Phase III Randomized Trial of Fludarabine and Cyclophosphamide Versus Fludarabine for Previously Untreated 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.