CONCOMITANT ADMINISTRATION OF CHLORAMBUCIL LIMITS DOSE INTENSITY OF FLUDARABINE IN PREVIOUSLY TREATED PATIENTS WITH CHRONIC LYMPHOCYTIC-LEUKEMIA

Fifteen patients with chronic lymphocytic leukemia (CLL) were treated in a phase I-II study of chlorambucil with an escalating dose of fluda rabine. The study was designed to identify a maximum tolerated dose (M TD) of fludarabine given in conjunction with a constant dose of chlora mbucil. Patients were eligible for study if they had Rai intermediate or high-risk disease which had relapsed from or was refractory to conv entional treatment. The initial cohort of patients received fludarabin e 10 mg/m(2)/d days 1-5 and chlorambucil 20 mg/m(2) days 1 and 15. Cyc les were repeated every 28 days. Unacceptable toxicity was encountered in this cohort. The protocol was then modified to give chlorambucil 2 0 mg/m(2) on day 1 (only). At this chlorambucil dose, cohorts of three patients were treated with fludarabine 10, 15, and 20 mg/m(2)/d x 5 d ays. The predominant toxicity was thrombocytopenia with 73% experienci ng grade greater than or equal to 3 toxicity. The dose-limiting non-he matologic toxicity was infection. We identified an MTD of fludarabine of 15 mg/m(2)/d x 5 days when given with chlorambucil 20 mg/m(2) for t his group of patients. One patient achieved a CR and three patients ac hieved a PR for a total response rate of 27%. We conclude that concomi tant administration of chlorambucil limits the dose intensity of fluda rabine which can be administered to previously treated patients with C LL.