Association of glutathione S-transferase M1 and T1 genetic polymorphisms with blood methotrexate concentration and adverse events in children with acute lymphoblastic leukemia

Abstract

Objective To 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). Methods Medical 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. Results A 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 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 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 0.05). 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). Conclusions The 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. Key words: Methotrexate; Hematologic neoplasms; Glutathione transferase; Polymorphism, genetic; Drug-related side effects and adverse reactions; Pharmacokinetics