title: High dose methotrexate treatment in childhood ALL: pilot study on the impact of the MTHFR 677C>T and 1298A>C polymorphisms on MTX-related toxicity.
abstract: Methotrexate (MTX) is commonly administered in high doses for treatment of childhood acute lymphoblastic leukemia (ALL). The aim of this analysis was to study the influence of 2 common MTHFR polymorphisms (MTHFR 677C>T and 1298 A>C) on MTX toxicity in children with ALL.Retrospective analysis of 129 MTX courses in 34 pediatric patients with ALL.677C>T variants (CT or TT) were found in 19 (14 heterozygous, 5 homozygous) and 1298A>C variants (AC or CC) in 20 (16 heterozygous, 4 homozygous) patients. The MTHFR 677C>T wild type was associated with an increased frequency of grade III and IV leukopenia (60% vs. 31%, p<0.05) compared to the variants. The rate of severe infections (21% vs. 0%, p<0.05) and grade III-IV anemia (26% vs. 5%, p<0.05) was increased in carriers of the MTHFR 677C>T wild type compared to patients with the TT variant. Grade III-IV anemia was more frequent in patients with the MTHFR 1298A>C CC variant compared to the wild type (56% vs. 21%, p<0.05). The differences were not significant in a patient-based analysis.MTX related toxicity might be influenced by the MTHFR 677C>T or the MTHFR 1298A>C polymorphisms. Differences in MTX toxicity are only partially explainable by these 2 polymorphisms.
authors.affiliation: Klinik für Kinder- und Jugendmedizin, Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Straße 40, Halle/ Saale, Germany. roland.haase@uk-halle.de
authors.forename: R
authors.initials: R
authors.lastname: Haase
authors.forename: K
authors.initials: K
authors.lastname: Elsner
authors.forename: N
authors.initials: N
authors.lastname: Merkel
authors.forename: M
authors.initials: M
authors.lastname: Stiefel
authors.forename: C
authors.initials: C
authors.lastname: Mauz-Körholz
authors.forename: C M
authors.initials: CM
authors.lastname: Kramm
authors.forename: D
authors.initials: D
authors.lastname: Körholz
mesh_terms: D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006580:Genetic Carrier Screening; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced / Q000235:genetics; D008297:Male; D008727:Methotrexate / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D010865:Pilot Projects; D011110:Polymorphism, Genetic / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000964:Antimetabolites, Antineoplastic; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate