Clinical and pharmacokinetic study of clofarabine in chronic lymphocytic leukemia: Strategy for treatment

Purpose: Based on its mechanistic similarity to fludarabine and cladribine and the success of these analogues for treatment of chronic lymphocyttc leukemia (CLL), we hypothesized that clofarabine would be effective for indolent leukemias, The present study was conducted to determine the efficacy and cellular pharmacology during clinical trials of single-agent clofarabine in CLL. Experimental Design: Previously treated patients with relapsed/refractory CLL were eligible for this study. Clofarabine was infused over 1 hour daily for 5 days. Most patients received 3 or 4 mg/m²/d × 5 days, whereas the other two were treated with 15 mg/m²/d × 5 days. Clinical outcome and associated pharmacologic end points were assessed. Results: Myelosuppression limited the maximum tolerated dose of clofarabine to 3 mg/m²/d on this schedule. Cellular pharmacokinetic studies showed a median clofarabine triphosphate concentration in CLL lymphocytes of 1.5 μmol/L (range, 0.2-2.3 μmol/L; n = 9). In the majority of cases, >50% of the analogue triphosphate was present 24 hours after infusion, indicattng prolonged retention of the triphosphate in CLL cells. Although cytoreduction was observed, no patients achieved a response. In vitro clofarabine incubation of leukemic lymphocytes from 29 CLL patients showed that clofarabine monophosphate accumulated to a higher concentration compared with the triphosphate. Nonetheless, the triphosphate increased in a dose-dependent fashion and upon successive clofarabine infusions, suggesting benefit from greater doses given at less frequent intervals. Conclusion: Levels of clofarabine triphosphate at higher doses and prolonged maintenance of clofarabine triphosphate in leukemic lymphocytes provide a rationale to treat CLL in a weekly clofarabine schedule.