Effects of genetic polymorphisms on methotrexate levels and toxicity in Chinese patients with acute lymphoblastic leukemia.

Methotrexate (MTX) has an antitumor effect when used for the treatment of acute lymphoblastic leukemia (ALL). This study aims at evaluating the associations between 14 polymorphisms of six genes involved in MTX metabolism with serum MTX concentration and toxicity accompanying high-dose MTX. Polymorphisms in 183 Chinese patients with ALL were analyzed using TaqMan single nucleotide polymorphism genotyping assay. The serum MTX concentration was determined using homogeneous enzyme immunoassay. MTX-related toxicities were also evaluated. Renal toxicity was significantly associated with higher serum MTX concentrations at 24, 48, and 72 hours, and MTX elimination delay ( = 0.001, < 0.001, < 0.001, and < 0.001, respectively), whereas rs4149056 was associated with serum MTX concentrations at 48 and 72 hours, and MTX elimination delay in candidate polymorphisms ( = 0.014, = 0.019, and = 0.007, respectively). rs2838958 and rs3788200 were associated with serum MTX concentrations at 24 hours ( = 0.016, = 0.043, respectively). rs1801394 was associated with serum MTX concentrations at 72 hours ( = 0.045). Neutropenia was related to rs4149056 (odds ratio [OR]: 3.172, 95% confidence interval [CI]: 1.310-7.681, = 0.011). Hepatotoxicity was associated with rs2273697 (OR: 3.494, 95% CI: 1.236-9.873, = 0.018) and rs1801394 (OR: 0.231, 95% CI: 0.084-0.632, = 0.004). Polymorphisms of , and genes help predict higher risk of increased MTX levels or MTX-related toxicities in adult ALL patients.