Defining the optimal dosage of methotrexate for childhood acute lymphoblastic leukemia. New insights from the lab and clinic.

Abstract

Until recently, relatively little was known about the intracellular disposition of methotrexate (MTX) in leukemic lymphoblasts in patients. One reason for the paucity of such data is the unavailability of blast cells after the initial 2–4 weeks of chemotherapy, at which time >95% of patients have achieved a complete remission. In the absence of cellular pharmacokinetic and pharmaco-dynamic studies in patients, selection of the optimal dosage, route, and schedule of antileukemic drugs must be based largely on imprecise clinical results and less than optimal preclinical models. For the past forty years, the dosage of MTX for children with acute lymphoblastic leukemia (ALL) has evolved largely on an empirical basis, such that today there is more than a 100-fold range in MTX dosages being used in different ALL treatment protocols worldwide (Table 1). Furthermore, childhood ALL comprises specific lineage and genetic subtypes that differ in their response to modern treatment protocols, yet little or no distinction is made for these differences in determining the dosage of MTX. This brief overview summarizes a series of clinical studies conducted at St. Jude Children’s Research Hospital, focused on the intracellular disposition and effects of methotrexate in leukemic lymphoblasts of children with newly diagnosed ALL.