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

Abstract

Key Points• Polymorphisms in the MTX pathway genes substantially influence the kinetics and response to high-dose MTX therapy in childhood ALL.• Germline variants in SLCO1B1, thymidylate synthase, and methylenetetrahydrofolate reductase are significantly associated with kinetics, toxicity, and outcome.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 AUC 0-48h was a significant predictor of overall toxic adverse events during MTX courses (R 2 5 0.043; P < .001), whereas the thymidylate synthase rs34743033 tandem repeat polymorphism was predictive of stomatitis (R 2 5 0.018; P 5 .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 5 .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. (Blood. 2013;121(26):5145-5153)

Role of Organic Anion-Transporting Polypeptides (OATPs) in Cancer Therapy

“…Similar findings have been reported with patients treated with methotrexate. In particular, recent reports validating the relevance of the OATP1B1*15 genotype in determining the pharmacokinetics and toxicities of methotrexate were from genome-wide association studies or studies involving a large number of patients and cohorts from different institutions (44)(45)(46). Continued investigations examining the prospective utility of the OATP1B1 genotypes in improving therapeutic effects and safety profiles of these anticancer drugs are warranted.…”

Pharmacogenetic Testing for Methotrexate Treatment in Leukemia Patients

“…SHMT plays a role in one carbon pathway, including the conversion of tetrahydrofolate to 5, 10-methyltetrahydrofolate [8,9]. Different studies have been done to determine how polymorphism in these genes affects methotrexate treatment.…”

Pharmacogenetics of methotrexate in pediatric hematological neoplasm treatment: does it need a personalized regimen based on MTHFR polymorphisms?

“…Many studies have reported that the two common functional polymorphisms of MTHFR, C677T and A1298C, are associated with MTX-related toxicity and survival both in adults and in children with ALL, while others showed controversial results [1][2][3].…”

“…Accordingly, the cure rates of acute lymphoblastic leukemia (ALL), which is the most common childhood cancer, are higher than 80% due to optimized chemotherapy protocols. Most protocols consist of methotrexate (MTX) as a key chemotherapeutic agent with high therapeutic efficiency [1]. Nevertheless, MTX causes severe dose-limiting adverse events and organ toxicities.…”

“…Based on the strength of evidence of previously published association studies, ) between MRD-slow early responder versus MRD standard risk [4] patients and (the hazard ratios were 3.1-95% CI: 1.2-7.7; p = 0.015) between homozygous carriers of the MTHFR A1298 C allele versus patients with the AA reference genotype [1]. As mentioned in this study, whether polymorphisms in a specific gene affect EFS rates may depend on the specific treatment protocol.…”