TY - JOUR
T1 - Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia
AU - Jeha, Sima
AU - Gandhi, Varsha
AU - Chan, Ka Wah
AU - McDonald, Lisa
AU - Ramirez, Irma
AU - Madden, Renee
AU - Rytting, Michael
AU - Brandt, Mark
AU - Keating, Michael
AU - Plunkett, William
AU - Kantarjian, Hagop
PY - 2004/2/1
Y1 - 2004/2/1
N2 - 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 μM and 19 μM, which resulted in complete and sustained inhibition of DNA synthesis. The DLT was reversible hepatotoxicity and skin rash at 70 mg/m2 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.
AB - 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 μM and 19 μM, which resulted in complete and sustained inhibition of DNA synthesis. The DLT was reversible hepatotoxicity and skin rash at 70 mg/m2 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.
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U2 - 10.1182/blood-2003-06-2122
DO - 10.1182/blood-2003-06-2122
M3 - Article
C2 - 14551141
AN - SCOPUS:9144222570
SN - 0006-4971
VL - 103
SP - 784
EP - 789
JO - Blood
JF - Blood
IS - 3
ER -