Frankston Hospital; Oncology/Haematology	Frankston	Victoria	Australia	3199
10	Peter Maccallum Cancer Institute; Medical Oncology	Melbourne	Victoria	Australia	3000
11	ZNA Stuivenberg	Antwerpen		Belgium	2060
12	Institut Jules Bordet	Bruxelles		Belgium	1000
13	UZ Leuven Gasthuisberg	Leuven		Belgium	3000
14	Uni of Alberta Hospital	Edmonton	Alberta	Canada	T6G 2R7
15	BCCA-Vancouver Cancer Centre	Vancouver	British Columbia	Canada	V5Z 4E6
16	Health Science Centre	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
17	QEII HSC; Oncology	Halifax	Nova Scotia	Canada	B3H 2Y9
18	Hamilton Health Sciences - Juravinski Cancer Centre; Hematology	Hamilton	Ontario	Canada	L8V 5C2
19	The Ottawa Regional Hospital - General Campus; Division of Hematology, Box 704	Ottawa	Ontario	Canada	K1H 1C4
20	Sunnybrook Odette Cancer Centre	Toronto	Ontario	Canada	M4N 3M5
21	University Health Network; Princess Margaret Hospital; Medical Oncology Dept	Toronto	Ontario	Canada	M5G 2M9
22	Mcgill University - Royal Victoria Hospital; Oncology	Montreal	Quebec	Canada	H3A 1A1
23	Righospitalet, Hæmatologisk Klinik	København Ø		Denmark	2100
24	Aarhus Universitetshospital, Hæmatologisk Afdeling R	Århus		Denmark	8000
25	Hopital Avicenne; Hematologie Biologique	Bobigny		France	93009
26	Hopital Clemenceau; Hematologie Clinique	Caen		France	14033
27	Chu Estaing; Hematologie Clinique Adultes	Clermont Ferrand		France	63003
28	Hopital Henri Mondor; Hematologie Clinique	Creteil		France	94010
29	Clinique Victor Hugo; Chimiotherapie	Le Mans		France	72015
30	Hopital Claude Huriez; Hematologie	Lille		France	59037
31	Hopital Edouard Herriot; Bat.E-Hematologie	Lyon		France	69003
32	Centre Leon Berard; Departement Oncologie Medicale	Lyon		France	69373
33	Institut J Paolii Calmettes; Onco Hematologie 1	Marseille		France	13273
34	Hôpital Lapeyronie; Hématologie Oncologie Médicale	Montpellier		France	34295
35	Hopital Hotel Dieu Et Hme;Hopital De Jour	Nantes		France	44093
36	Hotel Dieu; Hematologie- Oncologie	Paris		France	75181
37	Inserm Cic 9504	Paris		France	75475
38	Hopital Pitie Salpetriere; Hematologie Clinique	Paris		France	75651
39	Ch Lyon Sud; Hemato Secteur Jules Courmont	Pierre Benite		France	69495
40	Chu La Miletrie; Hdj Cons Hemato Cancerologie	Poitiers		France	86021
41	Centre Henri Becquerel; Hematologie	Rouen		France	76038
42	Hopital Bretonneau; Clinique D'Oncologie & de Radiotherapie	Tours		France	37044
43	Hopitaux De Brabois; Hematologie Medecine Interne	Vandoeuvre Les Nancy		France	54511
44	Szent Laszlo Hospital; Hematology Dept	Budapest		Hungary	1097
45	National Institute of Oncology, A Dept of Internal Medicine	Budapest		Hungary	1122
46	Országos Gyógyintézeti Központ; Haematologiai Osztaly	Budapest		Hungary	1135
47	Uni of Debrecen; 2Nd Clinic of Internal Medicine	Debrecen		Hungary	4004
48	University of Debrecen Medical and Health Science Center, Institute of Internal Medicine, Hematology	Debrecen		Hungary	4032
49	Uni of Pecs; Dept of Internal Medicine	Pecs		Hungary	7624
50	University of Szeged, II Dept of Internal Medicine	Szeged		Hungary	6720
51	A.O. Universitaria Federico II Di Napoli; Oncologia Ed Endocrinologia Clinica	Napoli	Campania	Italy	80131
52	A.O. Universitaria Policlinico S.Orsola-Malpighi Di Bologna	Bologna	Emilia-Romagna	Italy	40138
53	Ospedale S. Eugenio; Divisione Di Ematologia	Roma	Lazio	Italy	00144
54	Az. Osp. S. Camillo Forlanini; Uo Ematologia E Trapianti Di Midollo Osseo	Roma	Lazio	Italy	00152
55	Universita' Degli Studi La Sapienza-Ist.Di Ematologia;Dip. Biotecnologie Cel CELLULARI ED EMATOLOGIA	Roma	Lazio	Italy	00161
56	Asst Grande Ospedale Metropolitano Niguarda; Dipartimento Di Ematologia Ed Oncologia	Milano	Lombardia	Italy	20162
57	Irccs Policlinico San Matteo; Divisione Di Ematologia	Pavia	Lombardia	Italy	27100
58	Uni Degli Studi Di Bari, Policlinico; Cattedra Di Ematologia,Dipart. Di Medicina Interna E Publica	Bari	Puglia	Italy	70124
59	IRCCS Ospedale Casa Sollievo Della Sofferenza; Ematologia E Trapianto Di Midollo Osseo	San Giovanni Rotondo	Puglia	Italy	71013
60	Ospedale Di Vicenza; Nefrologia, Ematologia	Vicenza	Veneto	Italy	36100
