Shortening infusion time for high-dose methotrexate alters antileukemic effects: a randomized prospective clinical trial.

To determine whether shortening the infusion duration of high-dose methotrexate (HDMTX; 1 g/m(2)) affects the in vivo accumulation of active methotrexate polyglutamates (MTXPG(1-7)) in leukemia cells and whether this differs among major acute lymphoblastic leukemia (ALL) subtypes.
From June 2000 through October 2007, 356 children with ALL were randomly assigned to receive initial single-agent treatment with HDMTX (1 g/m(2)) 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 MTXPG(1-7) 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).
The 24-hour infusion resulted in significantly higher amounts of MTXPG(1-7) in bone marrow leukemia cells (median: 1,695 v 1,150 pmol/10(9) 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/10(9) cells, P = .0038); T-cell ALL exhibited smaller differences in MTXPG(1-7) 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 MTXPG(1-7) accumulation or antileukemic effects in ALL with the t(12;21)/(ETV6-RUNX1) chromosomal translocation.
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.
AuthorsTorben 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
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 29 Issue 13 Pg. 1771-8 (May 1 2011) ISSN: 1527-7755 [Electronic] United States
PMID21444869 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antimetabolites, Antineoplastic
  • Purines
  • Polyglutamic Acid
  • methotrexate polyglutamate
  • purine
  • Methotrexate
  • Adolescent
  • Antimetabolites, Antineoplastic (administration & dosage, pharmacokinetics)
  • Child, Preschool
  • Drug Administration Schedule
  • Humans
  • Infant
  • Methotrexate (administration & dosage, analogs & derivatives, pharmacokinetics)
  • Polyglutamic Acid (analogs & derivatives, pharmacokinetics)
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism)
  • Purines (biosynthesis)

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