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/m2/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.