PURPOSEA protocol was designed to test the hypothesis that fludarabine infusion before arabinosylcytosine (cytarabine [ara-C]) would increase the accumulation of the active metabolite ara-C triphosphate (ara-CTP) in acute myelogenous leukemia (AML) blasts during therapy.PATIENTS AND METHODSPatients (n = 5) received 1 g/m2 of ara-C infused intravenously (IV) for 2 hours, followed at 20 hours by 30 mg/m2 of fludarabine for 30 minutes. At 24 hours, another identical dose of ara-C was infused. To determine the optimal duration of ara-C infusion following fludarabine, five additional patients were treated on an amended protocol in which the ara-C infusion was extended to 3 g/m2 infused over 6 hours.RESULTSComparison of ara-CTP pharmacokinetics in circulating AML cells demonstrated that the area under the curve (AUC) of ara-CTP increased significantly (median, 1.8-fold; range, 1.6 to 2.4; P = .004) after fludarabine infusion. Neither the median plasma ara-C concentrations, the levels of its deamination product ...