title: Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia.
abstract: Despite progress in leukemia therapy, most children who experience relapse have a dismal prognosis. New, effective approaches are needed. We conducted a phase 1 study of a novel nucleoside analog, clofarabine, in pediatric patients with refractory and relapsed leukemia. Clofarabine was infused intravenously over 1 hour each day for 5 days. Six dose levels, between 11.25 and 70 mg/m(2) per day for 5 days, were studied in 25 patients. A modified 3 + 3 phase 1 design was followed with 30% dose escalation until the dose-limiting toxicity (DLT) was defined. The maximum tolerated dose (MTD) was 52 mg/m(2) per day for 5 days. At the end of infusion at MTD, clofarabine triphosphate levels in leukemia blasts varied between 6 microM and 19 microM, which resulted in complete and sustained inhibition of DNA synthesis. The DLT was reversible hepatotoxicity and skin rash at 70 mg/m(2) per day for 5 days. Twenty-five patients were treated. Five patients achieved complete remission (CR), and 3 achieved partial remission (PR), for an overall response rate of 32%. Clofarabine is well tolerated and shows significant antileukemic activity in heavily pretreated children. Multicenter phase 2 trials in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are ongoing.
authors.affiliation: Department of Hematology-Oncology, St Jude Children's Research Hospital, 332 N Lauderdale St, Memphis, TN 38105, USA. sima.jeha@stjude.org
authors.forename: Sima
authors.initials: S
authors.lastname: Jeha
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.forename: Ka Wah
authors.initials: KW
authors.lastname: Chan
authors.forename: Lisa
authors.initials: L
authors.lastname: McDonald
authors.forename: Irma
authors.initials: I
authors.lastname: Ramirez
authors.forename: Renee
authors.initials: R
authors.lastname: Madden
authors.forename: Michael
authors.initials: M
authors.lastname: Rytting
authors.forename: Mark
authors.initials: M
authors.lastname: Brandt
authors.forename: Michael
authors.initials: M
authors.lastname: Keating
authors.forename: William
authors.initials: W
authors.lastname: Plunkett
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
mesh_terms: D000227:Adenine Nucleotides; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001087:Arabinonucleosides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D000077866:Clofarabine; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004361:Drug Tolerance; D005260:Female; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D001087:Arabinonucleosides; D004273:DNA, Neoplasm; D000077866:Clofarabine