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, Hagop Kantarjian

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178 Scopus citations

Abstract

Clofarabine (2-chloro-2′-fluoro-deoxy-9-β-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 myejoid 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/m 2 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.

Original languageEnglish (US)
Pages (from-to)940-947
Number of pages8
JournalBlood
Volume105
Issue number3
DOIs
StatePublished - Feb 1 2005
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Faderl, S., Gandhi, V., O'Brien, S., Bonate, P., Cortes, J., Estey, E., Beran, M., Wierda, W., Garcia-Manero, G., Ferrajoli, A., Estrov, Z., Giles, F. J., Du, M., Kwari, M., Keating, M., Plunkett, W., & Kantarjian, H. (2005). Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood, 105(3), 940-947. https://doi.org/10.1182/blood-2004-05-1933