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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Leukemia

Intervention / Treatment
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* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Fludarabine Phosphate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fludarabine+Cyclophosphamide+Rituximab (FCR)<br> | Drug: Rituximab<br>* Intravenous repeating dose<br>Drug: Cyclophosphamide<br>* Intravenous repeating dose<br>Drug: Fludarabine Phosphate<br>* Intravenous repeating dose<br>|
| Active Comparator: Fludarabine+Cyclophosphamide (FC)<br> | Drug: Cyclophosphamide<br>* Intravenous repeating dose<br>Drug: Fludarabine Phosphate<br>* Intravenous repeating dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | 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. | Median observation time at time of analysis was approximately 21 months | 
| Final Analysis: Time to Progression-free Survival Event | 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. | Median observation time was approximately 66.4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival (EFS) | 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. | Median observation time at time of analysis was approximately 21 months | 
| Overall Survival (OS) | Overall survival (OS) was defined as the time between randomization and the date of death due to any cause. Median OS was not reached. | Median observation time at time of analysis was approximately 21 months | 
| Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR). | 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. | Median observation time at time of analysis was approximately 21 months | 
| Final Analysis: Time to Overall Survival Event | Overall survival (OS) was defined as the time between randomization and the date of death due to any cause. | Median observation time was approximately 66.4 months | 
| Final Analysis: Time to Event-free Survival Event | 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. | Median observation time was approximately 66.4 months | 
| Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR) | 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 observation time was approximately 66.4 months | 
| Final Analysis: Duration of Response | Duration of response was defined as the time from the first documented Complete Response, Partial Response to disease progression or death by any cause. | Median observation time was approximately 66.4 months | 
| Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response | 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. | Median observation time was approximately 66.4 months | 
| Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL) | The time from randomization to the start of a new treatment. | Median observation time was approximately 66.4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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