61	Meander Mc, Locatie Lichtenberg; Dept of Lung Diseases	Amersfoort		Netherlands	3818 ES
62	Academisch Medisch Centrum Universiteit Amsterdam	Amsterdam		Netherlands	1105 AZ
63	Leyenburg Ziekenhuis; Haematology	Den Haag		Netherlands	2545 CG
64	Erasmus Mc - Daniel Den Hoed Kliniek; Medical Oncology	Rotterdam		Netherlands	3075 EA
65	Auckland city hospital; Auckland Regional Cancer Centre and Blood Service	Auckland		New Zealand	1023
66	Christchurch Hospital; Canterbury Health Laboratories	Christchurch		New Zealand
67	Wellington Hospital; Regional Oncology Unit	Wellington		New Zealand	6002
68	Haukeland Universitetshospital; Medicine Dept	Bergen		Norway	5021
69	Rikshospitalet Uni Hospital	Oslo		Norway	0027
70	Medical University School; Dept. of Haematology	Lodz		Poland	93-510
71	Katedra i Klinika Hematoonkologii i Transplantacji Szpiku; Uniwersytetu Medycznego w Lublinie	Lublin		Poland	20-081
72	Akademii Medycznej W; Klinika Hematologii	Poznan		Poland	02-097
73	Klin. Chorob Wewnetrznych I Hemat. Z Osrodkiem Transplant. Szpiku	Warszawa		Poland	00-909
74	Instytut Hematologii I Transfuzjologii; Klinika Chorob Wewnetrznych I Hematologii	Warszawa		Poland	00-957
75	Samodzielny Publiczny Centralny Szpital Kliniczny; Haematology Dept.	Warszawa		Poland	02-097
76	Fundeni Clinical Inst. ; Hematology Dept	Bucharest		Romania	022328
77	Spitalul Clinic Coltea; Clinica de Hematologie	Bucuresti		Romania	030171
78	Spitalul Clinic Judetean de Urgenta Targu-Mures; compartiment Hematologie	Targu-mures		Romania	540136
79	Spitalul Clinic municipal de Urgenta Timisoara; Clinica de Hematologie	Timisoara		Romania	300079
80	N.N.Blokhin Russian Cancer Research Center; Dept. of Chemotherapy & Hemoblastosis	Moscow		Russian Federation	115478
81	Haematology Research Center; Haematology	Moscow		Russian Federation	125167
82	City Clinical Botkin's Hospital; City Hematological Center	Moscow		Russian Federation	125284
83	Medical Radiological Research Centre Rams; Dept. of Radiotherapy & Chemotherapy of Hemoblastosis	Obninsk		Russian Federation	249036
84	Regional Clinical Hospital N.A. Kalinin; Hematology Dept	Samara		Russian Federation	443095
85	Research Inst. Hematology /Blood Transfusion ; Hemablastosis, Supression Hemopoesis & B M Transplant	St Petersburg		Russian Federation	193024
86	Regional Clinical Hospital; Hematology Dept. #2 For B M Transplantation & High Dose Chemo.	St Petersburg		Russian Federation	194291
87	Pavlov State Medical Uni ; Bone Marrow Transplantation Clinic	St Petersburg		Russian Federation	197022
88	S.-Peterburg Pavlov State Medical University ; Haematology	St Petersburg		Russian Federation	197022
89	State Medical Inst. Municipal Hospital #31; Oncology & Hematology Dept. With the Usechemo. in Adult	St Petersburg		Russian Federation	197110
90	Hospital Universitario de la Princesa; Servicio de Hematologia	Madrid		Spain	28006
91	Hospital Univ. 12 de Octubre; Servicio de Hematologia	Madrid		Spain	28041
92	Hospital Clinico Universitario de Salamanca;Servicio de Hematologia	Salamanca		Spain	37007
93	Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia	Valencia		Spain	46010
94	Hospital Universitario Miguel Servet; Servicio Hematologia	Zaragoza		Spain	50009
95	Karolinska Inst. , Huddinge Uni Hospital; Depart. of Hematology	Huddinge		Sweden	14186
96	Universitetssjukhuset i Linköping, Hematologkliniken	Linkoeping		Sweden	581 85
97	Royal Bournemouth General Hospital; Haematology	Bournemouth		United Kingdom	BH7 7DW
98	Addenbrookes Hospital; Haematology	Cambridge		United Kingdom	CB2 0QQ
99	Stobhill Hospital; Dept of Haematology	Glasgow		United Kingdom	G83 8NG
100	Leeds General Infirmary; Medicine	Leeds		United Kingdom	LS1 3EX
101	Leicester Royal Infirmary; Dept of Haematology	Leicester		United Kingdom	LE1 5WW
102	Royal Liverpool Uni Hospital; Haematology	Liverpool		United Kingdom	L7 8XP
103	St. Bartholomew'S Hospital; Dept of Medical Oncology	London		United Kingdom	EC1A 7BE
104	King'S College Hospital; Haematology	London		United Kingdom	SE5 9RS
105	Royal Marsden Hospital; Academic Dept of Haematology	Sutton		United Kingdom	SW3 6JJ
106	Pinderfields General Hospital; Dept of Haematology	Wakefield		United Kingdom	WF1 4DG

