Chronic Lymphocytic Leukemia Trial 4: A Randomized Comparison of Chlorambucil, Fludarabine and Fludarabine Plus Cyclophosphamide

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.