Modulation of Ara-C Metabolism by Fludarabine: Therapy for Acute Myelogenous Leukemia

Abstract

Despite significant progress in the treatment of acute myelogenous leukemia (AML), about 70% of patients who achieve complete remission with induction therapy relapse [1,2]. The prognosis of patients with AML who relapse is ominous. The remission rates are less than 30% in first salvage and less than 10% in subsequent salvages [3]. The incidence of long-term survivors in AML is less than 5% after relapse [3,4]. This stresses the need for new active agents and combination therapies to improve the response. The most effective therapy for AML includes arabinosylcytosine (ara-C), which must be anabolized to its active 5′-triphosphate (araCTP). A strong relationship has been demonstrated between clinical response and the pharmacokinetics and pharmacodynamics of ara-CTP in leukemia cells of patients receiving high-dose ara-C therapy for acute leukemia in relapse [5,6]. Similar trends were observed for patients with chronic myelogenous leukemia in blast crisis (CML-BC) after treatment with high-dose ara-C [7]. In patients with relapsed acute leukemia treated with high-dose ara-C, the half-life of ara-CTP elimination from cells, the trough concentration, and the total intracellular exposure to ara-CTP (the area under the accumulation and retention curve, AUC) were each correlated with the likelihood of achieving complete remission [5,6,8].