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Blood, 1 February 2005, Vol. 105, No. 3, pp. 940-947.
Prepublished online as a Blood First Edition Paper on October 14, 2004; DOI 10.1182/blood-2004-05-1933.
 Previous Article | Table of Contents | Next Article 
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
Stefan Faderl,
Varsha Gandhi,
Susan O'Brien,
Peter Bonate,
Jorge Cortes,
Elihu Estey,
Miloslav Beran,
William Wierda,
Guillermo Garcia-Manero,
Alessandra Ferrajoli,
Zeev Estrov,
Francis J. Giles,
Min Du,
Monica Kwari,
Michael Keating,
William Plunkett, and
Hagop Kantarjian
From the Departments of Leukemia and Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and ILEX Oncology, San Antonio, TX.
Clofarabine (2-chloro-2'-fluoro-deoxy-9- -D-arabinofuranosyladenine) is a second-generation nucleoside analog with activity in acute leukemias. As clofarabine is a potent inhibitor of ribonucleotide reductase (RnR), we hypothesized that clofarabine will modulate ara-c triphosphate accumulation and increase the antileukemic activity of cytarabine (ara-C). We conducted a phase 1-2 study of clofarabine plus ara-C in 32 patients with relapsed acute leukemia (25 acute myeloid leukemia [AML], 2 acute lymphoblastic leukemia [ALL]), 4 high-risk myelodysplastic syndrome (MDS), and 1 blast-phase chronic myeloid leukemia (CML).1 Clofarabine 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 platelet recovery (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 less than or equal to 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.
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