Sponsors and Collaborators

• Hoffmann-La Roche
• Biogen
• Genentech, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00090051
• Other Study ID Numbers: 102-14; BO17072
• First Posted: Aug 25, 2004
• Last Update Posted: Aug 1, 2017
• Last Verified: Jul 1, 2017

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

Study Results

Participant Flow

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Period Title: Overall Study
STARTED	276	276
Safety Population; Received Study Drug	272	274
COMPLETED	167	181
NOT COMPLETED	109	95

Baseline Characteristics

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)	Total
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.	Total of all reporting groups
Overall Participants	276	276	552
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	61.3 (9.11)	62.1 (9.17)	61.7 (9.14)
Sex: Female, Male (Count of Participants)
Female	95 34.4%	89 32.2%	184 33.3%
Male	181 65.6%	187 67.8%	368 66.7%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) as Assessed by the Independent Review Committee (IRC)
Description	Progression-free survival as assessed by the IRC was defined as the time between randomization and the date of first documented disease progression, relapse after response, or death from any cause, whichever came first. Patients without a PFS event were censored at their last tumor assessment date.
Time Frame	Mean observation time at time of analysis was approximately 26 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	276	276
Median (95% Confidence Interval) [Days]	660	813

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fludarabine+Cyclophosphamide (FC), Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Comments	The null hypothesis was that there was no difference between the 2 treatment groups. The alternative hypothesis was that progression-free survival was longer in the fludarabine+cyclophosphamide+rituximab (FCR) group.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0218
	Comments
	Method	Log Rank
	Comments	non-stratified
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.60 to 0.96
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was estimated using Cox regression. The hazard ratio is relative to the fludarabine+cyclophosphamide(FC) group.

2. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival was determined from the date of randomization to the date of death irrespective of cause. Patients who had not died at the time of the final analysis (clinical data cut-off) were censored at the date of the last contact.
Time Frame	Mean observation time at time of analysis was approximately 26 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	276	276
Median (95% Confidence Interval) [Days]	1580	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fludarabine+Cyclophosphamide (FC), Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2874
	Comments
	Method	Log Rank
	Comments	non-stratified

3. Secondary Outcome

Title	Number of Participants With Overall Survival (OS) Events
Description	Overall survival was determined from the date of randomization to the date of death (OS event) irrespective of cause. Patients who had not died at the time of the final analysis (clinical data cut-off) were censored at the date of the last contact.
Time Frame	Mean observation time at time of analysis was approximately 26 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	276	276
Patients with event	68 24.6%	62 22.5%
Patients without events	208 75.4%	214 77.5%

4. Secondary Outcome

Title	Event-free Survival (EFS)
Description	Event free survival was measured from the day of randomization to the date of first documented PD, relapse after response, start of a new treatment or death from any cause. Patients without an EFS event were censored at their last tumor assessment date.
Time Frame	Mean observation time at time of analysis was approximately 26 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	276	276
Median (95% Confidence Interval) [Days]	586	874

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fludarabine+Cyclophosphamide (FC), Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Log Rank
	Comments	non-stratified

5. Secondary Outcome

Title	Number of Participants With Event-free Survival (EFS) Events
Description	Event free survival was measured from the day of randomization to the date of first documented Progressive Disease (PD), relapse after response, start of a new treatment or death from any cause (EFS events). Patients without an EFS event were censored at their last tumor assessment date.
Time Frame	Mean observation time at time of analysis was approximately 26 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	276	276
Patients with event	162 58.7%	134 48.6%
Patients without events	114 41.3%	142 51.4%

