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Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia

The Pharmacogenomics Journal volume 15, pages 248–254 (2015)Cite this article

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Abstract

Methotrexate (MTX) is an effective and toxic chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia(ALL). In this prospective study, we aimed to identify metabolic and genetic determinants of MTX toxicity. One hundred and thirty-four Dutch pediatric ALL patients were treated with four high infusions MTX (HD-MTX: 5 g m−2) every other week according to the DCOG-ALL-10 protocol. Mucositis (National Cancer Institute grade ⩾3) was the most frequent occurring toxicity during the HD-MTX phase (20%) and occurred especially after the first MTX course. Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher erythrocyte folate levels at the start of protocol M than patients without mucositis (median 1.4 vs 1.2 μmol l−1, P<0.008), this could reflect an increased MTX uptake in mucosal cells of patients with mucositis. From 17 single-nucleotide polymorphisms in the MTX pathway, only patients with the wild-type variant of rs7317112 SNP in the ABCC4 gene had more mucositis (AA (39%) vs AG/GG (15%), P=0.016). We found no evidence that erythrocyte folate levels mediate in the association between the rs7317112 and mucositis.

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Acknowledgements

This study was financially supported by Stichting Kinderen Kankervrij (KiKa errant, nr. 67) and an Erasmus MC translational grant (to EdB).

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Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, Erasmus MC–Sophia Children’s Hospital, Rotterdam, The Netherlands

    M A H den Hoed, M L te Winkel, J D E de Rooij, R Pieters, S M F Pluijm & M M van den Heuvel-Eibrink

  2. Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain

    E Lopez-Lopez, A Gutierrez-Camino & A Garcia-Orad

  3. Department of Oncology/Hematology, University of Groningen, University Medical Center Groningen-Beatrix Children’s Hospital, Groningen, The Netherlands

    W Tissing

  4. Department of Clinical Chemistry, Erasmus MC–University Medical Center, Rotterdam, The Netherlands

    E den Boer & R de Jonge

  5. Department of Pediatric Oncology/Hematology, Princess Maxima Center, Utrecht, The Netherlands

    R Pieters

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  1. M A H den Hoed
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den Hoed, M., Lopez-Lopez, E., te Winkel, M. et al. Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia. Pharmacogenomics J 15, 248–254 (2015). https://doi.org/10.1038/tpj.2014.63

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