The Role of Candidate Polymorphisms in Drug Transporter Genes on High-Dose Methotrexate in the Consolidation Phase of the AIEOP-BFM ALL 2009 Protocol

Abstract

High-dose methotrexate (HD-MTX) infusions are commonly used to consolidate remission in children with acute lymphoblastic leukemia (ALL). We investigate the potential role of candidate polymorphisms in SLCO1B1 (rs4149056 and rs2306283), ABCB1 (rs1045642), ABCC2 (rs717620), ABCC3 (rs9895420), and ABCC4 (rs7317112) drug transporters genes on HD-MTX pharmacokinetics and patients' outcome (meant both as relapse and drug-related toxicities) in an Italian cohort of 204 ALL pediatric patients treated according to the AIEOP-BFM ALL 2009 protocol. TaqMan SNP genotyping assays determined patient's genotypes. Measurements of HD-MTX plasma concentration were available for 814 HD-MTX courses in 204 patients; MTX clearance was estimated by a two-compartmental linear pharmacokinetic model with first-order elimination and a Bayesian approach, via ADAPT. Independent contributions of age and ABCC4 SNP rs7317112 (A>G, intronic) on MTX clearance were detected in a multivariate analysis (p = 1.57 × 10⁻⁸ and p = 2.06 × 10⁻⁵, respectively), suggesting a delayed elimination of the drug in older patients and an accelerated one in carriers of the variant GG genotype. After multiple corrections, the association between ABCC2 SNP rs717620 (−24 C>T) and severe hematological toxicity was found (p < 0.005). Moreover, SLCO1B1 SNP rs4149056 (c.521T>C, p.V174A) affected patients' outcomes: carriers of the variant C allele presented a reduced risk of relapse compared to wild-type TT (hazard risk: 0.27, 95% confidence interval [CI]: 0.08–0.90, p = 0.037). Taken together, these data highlighted the importance of variants in drug transporters genes on HD-MTX disposition in the AIEOP-BFM ALL 2009 protocol consolidation phase, and their putative role as predictive markers of outcome.