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Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants

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Abstract

Purpose

Folate-metabolizing single-nucleotide polymorphisms (SNPs) are emerging as important pharmacogenetic prognostic determinants of the response to chemotherapy. With high doses of methotrexate (MTX) in the consolidation phase, methylenetetrahydrofolate reductase (MTHFR) polymorphisms could be potential modulators of the therapeutic response to antifolate chemotherapeutics in identifying a possible correlation with the outcome. This study aims to analyse the potential role of the MTHFR C677T and A1298C genetic variants in modulating the clinical toxicity and efficacy of high doses of MTX in a cohort of paediatric ALL patients (n = 151) treated with AIEOP protocols.

Methods

This work includes DNA extraction by slides and RFLP-PCR.

Results

The first observation relative to early toxicities (haematological and non-haematological), after the first doses of MTX in all protocols, was an association between the 677T and 1298C carriers and global toxicity. We found that in the 2 g/m2 MTX group, patients harbouring 677TT homozygously exhibited a substantial 12-fold risk of developing toxicity. In this study, we demonstrate that the MTHFR 677TT variant is associated with an increased risk of relapse when compared to other genotypes. The Kaplan–Meier analysis showed that the 677TT variant had a lower 7-year DFS(disease-free survival) probability compared to the 677C carrier genotype (log-rank test P = 0.003) and OS (overall survival) and also confirms the lower probability of survival for patients with the 677TT variant (log-rank test, P = 0.006).

Conclusions

Our study provides further evidence of the critical role played by folate pathway enzymes in the outcome of ALL, possibly through the interference of MTX.

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Acknowledgments

The work was supported by Luciano Gaudio, Professor of Genetics Dept Biological Sciences, University of Naples ‘Federico II’ Chair.

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Authors and Affiliations

  1. Pediatric Department, Second University of Naples, Naples, Italy

    Velia D’Angelo, Maria Ramaglia, Adriana Iannotta, Paolo Indolfi, Matteo Francese, Maria Carmen Affinita, Giulia Pecoraro, Addolorata Napolitano, Claudia Fusco, Matilde Oreste, Cristiana Indolfi & Fiorina Casale

  2. Hematology Oncology Department, UOSC Hematology Oncology G Pascale Foundation, Naples, Italy

    Stefania Crisci

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  1. Velia D’Angelo
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  2. Maria Ramaglia
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Correspondence to Velia D’Angelo.

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D’Angelo, V., Ramaglia, M., Iannotta, A. et al. Methotrexate toxicity and efficacy during the consolidation phase in paediatric acute lymphoblastic leukaemia and MTHFR polymorphisms as pharmacogenetic determinants. Cancer Chemother Pharmacol 68, 1339–1346 (2011). https://doi.org/10.1007/s00280-011-1665-1

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