CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias

D-arabinofuranosyladenine) is a second-generation nucleoside analog with activ-ity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reduc-tase (RnR), we hypothesized that clofara-bine will modulate ara-c triphosphate ac-cumulation and increase the antileukemic activity of cytarabine (ara-C). We con-ducted a phase 1-2 study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 acute myeloid leuke-mia [AML], 2 acute lymphoblastic leuke-mia [ALL]), 4 high-risk myelodysplastic syndrome (MDS), and 1 blast-phase chronic myeloid leukemia (CML).1 Clofara-bine was given as a 1-hour intravenous infusion for 5 days (days 2 through 6) followed 4 hours later by ara-C at 1 g/m2 per day as a 2-hour intravenous infusion for 5 days (days 1 through 5). The phase 2 dose of clofarabine was 40 mg/m2 per day for 5 days. Among all patients, 7 (22%) achieved complete remission (CR), and 5 (16%) achieved CR with incomplete plate-let recovery (CRp), for an overall re-sponse rate of 38%. No responses oc-curred in 3 patients with ALL and CML. One patient (3%) died during induction. Adverse events were mainly less than or equal to grade 2, including transient liver test abnormalities, nausea/vomiting, diar-rhea, skin rashes, mucositis, and palmo-plantar erythrodysesthesias. Plasma clo-farabine levels generated clofarabine triphosphate accumulation, which re-sulted in an increase in ara-CTP in the leukemic blasts. The combination of clo-farabine with ara-C is safe and active. Cellular pharmacology data support the biochemical modulation strategy. (Blood