FCR or BR in Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia

OBJECTIVES:

• To compare the therapeutic efficacy of fludarabine phosphate, cyclophosphamide, and rituximab vs bendamustine hydrochloride and rituximab in patients with previously untreated B-cell chronic lymphocytic leukemia.
• To compare the incidence of major side effects (e.g., myelosuppression) associated with these regimens in these patients.
• To compare the rate of infections and secondary neoplasias in patients treated with these regimens.

OUTLINE: This is a multicenter study. Patients are stratified according to country and disease stage. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive fludarabine phosphate IV and cyclophosphamide IV on days 1-3. Patients also receive rituximab IV on day 0 of course 1 and on day 1 of courses 2-6. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive bendamustine hydrochloride IV on days 1 and 2. Patients also receive rituximab as in arm I. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients complete quality of life questionnaires (EORTC-C30 and EURO-QOL) at baseline and then at 12, 24, 36, 48, and 60 months.

After completion of study therapy, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then once a year thereafter.

DISEASE CHARACTERISTICS:

• Confirmed diagnosis of B-cell chronic lymphocytic leukemia (CLL) meeting 1 of the following criteria:
• Binet stage C disease or stage B or A disease requiring treatment
• Binet stage B or A disease meeting ≥ 1 of the following:
• B-symptoms (e.g., night sweats, weight loss ≥ 10% within the past 6 months, fevers > 38°C or 100.4°F for ≥ 2 weeks without evidence of infection) or constitutional symptoms (e.g., fatigue)

• Progressive lymphocytosis, defined as peripheral lymphocyte count > 5 x 10^9/L (i.e., > 50% increase over a 2-month period or doubling of peripheral blood lymphocyte count < 6 months)
• 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) or progressive or symptomatic lymphadenopathy

• No 17p deletion by FISH
• No aggressive B-cell cancer, such as Richter syndrome

PATIENT CHARACTERISTICS:

• WHO performance status 0-2
• Life expectancy ≥ 6 months
• Total bilirubin ≤ 2 times upper limit of normal (ULN) (unless directly attributable to CLL)
• AST and ALT ≤ 2 times ULN (unless directly attributable to CLL)
• Creatinine clearance ≥ 70 mL/min (creatinine clearance is to be calculated only in patients with serum creatinine ≥ 1.1 mg/dL)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 6 months after completion of study therapy
• Hepatitis B and C negative
• HIV negative
• CIRS score > 6 or a single score of 4 for one organ category
• No active secondary malignancy requiring treatment, except basal cell carcinoma or malignant tumor curatively treated by surgery, or successfully treated secondary malignancies in complete remission > 5 years prior to enrollment
• No history of anaphylaxis following exposure to monoclonal antibodies
• No active bacterial, viral, or fungal infection
• No medical condition requiring prolonged use of oral corticosteroids (i.e., > 1 month)
• No cerebral dysfunction or legal incapacity
• No circumstance that would preclude completion of the study or the required follow-up

PRIOR CONCURRENT THERAPY:

• No prior CLL specific-chemotherapy, radiotherapy, and/or immunotherapy

• Prednisolone administered immediately prior to initiation of study therapy allowed for very high lymphocyte counts
• No concurrent participation in another clinical trial