Intermediate-dose Cytarabine Treatment Delivered at Moderate Infusion Rates for De Novo Acute Myeloid Leukemia-Results of a phase I-II Study

Published randomized trials on different cytarabine doses for the treatment of acute myeloid leukemia (AML) provide evidence of a dose-response effect. However, high-dose cytarabine (HIDAC) regimens correlate with increased morbidity and toxicity related mortality. Typical HIDAC regimens deliver 6 g/m 2 /d in infusion rates of 500-3000 mg/m 2 /h. However, pharmacokinetic measurements indicate that intracellular Ara-CTP formation is saturated at lower infusion rates than used in HIDAC schedules, probably causing cytarabine accumulation in the plasma and increased toxicity. It was our objective to investigate in a prospective non-randomized phase I-II study feasibility and efficacy of intermediate doses of cytarabine delivered at the presumptive saturating moderate infusion rate (mir-IDAC), as induction therapy in order to optimize intensified treatment for acute myeloid leukemia. Forty previously untreated patients younger than 60 years of age with de novo AML received intermediate doses of cytarabine (2-4 g/m 2 /d) at moderate infusion rates (250-667 mg/m 2 /h) over 6 or 8 h. Cytarabine was applied on alternate days (day 1, 3, 5, 7) in combination with an anthracycline as induction and consolidation therapy. Thirty-two of the 40 patients (80%, 95%CI:64-91%) achieved CR after induction treatment. Treatment-related mortality during induction chemotherapy was 2.5%. No cerebellar toxicity was observed. After two to four mir-IDAC courses stem cell harvesting was successful in 71% of the patients eligible for high-dose chemotherapy. After three years 56% (95%CI:40-72%) of all patients are alive and 59% (95%CI:42-76%) of the patients who entered CR are free of leukemia. In conclusion, favorable long-term outcomes and moderate acute toxicities were observed in patients with de novo AML treated with IDAC schedules delivered at moderate infusion rates (mir-IDAC) starting as induction treatment. The data suggest that a randomized trial should now be undertaken to examine whether mir-IDAC has clinical advantages over HIDAC.