Clinical pharmacodynamic studies of high-dose methotrexate in acute lymphocytic leukemia

W. E. Evans, M. W.R. Abromowitch Crom, M. V. Relling, W. P. Bowman, C. H. Pui, J. Ochs, R. Dodge

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6 Scopus citations

Abstract

As the intensity of cancer chemotherapy has been reported to influence clinical response for several drug-sensitivity cancers, we have investigated the relation between systemic exposure to high-dose methotrexate (HDMTX) and clinical response in childhood acute lymphocytic leukemia (ALL). A total of 108 consecutive, previously untreated children with 'standard-intermediate risk' ALL were randomized to receive postinduction therapy with HDMTX (1000 mg/m2 iv over 24 hours weekly for 3 weeks, then every 6 weeks for 72 weeks), superimposed on conventional therapy with low-dose 6-mercaptopurine (6MP; 50 mg/m2 orally per day) and methotrexate (MTX; 25 mg/m2 orally per week). The systemic clearance of HDMTX ranged from 40 to 131 ml/minute/m2 among these patients, yielding MTX steady-state plasma concentrations (Cp(ss)) ranging from 9.3 to 25.4 μM during the infusion. The group of patients (n=59) with median MTX Cp(ss)<16 μM during the HDMTX infusion had a higher probability of having any relapse than patients (n=49) with MTX Cp(ss)>16 μM (P<0.05). In a previously reported univariate analysis, patients with MTX Cp(ss)≤16 μM were 3.2 times more likely to relapse on therapy (P=0.01) and 6.9 times more likely to have a hematologic relapse on therapy (P=0.001). Multivariate and stepwise Cox's regression analyses indicated that MTX Cp(ss) retains its prognostic importance even when other prognostic variables (i.e., DNA Index, WBC, hemoglobin) are considered. When Kaplan-Meier curves of the HDMTX trial (median follow-up>4 years) are compared to a St. Jude historical control of 258 children with ALL (median follow-up>7 years) receiving conventional 6MP and MTX maintenance (without HDMTX), only the group of patients with MTX Cp(ss)≥16 μM derived statistically significant benefit from the addition of high-dose MTX. This was true for both complete remission and hematologic remission curves. These results demonstrate the potential benefit of adding HDMTX to the maintenance therapy of childhood ALL, but indicate that a dose of 1000 mg/m2, given as a 24-hour infusion, may not be optimal for patients with reduced systemic exposure due to relatively fast drug clearance.

Original languageEnglish
Pages (from-to)81-85
Number of pages5
JournalNCI Monographs
Issue number5
StatePublished - 1987

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    Evans, W. E., Abromowitch Crom, M. W. R., Relling, M. V., Bowman, W. P., Pui, C. H., Ochs, J., & Dodge, R. (1987). Clinical pharmacodynamic studies of high-dose methotrexate in acute lymphocytic leukemia. NCI Monographs, (5), 81-85.