Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: Results from the NOPHO ALL-92 study

Kjeld Schmiegelow, Ibrahim Al-Modhwahi, Mette Klarskov Andersen, Mikael Behrendtz, Erik Forestier, Henrik Hasle, Mats Heyman, Jon Kristinsson, Jacob Nersting, Randi Nygaard, Anne Louise Svendsen, Kim Vettenranta, Richard Weinshilboum

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103 Scopus citations

Abstract

Among 1614 children with acute lymphoblastic leukemia (ALL) treated with the Nordic Society for Paediatric Haematology and Oncology (NOPHO)ALL-92 protocol, 20 patients developed a second malignant neoplasm (SMN) with a cumulative risk of 1.6% at 12 years from the diagnosis of ALL. Nine of the 16 acute myeloid leukemias or myelodysplastic syndromes had monosomy 7 (n = 7) or 7q deletions (n = 2). In Cox multivariate analysis, longer duration of oral 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy (P = .02; longest for standard-risk patients) and presence of high hyperdiploidy (P = .07) were related to increased risk of SMN. Thiopurine methyl-transferase (TPMT) methylates 6MP and its metabolites, and thus reduces cellular levels of cytotoxic 6-thioguanine nucleotides. Of 524 patients who had erythrocyte TPMT activity measured, the median TPMT activity in 9 patients developing an SMN was significantly lower than in the 515 that did not develop an SMN (median, 12.1 vs 18.1 IU/mL; P = .02). Among 427 TPMT wild-type patients for whom the 6MP dose was registered, those who developed SMN received higher average 6MP doses than the remaining patients (69.7 vs 60.4 mg/m2; P = .03). This study indicates that the duration and intensity of 6MP/MTX maintenance therapy of childhood ALL may influence the risk of SMNs in childhood ALL.

Original languageEnglish (US)
Pages (from-to)6077-6084
Number of pages8
JournalBlood
Volume113
Issue number24
DOIs
StatePublished - Nov 19 2009

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Schmiegelow, K., Al-Modhwahi, I., Andersen, M. K., Behrendtz, M., Forestier, E., Hasle, H., Heyman, M., Kristinsson, J., Nersting, J., Nygaard, R., Svendsen, A. L., Vettenranta, K., & Weinshilboum, R. (2009). Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: Results from the NOPHO ALL-92 study. Blood, 113(24), 6077-6084. https://doi.org/10.1182/blood-2008-11-187880