CLL-8: Fludarabine and Cyclophosphamide With or Without Rituximab in Patients With Previously Untreated Chronic B-Cell Lymphocytic Leukemia

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00281918
• Collaborator: German CLL Study Group (Other)
• Enrollment: 817
• Locations: 162
• Arms: 2
• Duration (Months): 99
• Patients Per Site: 5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This randomized phase III trial is studying fludarabine, cyclophosphamide, and rituximab to see how well they work compared to fludarabine and cyclophosphamide in treating patients with B-cell chronic lymphocytic leukemia.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 817 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase III Trial of Combined Immunochemotherapy With Fludarabine, Cyclophosphamide and Rituximab (FCR) Versus Chemotherapy With Fludarabine and Cyclophosphamide (FC) Alone in Patients With Previously Untreated Chronic Lymphocytic Leukaemia
• Study Start Date: Jul 1, 2003
• Actual Primary Completion Date: Jul 1, 2007
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [Median observation time at time of analysis was approximately 21 months]

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

2. Final Analysis: Time to Progression-free Survival Event [Median observation time was approximately 66.4 months]

   Progression-free survival was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.

Secondary Outcome Measures

1. Event-free Survival (EFS) [Median observation time at time of analysis was approximately 21 months]

   Event-free survival (EFS) was defined as the time between randomization and the date of disease progression, relapse, start of new CLL treatment or death by any cause.

2. Overall Survival (OS) [Median observation time at time of analysis was approximately 21 months]

   Overall survival (OS) was defined as the time between randomization and the date of death due to any cause. Median OS was not reached.

3. Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR). [Median observation time at time of analysis was approximately 21 months]

   CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death. Median DFS was not reached.

4. Final Analysis: Time to Overall Survival Event [Median observation time was approximately 66.4 months]

   Overall survival (OS) was defined as the time between randomization and the date of death due to any cause.

5. Final Analysis: Time to Event-free Survival Event [Median observation time was approximately 66.4 months]

   Event-free survival was defined as the time between randomization and the date of disease progression, relapse, start of new Chronic Lymphocytic Leukemia treatment or death by any cause.

6. Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR) [Median observation time was approximately 66.4 months]

   CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death

7. Final Analysis: Duration of Response [Median observation time was approximately 66.4 months]

   Duration of response was defined as the time from the first documented Complete Response, Partial Response to disease progression or death by any cause.

8. Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response [Median observation time was approximately 66.4 months]

   CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. Partial response is defined as a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment.

9. Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL) [Median observation time was approximately 66.4 months]

   The time from randomization to the start of a new treatment.

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Diagnosed B-cell chronic lymphocytic leukemia (CLL) defined by the National Cancer Institute (NCI) Working Group criteria

• Meets 1 of the following criteria:

• Binet stage C disease

• Binet stage B disease AND ≥ 1 of the following signs or symptoms*:

• B symptoms (night sweats, weight loss ≥ 10% within the previous 6 months, fevers > 38°C or 100.4°F for ≥ 2 weeks without evidence of infection), or constitutional symptoms (fatigue)

• Continuous progression (doubling of peripheral lymphocyte count within the past 6 months and absolute lymphocyte count > 50 G/I)

• Evidence of progressive marrow failure as manifested by the development/worsening of anemia and/or thrombocytopenia

• Massive, progressive or painful splenomegaly or hypersplenism

• Massive lymph nodes or lymph node clusters (> 10 cm in longest diameter), danger of organ complications through large lymphoma (e.g., vascular compression or tracheal narrowing), or progressive lymphadenopathy

• Occurrence of symptomatic hyperviscosity problems at leukocyte counts > 200 G/I (symptomatic leukostasis) NOTE: * Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for eligibility

• No Binet stage A disease

• No transformation to an aggressive B-cell malignancy (e.g., diffuse large cell lymphoma, Richter's syndrome, or prolymphocytic leukemia)

PATIENT CHARACTERISTICS:

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Cumulative Illness Rating Scale (CIRS) score > 6

• Life expectancy > 6 months

• Bilirubin ≤ 2 times upper limit of normal (ULN)

• Alkaline phosphatase and transaminases ≤ 2 times ULN

• Creatinine clearance ≥ 70 mL/min

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 2 months after study treatment

• No known hypersensitivity with anaphylactic reaction to humanized monoclonal antibodies or any of the study drugs

• No cerebral dysfunction that precludes chemotherapy

• No active bacterial, viral, or fungal infection

• No clinically significant autoimmune cytopenia or Coombs-positive hemolytic anemia

• No other active malignancy requiring concurrent treatment except basal cell carcinoma or tumors treated curatively by surgery

• No medical or psychological condition that would preclude study therapy

• No concurrent disease that requires prolonged (> 1 month) therapy involving glucocorticoids

PRIOR CONCURRENT THERAPY:

• No previous treatment of CLL by chemotherapy, radiotherapy, or immunotherapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Gosford Hospital	Gosford	New South Wales	Australia	2250
2	Westmead Institute for Cancer Research at Westmead Hospital	Westmead - Wentworthville	New South Wales	Australia	2145
3	Royal Brisbane and Women's Hospital	Brisbane	Queensland	Australia	4029
4	Princess Alexandra Hospital	Brisbane	Queensland	Australia	4102
5	Peter MacCallum Cancer Centre	East Melbourne	Victoria	Australia	3002
6	Frankston Hospital	Frankston	Victoria	Australia	3199
7	Hanuschkrankenhaus	Vienna		Austria	A-1140
8	Rudolfinerhaus	Vienna		Austria	A-1190
9	Allg. Krankenhaus der Stadt Wien Universitaets-Kinderklinik	Wien		Austria	1090
10	AZ Sint-Jan	Brugge		Belgium	8000
11	Institut Jules Bordet	Brussels		Belgium	1000
12	Cliniques Universitaires Saint-Luc	Brussels		Belgium	1200
13	Universitair Ziekenhuis Antwerpen	Edegem		Belgium	B-2650
14	U.Z. Gasthuisberg	Leuven		Belgium	B-3000
15	Clinique Universitaire De Mont-Godinne	Mont-Godinne Yvoir		Belgium	5530
16	Masaryk University Hospital	Brno		Czech Republic	62500
17	Fakultni Nemocnice Hradec Kralove	Hradec Kralove		Czech Republic	50005
18	University Hospital - Olomouc	Olomouc		Czech Republic	775 20
19	University Hospital in Pilsen - Lochotin	Pilsen-Lochotin		Czech Republic	30460
20	First Medical Clinic of Charles University Hospital	Prague		Czech Republic	128 08
21	Copenhagen County Herlev University Hospital	Copenhagen		Denmark	DK-2730
22	Vejle Sygehus	Vejle		Denmark	DK-7100
23	Hopital Louis Pasteur	Colmar		France	68024
24	Hopital Andre Mignot	Le Chesnay		France	78157
25	Centre Leon Berard	Lyon		France	69373
26	Marseille Institute of Cancer - Institut J. Paoli and I. Calmettes	Marseille		France	13273
27	Centre Hospitalier Universitaire de Rennes	Rennes		France	35033
28	Institut de Cancerologie de la Loire	Saint Priest en Jarez		France	42270
29	Praxis Fur Hamatologie und Onkologie Ahaus	Ahaus		Germany	48683
30	Gemeinschaftspraxis Fuer Innere Medizin, Haematologie Und Internistische Onkologie	Ansbach		Germany	91522
31	Hamatologische/Onkologische Gemeinschaftspraxis - Augsburg	Augsburg		Germany	86150
32	Klinikum Augsburg	Augsburg		Germany	DOH-86156
33	Humaine - Clinic	Bad Saarow		Germany	15526
34	Internistische Praxis - Bayreuth	Bayreuth		Germany	95448
35	Internistische Gemeinschaftspraxis - Berlin	Berlin		Germany	13347
36	Charite - Universitaetsmedizin Berlin - Campus Benjamin Franklin	Berlin		Germany	D-12200
37	Onkologische Schwerpunktpraxis Bielefeld	Bielefeld		Germany	D-33602
38	Krankenhaus Bietigheim	Bietigheim		Germany	D-74321
39	Augusta-Kranken-Anstalt gGmbH	Bochum		Germany	D-44791
40	Marienhospital Bottrop gGmbH	Bottrop		Germany	D-46236
41	DIAKO Ev. Diakonie Krankenhaus gGmbH	Bremen		Germany	D-28239
42	Krankenhaus Burglengenfeld	Burglengenfeld		Germany	D-93133
43	Onkologische Schwerpunktpraxis at Facharzt fuer Innere Medizin	Coesfeld		Germany	48653
44	Praxis Fuer Haematologie Internistische Onkologie	Cologne		Germany	D-50677
45	Medizinische Universitaetsklinik I at the University of Cologne	Cologne		Germany	D-50924
46	Onkologische Schwerpunktpraxis	Cottbus		Germany	D-03046
47	Onkologische Gemeinschaftspraxis - Dresden	Dresden		Germany	01127
48	Universitaetsklinikum Duesseldorf	Duesseldorf		Germany	D-40225
49	Internistische Praxis - Dusseldorf	Dusseldorf		Germany	40211
50	Florence-Nightingale-Krankenhause, Deaconess Kaiserswerth	Dusseldorf		Germany	40489
51	Krankenhaus Benrath	Dusseldorf		Germany	40593
52	St. Georg Klinikum Eisenach GmbH	Eisenach		Germany	99817
53	Helios Klinikum Erfurt	Erfurt		Germany	99012
54	Internistiche Praxis	Erfurt		Germany	99084
55	Onkologische Schwerpunkt Praxis	Erlangen		Germany	D-91052
56	St. Antonius Hospital	Eschweiler		Germany	DOH-52249
57	Universitaetsklinikum Essen	Essen		Germany	D-45122
58	Evangelisches Krankenhaus Essen Werden	Essen		Germany	D-45239
59	Staedtische Kliniken Esslingen	Esslingen		Germany	D-73730
60	Internistische Gemeinschaftspraxis - Forchheim	Forchheim		Germany	91301
61	Klinikum Frankfurt (Oder) GmbH	Frankfurt (Oder)		Germany	D-15236
62	Staedtische Kliniken Frankfurt am Main - Hoechst	Frankfurt		Germany	D-65929
63	Gemeinschaftspraxis - Freiburg	Freiburg		Germany	79098
64	Klinikum Garmisch - Partenkirchen GmbH	Garmisch-Partenkirchen		Germany	D-82467
65	Internistische Praxis - Gerlingen	Gerlingen		Germany	70839
66	Gemeinschaftspraxis Fuer Innere Medizin, Hematologie Und Onkologie	Giessen		Germany	35392
67	Universitaetsklinikum Goettingen	Goettingen		Germany	D-37075
68	Klinik Fuer Innere Medizin, Hematology/Oncology, Ernst Moritz Armdt Universitaet	Greifswald		Germany	D-17475
69	St. Marien Hospital - Katholisches Krankenhaus Hagen gGmbH	Hagen		Germany	D-58095
70	Internistische Praxis - Halle	Halle		Germany	06108
71	Universitaetsklinikum Halle	Halle		Germany	D-06120
72	Asklepios Klinik St. Georg	Hamburg		Germany	D-20099
73	University Medical Center Hamburg - Eppendorf	Hamburg		Germany	D-20246
74	St. Marien-Hospital Hamm - Klinik Knappenstrasse	Hamm		Germany	D-59071
75	Evangelische Krankenhaus Hamm	Hamm		Germany	DOH-59063
76	Krankenhaus Siloah - Medizinische Klinik II	Hannover		Germany	D-30449
77	Universitatsklinikum Heidelberg	Heidelberg		Germany	D-69115
78	Marienhospital at Ruhr University Bochum	Herne		Germany	D-44625
79	Privatklinik Dr. R. Schindlbeck GmbH & Co. KG	Herrsching		Germany	D-82211
80	Universitaetsklinikum des Saarlandes	Homburg		Germany	D-66424
