急性淋巴细胞白血病患儿亚甲基四氢叶酸还原酶基因多态性与甲氨蝶呤血药浓度和不良反应的相关性

Association of Methylenetetrahydrofolate Reductase Gene Polymorphism with Blood Methotrexate Concentration and Adverse Reactions in Children with Acute Lymphoblastic Leukemia

目的研究MTHFR(1298A>C)和MTHFR(677C>T)位点多态性与甲氨蝶呤(methotrexate,MTX)血药浓度和不良反应的相关性。方法选取2014年10月—2021年12月上海市儿童医院收治的185例急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)患儿,收集MTHFR(1298A>C)和MTHFR(677C>T)基因分型、不良反应和血药浓度等实验室检查指标结果。结果185例患儿使用MTX后的总体不良反应发生率为95.1%。MTHFR(1298A>C)2种基因型不良反应发生率除粒细胞缺乏差异有统计学意义(P=0.006)外,其他均无统计学意义;MTHFR(677C>T)3种基因型的ALL患儿不良反应发生率除粒细胞缺乏(P=0.041/0.012)、消化道反应(P=0.037/0.011)和黏膜毒性(P=0.039/0.016)差异有统计学意义外,其他均无统计学意义;MTHFR(677C>T)3种基因型的ALL患儿在24 h时的MTX血药浓度差异有统计学意义(P=0.021);MTHFR(677C>T)3种基因型的ALL患儿进行亚叶酸钙翻倍解救发生率差异有统计学意义(P=0.007/0.002)。结论MTHFR(1298A>C)和MTHFR(677C>T)多态性可能不是预测儿童ALL进行MTX化疗的良好指标,结局提示了翻倍解救的重要性,即翻倍解救可以明显降低黏膜毒性和骨髓毒性高发患儿的此类不良反应发生率。

OBJECTIVE To investigate the correlation between polymorphisms of MTHFR(1298A>C)and MTHFR(677C>T)and the blood concentration and adverse reactions of methotrexate(MTX).METHODS A total of 185 children with acutelymphoblastic leukemia(ALL)admitted to Shanghai Children′s Hospital from October 2014 to December 2021 were selected to collect laboratory test indicators such as MTHFR(1298A>C)and MTHFR(677C>T)genotype,adverse reactions,and blood concentration.RESULTS The overall incidence of adverse reactions after using MTX in 185 children was 95.1%.The incidence of adverse reactions between the two genotypes of MTHFR(A1298C)was not statistically significant,except for the difference in neutropenia(P=0.006);the incidence of adverse reactions in ALL children with three genotypes of MTHFR(C677T)was not statistically significant except for neutropenia(P=0.041/0.012),gastrointestinal reactions(P=0.037/0.011),and mucosal toxicity(P=0.039/0.016);there was a statistically significant difference in MTX plasma concentration among ALL patients with three genotypes of MTHFR(C677T)at 24 h(P=0.021);there was a statistically significant difference in the incidence of calcium folinate doubling rescue among ALL patients with three genotypes of MTHFR(677C>T)(P=0.007/0.002).CONCLUSION Polymorphisms in MTHFR(1298A>C)and MTHFR(677C>T)may not be good indicators for predicting MTX chemotherapy in children with ALL.The importance of doubling rescue is emphasized,as doubling rescue can significantly reduce the incidence of such adverse reactions in children with high incidence of mucosal toxicity and bone marrow toxicity.