Prolonged methotrexate infusions in children with acute leukemia in relapse and in remission and with medulloblastoma. Pharmacokinetics, toxicity and clinical results.

In 86 children with acute lymphocytic leukemia (ALL) and in 6 children with medulloblastoma 253 24-hour methotrexate (MTX) infusions with 150, 500, and 700 mg/m2 were performed. MTX concentrations in plasma and cerebrospinal fluid (CSF) were measured with a specific radioimmunoassay. In 131 infusions with 500 mg/m2 given to patients with ALL in remission, the MTX plasma concentration 24 h after the end of infusion did not exceed 7 X 10(-7) mol/1. Mild hematologic toxicity occurred in 22% of the treatment cycles. In contrast 8/45 infusions given to patients with ALL in relapse were associated with delayed MTX elimination followed by severe toxicity. The CSF: plasma ratio of MTX measured during 58 infusions did not exceed 11% in patients with ALL in remission, but was above this value in 13/34 infusions in patients with leukemia of the central nervous system (CNS). 24-hour MTX infusions with 500 mg/m2 were as hepatotoxic as 4- to 6-hour infusions with 3-8.5 g/m2. With MTX as single agent no remissions were achieved in 8 patients with ALL in relapse. The addition of asparaginase in 10 patients resulted in 3 complete and 2 partial remissions. In patients with ALL in first remission clinical results confirmed the value of intensive MTX therapy for disease-free survival.