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

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.

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