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

Abstract

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 (P = 0.001, P < 0.001, P < 0.001, and P < 0.001, respectively), whereas SLCO1B1 rs4149056 was associated with serum MTX concentrations at 48 and 72 hours, and MTX elimination delay in candidate polymorphisms (P = 0.014, P = 0.019, and P = 0.007, respectively). SLC19A1 rs2838958 and rs3788200 were associated with serum MTX concentrations at 24 hours (P = 0.016, P = 0.043, respectively). MTRR rs1801394 was associated with serum MTX concentrations at 72 hours (P = 0.045). Neutropenia was related to SLC19A1 rs4149056 (odds ratio [OR]: 3.172, 95% confidence interval [CI]: 1.310-7.681, P = 0.011). Hepatotoxicity was associated with ABCC2 rs2273697 (OR: 3.494, 95% CI: 1.236-9.873, P = 0.018) and MTRR rs1801394 (OR: 0.231, 95% CI: 0.084-0.632, P = 0.004). Polymorphisms of SLCO1B1, SLC19A1, ABCC2, and MTRR genes help predict higher risk of increased MTX levels or MTX-related toxicities in adult ALL patients.

Genetic polymorphisms and clinical parameters associated with renal toxicity in Thai hematologic malignancy patients receiving high dose methotrexate

“…Our study showed the possible association between exceeding MTX levels at 24 h after dosing and the risk of renal toxicity. This was in line with the result of a study by Hao et al 6 in which a significant association was reported between renal toxicity and higher serum MTX concentrations at 24, 48, and 72 h and delay in MTX elimination 6 . A study by Miguel et al, also supported that there was an association between the MTX concentration at 24 h after dosing and the risk of renal toxicity 24 .…”

“…Another study on folate-related genes and MTX sensitivity in pediatric ALL reported that the MTRR 66A > G allele was less sensitive to MTX, which determined the efficacy of MTX in each individual 22 . In parallel with our study, a study conducted in pediatric ALL by Hoed et al 23 found that the wild-type MTRR was associated with higher MTX levels at 24 h. A study by Hao et al 6 showed that patients with the variant genotype MTRR rs1801394 (AG or GG) had a significant increase in serum MTX levels at 48 h and that change was not associated with renal toxicity from MTX which was discordance to our study. The population and method used in the study by Hao et al were different from our study in the following ways: 1) enrolled only Chinese patients diagnosed with ALL, 2) different doses and leucovorin infusion protocol, and 3) different starting point of the monitoring time.…”

“…We found a potential association between wild-type allele A of MTRR rs1801394 and the risk of renal toxicity at 24 h after MTX dosing (OR (95% CI) = 2.084 (1.001–4.301); p = 0.047). In contrast, the previous reports showed conflicting results on the relationship between MTRR and MTX side effects, including renal toxicity 6 , 19 . The MTRR gene is responsible for maintaining optimal levels of methylcobalamin and activating cobalamin-dependent methionine synthase 17 , 18 .…”

“…The MTRR gene is responsible for maintaining optimal levels of methylcobalamin and activating cobalamin-dependent methionine synthase 17 , 18 . Variations in the MTRR gene are associated with a reduction in MTRR activity leading to dysregulation of folate metabolism and changes in homocysteine levels, which may influence the overall intracellular metabolism of MTX 6 , 7 , 20 . To date, the exact mechanism of MTRR gene affecting efficacy or toxicities of MTX treatment has not been fully investigated 19 .…”

“…Several previous studies focused on host genetic factors involved in the MTX metabolism pathway 5 . Example variants of MTHFR C677T (rs1801133), ABCB1 C3435T (rs1045642), and SLCO1B1 (rs11045879), and MTRR (rs1801394) were reported to be associated with MTX toxicity in hematologic malignancy conditions 2 , 6 , 7 . MTX is also used in autoimmune diseases.…”