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Blood, 1 February 2004, Vol. 103, No. 3, pp. 784-789.
Prepublished online as a Blood First Edition Paper on October 9, 2003; DOI 10.1182/blood-2003-06-2122.
Submitted June 26, 2003
Accepted August 21, 2003
Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia
Sima Jeha*, Varsha Gandhi, Ka Wah Chan, Lisa McDonald, Irma Ramirez, Renee Madden, Michael Rytting, Mark Brandt, Michael Keating, William Plunkett, and Hagop Kantarjian
Department of Pediatrics, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
* Corresponding author; email: sjeha{at}mdanderson.org.
Background: Despite progress in leukemia therapy, most children who relapse have a dismal prognosis. New effective approaches are needed. We conducted a Phase I study of the novel nucleoside analog clofarabine in pediatric patients with refractory and relapsed leukemia. Methods: Clofarabine was infused intravenously over one hour daily for 5 days. Six dose levels between 11.25 and 70 mg/m2/day for five days were studied in 25 patients. A modified 3 + 3 phase I design was followed with 30% dose escalation until the dose-limiting toxicity (DLT) was defined. Results: The maximum tolerated dose (MTD) was 52 mg/m2/day x five days. At the end of infusion at MTD, clofarabine triphosphate levels in leukemia blasts varied between 6 and 19µM, which resulted in complete and sustained inhibition of DNA synthesis. The DLT was reversible hepatotoxicity and skin rash at 70 mg/m2/day x 5. Twenty-five patients were treated. Five patients achieved a complete remission (CR) and three had a partial remission (PR), for an overall response rate of 32%. Conclusions: Clofarabine is well tolerated and shows significant antileukemic activity in heavily pretreated children. Multicenter phase II trials in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are ongoing.
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