81	Clinic for Bone Marrow Transplantation and Hematology and Oncology	Idar-Oberstein		Germany	D-55743
82	Gemeinschaftspraxis Innere Medizin	Jena		Germany	D-07743
83	Staedtisches Klinikum Karlsruhe gGmbH	Karlsruhe		Germany	76133
84	St. Vincentius-Kliniken	Karlsruhe		Germany	D-76137
85	Internistische Gemeinschaftspraxis - Kassel	Kassel		Germany	D-34117
86	Klinikum Kempten Oberallgaeu	Kempten		Germany	D-87439
87	Internistische Praxis - Kiel	Kiel		Germany	24105
88	University Hospital Schleswig-Holstein - Kiel Campus	Kiel		Germany	D-24116
89	Praxis fuer Haematologie und Onkologie	Koblenz		Germany	D-56068
90	Stiftungsklinikum Mittelrhein - Gesundheitszentrum Evangelisches Stift Sankt Martin Koblenz gGmbH	Koblez		Germany	D-56068
91	Internistische Onkologische Praxis - Kronach	Kronach		Germany	96317
92	Klinikum Landshut	Landshut		Germany	84034
93	Onkologische Schwerpunktpraxis - Leer	Leer		Germany	D-26789
94	Klinikum "St. Georg" Leipzig	Leipzig		Germany	D-04126
95	Klinikum Lippe - Lemgo	Lemgo		Germany	D-32657
96	Internistische Praxis - Loerrach	Loerrach		Germany	D-79539
97	Gemeinschaftspraxis - Ludwigshafen	Ludwigshafen		Germany	67061
98	Sana Kliniken Luebeck	Luebeck		Germany	23560
99	Internistische Gemeinschaftspraxis - Magdeburg	Magdeburg		Germany	D-39104
100	Staedtisches Klinikum Magdeburg - Altstadt	Magdeburg		Germany	D-39104
101	Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg	Magdeburg		Germany	D-39120
102	Universitatsklinik Mainz	Mainz		Germany	D-55101
103	III Medizinische Klinik Mannheim	Mannheim		Germany	D-68305
104	Krankenhaus Maria Hilf GmbH	Moenchengladbach		Germany	D-41063
105	Hamatologie/Onkologie Praxisgemeinschaft - Muenchen	Muenchen		Germany	D-81241
106	University of Muenster	Muenster		Germany	D-48129
107	Haematologisch - Onkologische Gemeinschaftspraxis	Muenster		Germany	D-48149
108	Klinikum der Universitaet Muenchen - Grosshadern Campus	Munich		Germany	D-81377
109	Staedtisches Krankenhaus Muenchen - Harlaching	Munich		Germany	D-81545
110	Klinikum Rechts Der Isar - Technische Universitaet Muenchen	Munich		Germany	D-81675
111	Haematologische Schwerpunktpraxis	Munich		Germany	D-81679
112	Onkologische Schwerpunktpraxis Dr. Schmidt	Neunkirchen		Germany	D-66538
113	Praxis fuer Haematologie und Interne Onkologie	Norderstedt		Germany	22844
114	Klinikum Nuernberg - Klinikum Nord	Nuernberg		Germany	D-90419
115	Gemeinschaftspraxis - Oberhausen	Oberhausen		Germany	D-46045
116	Internistische Gemeinschaftspraxis - Offenbach	Offenbach		Germany	D-63065
117	Internistische Gemeinschaftspraxis - Oldenburg	Oldenburg		Germany	D-26121
118	Klinikum Oldenburg	Oldenburg		Germany	D-26133
119	Asklepios Klinik Pasewalk	Pasewalk		Germany	17309
120	Municipal Hospital Complex	Pforzheim		Germany	D-75178
121	Klinikum Ernst Von Bergmann	Potsdam		Germany	D-14467
122	Elisabeth Krankenhaus	Recklinghausen		Germany	45661
123	Krankenhaus Barmherzige Brueder Regensburg	Regensburg		Germany	D-93049
124	Klinik und Poliklinik fuer Innere Medizin - Universitaet Rostock	Rostock		Germany	D-18055
125	Caritasklinik St. Theresia	Saarbrucken		Germany	D-66113
126	Nordwestkrankenhaus Sanderbusch	Sanderbusch		Germany	26452
127	St. Marien - Krankenhaus Siegen GMBH	Siegen		Germany	D-57072
128	Internistische Gemeinschaftspraxis - Stuttgart	Stuttgart		Germany	70176
129	Haematologische Praxis	Stuttgart		Germany	D-70173
130	Klinik fuer Onkologie - Katharinenhospital Stuttgart	Stuttgart		Germany	D-70174
131	Diakonie Klinikum Stuttgart	Stuttgart		Germany	D-70176
132	Marienhospital Stuttgart	Stuttgart		Germany	D-70199
133	KKH Torgau	Torgau		Germany	04860
134	Onkologische Gemeinschaftspraxis - Trier	Trier		Germany	54290
135	Krankenanstalt Mutterhaus der Borromaerinnen	Trier		Germany	D-54219
136	Praxis Fuer Internistische Haematologie / Onkologie	Troisdorf		Germany	53840
137	Universitaetsklinikum Tuebingen	Tuebingen		Germany	D-72076
138	Comprehensive Cancer Center Ulm at Universitaetsklinikum Ulm	Ulm		Germany	D-89081
139	Municipal Hospital Complex	Villingen-Schwenningen		Germany	D-78045
140	Praxis fur Innere Medizin - Wanzleben	Wanzleben		Germany	39164
141	Haematologische Praxis	Weiden		Germany	D-92637
142	Schwerpunktpraxis Hamatologie/Onkologie - Wesel	Wesel		Germany	46483
143	Dr. Horst-Schmidt-Kliniken	Wiesbaden		Germany	D-65199
144	Medizinische Klinik und Poliklinik II - Universitaetsklinikum Wuerzburg	Wuerzburg		Germany	D-97080
145	Kliniken St. Antonius	Wuppertal 2		Germany	D-42283
146	Hamatologisch - Onkologische Praxis Wurzburg	Wurzburg		Germany	97070
147	Soroka University Medical Center	Beer-Sheva		Israel	84101
148	BNAI Zion Medical Center	Haifa		Israel	31048
149	Rambam Medical Center	Haifa		Israel	31096
150	Hadassah University Hospital	Jerusalem		Israel	91120
151	Riverview Cancer Care Medical Associates, PC	Kfar Saba		Israel	44281
152	Kaplan Hospital	Rehovot		Israel	76100
153	Ospedale Oncologico A. Businco	Cagliari		Italy	09121
154	Fondazione Centro San Raffaele Del Monte Tabor	Milano		Italy	20132
155	Perugia Regional Cancer Center	Perugia		Italy	06122
156	Ospedale Sant' Eugenio	Rome		Italy	00144
157	Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore	Rome		Italy	00168
158	Auckland City Hospital	Auckland		New Zealand	1
159	Canterbury Health Laboratories	Christchurch		New Zealand
160	Palmerston North Hospital	Palmerston North		New Zealand
161	Hospital General Universitario Morales Meseguer	Murcia		Spain	30008
162	Hospital Virgen Del La Salud	Toledo		Spain	45004

