Clofarabine in adult acute leukemias: Clinical success and pharmacokinetics

Clofarabine is a deoxyadenosine analog synthesized with the intention of retaining the favorable mechanistic properties of fludarabine and cladribine while eliminating their undesirable characteristics. Phase I studies among 32 patients with acute leukemia defined a maximum tolerated dose (MTD) of 40 mg/m(2)/d given as a one hour infusion daily for 5 days. The dose limiting toxicity (DLT) was transient hepatotoxicity. In a phase II study, 62 patients with acute leukemias received clofarabine at the MTD over 1 hour daily for 5 days. Twenty patients (32%) achieved complete response (CR), 1 had a partial response (PR), and 9 had a CR but without platelet recovery (CRp), for an overall response rate of 48%. Pharmacokinetic studies in the phase I trial revealed marked heterogeneity in peak levels of clofarabine among patients at the end of infusion, however; there was a linear, dose dependent increase in clofarabine concentration in the plasma. Pharmacodynamically, at the MTD, DNA synthesis was inhibited by more than 80% at the end of infusion. In phase II studies, the relationship between the pharmacokinetics of clofarabine triphosphate accumulation and clinical response at the MTD was explored, revealing an accumulation advantage of the cytotoxic triphosphate in leukemia cells of responders. The circulating leukemia blasts of patients who respond to clofarabine therapy exhibited a favorable pharmacokinetic profile. In conclusion, clofarabine is an active agent in the treatment of acute leukemias and MDS, and cellular pharmacokinetics has prognostic significance.