Methotrexate polyglutamation may lack prognostic significance in children with B-cell precursor acute lymphoblastic leukemia treated with intensive oral methotrexate

Elpis Mantadakis, Angela K. Smith, Linda Hynan, Naomi J. Winick, Barton A. Kamen

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10 Citations (Scopus)

Abstract

Background: The purpose of this study was to determine if a correlation exists between clinical outcome and accumulation and polyglutamation of methotrexate by lymphoblasts in vitro in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Patients and Methods: The amount of accumulated methotrexate and of long-chain methotrexate polyglutamates (MTXPG3-7) by lymphoblasts was determined in 52 children newly diagnosed with BCP-ALL after incubation with 1 μmol/L [3H]MTX for 24 hours in vitro. All patients then received intensive multiagent chemotherapy that used divided-dose oral methotrexate during consolidation and intensive continuation and standard oral weekly methotrexate during maintenance. Results: Eight patients had a bone marrow relapse at a median of 40.4 months (range 18.5-48.3 months) after diagnosis. The median follow-up for the remaining 44 patients is 69.0 months (range 22-92.8 months). There was no significant difference in the amount of accumulated methotrexate (1450.0 ± 896.3 vs. 640 ± 472.5 pmol/109 cells) or of accumulated MTXPG3-7 (1450.0 ± 919.4 vs. 617.4 ± 482.7 pmol/109 cells) (median ± semiinterquartile ranges) between patients who relapsed and those who remained in continuous complete remission. The estimated 5-year event-free survival rate for patients whose lymphoblasts accumulated more than 500 pmol MTXPG3-7/109 cells was 80.0% ± 7.3% versus 90.5% ± 6.4% for those whose lymphoblasts accumulated less than 500 pmol MTXPG3-7/109 cells. Conclusions: In the context of effective prolonged divided-dose oral methotrexate-based therapy in the treatment of BCP-ALL, methotrexate accumulation and polyglutamation no longer seem to have prognostic significance.

Original languageEnglish (US)
Pages (from-to)636-642
Number of pages7
JournalJournal of Pediatric Hematology/Oncology
Volume24
Issue number8
DOIs
StatePublished - Nov 2002

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B-Lymphoid Precursor Cells
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Methotrexate
Disease-Free Survival
Survival Rate
Bone Marrow
Maintenance
Recurrence
Drug Therapy
Therapeutics

Keywords

  • B-cell precursor acute lymphoblastic leukemia
  • Methotrexate
  • Polyglutamation
  • Survival

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Oncology
  • Hematology

Cite this

@article{57156d16129b46b8a481d544350b43ff,
title = "Methotrexate polyglutamation may lack prognostic significance in children with B-cell precursor acute lymphoblastic leukemia treated with intensive oral methotrexate",
abstract = "Background: The purpose of this study was to determine if a correlation exists between clinical outcome and accumulation and polyglutamation of methotrexate by lymphoblasts in vitro in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Patients and Methods: The amount of accumulated methotrexate and of long-chain methotrexate polyglutamates (MTXPG3-7) by lymphoblasts was determined in 52 children newly diagnosed with BCP-ALL after incubation with 1 μmol/L [3H]MTX for 24 hours in vitro. All patients then received intensive multiagent chemotherapy that used divided-dose oral methotrexate during consolidation and intensive continuation and standard oral weekly methotrexate during maintenance. Results: Eight patients had a bone marrow relapse at a median of 40.4 months (range 18.5-48.3 months) after diagnosis. The median follow-up for the remaining 44 patients is 69.0 months (range 22-92.8 months). There was no significant difference in the amount of accumulated methotrexate (1450.0 ± 896.3 vs. 640 ± 472.5 pmol/109 cells) or of accumulated MTXPG3-7 (1450.0 ± 919.4 vs. 617.4 ± 482.7 pmol/109 cells) (median ± semiinterquartile ranges) between patients who relapsed and those who remained in continuous complete remission. The estimated 5-year event-free survival rate for patients whose lymphoblasts accumulated more than 500 pmol MTXPG3-7/109 cells was 80.0{\%} ± 7.3{\%} versus 90.5{\%} ± 6.4{\%} for those whose lymphoblasts accumulated less than 500 pmol MTXPG3-7/109 cells. Conclusions: In the context of effective prolonged divided-dose oral methotrexate-based therapy in the treatment of BCP-ALL, methotrexate accumulation and polyglutamation no longer seem to have prognostic significance.",
keywords = "B-cell precursor acute lymphoblastic leukemia, Methotrexate, Polyglutamation, Survival",
author = "Elpis Mantadakis and Smith, {Angela K.} and Linda Hynan and Winick, {Naomi J.} and Kamen, {Barton A.}",
year = "2002",
month = "11",
doi = "10.1097/00043426-200211000-00007",
language = "English (US)",
volume = "24",
pages = "636--642",
journal = "Journal of Pediatric Hematology/Oncology",
issn = "1077-4114",
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T1 - Methotrexate polyglutamation may lack prognostic significance in children with B-cell precursor acute lymphoblastic leukemia treated with intensive oral methotrexate

