Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Jonsson, Olafur G
Bechensteen, Anne Grete
Frandsen, Thomas L
Weinshilboum, Richard M
MetadataShow full item record
CitationCancer Chemother. Pharmacol. 2015, 75 (1):59-66
AbstractThrough 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.
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 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).
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.
DescriptionTo access publisher's full text version of this article click on the hyperlink at the bottom of the page
RightsArchived with thanks to Cancer chemotherapy and pharmacology
- Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia.
- Authors: Nielsen SN, Grell K, Nersting J, Frandsen TL, Hjalgrim LL, Schmiegelow K
- Issue date: 2016 Nov
- Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia.
- Authors: Vang SI, Schmiegelow K, Frandsen T, Rosthøj S, Nersting J
- Issue date: 2015 May
- Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia.
- Authors: Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE
- Issue date: 1999 May 1
- 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.
- Authors: Schmiegelow K, Al-Modhwahi I, Andersen MK, Behrendtz M, Forestier E, Hasle H, Heyman M, Kristinsson J, Nersting J, Nygaard R, Svendsen AL, Vettenranta K, Weinshilboum R, Nordic Society for Paediatric Haematology and Oncology.
- Issue date: 2009 Jun 11
- 6-mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia.
- Authors: Schmiegelow K, Bretton-Meyer U
- Issue date: 2001 Jan