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

M. A.H. Den Hoed, E. Lopez-Lopez, M. L. Te Winkel, W. Tissing, J. D.E. De Rooij, A. Gutierrez-Camino, A. Garcia-Orad, E. Den Boer, R. Pieters, S. M.F. Pluijm, R. De Jonge, M. M. Van Den Heuvel-Eibrink*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)248-254
Number of pages7
JournalPharmacogenomics Journal
Volume15
Issue number3
DOIs
Publication statusPublished - 26 Jun 2015

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