Association of glutathione S-transferase M1 and T1 genetic polymorphisms with blood methotrexate concentration and adverse events in children with acute lymphoblastic leukemia
Department of Pharmacy, the First Affiliated Hospital of Xiamen University, Xiamen 361003, China
Abstract：ObjectiveTo explore the association between glutathione S-transferase (GST) M1 and T1 genetic polymorphisms and the blood methotrexate concentration at 48 hours (C48 h) after initiation of high-dose methotrexate (HDMTX) infusion and major adverse events within 72 hours in children with acute lymphoblastic leukemia (ALL).MethodsMedical records of ALL children in the First Affiliated Hospital of Xiamen University who received HDMTX-containing chemotherapy regimen, blood concentration monitoring of methotrexate at 48 hours after initiation of infusion, and GST M1 and T1 genetic polymorphism detection were collected and retrospectively analyzed.ResultsA total of 94 children with ALL were enrolled in the study, including 52 males and 42 females, aged 2-15 years with the average age of (5±3) years. Within 72 hours after the HDMTX chemotherapy, 44 children (46.8%) developed liver injury, 43 children (45.7%) developed gastrointestinal reactions, 15 children (16.0%) developed myelosuppression, and 45 children (47.9%) developed skin and mucosa injury. The children were divided into the <0.5 μmol/L group, the 0.5-1.0 μmol/L group, and the >1.0 μmol/L group according to their C48 h of methotrexate. The incidences of adverse events such as liver injury, gastrointestinal reaction, and skin and mucosa injury in the <0.5 μmol/L group were significantly lower than those in the >1.0 μmol/L group ［17.9% (5/28) vs. 78.6% (11/14), 21.4% (6 /28) vs. 85.7% (12/14), 17.9% (5/28) vs. 71.4% (10/14), all P<0.001］. Significant differences of methotrexate C48 h/dose ratio were found neither between children with functional wild-type alleles of GST M1 (GST M1 non-null genotypes) and those with GST M1 null-genotypes nor between children with GST T1 non-null genotypes and those with GST T1 null genotypes (both P>0.05). But the incidences of liver injury within 72 hours after HDMTX chemotherapy in children with GST M1 and GST T1 null-genotypes were significantly higher than those in children with GST M1 and GST T1 non-null genotypes, respectively ［GST M1: 50.7% (36/71) vs. 34.8% (8/23); GST T1: 55.2% (32/58) vs. 33.3% (12/36), both P<0.05］. Multivariate logistic regression analysis showed that GST M1 and GST T1 genetic polymorphisms were associated with increased risk of liver injury (OR=1.928, 95%CI: 1.353-2.745, P<0.001; OR=2.462, 95%CI: 1.046-5.793, P=0.039).ConclusionsThe C48 h of methotrexate in children with ALL and receiving HDMTX chemotherapy was associated with the occurrence of adverse events. GST M1 and GST T1 genetic polymorphisms had no significant effects on C48 h of methotrexate, but might increase the risk of liver injury in children.
陈秋林, 孙洲亮, 王昆, 颜志文. 急性淋巴细胞白血病患儿谷胱甘肽硫基转移酶M1和T1基因多态性与甲氨蝶呤血药浓度及不良事件的关系[J]. 药物不良反应杂志社, 2019, 21(3): 176-182.
Chen Qiulin, Sun Zhouliang, Wang Kun, Yan Zhiwen. Association of glutathione S-transferase M1 and T1 genetic polymorphisms with blood methotrexate concentration and adverse events in children with acute lymphoblastic leukemia. Adverse Drug Reactions Journal, 2019, 21(3): 176-182.
