Clinical pharmacodynamics of high-dose methotrexate in acute lymphocytic leukemia. Identification of a relation between concentration and effect

N Engl J Med. 1986 Feb 20;314(8):471-7. doi: 10.1056/NEJM198602203140803.


High-dose methotrexate (500 to 33,600 mg per square meter of body-surface area) with leucovorin rescue is a common component of therapy for acute lymphocytic leukemia. To increase understanding of the relation between the serum concentration and the effect of methotrexate, we conducted a randomized, prospective study of 108 children with "standard-risk" acute lymphocytic leukemia who were treated with 15 doses of methotrexate (1000 mg per square meter) that were infused over 24 hours. The median length of follow-up was 3.5 years from diagnosis for patients still in remission. Variability between patients in methotrexate clearance produced steady-state serum concentrations that ranged from 9.3 to 25.4 microM. Patients with median methotrexate concentrations of less than 16 microM (n = 59) had a lower probability of remaining in remission (P less than 0.05) than patients with concentrations of 16 microM or more (n = 49). Multivariate analyses indicated that patients with methotrexate concentrations of less than 16 microM were 3 times more likely to have any kind of relapse during therapy (P = 0.01) and 7 times more likely to have a hematologic relapse during therapy (P = 0.001). Stepwise Cox's regression identified leukemic-cell DNA content, methotrexate concentration, and hemoglobin as significant prognostic variables for hematologic relapse (P = 0.0005). We conclude that there is a concentration-effect relation for high-dose methotrexate in acute lymphocytic leukemia and that 1000 mg per square meter infused over a period of 24 hours may not be optimal for patients with relatively fast drug clearance.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adolescent
  • Analysis of Variance
  • Child
  • Child, Preschool
  • DNA, Neoplasm / analysis
  • Dose-Response Relationship, Drug
  • Female
  • Flow Cytometry
  • Hemoglobins / analysis
  • Humans
  • Infant
  • Infusions, Parenteral
  • Leukemia, Lymphoid / blood
  • Leukemia, Lymphoid / drug therapy*
  • Leukocyte Count
  • Male
  • Metabolic Clearance Rate
  • Methotrexate / administration & dosage*
  • Methotrexate / blood
  • Prospective Studies
  • Random Allocation
  • Recurrence


  • DNA, Neoplasm
  • Hemoglobins
  • Methotrexate