Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity

Mette Levinsen, Susanne Rosthøj, Ulrikka Nygaard, Jesper Heldrup, Arja Harila-Saari, Olafur G. Jonsson, Anne Grete Bechensteen, Jonas Abrahamsson, Birgitte Lausen, Thomas L. Frandsen, Richard M. Weinshilboum, Kjeld Schmiegelow

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Purpose: Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMTIA) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT. Methods: Using linear mixed models, we explored myelo-and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy. Results: The degree of myelosuppression following HD-MTX was similar for patients with TPMTIA and patients with high TPMT activity (TPMTHA), when HD-MTX started with same blood counts and 6MP doses. However, since TPMTIA had lower blood counts at initiation of HD-MTX compared with TPMTHA patients (median WBC 2.8 vs. 3.3 × 109/L, P = 0.01; median ANC 1.4 vs. 1.7 × 109/L, P = 0.02), TPMTIA continued to have lower WBC and ANC levels compared with TPMTHA during all 28 days after HD-MTX [relative difference 9 % (95 % CI 2-17), P = 0.02 and 21 % (95 % CI 6-39), P = 0.005]. Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMTIA and TPMTHA patients (P = 0.47; P = 0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose (P < 0.001 for all analyses). Conclusion For both TPMTIA and TPMTHA patients, dose of 6MP prior to HD-MTX should be guided by preHD-MTX blood counts, but not by TPMT activity.

Original languageEnglish (US)
Pages (from-to)59-66
Number of pages8
JournalCancer chemotherapy and pharmacology
Volume75
Issue number1
DOIs
StatePublished - Jan 1 2015

Keywords

  • Chemotherapy
  • Oncology
  • Pediatric
  • Toxicity

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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  • Cite this

    Levinsen, M., Rosthøj, S., Nygaard, U., Heldrup, J., Harila-Saari, A., Jonsson, O. G., Bechensteen, A. G., Abrahamsson, J., Lausen, B., Frandsen, T. L., Weinshilboum, R. M., & Schmiegelow, K. (2015). Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity. Cancer chemotherapy and pharmacology, 75(1), 59-66. https://doi.org/10.1007/s00280-014-2613-7