Sponsors and Collaborators

• Hoffmann-La Roche
• German CLL Study Group

Investigators

• Study Chair: Michael Hallek, MD, Medizinische Universitaetsklinik I at the University of Cologne

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Clinical Study Report Synopsis

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00281918
• Other Study ID Numbers: CDR0000454560; GCLLSG-CLL-8; EU-20560; ML17102
• First Posted: Jan 25, 2006
• Last Update Posted: Sep 19, 2013
• Last Verified: Sep 1, 2013

• Keywords provided by Hoffmann-La Roche: B-cell chronic lymphocytic leukemia; stage I chronic lymphocytic leukemia; stage II chronic lymphocytic leukemia; stage III chronic lymphocytic leukemia; stage IV chronic lymphocytic leukemia
• 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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Period Title: Overall Study
STARTED	409	408
Safety Population; Received Study Drug	398	402
COMPLETED	267	300
NOT COMPLETED	142	108

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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.	Total of all reporting groups
Overall Participants	407	403	810
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.3 (8.55)	59.6 (8.70)	59.5 (8.62)
Sex: Female, Male (Count of Participants)
Female	105 25.8%	105 26.1%	210 25.9%
Male	302 74.2%	298 73.9%	600 74.1%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival (PFS) was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.
Time Frame	Median observation time at time of analysis was approximately 21 months

Outcome Measure Data

Analysis Population Description

The Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not. Informed consent was unavailable at the time of analysis for 2 patients in the FC group and 5 patients in the FCR group. ITT population: FC = 407; FCR = 403.

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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Measure Participants	407	403
Median (Full Range) [Days]	981.0	1212.0

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

2. Secondary Outcome

Title	Event-free Survival (EFS)
Description	Event-free survival (EFS) was defined as the time between randomization and the date of disease progression, relapse, start of new CLL treatment or death by any cause.
Time Frame	Median observation time at time of analysis was approximately 21 months

Outcome Measure Data

Analysis Population Description

The ITT population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not. Informed consent was unavailable at the time of analysis for 2 patients in the FC group and 5 patients in the FCR group. ITT population: FC = 407; FCR = 403.

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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Measure Participants	407	403
Median (Full Range) [Days]	947.0	1212.0

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

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival (OS) was defined as the time between randomization and the date of death due to any cause. Median OS was not reached.
Time Frame	Median observation time at time of analysis was approximately 21 months

Outcome Measure Data

Analysis Population Description

The ITT population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not. Informed consent was unavailable at the time of analysis for 2 patients in the FC group and 5 patients in the FCR group. ITT population: FC = 407; FCR = 403.

