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.
Publication types
- Research Support, Non-U.S. Gov't
MeSH terms
- Adolescent
- Antimetabolites, Antineoplastic / adverse effects
- Antimetabolites, Antineoplastic / pharmacokinetics
- Biomarkers, Tumor / genetics*
- Child
- Child, Preschool
- Cohort Studies
- Female
- Follow-Up Studies
- Germ-Line Mutation / genetics*
- Humans
- Infant
- Liver-Specific Organic Anion Transporter 1
- Male
- Methotrexate / adverse effects*
- Methotrexate / pharmacokinetics*
- Methylenetetrahydrofolate Reductase (NADPH2) / genetics
- Multidrug Resistance-Associated Protein 2
- Multidrug Resistance-Associated Proteins / genetics
- Neoplasm Staging
- Neoplasm, Residual
- Organic Anion Transporters / genetics
- Pharmacogenetics*
- Polymorphism, Single Nucleotide / genetics*
- Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
- Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
- Precursor Cell Lymphoblastic Leukemia-Lymphoma / mortality
- Reduced Folate Carrier Protein / genetics
- Stomatitis / chemically induced
- Stomatitis / genetics
- Survival Rate
- Thymidylate Synthase / genetics
- Tissue Distribution
- Treatment Outcome
Substances
- Antimetabolites, Antineoplastic
- Biomarkers, Tumor
- Liver-Specific Organic Anion Transporter 1
- Multidrug Resistance-Associated Protein 2
- Multidrug Resistance-Associated Proteins
- Organic Anion Transporters
- Reduced Folate Carrier Protein
- SLC19A1 protein, human
- SLCO1B1 protein, human
- MTHFR protein, human
- Methylenetetrahydrofolate Reductase (NADPH2)
- Thymidylate Synthase
- Methotrexate