6. Primary Outcome

Title	Number of Participants With Progression-free Survival (PFS) Events Assessed by the Independent Review Committee (IRC)
Description	Progression-free survival as assessed by the IRC was defined as the time between randomization and the date of first documented disease progression, relapse after response, or death from any cause (PFS events), whichever came first. Patients without a PFS event were censored at their last tumor assessment date.
Time Frame	Mean observation time at time of analysis was approximately 26 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	276	276
Patients with event	148 53.6%	137 49.6%
Patients without events	128 46.4%	139 50.4%

7. Secondary Outcome

Title	Disease-free Survival (DFS)
Description	Disease free survival was defined for all patients with a best overall response (BOR) of Complete Response (CR) and measured the time from first documented CR in a sequence of consecutive CRs until documented disease progression, relapse or death from any cause. Patients without a DFS event at the time of the analysis (clinical data cut-off) were censored at their last tumor assessment date.
Time Frame	Mean observation time at time of analysis was approximately 26 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population for patients with a Best Overall Response of Complete Response.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	36	67
Median (95% Confidence Interval) [Days]	1285	1204

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fludarabine+Cyclophosphamide (FC), Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8842
	Comments
	Method	Log Rank
	Comments	non-stratified

8. Secondary Outcome

Title	Number of Participants With Disease-free Survival (DFS) Events
Description	Disease free survival was defined for all patients with a best overall response (BOR) of Complete Response (CR) and measured the time from first documented CR in a sequence of consecutive CRs until documented disease progression, relapse or death from any cause (DFS events). Patients without a DFS event at the time of the analysis (clinical data cut-off) were censored at their last tumor assessment date.
Time Frame	Mean observation time at time of analysis was approximately 26 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population with a Best Overall Response of Complete Response.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	36	67
Patients with event	10 3.6%	19 6.9%
Patients without event	26 9.4%	48 17.4%

9. Primary Outcome

Title	Final Analysis: Time to Progression-Free Survival Event
Description	Time to progression-free survival (PFS) event was defined as the time between randomization and the date of first documented PFS event: disease progression, relapse or death by any cause, whichever came first.
Time Frame	Median observation time was approximately 5 years

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-treat population, all randomized participants, who experienced a PFS event. Participants who did not have a PFS event at the time of the final analysis were censored at the date of the last contact.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	217	205
Median (95% Confidence Interval) [Days]	683.0	969.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fludarabine+Cyclophosphamide (FC), Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; 0.54 to 0.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Final Analysis: Time to Overall Survival Event
Description	Overall survival (OS) was determined from the date of randomization to the date of death (OS event) irrespective of cause.
Time Frame	Median observation time was approximately 5 years

Outcome Measure Data

Analysis Population Description

The analysis included only those participants from the Intent-to-treat population,all randomized participants, who died. Participants who had not died at the time of the final analysis were censored at the date of the last contact.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	138	144
Median (95% Confidence Interval) [Days]	2056.0	2167.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fludarabine+Cyclophosphamide (FC), Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5976
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.74 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Final Analysis: Time to Event-Free Survival Event
Description	Event free survival (EFS) was defined as the time from the day of randomization to the date of first EFS event: documented disease progression, relapse after response, start of a new treatment or death from any cause.
Time Frame	Median observation time was approximately 5 years

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-treat population, all randomized participants, who had an EFS event. Participants who did not have an ESF event at the time of the final analysis were censored at the date of the last contact.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	218	207
Median (95% Confidence Interval) [Days]	630.0	932.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fludarabine+Cyclophosphamide (FC), Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.54 to 0.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Final Analysis: Percentage of Participants With Complete Response
Description	Complete response was defined as the disappearance of all signs of cancer in response to treatment.
Time Frame	Median observation time was approximately 5 years

Outcome Measure Data

Analysis Population Description

Intent-to-treat population included all randomized participants.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	276	276
Number [Percentage of participants]	13.4 4.9%	25.0 9.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fludarabine+Cyclophosphamide (FC), Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.15
	Confidence Interval	(2-Sided) 95%; 1.39 to 3.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Final Analysis: Time to Disease-Free Survival Event
Description	Time to disease-free survival (DFS) event was defined as the time from first documented response until the first documented DFS event: disease progression, relapse or death from any cause.
Time Frame	Median observation time was approximately 5 years

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-treat population, all randomized participants, with complete response. .

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	37	69
Median (95% Confidence Interval) [Days]	1285.0	1803.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fludarabine+Cyclophosphamide (FC), Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3085
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.46 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Final Analysis: Duration of Response
Description	Duration of response was defined as the time between the date of the earliest qualifying response and the date of disease progression or death due to any cause.
Time Frame	Median observation time was approximately 5 years

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-treat population, all randomized participants, with complete or partial response.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	160	194
Median (95% Confidence Interval) [Days]	869.0	1333.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fludarabine+Cyclophosphamide (FC), Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.51 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Final Analysis: Time to New Chronic Lymphocytic Leukemia (CLL) Treatment
Description	Time to new CCL treatment was defined as the time from randomization to the first day of new treatment for CCL or death.
Time Frame	Median observation time was approximately 5 years

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-treat population,all randomized participants, who started a new treatment for CLL or died.