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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Measure Participants	407	403
Minimum number of days to an event	5	4
Maximum number of days to an event	1373	1372

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	0.0427
	Comments
	Method	Log Rank
	Comments

4. Secondary Outcome

Title	Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR).
Description	CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death. Median DFS was not reached.
Time Frame	Median observation time at time of analysis was approximately 21 months

Outcome Measure Data

Analysis Population Description

The ITT population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not. Informed consent was unavailable at the time of analysis for 2 patients in the FC group and 5 patients in the FCR group. ITT population: FC = 407; FCR = 403.

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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Measure Participants	407	403
Minimum number of days to an event	84	91
Maximum number of days to an event	1164	1226

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	0.7882
	Comments
	Method	Log Rank
	Comments

5. Primary Outcome

Title	Final Analysis: Time to Progression-free Survival Event
Description	Progression-free survival was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.
Time Frame	Median observation time was approximately 66.4 months

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-treat population, that included all randomized participants, with PFS events.

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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Measure Participants	297	253
Median (95% Confidence Interval) [Days]	998.0	1703.0

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	0.57
	Confidence Interval	(2-Sided) 95%; 0.48 to 0.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Final Analysis: Time to Overall Survival Event
Description	Overall survival (OS) was defined as the time between randomization and the date of death due to any cause.
Time Frame	Median observation time was approximately 66.4 months

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-treat population, that included all randomized participants who 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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Measure Participants	154	125
Median (95% Confidence Interval) [Days]	2613.0	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	0.0010
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.54 to 0.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Final Analysis: Time to Event-free Survival Event
Description	Event-free survival was defined as the time between randomization and the date of disease progression, relapse, start of new Chronic Lymphocytic Leukemia treatment or death by any cause.
Time Frame	Median observation time was approximately 66.4 months

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-treat population, that included all randomized participants, with disease progression, relapse, start of new Chronic Lymphocytic Leukemia treatment or death.

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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Measure Participants	301	257
Median (95% Confidence Interval) [Days]	951.0	1666.0

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	0.57
	Confidence Interval	() 95%; 0.48 to 0.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR)
Description	CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death
Time Frame	Median observation time was approximately 66.4 months

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-treat population, all randomized participants, with complete response who experienced a disease free survival event (disease relapse or death).

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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Measure Participants	58	97
Median (95% Confidence Interval) [Days]	1488.0	1854.0

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	0.0523
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.52 to 1.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Final Analysis: Duration of Response
Description	Duration of response was defined as the time from the first documented Complete Response, Partial Response to disease progression or death by any cause.
Time Frame	Median observation time was approximately 66.4 months

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-treat population, all randomized participants, with complete response or partial response who experienced an event (disease progression or death due to any cause).

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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Measure Participants	214	207
Median (95% Confidence Interval) [Days]	1102.0	1718.0

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	0.58
	Confidence Interval	(2-Sided) 95%; 0.48 to 0.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response
Description	CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. Partial response is defined as a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment.
Time Frame	Median observation time was approximately 66.4 months

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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Measure Participants	409	408
Number (95% Confidence Interval) [Percentage of participants]	72.4 17.8%	85.8 21.3%

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	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.30
	Confidence Interval	(2-Sided) 95%; 1.62 to 3.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL)
Description	The time from randomization to the start of a new treatment.
Time Frame	Median observation time was approximately 66.4 months

Outcome Measure Data

Analysis Population Description

Participants from the Intent-to-treat population, that included all randomized participants, who started a new CLL treatment.

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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Measure Participants	251	206
Median (95% Confidence Interval) [Days]	1455.0	2082.0

