Rituximab, Fludarabine, and Cyclophosphamide or Observation Alone in Treating Patients With Stage 0, Stage I, or Stage II Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some find cancer cells and kill them or carry cancer-killing substances to them. Others interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as fludarabine and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Sometimes the cancer may not need treatment until it progresses. In this case, observation may be sufficient. It is not yet known whether giving rituximab together with fludarabine and cyclophosphamide is more effective than observation alone in treating chronic lymphocytic leukemia. PURPOSE: This randomized phase III trial is studying rituximab, fludarabine, and cyclophosphamide to see how well they work compared to observation alone in treating patients with stage 0, stage I, or stage II B-cell chronic lymphocytic leukemia.

Detailed Description
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OBJECTIVES: Primary Compare the effect, in terms of event-free survival, of deferred versus immediate treatment with rituximab, fludarabine, and cyclophosphamide in patients with previously untreated Binet stage A chronic lymphocytic leukemia at high risk for disease progression. Investigate and define a new prognostic staging system for patients with Binet stage A chronic lymphocytic leukemia. Secondary Compare the time to progression to Binet stages B and C in patients treated with these regimens. Compare the overall and progression-free survival of patients treated with these regimens. Compare the quality of life of patients treated with these regimens. Compare the time to treatment in patients treated with these regimens. Analyze the pharmacoeconomics of these regimens in these patients. Determine the overall response rate (partial and complete) in patients included in the early treatment arm. For patients included in the early treatment arm in complete remission, determine the percentage achieving complete molecular remission using the clone-specific CDR-III region as follow-up parameter. Determine the duration of response in patients included in the early treatment arm. Determine any adverse events related to treatment/safety of treatment. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to risk factor profile (< 2 risk factors [low risk] vs ≥ 2 risk factors [high risk]). Low-risk patients are assigned to arm II. High-risk patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive rituximab IV on day 1, fludarabine IV on days 1-3, and cyclophosphamide IV on days 1-3. Treatment repeats every 28 days for up to 6 courses. Arm II: Patients undergo observation only until disease progression. PROJECTED ACCRUAL: A total of 600 patients will be accrued for this study.

Official Title
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Randomized Phase III Trial Comparing Early Treatment With Fludarabine/Cyclophosphamide + Rituximab Versus Deferred Treatment in Untreated Binet Stage A Patients With CLL and High Risk of Progression

Conditions
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Chronic Lymphocytic Leukemia

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


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Established diagnosis of B-cell chronic lymphocytic leukemia First diagnosis within 12 months before inclusion in study Previously untreated disease Binet stage A disease (Rai stage 0, I, or II) PATIENT CHARACTERISTICS: Life expectancy > 6 months ECOG performance status 0-2 Willingness to accept contraception (if randomized to arm I) for the duration of therapy and 12 months thereafter Negative serum pregnancy test All parameters for risk stratification (lymphocyte doubling time, cytogenetics, unmutated IgVH, and serum thymidine kinase level > 10) present PRIOR CONCURRENT THERAPY: No prior chemotherapy, radiotherapy, or antibody treatment No other concurrent chemotherapy

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: Cohort I (FCR)<br>Patients with 2 or more risk factors out of 4 (1. unfavorable molecular cytogenetics, 2. high serum thymidine kinase levels, 3. lymphocyte doubling time shorter than 12 months, 4. unmutated IgVH gene) who are randomized into cohort I receive Fludarabine, Cyclophosphamide and Rituximab (FCR) chemoimmunotherapy. | Drug: Fludarabine<br>* cycles 1-6: 25 mg/m² i.v., d2-4, q28d<br>* Other names: Fludura;Drug: Cyclophosphamide<br>* cycles 1-6: 250 mg/m² i.v., d2-4, q28d<br>* Other names: Endoxan;Biological: Rituximab<br>* cycle1: 375 mg/m² i.v., d1, q28d cycles 2-6: 500 mg/m² i.v., d1, q28d<br>* Other names: Rituxan;|
| No Intervention: Cohort II (W&W)<br>Patients with 2 or more risk factors out of 4 (1. unfavorable molecular cytogenetics, 2. high serum thymidine kinase levels, 3. lymphocyte doubling time shorter than 12 months, 4. unmutated IgVH gene) who are randomized into cohort II receive no treatment at all (watch & wait). | |
| No Intervention: Cohort III (W&W)<br>Patients with less than 2 risk factors out of 4 (1. unfavorable molecular cytogenetics, 2. high serum thymidine kinase levels, 3. lymphocyte doubling time shorter than 12 months, 4. unmutated IgVH gene) are assigned directly to cohort III and receive no treatment at all (watch & wait). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival |  |  | 
| Development of a new prognostic staging system |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival |  |  | 
| Overall survival |  |  | 
| Time to progression to Binet stages B and C |  |  | 
| Time to treatment |  |  | 
| Quality of life |  |  | 
| Pharmacoeconomic analysis |  |  | 
| Overall response (complete and partial) rate in patients in the early treatment arm |  |  | 
| Percentage of patients achieving complete molecular remission in the early treatment arm |  |  | 
| Duration of response in patients in the early treatment arm |  |  | 
| Adverse events in patients in the early treatment arm |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage 0 chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia