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

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

目的探讨急性淋巴细胞白血病(ALL)患儿谷胱甘肽硫基转移酶(GST)M1和T1基因多态性与大剂量甲氨蝶呤(HDMTX)输注开始后48h甲氨蝶呤血药浓度(48h血药浓度)及72h内主要不良事件的关系。方法收集在厦门大学附属第一医院住院接受含HDMTX方案化疗且进行过48h血药浓度和GSTM1、GSTT1基因多态性检测的ALL患儿病历资料进行回顾性分析。结果纳入分析的ALL患儿共94例,男性52例,女性42例;年龄2~15岁,平均(5±3)岁;HDMTX化疗后72h内出现肝损伤者44例(46.8%),胃肠道反应43例(45.7%),骨髓抑制15例(16.0%),皮肤黏膜损伤45例(47.9%)。将患儿按48h血药浓度分为<0.5μmol/L组、0.5~1.0μmol/L组和>1.0μmol/L组,48h血药浓度<0.5μmol/L组患儿肝损伤、胃肠道反应和皮肤黏膜损伤等不良事件发生率均明显低于48h血药浓度>1.0μmol/L组[17.9%(5/28)比78.6%(11/14),21.4%(6/28)比85.7%(12/14),17.9%(5/28)比71.4%(10/14),均P<0.001]。GSTM1功能基因型与缺失基因型患儿之间以及GSTT1功能基因型与缺失基因型患儿之间48h血药浓度/剂量比值的差异均无统计学意义(均P>0.05),但GSTM1和GSTT1缺失基因型患儿大剂量MTX化疗后72h内肝损伤发生率均明显高于相应功能基因型患儿[GSTM1:50.7%(36/71)比34.8%(8/23);GSTT1:55.2%(32/58)比33.3%(12/36),均P<0.05]。多因素Logistic回归分析结果显示,GSTM1、GSTT1基因多态性与肝损伤发生风险增加有关(OR=1.928,95%CI:1.353~2.745,P<0.001;OR=2.462,95%CI:1.046~5.793,P=0.039)。结论接受HDMTX化疗的ALL患儿48h血药浓度与不良事件的发生有关,GSTM1和GSTT1基因多态性对48h血药浓度无明显影响,但可能增加肝损伤的发生风险。

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).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.