TY - JOUR
T1 - Shortening infusion time for high-dose methotrexate alters antileukemic effects
T2 - A randomized prospective: Clinical trial
AU - Mikkelsen, Torben S.
AU - Sparreboom, Alex
AU - Cheng, Cheng
AU - Zhou, Yinmei
AU - Boyett, James M.
AU - Raimondi, Susana C.
AU - Panetta, John C.
AU - Bowman, W. Paul
AU - Sandlund, John T.
AU - Pui, Ching Hon
AU - Relling, Mary V.
AU - Evans, William E.
PY - 2011/5/1
Y1 - 2011/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79955582395&partnerID=8YFLogxK
U2 - 10.1200/JCO.2010.32.5340
DO - 10.1200/JCO.2010.32.5340
M3 - Article
C2 - 21444869
AN - SCOPUS:79955582395
SN - 0732-183X
VL - 29
SP - 1771
EP - 1778
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 13
ER -