Arm/Group Title	Fludarabine+Cyclophosphamide (FC)	Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
Measure Participants	186	173
Median (95% Confidence Interval) [Days]	1085.0	1625.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fludarabine+Cyclophosphamide (FC), Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.55 to 0.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse Events were collected from study start to 28 days after treatment completion (Median observation time= 26 months). Serious Adverse Events were collected 1 year after treatment completion (Median observation time= 37 months).
Adverse Event Reporting Description	The safety analysis population included all patients who received at least one dose of trial treatment and had at least one safety follow-up, whether withdrawn prematurely or not. 272 patients received FC only and 274 patients received FCR.
Arm/Group Title	Fludarabine+Cyclophosphamide (FC)		Fludarabine+Cyclophosphamide+Rituximab (FCR)
Arm/Group Description	Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.		Rituximab and FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: rituximab 375 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 2, 3, 4; cyclophosphamide 250 mg/m² IV on Days 2, 3, 4. Cycles 2-6: rituximab 500 mg/m² IV on Day 1; fludarabine 25 mg/m² IV on Days 1, 2, 3; cyclophosphamide 250 mg/m² IV on Days 1, 2, 3.
All Cause Mortality
	Fludarabine+Cyclophosphamide (FC)		Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Fludarabine+Cyclophosphamide (FC)		Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	132/272 (48.5%)		138/274 (50.4%)
Blood and lymphatic system disorders
Agranulocytosis	0/272 (0%)		1/274 (0.4%)
Anaemia	11/272 (4%)		3/274 (1.1%)
Anaemia Haemolytic Autoimmune	5/272 (1.8%)		2/274 (0.7%)
Aplasia Pure Red Cell	1/272 (0.4%)		2/274 (0.7%)
Autoimmune Thrombocytopenia	0/272 (0%)		1/274 (0.4%)
Bicytopenia	2/272 (0.7%)		0/274 (0%)
Bone Marrow Failure	1/272 (0.4%)		1/274 (0.4%)
Evans Syndrome	1/272 (0.4%)		0/274 (0%)
Febrile Bone Marrow Aplasia	2/272 (0.7%)		3/274 (1.1%)
Febrile Neutropenia	21/272 (7.7%)		29/274 (10.6%)
Granulocytopenia	0/272 (0%)		2/274 (0.7%)
Haematotoxicity	1/272 (0.4%)		0/274 (0%)
Haemolysis	0/272 (0%)		1/274 (0.4%)
Haemolytic Anaemia	3/272 (1.1%)		2/274 (0.7%)
Leukopenia	1/272 (0.4%)		3/274 (1.1%)
Neutropenia	7/272 (2.6%)		8/274 (2.9%)
Pancytopenia	5/272 (1.8%)		5/274 (1.8%)
Thrombocytopenia	4/272 (1.5%)		2/274 (0.7%)
Cardiac disorders
Acute Coronary Syndrome	0/272 (0%)		1/274 (0.4%)
Angina Pectoris	0/272 (0%)		1/274 (0.4%)
Angina Unstable	0/272 (0%)		1/274 (0.4%)
Arrhythmia	0/272 (0%)		1/274 (0.4%)
Atrial Fibrillation	1/272 (0.4%)		0/274 (0%)
Atrial Flutter	1/272 (0.4%)		0/274 (0%)
Cardiac Arrest	2/272 (0.7%)		1/274 (0.4%)
Cardiopulmonary Failure	0/272 (0%)		1/274 (0.4%)
Coronary Artery Insufficiency	1/272 (0.4%)		0/274 (0%)
Myocardial Infarction	2/272 (0.7%)		2/274 (0.7%)
Supraventricular Tachyarrhythmia	1/272 (0.4%)		0/274 (0%)
Tachycardia	0/272 (0%)		1/274 (0.4%)
Ventricular Arrhythmia	1/272 (0.4%)		0/274 (0%)
Endocrine disorders
Hypothyroidism	1/272 (0.4%)		0/274 (0%)
