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Rigshospitalet - a part of Copenhagen University Hospital
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Methotrexate polyglutamate levels and co-distributions in childhood acute lymphoblastic leukemia maintenance therapy

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  1. Role of TPMT and ITPA variants in mercaptopurine disposition

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  2. Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia

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  1. Selection criteria for assembling a pediatric cancer predisposition syndrome gene panel

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  2. Parenthood among men diagnosed with cancer in childhood and early adulthood: trends over time in a Danish national cohort

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  3. Genomforskningsprojekt påviser TP53-mutation hos en pige med rabdomyosarkom

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  4. Value of flow cytometry for MRD-based relapse prediction in B-cell precursor ALL in a multicenter setting

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PURPOSE: Methotrexate polyglutamates (MTXpg) facilitate incorporation of thioguanine nucleotides into DNA (DNA-TG, the primary cytotoxic thiopurine metabolite and outcome determinant in MTX/6-mercaptopurine treatment of childhood ALL). We hypothesized that mapping erythrocyte levels of MTXpg with 1-6 glutamates and their associations with DNA-TG formation would facilitate future guidelines for maintenance therapy dosing.

METHODS AND RESULTS: Summed MTX with 1-6 glutamates resolved by LCMS [median (interquartile): 5.47 (3.58-7.69) nmol/mmol hemoglobin] was in agreement with total MTX by radio ligand assay. In 16,389 blood samples from 1426 ALL maintenance therapy patients, MTXpg3 21.0 (15.2-27.4)% was the predominant metabolite, and MTXpg1 (the maternal drug) constituted 38.6 (27.2-50.2)% of MTXpg1-6. All subsets correlated; the strongest associations were between metabolites with similar polyglutamate lengths. Correlations of MTXpg1 with MTXpg2 and MTXpg3,4,5,6 were rs = 0.68 and rs = 0.25-0.42, respectively. Intercorrelations of MTXpg3,4,5,6 were all rs ≥ 0.51. MTXpg4 accounted for 29.8 (24.7-33.3)% of MTXpg3-6, yet explained 96% of the summed MTXpg3-6 variation. MTXpg1-4, MTXpg1-6, MTXpg2-6 and MTXpg3 were all associated with DNA-TG levels (p < 0.00001), but collinearity precluded identification of the most informative subset.

CONCLUSIONS: Measuring erythrocyte MTXpg4 simplifies and can replace longer chain MTXpg monitoring. Resolving individual MTXpg identifies samples that are unsuitable for dose guidance due to high levels of MTXpg1 remaining in the plasma fraction because of recent MTX intake. All tested MTXpg subsets correlated with DNA-TG and may be used for ALL maintenance therapy dose adjustments, but the most informative subset remains to be identified.

Original languageEnglish
JournalCancer Chemotherapy and Pharmacology
Volume83
Issue number1
Pages (from-to)53-60
Number of pages8
ISSN0344-5704
DOIs
Publication statusPublished - 2019

    Research areas

  • Adolescent, Antimetabolites, Antineoplastic/administration & dosage, Child, Child, Preschool, Erythrocytes/metabolism, Female, Follow-Up Studies, Humans, Infant, Male, Methotrexate/administration & dosage, Polyglutamic Acid/analogs & derivatives, Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy, Prognosis

ID: 59084054