Fludarabine With or Without Cyclophosphamide in Treating Patients With Chronic Lymphocytic Leukemia

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells. It is not yet known whether combining cyclophosphamide with fludarabine is more effective than fludarabine alone in treating chronic lymphocytic leukemia. PURPOSE: Randomized phase III trial to study the effectiveness of fludarabine with or without cyclophosphamide in treating patients who have chronic lymphocytic leukemia that has not been treated previously.

Detailed Description
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OBJECTIVES: Compare the efficacy of fludarabine with or without cyclophosphamide in terms of complete remission rate and overall survival in patients with previously untreated B cell chronic lymphocytic leukemia (CLL). Compare the toxicities of these 2 regimens in this patient population. Determine whether the expression of proteins specifically implicated in the regulation of DNA damage induced apoptosis of lymphoid cells (i.e., p53; mdm2; GST; Bcl-2; Mcl-1; Bax; p27; and caspase-3) correlates with response to chemotherapy in these patients. Determine whether there is a relationship between clinical response or resistance and differential expression of genes in the CLL cells either at initiation of therapy or following relapse and progression. Correlate mutations in immunoglobulin heavy chain variable region genes with clinical response or resistance in this patient population. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to stage of disease (O-II vs III-IV). Patients are randomized to one of two treatment arms. Arm I: Patients receive fludarabine IV over 30 minutes on days 1-5. Arm II: Patients receive fludarabine as in arm I plus cyclophosphamide IV over 1 hour on day 1. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years and then every 6 months until disease progression. PROJECTED ACCRUAL: A total of 280 patients will be accrued for this study over 2 to 2.5 years.

Official Title
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Phase III Randomized Trial of Fludarabine and Cyclophosphamide Versus Fludarabine for Previously Untreated Chronic Lymphocytic Leukemia

Conditions
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Leukemia

Intervention / Treatment
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* Drug: cyclophosphamide
* Drug: fludarabine phosphate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Diagnosis of chronic lymphocytic leukemia (CLL) of any stage as defined by the following: Peripheral blood absolute lymphocyte count greater than 5,000/mm^3 within 14 days prior to study Lymphocytes must be small to moderate size with no more than 55% prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically Phenotypically characterized as B-CLL Must have one of the following characteristics indicating need for chemotherapy: Progressive marrow failure (hemoglobin less than 10 g/dL and/or platelet count less than 100,000/mm^3) Progressive lymphocytosis with an increase of more than 50% over a 2 month period or anticipated doubling time of less than 6 months Massive (i.e., greater than 6 cm below left costal margin) or progressive splenomegaly Massive nodes or clusters (i.e., greater than 10 cm in longest diameter) or progressive adenopathy At least 10% weight loss within 6 months of study Extreme fatigue Fevers greater than 100.5 degrees F for 2 weeks without evidence of infection Night sweats without evidence of infection No autoimmune anemia or autoimmune thrombocytopenia PATIENT CHARACTERISTICS: Age: 18 and over Performance status: ECOG 0-2 Life expectancy: Not specified Hematopoietic: See Disease Characteristics Hepatic: Bilirubin no greater than 2 mg/dL unless secondary to tumor Renal: Creatinine no greater than 2.0 mg/dL Creatinine clearance at least 40 mL/min if creatinine is greater than 1.5 mg/dL Other: No other prior or concurrent malignancy within the past 2 years except basal cell carcinoma of the skin or carcinoma in situ of the cervix No active infection requiring oral or intravenous antibiotics Not pregnant or nursing Fertile patients must use effective contraception PRIOR CONCURRENT THERAPY: Biologic therapy: Not specified Chemotherapy: No prior cytotoxic chemotherapy Endocrine therapy: No prior steroid treatment for CLL Radiotherapy: Not specified Surgery: Not specified

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: cyclophosphamide|nan|
|Drug: fludarabine phosphate|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |

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