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 evaluated the feasibility and efficacy of dose intensification, accomplished through the concomitant use of G-CSF. Tn lower risk patients we are piloting a trial evaluating the role of thioguanine (in place of the standard agent, mercaptopurine) based on extensive preclinical studies that we have performed demonstrating that thioguanine is more potent and less schedule-dependent. 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 studying the utility of a new MTX rescue agent carboxypeptidase-G2 and we continue to be involved in the preclinical and clinical development of the retinoids.
