Shortening infusion time for high-dose methotrexate alters antileukemic effects: A randomized prospective: Clinical trial

Torben S. Mikkelsen, Alex Sparreboom, Cheng Cheng, Yinmei Zhou, James M. Boyett, Susana C. Raimondi, John C. Panetta, W. Paul Bowman, John T. Sandlund, Ching Hon Pui, Mary V. Relling, William E. Evans

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33 Scopus citations

Abstract

Purpose: To determine whether shortening the infusion duration of high-dose methotrexate (HDMTX; 1 g/m2) affects the in vivo accumulation of active methotrexate polyglutamates (MTXPG1-7) in leukemia cells and whether this differs among major acute lymphoblastic leukemia (ALL) subtypes. Methods: From June 2000 through October 2007, 356 children with ALL were randomly assigned to receive initial single-agent treatment with HDMTX (1 g/m2) as either a 24-hour infusion or a 4-hour infusion at two pediatric hospitals in the United States. The primary outcome measures were the accumulation of MTXPG1-7 in leukemia cells and the antileukemic effects (eg, inhibition of de novo purine synthesis in bone marrow ALL cells, and decrease in circulating ALL cells). Results: The 24-hour infusion resulted in significantly higher amounts of MTXPG1-7 in bone marrow leukemia cells (median: 1,695 v 1,150 pmol/109 cells, P = .0059), and better antileukemic effects. The 24-hour infusion had the greatest effect on MTXPG 1-7 accumulation in hyperdiploid ALL (median: 3,919 v 2,417 pmol/109 cells, P = .0038); T-cell ALL exhibited smaller differences in MTXPG1-7 but greater antileukemic effects with the longer infusion (median decrease in leukemia cells: 88.4% v 51.8%, P = .0075). In contrast, infusion duration had no significant impact on MTXPG1-7 accumulation or antileukemic effects in ALL with the t(12;21)/(ETV6-RUNX1) chromosomal translocation. Conclusion: Shortening the infusion time of HDMTX reduces accumulation of active methotrexate in leukemia cells and decreases antileukemic effects, with differing consequences among major ALL subtypes.

Original languageEnglish
Pages (from-to)1771-1778
Number of pages8
JournalJournal of Clinical Oncology
Volume29
Issue number13
DOIs
StatePublished - 1 May 2011

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    Mikkelsen, T. S., Sparreboom, A., Cheng, C., Zhou, Y., Boyett, J. M., Raimondi, S. C., Panetta, J. C., Bowman, W. P., Sandlund, J. T., Pui, C. H., Relling, M. V., & Evans, W. E. (2011). Shortening infusion time for high-dose methotrexate alters antileukemic effects: A randomized prospective: Clinical trial. Journal of Clinical Oncology, 29(13), 1771-1778. https://doi.org/10.1200/JCO.2010.32.5340