Studies of childhood acute lymphoblastic leukemia (ALL) focus on the development of more effective and less toxic treatment regimens for the prevention of CNS leukemia and the therapy of patients with high risk prognostic features; and investigation of the clinical pharmacology of antileukemic drugs to identify more rational approaches to their use and develop new antileukemic agents. Our clinical trials have identified alternative CNS preventive regimens (chemotherapy-based) that are as efficacious and less neurotoxic than the standard regimen of cranial radiation and intrathecal methotrexate. Our current trial in high risk patients is evaluating the feasibility and efficacy of dose intensification, accomplished through the concomitant use of G-CSF. In relapsed patients we have concentrated on the development of new systemic and intrathecal agents. We have conducted a number of studies to evaluate the biochemical pharmacology, pharmacodynamics, and pharmacokinetics of antileukemic agents used for maintenance therapy in ALL. A prospective study of the bioavailability of oral mercaptopurine (MP) and methotrexate (MTX) maintenance therapy in a large cohort of low and average patients revealed considerable inter- and intra-patient variability of plasma drug concentrations with both agents (MP> MTX), a poor correlation between dose and plasma drug exposure, and no relationship between plasma drug levels and disease outcome. Laboratory studies of the cytotoxicity and biochemical pharmacology of the thiopurines have provided new insights into their clinical use. We are also continuing to pursue methods of chemosensitivity testing for lymphoblasts from patients as a means of individualizing therapy. In our long term follow-up studies of survivors we are documenting and characterizing the adverse sequelae of antileukemic therapy. Finally, we are facilitating studies of the molecular characterization of ALL aimed at improving our basic understanding of the biology of this disease, identifying new diagnostic and prognostic tests and providing insight into the biologic basis for treatment failure.