Gastrointestinal disorders
Abdominal Distension	1/272 (0.4%)		0/274 (0%)
Abdominal Pain	1/272 (0.4%)		1/274 (0.4%)
Colitis Ulcerative	1/272 (0.4%)		0/274 (0%)
Diarrhoea	1/272 (0.4%)		2/274 (0.7%)
Gastric Polyps	1/272 (0.4%)		0/274 (0%)
Gastritis	1/272 (0.4%)		0/274 (0%)
Gastrointestinal Disorder	1/272 (0.4%)		0/274 (0%)
Gastrointestinal Haemorrhage	1/272 (0.4%)		0/274 (0%)
Gingival Bleeding	1/272 (0.4%)		0/274 (0%)
Haemorrhoids	0/272 (0%)		1/274 (0.4%)
Mesenteric Artery Embolism	1/272 (0.4%)		0/274 (0%)
Pancreatitis	1/272 (0.4%)		0/274 (0%)
Stomatitis	0/272 (0%)		1/274 (0.4%)
Vomiting	3/272 (1.1%)		1/274 (0.4%)
General disorders
Chills	1/272 (0.4%)		1/274 (0.4%)
General Physical Health Deterioration	0/272 (0%)		1/274 (0.4%)
Malaise	1/272 (0.4%)		0/274 (0%)
Multi-Organ Failure	1/272 (0.4%)		1/274 (0.4%)
Performance Status Decreased	0/272 (0%)		1/274 (0.4%)
Pyrexia	9/272 (3.3%)		14/274 (5.1%)
Hepatobiliary disorders
Cholecystitis	1/272 (0.4%)		0/274 (0%)
Cholecystitis Acute	1/272 (0.4%)		0/274 (0%)
Hepatitis	0/272 (0%)		1/274 (0.4%)
Hepatitis Acute	0/272 (0%)		1/274 (0.4%)
Immune system disorders
Anaphylactic Reaction	1/272 (0.4%)		0/274 (0%)
Cytokine Release Syndrome	0/272 (0%)		1/274 (0.4%)
Drug Hypersensitivity	0/272 (0%)		1/274 (0.4%)
Hypersensitivity	1/272 (0.4%)		0/274 (0%)
Infections and infestations
Acute Sinusitis	0/272 (0%)		1/274 (0.4%)
Alpha Haemolytic Streptococcal Infection	0/272 (0%)		1/274 (0.4%)
Aspergillosis	1/272 (0.4%)		1/274 (0.4%)
Bacterial Infection	0/272 (0%)		1/274 (0.4%)
Brain Abscess	0/272 (0%)		1/274 (0.4%)
Bronchitis	2/272 (0.7%)		6/274 (2.2%)
Bronchitis Viral	1/272 (0.4%)		0/274 (0%)
Bronchopneumonia	0/272 (0%)		1/274 (0.4%)
Bronchopulmonary Aspergillosis	0/272 (0%)		1/274 (0.4%)
Cellulitis	0/272 (0%)		1/274 (0.4%)
Chest Wall Abscess	0/272 (0%)		1/274 (0.4%)
Cytomegalovirus Gastrointestinal Infection	1/272 (0.4%)		0/274 (0%)
Cytomegalovirus Infection	2/272 (0.7%)		1/274 (0.4%)
Diverticulitis	0/272 (0%)		1/274 (0.4%)
Endocarditis	1/272 (0.4%)		0/274 (0%)
Endocarditis Bacterial	1/272 (0.4%)		0/274 (0%)
Fungal Sepsis	0/272 (0%)		1/274 (0.4%)
Furuncle	0/272 (0%)		1/274 (0.4%)
Gastroenteritis	1/272 (0.4%)		0/274 (0%)
Hepatitis B	0/272 (0%)		5/274 (1.8%)
Herpes Zoster	3/272 (1.1%)		1/274 (0.4%)
Infection	3/272 (1.1%)		1/274 (0.4%)
Klebsiella Sepsis	1/272 (0.4%)		0/274 (0%)
Listeria Sepsis	1/272 (0.4%)		0/274 (0%)
Localised Infection	1/272 (0.4%)		0/274 (0%)
Lower Respiratory Tract Infection	3/272 (1.1%)		0/274 (0%)
Lung Infection	1/272 (0.4%)		2/274 (0.7%)
Mycobacterium Avium Complex Infection	1/272 (0.4%)		0/274 (0%)
Neutropenic Infection	1/272 (0.4%)		0/274 (0%)
Neutropenic Sepsis	4/272 (1.5%)		2/274 (0.7%)
Oral Herpes	1/272 (0.4%)		0/274 (0%)
Parainfluenzae Virus Infection	1/272 (0.4%)		0/274 (0%)
Pneumocystis Jiroveci Infection	1/272 (0.4%)		0/274 (0%)
Pneumocystis Jiroveci Pneumonia	3/272 (1.1%)		1/274 (0.4%)
Pneumonia	18/272 (6.6%)		15/274 (5.5%)
Pneumonia Herpes Viral	0/272 (0%)		1/274 (0.4%)
Pneumonia Primary Atypical	0/272 (0%)		1/274 (0.4%)
Pseudomonal Sepsis	0/272 (0%)		1/274 (0.4%)
Rectal Abscess	1/272 (0.4%)		0/274 (0%)
