Chemotherapy in Treating Patients With Newly Diagnosed Chronic Lymphocytic Leukemia

OBJECTIVES:

• Compare the survival rate of patients with newly diagnosed chronic lymphocytic leukemia treated with chlorambucil alone vs fludarabine with or without cyclophosphamide.
• Compare the response rate and duration of remission in patients treated with these regimens.
• Compare the toxic effects of these regimens in these patients.
• Compare the quality of life of patients treated with these regimens.
• Determine the impact of the drug response information provided by the DiSC assay on response rate and survival in relapsed or nonresponding patients.
• Assess the prognostic value of five genetic markers: trisomy 12 and deletions at 11q23, 13q14, p53, and 6q21 in patients treated with these regimens.

OUTLINE: This is a randomized study. Patients enter one of three treatment arms in the first randomization. Depending on response, some patients may also participate in a second randomization to one of two treatment arms.

• First randomization:

• Arm I: Patients receive oral chlorambucil daily for 7 days. Treatment repeats every 4 weeks until maximum response or up to 1 year.
• Arm II: Patients receive fludarabine IV or orally daily for 5 days. Treatment repeats every 4 weeks for 3-8 courses.
• Arm III: Patients receive cyclophosphamide IV and fludarabine IV for 3 days or orally daily for 5 days. Treatment repeats every 4 weeks for 3-8 courses.

Patients who relapse after being in remission for at least 1 year may repeat the initial therapy or may participate in a second randomization. Patients who experience progressive disease or relapse within 1 year after treatment proceed to a second randomization.

• Second randomization:

• Arm I: Treatment is guided by the results of the DiSC assay. Treatment may be one of the first-line treatments with fludarabine or standard CHOP chemotherapy repeated every 4 weeks (cyclophosphamide IV, doxorubicin IV, vincristine IV, and oral prednisolone on days 1-5) or any other therapy guided by the results of the DiSC assay.
• Arm II: Treatment is physician's choice, which may include any of the options in arm I.

Quality of life is assessed prior to initial therapy; at 3, 6, and 12 months; and then annually thereafter.

Patients are followed annually for survival.

PROJECTED ACCRUAL: A total of 750 patients will be accrued for this study within 6-7 years.

DISEASE CHARACTERISTICS:

• Diagnosis of B-cell chronic lymphocytic leukemia (CLL) requiring therapy and meeting the following criteria:

• Previously untreated disease
• Peripheral blood morphology, excluding other leukemia and low-grade lymphoma in leukemic phase
• Cell markers: CD5+, CD23+, SmIg (weak), CD79b-, FMC7-
• Persistent lymphocytosis (greater than 10,000/mm^3)
• At least 40% bone marrow infiltration
• Stage 0 or I progressive disease indicated by at least one of the following:

• Persistent rise in lymphocyte count with doubling time less than 12 months
• Downward trend in hemoglobin and/or platelet count
• At least 50% increase in size of liver and/or spleen and/or lymph nodes
• Appearance of lymphadenopathy, hepatomegaly, or splenomegaly
• Constitutional symptoms caused by disease

• Pyrexia
• Night sweats
• Weight loss OR
• Stage II or III

PATIENT CHARACTERISTICS:

Age:

• Not specified

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin no greater than 2 times upper limit of normal (ULN)*
• SGOT/SGPT no greater than 2 times ULN* NOTE: * Unless due to CLL

Renal:

• Creatinine clearance at least 30 mL/min

Other:

• No other cancer or life-threatening disease
• Not pregnant
• Fertile patients must use effective contraception during and for 6 months after study therapy

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• No concurrent corticosteroids (e.g., dexamethasone) as antiemetics

Radiotherapy

• Not specified

Surgery

• Not specified