Cytarabine (Ara-C) in Relapsed and Refractory Acute Leukemias

ABSTRACT Clofarabine is a second-generation nucleoside analogue with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-CTP accumulation and increase the antileukemic activity of ara-C. We conducted a phase I-II study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 AML, 2 ALL), high-risk MDS (4), and blast phase CML (1). Clofarabine was given as a 1-hour i.v. infusion x 5 days (d 2-6) followed 4 hours later by ara-C at 1 g/m 2 /d as a 2-hour i.v. infusion x 5 days (d 1-5). 40 mg/m 2 /d x 5 days was chosen as the phase II dose of clofarabine. Among all patients, 7 (22%) achieved CR, and 5 (16%) CRp, for an overall response rate of 38%. No responses occurred in 3 patients with ALL and CML. One patient (3%) died during induction. Adverse events were mainly grade 2 including transient liver test abnormalities, nausea/vomiting, diarrhea, skin rashes, mucositis, and palmoplantar erythrodysesthesias. Plasma clofarabine levels generated clofarabine triphosphate accumulation, which resulted in an increase in ara-CTP in the leukemic blasts. The combination of clofarabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy. (Word count: 199) From bloodjournal.hematologylibrary.org by guest on June 6, 2013. For personal use only.