Clinical Pharmacodynamics of High-Dose Methotrexate in Acute Lymphocytic Leukemia

William E. Evans, William R. Crom, Minnie Abromowitch, Richard Dodge, A. Thomas Look, W. Paul Bowman, Stephen L. George, Ching Hon Pui

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Abstract

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 μM. Patients with median methotrexate concentrations of less than 16 μM (n = 59) had a lower probability of remaining in remission (P<0.05) than patients with concentrations of 16 μM or more (n = 49). Multivariate analyses indicated that patients with methotrexate concentrations of less than 16 μM 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. (N Engl J Med 1986; 314:471–7.), VARIOUS studies have shown that the intensity of cancer chemotherapy, as measured by either drug dosage or dose rate, can significantly affect the clinical outcome in patients with some drug-sensitive cancers, including breast cancer,1,2 Hodgkin's and non-Hodgkin's lymphoma,3 4 5 small-cell carcinoma of the lung,6 and childhood acute lymphocytic leukemia.7 In those investigations, patients who were given full-dose chemotherapy or a larger percentage of the chemotherapy planned for them responded better than those given half doses or a lower percentage of planned chemotherapy. For most anticancer drugs, the maximum dosage is determined by host tolerance to adverse effects. One exception is methotrexate.

Original languageEnglish (US)
Pages (from-to)471-477
Number of pages7
JournalNew England Journal of Medicine
Volume314
Issue number8
DOIs
StatePublished - Feb 20 1986

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Methotrexate
Drug Therapy
Recurrence
Pharmaceutical Preparations
Breast Neoplasms
Leucovorin
Body Surface Area
Small Cell Lung Carcinoma
Serum
Hodgkin Disease
Non-Hodgkin's Lymphoma
Hemoglobins
Therapeutics
Multivariate Analysis
Prospective Studies
DNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Clinical Pharmacodynamics of High-Dose Methotrexate in Acute Lymphocytic Leukemia. / Evans, William E.; Crom, William R.; Abromowitch, Minnie; Dodge, Richard; Look, A. Thomas; Bowman, W. Paul; George, Stephen L.; Pui, Ching Hon.

In: New England Journal of Medicine, Vol. 314, No. 8, 20.02.1986, p. 471-477.

Research output: Contribution to journalArticle

Evans, WE, Crom, WR, Abromowitch, M, Dodge, R, Look, AT, Bowman, WP, George, SL & Pui, CH 1986, 'Clinical Pharmacodynamics of High-Dose Methotrexate in Acute Lymphocytic Leukemia', New England Journal of Medicine, vol. 314, no. 8, pp. 471-477. https://doi.org/10.1056/NEJM198602203140803
Evans, William E. ; Crom, William R. ; Abromowitch, Minnie ; Dodge, Richard ; Look, A. Thomas ; Bowman, W. Paul ; George, Stephen L. ; Pui, Ching Hon. / Clinical Pharmacodynamics of High-Dose Methotrexate in Acute Lymphocytic Leukemia. In: New England Journal of Medicine. 1986 ; Vol. 314, No. 8. pp. 471-477.
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abstract = "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 μM. Patients with median methotrexate concentrations of less than 16 μM (n = 59) had a lower probability of remaining in remission (P<0.05) than patients with concentrations of 16 μM or more (n = 49). Multivariate analyses indicated that patients with methotrexate concentrations of less than 16 μM 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. (N Engl J Med 1986; 314:471–7.), VARIOUS studies have shown that the intensity of cancer chemotherapy, as measured by either drug dosage or dose rate, can significantly affect the clinical outcome in patients with some drug-sensitive cancers, including breast cancer,1,2 Hodgkin's and non-Hodgkin's lymphoma,3 4 5 small-cell carcinoma of the lung,6 and childhood acute lymphocytic leukemia.7 In those investigations, patients who were given full-dose chemotherapy or a larger percentage of the chemotherapy planned for them responded better than those given half doses or a lower percentage of planned chemotherapy. For most anticancer drugs, the maximum dosage is determined by host tolerance to adverse effects. One exception is methotrexate.",
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