Fludarabine and Darbepoetin Alfa in Treating Older Patients With Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Darbepoetin alfa may cause the body to make more red blood cells. It is not yet known whether fludarabine is more effective with or without darbepoetin alfa in treating chronic lymphocytic leukemia. PURPOSE: This phase III trial is studying fludarabine to see how well it works when given together with or without darbepoetin alfa in treating older patients with chronic lymphocytic leukemia.

Detailed Description
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OBJECTIVES: Compare the efficacy of fludarabine with or without darbepoetin alfa in geriatric patients with chronic lymphocytic leukemia and relevant comorbidities. Determine the effect of these regimens in reducing anemia, lowering the requirements of transfusion, and reducing the duration and frequency of hospitalization in these patients. Determine the quality of life of patients treated with these regimens. Determine event-free, progression-free, and overall survival of patients treated with these regimens. Evaluate the medical-economical aspects of these regimens in these patients OUTLINE: This is a multicenter study. Patients are stratified according to hemoglobin value (< 12 g/dL [stratum 1] vs > 12 g/dL [stratum 2]). Patients are assigned to 1 of 2 treatment strata. Stratum 1: Patients receive fludarabine IV on days 1, 3, and 5. Treatment repeats every 28 days for up to 6 courses. Patients also receive darbepoetin alfa subcutaneously once weekly for up to 6 weeks. Stratum 2: Patients receive fludarabine as in stratum 1. Quality of life is evaluated periodically. PROJECTED ACCRUAL: A total of 348 patients will be accrued for this study.

Official Title
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Darbepoetin Alfa in Patients With Chronic Lymphocytic Leukemia and Comorbidity

Conditions
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Chronic Lymphocytic Leukemia, Anemia

Intervention / Treatment
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* Biological: Fludarabine plus Darbopoetin
* Drug: Fludarabine mono


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of chronic lymphocytic leukemia (CLL) meeting 1 of the following criteria: Previously untreated disease Progressive or relapsed CLL after treatment with nonpurine analog-containing regimens as chlorambucil or bendamustine hydrochloride Meets 1 of the following staging criteria: Binet stage A disease with B symptoms requiring treatment Binet stage B disease requiring treatment, meeting ≥ 1 of the following criteria: Rapid disease progression Enlarged lymph nodes and organs Severe B symptoms Binet stage C disease Must have comorbidities (i.e., CIRS score > 6) Must have restricted kidney function (i.e., creatinine clearance < 70mL/min) No transformation to aggressive non-Hodgkin's lymphoma (Richter's syndrome) PATIENT CHARACTERISTICS: Life expectancy > 6 months Creatinine clearance > 30 mL/min No active second malignancy No active bacterial, viral, or fungal infection No conditions that would preclude substitution of iron No severe myocardial, coronary, or respiratory insufficiency No severe liver insufficiency No known hypersensitivity to darbepoetin alfa No cerebral dysfunction that would preclude participation in the required study procedures PRIOR CONCURRENT THERAPY: See Disease Characteristics No concurrent participation in another clinical trial
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 plus Darbopoetin<br>Group 1 - Patients with an initial Hb-value of less than 12 g/dl receive fludarabine (30 mg/m² intravenously on day 1, 3, 5; repeated every 28 days for 6 cycles and 500 mcg of darbepoetin alfa subcutaneously every 3 weeks | Biological: Fludarabine plus Darbopoetin<br>* Group 1 - Patients with an initial Hb-value of less than 12 g/dl receive fludarabine (30 mg/m² intravenously on day 1, 3, 5; repeated every 28 days for 6 cycles and 500 mcg of darbepoetin alfa subcutaneously every 3 weeks<br>|
| Active Comparator: fludarabine mono<br>Group 1 - Patients with an initial Hb-value of less than 12 g/dl receive fludarabine (30 mg/m² intravenously on day 1, 3, 5; repeated every 28 days for 6 cycles with no additional growth factor support. Group 2 - Patients with an initial Hb-value more than 12 g/dl start to receive fludarabine (30 mg/m² intravenously on day 1, 3, 5; repeated every 28 days for 6 cycles . Patients of group 2 will be eventually randomized at later timepoints, if the Hb-value drops below 12 g/dl. Randomized patients will receive either 500 mcg darbepoetin alfa subcutaneously every 3 weeks or continue therapy with fludarabine without additional administration of darbepoetin alfa. | Drug: Fludarabine mono<br>* Group 1 - Patients with an initial Hb-value of less than 12 g/dl receive fludarabine (30 mg/m² intravenously on day 1, 3, 5; repeated every 28 days for 6 cycles with no additional growth factor support. Group 2 - Patients with an initial Hb-value more than 12 g/dl start to receive fludarabine (30 mg/m² intravenously on day 1, 3, 5; repeated every 28 days for 6 cycles . Patients of group 2 will be eventually randomized at later timepoints, if the Hb-value drops below 12 g/dl. Randomized patients will receive either 500 mcg darbepoetin alfa subcutaneously every 3 weeks or continue therapy with fludarabine without additional administration of darbepoetin alfa.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival | defined as the time from initial randomization/stratification to the time-point of progressive disease, new therapy, or death) | up to 24 months after the last dose of study medication | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Restaging after the end of treatment included evaluation of the peripheral blood and physical examination; use of imaging techniques (ultrasound and conventional radiography or computertomography) and evaluation of the bone marrow were mandatory to assign a complete remission | 2 months after the end of the last cycle | 
| toxicity | adverse events were reported according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC version 2.0). | 28 days after the end of the last cycle | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anemia, refractory chronic lymphocytic leukemia, stage 0 chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia