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

Background: 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 1298A>C) on MTX toxicity in children with ALL. Patients and methods: Retrospective analysis of 129 MIX courses in 34 pediatric patients with ALL. Results: 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 IT 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 patientbased analysis. Conclusions: MIX related toxicity might be influenced by the MTHFR 677C>T or the MTHFR 1298A>C polymorphisms. Differences in MIX toxicity are only partially explainable by these 2 polymorphisms.