Influence of folate pathway polymorphisms on high-dose methotrexate-related toxicity and survival in childhood acute lymphoblastic leukemia

Abstract

The prediction of high-dose methotrexate (HD-MTX) toxicity is a key issue in the individualization of treatment in childhood acute lymphoblastic leukemia (ALL). Our aim was to evaluate the influence of MTX pathway polymorphisms on HD-MTX treat- ment outcome in children with ALL. In total, 167 children with ALL were genotyped for methylenetetrahydrofolate dehydrogenase (MTHFD1) 1958G > A, methylenetetrahydrofolate reductase (MTHFR) 677C > T and 1298A > C and thymidylate synthase (TYMS) 2R > 3R polymorphisms. The MTHFD1 1958A allele significantly reduced the odds of hepatotoxicity (adjusted p = 0.009), while the TYMS 3R allele significantly reduced the odds of leukocytopenia and thrombocytopenia (adjusted p = 0.005 and adjusted p = 0.002, respectively). MTHFR polymorphisms did not influence HD-MTX-related toxicity, but a significant effect of MTHFR 677C > T–TYMS 2R > 3R and MTHFD1 1958G > A–MTHFR 677C > T interactions on HD-MTX-related toxicity was observed. None of the investigated polymorphisms influenced survival. Our study suggests an important role of polymorphisms and gene–gene interactions within the folate pathway in HD-MTX-related toxicity in childhood ALL.

Keywords::

• Polymorphisms
• folate pathway
• childhood leukemia
• methotrexate
• toxicity
• survival

Acknowledgements

The authors wish to thank Petra Bohanec Grabar, PhD, for her contribution to the initial part of the study. This work was financially supported by the Slovenian Research Agency (ARRS Grant Nos. P1-0170 and P3-0343).

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