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	0.59
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse Events were recorded until 28 days after completion of study treatment (median time approximately 21 months). Serious Adverse Events reported until 1 year post-treatment or initiation of new CLL treatment (median time approximately 42 months).
Adverse Event Reporting Description	The safety population included all participants who received at least one dose of study drug.
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 intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
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	164/398 (41.2%)		186/402 (46.3%)
Blood and lymphatic system disorders
Febrile Neutropenia	22/398 (5.5%)		31/402 (7.7%)
Anaemia	10/398 (2.5%)		6/402 (1.5%)
Leukopenia	3/398 (0.8%)		9/402 (2.2%)
Neutropenia	3/398 (0.8%)		8/402 (2%)
Thrombocytopenia	6/398 (1.5%)		6/402 (1.5%)
Pancytopenia	3/398 (0.8%)		7/402 (1.7%)
Haemolysis	3/398 (0.8%)		1/402 (0.2%)
Febrile Bone Marrow Aplasia	0/398 (0%)		3/402 (0.7%)
Granulocytopenia	0/398 (0%)		2/402 (0.5%)
Haemolytic Anaemia	1/398 (0.3%)		1/402 (0.2%)
Agranulocytosis	0/398 (0%)		1/402 (0.2%)
Bone Marrow Failure	1/398 (0.3%)		0/402 (0%)
Coombs Positive Haemolytic Anaemia	1/398 (0.3%)		0/402 (0%)
Evans Syndrome	1/398 (0.3%)		0/402 (0%)
Haematotoxicity	0/398 (0%)		1/402 (0.2%)
Lymphadenitis	0/398 (0%)		1/402 (0.2%)
Splenomegaly	0/398 (0%)		1/402 (0.2%)
Cardiac disorders
Angina Pectoris	2/398 (0.5%)		5/402 (1.2%)
Cardiac Failure	1/398 (0.3%)		1/402 (0.2%)
Coronary Artery Disease	2/398 (0.5%)		0/402 (0%)
Myocardial Infarction	0/398 (0%)		2/402 (0.5%)
Myocardial Ischaemia	2/398 (0.5%)		0/402 (0%)
Tachycardia	0/398 (0%)		2/402 (0.5%)
Acute Myocardial Infarction	1/398 (0.3%)		0/402 (0%)
Arrhythmia	1/398 (0.3%)		0/402 (0%)
Cardiac Failure Congestive	1/398 (0.3%)		0/402 (0%)
Cardiopulmonary Failure	0/398 (0%)		1/402 (0.2%)
Sinus Bradycardia	0/398 (0%)		1/402 (0.2%)
Supraventricular Extrasystoles	1/398 (0.3%)		0/402 (0%)
Tachyarrhythmia	0/398 (0%)		1/402 (0.2%)
Ventricular Fibrillation	1/398 (0.3%)		0/402 (0%)
Ear and labyrinth disorders
Vertigo	0/398 (0%)		1/402 (0.2%)
Eye disorders
Retinal Detachment	1/398 (0.3%)		1/402 (0.2%)
Amaurosis Fugax	0/398 (0%)		1/402 (0.2%)
Dacryostenosis Acquired	0/398 (0%)		1/402 (0.2%)
Uveitis	0/398 (0%)		1/402 (0.2%)
Vitreous Haemorrhage	1/398 (0.3%)		0/402 (0%)
Gastrointestinal disorders
Diarrhoea	2/398 (0.5%)		5/402 (1.2%)
Vomiting	2/398 (0.5%)		3/402 (0.7%)
Abdominal Pain	3/398 (0.8%)		1/402 (0.2%)
Inguinal Hernia	1/398 (0.3%)		1/402 (0.2%)
Abdominal Symptom	0/398 (0%)		1/402 (0.2%)
Constipation	0/398 (0%)		1/402 (0.2%)
Duodenal Ulcer Perforation	0/398 (0%)		1/402 (0.2%)
Gastrointestinal Ulcer	0/398 (0%)		1/402 (0.2%)
Haematemesis	1/398 (0.3%)		0/402 (0%)
Inguinal Hernia, Obstructive	0/398 (0%)		1/402 (0.2%)
Nausea	0/398 (0%)		1/402 (0.2%)
Pancreatitis	1/398 (0.3%)		0/402 (0%)
Tongue Ulceration	0/398 (0%)		1/402 (0.2%)
General disorders
Pyrexia	20/398 (5%)		18/402 (4.5%)
Chest Pain	1/398 (0.3%)		3/402 (0.7%)
Chills	0/398 (0%)		2/402 (0.5%)
Adverse Drug Reaction	0/398 (0%)		1/402 (0.2%)
Chest Discomfort	0/398 (0%)		1/402 (0.2%)
Death	1/398 (0.3%)		0/402 (0%)
General Physical Health Deterioration	1/398 (0.3%)		0/402 (0%)
General Symptom	1/398 (0.3%)		0/402 (0%)
Ill-Defined Disorder	1/398 (0.3%)		0/402 (0%)
Mucosal Inflammation	0/398 (0%)		1/402 (0.2%)
Multi-Organ Failure	0/398 (0%)		1/402 (0.2%)
Pain	1/398 (0.3%)		0/402 (0%)
Device occlusion	1/398 (0.3%)		0/402 (0%)
Hepatobiliary disorders
Cholelithiasis	2/398 (0.5%)		1/402 (0.2%)
Cholecystitis	1/398 (0.3%)		1/402 (0.2%)
Hepatitis	0/398 (0%)		1/402 (0.2%)
Cholangitis	1/398 (0.3%)		0/402 (0%)
Cholecystitis Acute	1/398 (0.3%)		0/402 (0%)
Hepatic Siderosis	0/398 (0%)		1/402 (0.2%)
Hepatotoxicity	0/398 (0%)		1/402 (0.2%)