AU - Mantadakis, Elpis

AU - Smith, Angela K.

AU - Hynan, Linda

AU - Winick, Naomi J.

AU - Kamen, Barton A.

PY - 2002/11

Y1 - 2002/11

N2 - Background: The purpose of this study was to determine if a correlation exists between clinical outcome and accumulation and polyglutamation of methotrexate by lymphoblasts in vitro in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Patients and Methods: The amount of accumulated methotrexate and of long-chain methotrexate polyglutamates (MTXPG3-7) by lymphoblasts was determined in 52 children newly diagnosed with BCP-ALL after incubation with 1 μmol/L [3H]MTX for 24 hours in vitro. All patients then received intensive multiagent chemotherapy that used divided-dose oral methotrexate during consolidation and intensive continuation and standard oral weekly methotrexate during maintenance. Results: Eight patients had a bone marrow relapse at a median of 40.4 months (range 18.5-48.3 months) after diagnosis. The median follow-up for the remaining 44 patients is 69.0 months (range 22-92.8 months). There was no significant difference in the amount of accumulated methotrexate (1450.0 ± 896.3 vs. 640 ± 472.5 pmol/109 cells) or of accumulated MTXPG3-7 (1450.0 ± 919.4 vs. 617.4 ± 482.7 pmol/109 cells) (median ± semiinterquartile ranges) between patients who relapsed and those who remained in continuous complete remission. The estimated 5-year event-free survival rate for patients whose lymphoblasts accumulated more than 500 pmol MTXPG3-7/109 cells was 80.0% ± 7.3% versus 90.5% ± 6.4% for those whose lymphoblasts accumulated less than 500 pmol MTXPG3-7/109 cells. Conclusions: In the context of effective prolonged divided-dose oral methotrexate-based therapy in the treatment of BCP-ALL, methotrexate accumulation and polyglutamation no longer seem to have prognostic significance.

AB - Background: The purpose of this study was to determine if a correlation exists between clinical outcome and accumulation and polyglutamation of methotrexate by lymphoblasts in vitro in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Patients and Methods: The amount of accumulated methotrexate and of long-chain methotrexate polyglutamates (MTXPG3-7) by lymphoblasts was determined in 52 children newly diagnosed with BCP-ALL after incubation with 1 μmol/L [3H]MTX for 24 hours in vitro. All patients then received intensive multiagent chemotherapy that used divided-dose oral methotrexate during consolidation and intensive continuation and standard oral weekly methotrexate during maintenance. Results: Eight patients had a bone marrow relapse at a median of 40.4 months (range 18.5-48.3 months) after diagnosis. The median follow-up for the remaining 44 patients is 69.0 months (range 22-92.8 months). There was no significant difference in the amount of accumulated methotrexate (1450.0 ± 896.3 vs. 640 ± 472.5 pmol/109 cells) or of accumulated MTXPG3-7 (1450.0 ± 919.4 vs. 617.4 ± 482.7 pmol/109 cells) (median ± semiinterquartile ranges) between patients who relapsed and those who remained in continuous complete remission. The estimated 5-year event-free survival rate for patients whose lymphoblasts accumulated more than 500 pmol MTXPG3-7/109 cells was 80.0% ± 7.3% versus 90.5% ± 6.4% for those whose lymphoblasts accumulated less than 500 pmol MTXPG3-7/109 cells. Conclusions: In the context of effective prolonged divided-dose oral methotrexate-based therapy in the treatment of BCP-ALL, methotrexate accumulation and polyglutamation no longer seem to have prognostic significance.

KW - B-cell precursor acute lymphoblastic leukemia

KW - Methotrexate

KW - Polyglutamation

KW - Survival

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