Respiratory Tract Infection	3/272 (1.1%)		2/274 (0.7%)
Sepsis	3/272 (1.1%)		4/274 (1.5%)
Septic Shock	2/272 (0.7%)		5/274 (1.8%)
Staphylococcal Sepsis	0/272 (0%)		1/274 (0.4%)
Tonsillitis	0/272 (0%)		1/274 (0.4%)
Tuberculosis	0/272 (0%)		2/274 (0.7%)
Upper Respiratory Tract Infection	2/272 (0.7%)		2/274 (0.7%)
Varicella	1/272 (0.4%)		0/274 (0%)
Viral Upper Respiratory Tract Infection	0/272 (0%)		1/274 (0.4%)
West Nile Viral Infection	0/272 (0%)		1/274 (0.4%)
Wound Infection Staphylococcal	1/272 (0.4%)		0/274 (0%)
Infective Exacerbation of Chronic Obstructive Airways Disease	1/272 (0.4%)		0/274 (0%)
Zygomycosis	1/272 (0.4%)		0/274 (0%)
Mycobacterial Infection	1/272 (0.4%)		0/274 (0%)
Injury, poisoning and procedural complications
Open Wound	1/272 (0.4%)		0/274 (0%)
Radius Fracture	0/272 (0%)		1/274 (0.4%)
Subdural Haematoma	0/272 (0%)		1/274 (0.4%)
Investigations
Haemoglobin Decreased	1/272 (0.4%)		0/274 (0%)
Oxygen Saturation Decreased	0/272 (0%)		1/274 (0.4%)
Metabolism and nutrition disorders
Tumour Lysis Syndrome	3/272 (1.1%)		1/274 (0.4%)
Dehydration	1/272 (0.4%)		0/274 (0%)
Diabetes Mellitus Inadequate Control	0/272 (0%)		1/274 (0.4%)
Metabolic Acidosis	0/272 (0%)		1/274 (0.4%)
Musculoskeletal and connective tissue disorders
Intervertebral Disc Disorder	0/272 (0%)		2/274 (0.7%)
Bone Pain	0/272 (0%)		1/274 (0.4%)
Dactylitis	1/272 (0.4%)		0/274 (0%)
Metatarsalgia	1/272 (0.4%)		0/274 (0%)
Soft Tissue Necrosis	0/272 (0%)		1/274 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma	3/272 (1.1%)		0/274 (0%)
Bladder Cancer	0/272 (0%)		1/274 (0.4%)
Breast Cancer	1/272 (0.4%)		0/274 (0%)
Chondrosarcoma	0/272 (0%)		1/274 (0.4%)
Chronic Myelomonocytic Leukaemia	1/272 (0.4%)		0/274 (0%)
Colon Cancer	0/272 (0%)		2/274 (0.7%)
Hepatic Neoplasm Malignant	0/272 (0%)		1/274 (0.4%)
Hodgkin's Disease	0/272 (0%)		1/274 (0.4%)
Laryngeal Cancer	0/272 (0%)		1/274 (0.4%)
Lung Neoplasm Malignant	0/272 (0%)		1/274 (0.4%)
Metastases to Central Nervous System	0/272 (0%)		1/274 (0.4%)
Metastatic Neoplasm	0/272 (0%)		1/274 (0.4%)
Multiple Myeloma	0/272 (0%)		1/274 (0.4%)
Myelodysplastic Syndrome	2/272 (0.7%)		2/274 (0.7%)
Neoplasm Malignant	0/272 (0%)		1/274 (0.4%)
Ovarian Cancer	0/272 (0%)		1/274 (0.4%)
Paraneoplastic Pemphigus	0/272 (0%)		1/274 (0.4%)
Plasmacytoma	0/272 (0%)		1/274 (0.4%)
Prostate Cancer	1/272 (0.4%)		1/274 (0.4%)
Rectal Cancer	0/272 (0%)		1/274 (0.4%)
Squamous Cell Carcinoma	1/272 (0.4%)		1/274 (0.4%)
Squamous Cell Carcinoma of Skin	4/272 (1.5%)		1/274 (0.4%)
Vulval Cancer	0/272 (0%)		1/274 (0.4%)
Renal Cancer	1/272 (0.4%)		0/274 (0%)
Thyroid Cancer	0/272 (0%)		1/274 (0.4%)
Acute Myeloid Leukaemia	1/272 (0.4%)		1/274 (0.4%)
Nervous system disorders
Cerebral Haemorrhage	2/272 (0.7%)		0/274 (0%)
Cerebrovascular Accident	2/272 (0.7%)		0/274 (0%)
Capsular Warning Syndrome	1/272 (0.4%)		0/274 (0%)
Cerebral Ischaemia	0/272 (0%)		1/274 (0.4%)
Cerebral Thrombosis	0/272 (0%)		1/274 (0.4%)
Encephalopathy	0/272 (0%)		1/274 (0.4%)
Headache	1/272 (0.4%)		0/274 (0%)
Nervous System Disorder	0/272 (0%)		1/274 (0.4%)
Peripheral Motor Neuropathy	0/272 (0%)		1/274 (0.4%)
