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. 2013 Jun 27;121(26):5145-53.
doi: 10.1182/blood-2013-01-480335. Epub 2013 May 7.

Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia

Susanne Radtke  1 , Oliver Zolk, Bertold Renner, Marios Paulides, Martin Zimmermann, Anja Möricke, Martin Stanulla, Martin Schrappe, Thorsten Langer
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Free article

Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia

Susanne Radtke et al. Blood. .
Free article

Abstract

The pharmacogenetics of methotrexate (MTX) was investigated in a large cohort of pediatric patients with acute lymphoblastic leukemia (ALL). Four hundred ninety-nine children with ALL from the ALL-BFM (Berlin-Frankfurt-Münster) 2000 trial who received 1996 courses of MTX at 5 g/m(2) were genotyped for 8 single nucleotide polymorphisms in 5 candidate genes of the MTX/folate pathway. Patients' MTX pharmacokinetics, MTX toxicities, and outcomes were correlated with the genotypes. The interindividual variability in MTX kinetics had a substantial genetic component between 68% and 75%. The SLCO1B1 rs4149056 variant was significantly associated with MTX kinetics. In a multiple regression model, MTX area under the concentration time curve (AUC)0-48h increased by 26% (P < .001) per SLCO1B1 rs4149056 C allele. MTX AUC0-48h was a significant predictor of overall toxic adverse events during MTX courses (R(2) = 0.043; P < .001), whereas the thymidylate synthase rs34743033 tandem repeat polymorphism was predictive of stomatitis (R(2) = 0.018; P = .009), a frequent side effect of high-dose MTX. Multiple Cox regression analyses revealed an association of minimal residual disease (hazard ratio 7.3; P < .001) and methylenetetrahydrofolate reductase rs1801131 (hazard ratio 3.1; P = .015) with event-free survival in the ALL-BFM 2000 study population. Genetic variations substantially influence the kinetics and response to high-dose MTX therapy in childhood ALL.

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