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

Levinsen, Mette; Rosthoj, Susanne; Nygaard, Ulrikka; Heldrup, Jesper LU ; Harila-Saari, Arja; Jonsson, Olafur G.; Bechensteen, Anne Grete; Abrahamsson, Jonas; Lausen, Birgitte and Frandsen, Thomas L., et al. (2015) In Cancer Chemotherapy and Pharmacology 75(1). p.59-66
Abstract
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. 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. The degree of myelosuppression following HD-MTX was similar... (More)
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. 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. 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 x 10(9)/L, P = 0.01; median ANC 1.4 vs. 1.7 x 10(9)/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). For both TPMTIA and TPMTHA patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity. (Less)
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keywords
Chemotherapy, Oncology, Pediatric, Toxicity
in
Cancer Chemotherapy and Pharmacology
volume
75
issue
1
pages
59 - 66
publisher
Springer
external identifiers
  • wos:000347153200007
  • scopus:84925230908
ISSN
0344-5704
DOI
10.1007/s00280-014-2613-7
language
English
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yes
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f7fbc0ab-6df0-4cfc-80dc-410252f423b0 (old id 5085132)
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2015-03-02 07:11:37
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2017-06-18 04:03:38
@article{f7fbc0ab-6df0-4cfc-80dc-410252f423b0,
  abstract     = {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. 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. 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 x 10(9)/L, P = 0.01; median ANC 1.4 vs. 1.7 x 10(9)/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 &lt; 0.001 for all analyses). For both TPMTIA and TPMTHA patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity.},
  author       = {Levinsen, Mette and Rosthoj, Susanne and Nygaard, Ulrikka and Heldrup, Jesper and Harila-Saari, Arja and Jonsson, Olafur G. and Bechensteen, Anne Grete and Abrahamsson, Jonas and Lausen, Birgitte and Frandsen, Thomas L. and Weinshilboum, Richard M. and Schmiegelow, Kjeld},
  issn         = {0344-5704},
  keyword      = {Chemotherapy,Oncology,Pediatric,Toxicity},
  language     = {eng},
  number       = {1},
  pages        = {59--66},
  publisher    = {Springer},
  series       = {Cancer Chemotherapy and Pharmacology},
  title        = {Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity},
  url          = {http://dx.doi.org/10.1007/s00280-014-2613-7},
  volume       = {75},
  year         = {2015},
}