Drug-induced liver injury	0/398 (0%)		1/402 (0.2%)
Immune system disorders
Hypersensitivity	1/398 (0.3%)		3/402 (0.7%)
Drug Hypersensitivity	0/398 (0%)		2/402 (0.5%)
Anaphylactic Reaction	0/398 (0%)		1/402 (0.2%)
Cytokine Release Syndrome	0/398 (0%)		1/402 (0.2%)
Infections and infestations
Pneumonia	21/398 (5.3%)		18/402 (4.5%)
Herpes Zoster	6/398 (1.5%)		8/402 (2%)
Sepsis	8/398 (2%)		5/402 (1.2%)
Bronchitis	5/398 (1.3%)		5/402 (1.2%)
Infection	2/398 (0.5%)		5/402 (1.2%)
Gastroenteritis	3/398 (0.8%)		2/402 (0.5%)
Sinusitis	1/398 (0.3%)		4/402 (1%)
Erysipelas	1/398 (0.3%)		2/402 (0.5%)
Hepatitis B	2/398 (0.5%)		1/402 (0.2%)
Pneumocystis Jiroveci Infection	1/398 (0.3%)		2/402 (0.5%)
Pneumocystis Jiroveci Pneumonia	1/398 (0.3%)		2/402 (0.5%)
Pneumonia Primary Atypical	1/398 (0.3%)		2/402 (0.5%)
Viral Infection	0/398 (0%)		3/402 (0.7%)
Cellulitis	1/398 (0.3%)		1/402 (0.2%)
Cerebral Toxoplasmosis	1/398 (0.3%)		1/402 (0.2%)
Diverticulitis	0/398 (0%)		2/402 (0.5%)
Neutropenic Infection	0/398 (0%)		2/402 (0.5%)
Oral Herpes	2/398 (0.5%)		0/402 (0%)
Pneumonia Fungal	1/398 (0.3%)		1/402 (0.2%)
Respiratory Tract Infection	1/398 (0.3%)		1/402 (0.2%)
Abscess	0/398 (0%)		1/402 (0.2%)
Appendicitis	0/398 (0%)		1/402 (0.2%)
Bronchiolitis	1/398 (0.3%)		0/402 (0%)
Bronchopneumonia	1/398 (0.3%)		0/402 (0%)
Chronic Sinusitis	1/398 (0.3%)		0/402 (0%)
Cytomegalovirus Infection	0/398 (0%)		1/402 (0.2%)
Enterococcal Bacteraemia	0/398 (0%)		1/402 (0.2%)
Gastroenteritis Cryptosporidial	0/398 (0%)		1/402 (0.2%)
Hepatitis C	0/398 (0%)		1/402 (0.2%)
Hepatobiliary Infection	1/398 (0.3%)		0/402 (0%)
Herpes Simplex	0/398 (0%)		1/402 (0.2%)
Herpes Virus Infection	0/398 (0%)		1/402 (0.2%)
Herpes Zoster Ophthalmic	1/398 (0.3%)		0/402 (0%)
Infected Skin Ulcer	1/398 (0.3%)		0/402 (0%)
Lower Respiratory Tract Infection	0/398 (0%)		1/402 (0.2%)
Lung Infection	0/398 (0%)		1/402 (0.2%)
Lung Infection Pseudomonal	0/398 (0%)		1/402 (0.2%)
Neutropenic Sepsis	1/398 (0.3%)		0/402 (0%)
Oesophageal Candidiasis	0/398 (0%)		1/402 (0.2%)
Orchitis	0/398 (0%)		1/402 (0.2%)
Osteomyelitis	0/398 (0%)		1/402 (0.2%)
Otitis Media	0/398 (0%)		1/402 (0.2%)
Periorbital Cellulitis	0/398 (0%)		1/402 (0.2%)
Pneumonia Respiratory Syncytial Viral	1/398 (0.3%)		0/402 (0%)
Pseudomonal Sepsis	0/398 (0%)		1/402 (0.2%)
Septic Shock	0/398 (0%)		1/402 (0.2%)
Skin Infection	1/398 (0.3%)		0/402 (0%)
Staphylococcal Infection	0/398 (0%)		1/402 (0.2%)
Subcutaneous Abscess	0/398 (0%)		1/402 (0.2%)
Tonsillitis	1/398 (0.3%)		0/402 (0%)
Tuberculosis	0/398 (0%)		1/402 (0.2%)
Urosepsis	0/398 (0%)		1/402 (0.2%)
Device related infection	1/398 (0.3%)		1/402 (0.2%)
Infectious pleural effusion	0/398 (0%)		1/402 (0.2%)
Endophthalmitis	1/398 (0.3%)		1/402 (0.2%)
Injury, poisoning and procedural complications
Humerus Fracture	1/398 (0.3%)		0/402 (0%)
Post Procedural Complication	0/398 (0%)		1/402 (0.2%)
Investigations
Catheterisation Cardiac	0/398 (0%)		1/402 (0.2%)
Body Temperature Increased	0/398 (0%)		1/402 (0.2%)
Metabolism and nutrition disorders
Tumour Lysis Syndrome	2/398 (0.5%)		1/402 (0.2%)
Dehydration	1/398 (0.3%)		0/402 (0%)
Hyperuricaemia	1/398 (0.3%)		0/402 (0%)
Gout	1/398 (0.3%)		0/402 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral Disc Protrusion	1/398 (0.3%)		0/402 (0%)
Kyphosis	1/398 (0.3%)		0/402 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal Cell Carcinoma	2/398 (0.5%)		1/402 (0.2%)
Malignant Melanoma	2/398 (0.5%)		1/402 (0.2%)
Prostate Cancer	1/398 (0.3%)		2/402 (0.5%)
Acute Myeloid Leukaemia	0/398 (0%)		2/402 (0.5%)
Lung Squamous Cell Carcinoma Stage Unspecified	2/398 (0.5%)		0/402 (0%)
Adenocarcinoma	1/398 (0.3%)		0/402 (0%)
Bladder Cancer	0/398 (0%)		1/402 (0.2%)
Breast Cancer	0/398 (0%)		1/402 (0.2%)
Central Nervous System Lymphoma	0/398 (0%)		1/402 (0.2%)
Histiocytosis Haematophagic	0/398 (0%)		1/402 (0.2%)
