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

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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

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thiopurine methyltransferase
6-Mercaptopurine
Methotrexate
Leukemia
Blood
Leukopenia
Metabolites
Transaminases
Neutropenia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Thrombocytopenia
Cytosol

Keywords

  • Chemotherapy
  • Oncology
  • Pediatric
  • Toxicity

ASJC Scopus subject areas

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

Cite this

Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity. / Levinsen, Mette; Rosthøj, Susanne; Nygaard, Ulrikka; Heldrup, Jesper; Harila-Saari, Arja; Jonsson, Olafur G.; Bechensteen, Anne Grete; Abrahamsson, Jonas; Lausen, Birgitte; Frandsen, Thomas L.; Weinshilboum, Richard M; Schmiegelow, Kjeld.

In: Cancer Chemotherapy and Pharmacology, Vol. 75, No. 1, 01.01.2015, p. 59-66.

Research output: Contribution to journalArticle

Levinsen, M, Rosthøj, S, Nygaard, U, Heldrup, J, Harila-Saari, A, Jonsson, OG, Bechensteen, AG, Abrahamsson, J, Lausen, B, Frandsen, TL, Weinshilboum, RM & 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, vol. 75, no. 1, pp. 59-66. https://doi.org/10.1007/s00280-014-2613-7
Levinsen, Mette ; Rosthøj, Susanne ; Nygaard, Ulrikka ; Heldrup, Jesper ; Harila-Saari, Arja ; Jonsson, Olafur G. ; Bechensteen, Anne Grete ; Abrahamsson, Jonas ; Lausen, Birgitte ; Frandsen, Thomas L. ; Weinshilboum, Richard M ; Schmiegelow, Kjeld. / Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity. In: Cancer Chemotherapy and Pharmacology. 2015 ; Vol. 75, No. 1. pp. 59-66.
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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.",
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T1 - Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity

AU - Levinsen, Mette

AU - Rosthøj, Susanne

AU - Nygaard, Ulrikka

AU - Heldrup, Jesper

AU - Harila-Saari, Arja

AU - Jonsson, Olafur G.

AU - Bechensteen, Anne Grete

AU - Abrahamsson, Jonas

AU - Lausen, Birgitte

AU - Frandsen, Thomas L.

AU - Weinshilboum, Richard M

AU - Schmiegelow, Kjeld

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

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KW - Oncology

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