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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.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2015 Jan; Vol. 75 (1), pp. 59-66. Date of Electronic Publication: 2014 Oct 28. - Publication Year :
- 2015
-
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 (TPMT(IA)) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT.<br />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.<br />Results: The degree of myelosuppression following HD-MTX was similar for patients with TPMT(IA) and patients with high TPMT activity (TPMT(HA)), when HD-MTX started with same blood counts and 6MP doses. However, since TPMT(IA) had lower blood counts at initiation of HD-MTX compared with TPMT(HA) 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), TPMT(IA) continued to have lower WBC and ANC levels compared with TPMT(HA) 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 TPMT(IA) and TPMT(HA) 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).<br />Conclusion: For both TPMT(IA) and TPMT(HA) patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity.
- Subjects :
- Antimetabolites, Antineoplastic administration & dosage
Antimetabolites, Antineoplastic adverse effects
Antimetabolites, Antineoplastic therapeutic use
Antineoplastic Combined Chemotherapy Protocols administration & dosage
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Child
Child, Preschool
Dose-Response Relationship, Drug
Female
Follow-Up Studies
Heterozygote
Humans
Leukopenia chemically induced
Leukopenia epidemiology
Maintenance Chemotherapy adverse effects
Male
Mercaptopurine administration & dosage
Mercaptopurine therapeutic use
Methotrexate administration & dosage
Methotrexate therapeutic use
Methyltransferases genetics
Nucleic Acid Synthesis Inhibitors administration & dosage
Nucleic Acid Synthesis Inhibitors therapeutic use
Precursor Cell Lymphoblastic Leukemia-Lymphoma enzymology
Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology
Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
Retrospective Studies
Risk
Scandinavian and Nordic Countries epidemiology
Survival Analysis
Antineoplastic Combined Chemotherapy Protocols adverse effects
Mercaptopurine adverse effects
Methotrexate adverse effects
Methyltransferases metabolism
Myelopoiesis drug effects
Nucleic Acid Synthesis Inhibitors adverse effects
Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0843
- Volume :
- 75
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 25347948
- Full Text :
- https://doi.org/10.1007/s00280-014-2613-7