Hodgkin's Disease	0/398 (0%)		1/402 (0.2%)
Lung Neoplasm Malignant	1/398 (0.3%)		0/402 (0%)
Lymphoma	1/398 (0.3%)		0/402 (0%)
Lymphoma Transformation	1/398 (0.3%)		0/402 (0%)
Non-Small Cell Lung Cancer	0/398 (0%)		1/402 (0.2%)
Pancreatic Carcinoma	1/398 (0.3%)		1/402 (0.2%)
Pharyngeal Cancer Stage Unspecified	1/398 (0.3%)		0/402 (0%)
Rectal Cancer	0/398 (0%)		1/402 (0.2%)
Skin Cancer	1/398 (0.3%)		0/402 (0%)
Squamous Cell Carcinoma	0/398 (0%)		1/402 (0.2%)
Squamous Cell Carcinoma of Skin	0/398 (0%)		1/402 (0.2%)
Transitional Cell Carcinoma	0/398 (0%)		1/402 (0.2%)
Anogenital warts	0/398 (0%)		1/402 (0.2%)
Nervous system disorders
Syncope	2/398 (0.5%)		2/402 (0.5%)
Headache	1/398 (0.3%)		2/402 (0.5%)
Cerebrovascular Accident	0/398 (0%)		2/402 (0.5%)
Convulsion	0/398 (0%)		1/402 (0.2%)
Diabetic Neuropathy	0/398 (0%)		1/402 (0.2%)
Encephalitis	1/398 (0.3%)		0/402 (0%)
Epilepsy	1/398 (0.3%)		0/402 (0%)
Hemiparesis	1/398 (0.3%)		0/402 (0%)
Hydrocephalus	1/398 (0.3%)		0/402 (0%)
Migraine	1/398 (0.3%)		0/402 (0%)
Optic Neuritis	0/398 (0%)		1/402 (0.2%)
Stupor	1/398 (0.3%)		0/402 (0%)
Transient Ischaemic Attack	1/398 (0.3%)		0/402 (0%)
Cerebral Infarction	0/398 (0%)		1/402 (0.2%)
Psychiatric disorders
Completed Suicide	1/398 (0.3%)		0/402 (0%)
Renal and urinary disorders
Calculus Ureteric	1/398 (0.3%)		2/402 (0.5%)
Cystitis Haemorrhagic	0/398 (0%)		2/402 (0.5%)
Renal Failure	1/398 (0.3%)		1/402 (0.2%)
Nephrolithiasis	1/398 (0.3%)		0/402 (0%)
Urinary Retention	0/398 (0%)		1/402 (0.2%)
Urinary Tract Obstruction	0/398 (0%)		1/402 (0.2%)
Renal Failure Acute	1/398 (0.3%)		0/402 (0%)
Reproductive system and breast disorders
Benign Prostatic Hyperplasia	1/398 (0.3%)		0/402 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism	2/398 (0.5%)		2/402 (0.5%)
Dyspnoea	2/398 (0.5%)		1/402 (0.2%)
Bronchospasm	0/398 (0%)		2/402 (0.5%)
Dyspnoea Exertional	0/398 (0%)		2/402 (0.5%)
Epistaxis	2/398 (0.5%)		1/402 (0.2%)
Interstitial Lung Disease	0/398 (0%)		2/402 (0.5%)
Lung Disorder	0/398 (0%)		2/402 (0.5%)
Lung Infiltration	1/398 (0.3%)		1/402 (0.2%)
Alveolitis	0/398 (0%)		1/402 (0.2%)
Alveolitis Allergic	1/398 (0.3%)		0/402 (0%)
Chronic Obstructive Pulmonary Disease	0/398 (0%)		1/402 (0.2%)
Chylothorax	1/398 (0.3%)		0/402 (0%)
Dyspnoea at Rest	0/398 (0%)		1/402 (0.2%)
Laryngeal Stenosis	0/398 (0%)		1/402 (0.2%)
Pleural Effusion	1/398 (0.3%)		0/402 (0%)
Respiration Abnormal	0/398 (0%)		1/402 (0.2%)
Skin and subcutaneous tissue disorders
Dermatitis Exfoliative	1/398 (0.3%)		1/402 (0.2%)
Leukocytoclastic Vasculitis	2/398 (0.5%)		0/402 (0%)
Urticaria	2/398 (0.5%)		0/402 (0%)
Dermatitis Allergic	0/398 (0%)		1/402 (0.2%)
Drug Eruption	0/398 (0%)		1/402 (0.2%)
Erythema	1/398 (0.3%)		0/402 (0%)
Pruritus	1/398 (0.3%)		0/402 (0%)
Pustular Psoriasis	1/398 (0.3%)		0/402 (0%)
Rash	0/398 (0%)		1/402 (0.2%)
Skin Ulcer	1/398 (0.3%)		0/402 (0%)
Surgical and medical procedures
Cholecystectomy	1/398 (0.3%)		0/402 (0%)
Coronary Revascularisation	1/398 (0.3%)		0/402 (0%)
Haemorrhoid Operation	1/398 (0.3%)		0/402 (0%)
Prostatectomy	0/398 (0%)		1/402 (0.2%)
Surgery	1/398 (0.3%)		0/402 (0%)
Vascular disorders
Hypotension	1/398 (0.3%)		2/402 (0.5%)
Deep Vein Thrombosis	2/398 (0.5%)		0/402 (0%)
Circulatory Collapse	0/398 (0%)		1/402 (0.2%)
Thrombosis	1/398 (0.3%)		0/402 (0%)
Vasculitis Necrotising	0/398 (0%)		1/402 (0.2%)
Venous Thrombosis Limb	0/398 (0%)		1/402 (0.2%)
Other (Not Including Serious) Adverse Events
	Fludarabine+Cyclophosphamide (FC)		Fludarabine+Cyclophosphamide+Rituximab (FCR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	122/398 (30.7%)		185/402 (46%)
Blood and lymphatic system disorders
Neutropenia	71/398 (17.8%)		116/402 (28.9%)
Leukopenia	45/398 (11.3%)		88/402 (21.9%)
Thrombocytopenia	35/398 (8.8%)		21/402 (5.2%)

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.