Neurological Decompensation	1/272 (0.4%)		0/274 (0%)
Renal and urinary disorders
Renal Failure Acute	2/272 (0.7%)		1/274 (0.4%)
Haematuria	0/272 (0%)		2/274 (0.7%)
Nephrolithiasis	1/272 (0.4%)		1/274 (0.4%)
Renal Failure	1/272 (0.4%)		1/274 (0.4%)
Calculus Ureteric	1/272 (0.4%)		0/274 (0%)
Cystitis Haemorrhagic	1/272 (0.4%)		0/274 (0%)
Nephrotic Syndrome	1/272 (0.4%)		0/274 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/272 (0.4%)		1/274 (0.4%)
Epistaxis	0/272 (0%)		1/274 (0.4%)
Haemoptysis	0/272 (0%)		1/274 (0.4%)
Hydrothorax	0/272 (0%)		1/274 (0.4%)
Interstitial Lung Disease	1/272 (0.4%)		0/274 (0%)
Lung Disorder	1/272 (0.4%)		1/274 (0.4%)
Pleurisy	0/272 (0%)		1/274 (0.4%)
Pneumonitis	1/272 (0.4%)		1/274 (0.4%)
Pulmonary Embolism	0/272 (0%)		2/274 (0.7%)
Respiratory Distress	0/272 (0%)		1/274 (0.4%)
Respiratory Failure	1/272 (0.4%)		0/274 (0%)
Asthma	1/272 (0.4%)		0/274 (0%)
Skin and subcutaneous tissue disorders
Eczema	1/272 (0.4%)		0/274 (0%)
Night Sweats	1/272 (0.4%)		0/274 (0%)
Palmar Erythema	1/272 (0.4%)		0/274 (0%)
Rash Maculo-Papular	0/272 (0%)		1/274 (0.4%)
Rash Papular	1/272 (0.4%)		0/274 (0%)
Stevens-Johnson Syndrome	0/272 (0%)		1/274 (0.4%)
Toxic Epidermal Necrolysis	1/272 (0.4%)		0/274 (0%)
Vascular disorders
Hypotension	0/272 (0%)		2/274 (0.7%)
Aortic Aneurysm	0/272 (0%)		1/274 (0.4%)
Embolism	0/272 (0%)		1/274 (0.4%)
Femoral Artery Occlusion	0/272 (0%)		1/274 (0.4%)
Haemorrhage	1/272 (0.4%)		0/274 (0%)
Hypertension	0/272 (0%)		1/274 (0.4%)
Peripheral Embolism	0/272 (0%)		1/274 (0.4%)
Other (Not Including Serious) Adverse Events
	Fludarabine+Cyclophosphamide (FC)		Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	232/272 (85.3%)		251/274 (91.6%)
Blood and lymphatic system disorders
Neutropenia	110/272 (40.4%)		120/274 (43.8%)
Anaemia	47/272 (17.3%)		55/274 (20.1%)
Thrombocytopenia	33/272 (12.1%)		36/274 (13.1%)
Granulocytopenia	12/272 (4.4%)		18/274 (6.6%)
Febrile Neutropenia	14/272 (5.1%)		16/274 (5.8%)
Gastrointestinal disorders
Nausea	96/272 (35.3%)		110/274 (40.1%)
Vomiting	50/272 (18.4%)		57/274 (20.8%)
Constipation	30/272 (11%)		40/274 (14.6%)
Diarrhoea	32/272 (11.8%)		31/274 (11.3%)
General disorders
Pyrexia	36/272 (13.2%)		60/274 (21.9%)
Fatigue	45/272 (16.5%)		45/274 (16.4%)
Chills	5/272 (1.8%)		41/274 (15%)
Asthenia	30/272 (11%)		28/274 (10.2%)
Oedema peripheral	11/272 (4%)		14/274 (5.1%)
Infections and infestations
Upper Respiratory Tract Infection	17/272 (6.3%)		23/274 (8.4%)
Bronchitis	15/272 (5.5%)		13/274 (4.7%)
Nasopharyngitis	15/272 (5.5%)		12/274 (4.4%)
Metabolism and nutrition disorders
Decreased appetite	11/272 (4%)		20/274 (7.3%)
Musculoskeletal and connective tissue disorders
Back Pain	16/272 (5.9%)		15/274 (5.5%)
Nervous system disorders
Headache	29/272 (10.7%)		25/274 (9.1%)
Respiratory, thoracic and mediastinal disorders
Cough	24/272 (8.8%)		34/274 (12.4%)
Skin and subcutaneous tissue disorders
Rash	19/272 (7%)		23/274 (8.4%)
Pruritus	13/272 (4.8%)		20/274 (7.3%)
Urticaria	3/272 (1.1%)		15/274 (5.5%)
Vascular disorders
Hypotension	2/272 (0.7%)		20/274 (7.3%)

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.