Clofarabine a novel nucleoside analog is active in pediatric patients with advanced leukemia
From the Departments of Pediatrics, Experimental Therapeutics, and Leukemia, University of Texas MD Anderson Cancer Center, Houston.k*wm, 百拇医药
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/m2 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/m2 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.(Sima Jeha Varsha Gandhi Ka Wah Chan Lisa McDonald Irma Ramirez Renee Madden Michael Rytting Mark Bra)
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/m2 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/m2 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.(Sima Jeha Varsha Gandhi Ka Wah Chan Lisa McDonald Irma Ramirez Renee Madden Michael Rytting Mark Bra)