Tan Yinli, Kong Qian, Li Xinyu, Tang Yanlai, Mai Huirong, Zhen Zijun, Zhou Dunhua, Chen Huiqin
Department of Pediatrics, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Department of Pediatric Hematology/Oncology, Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Transl Pediatr. 2023 Jan 31;12(1):31-45. doi: 10.21037/tp-22-671. Epub 2023 Jan 16.
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, and methotrexate (MTX) is the key drug for ALL. Studies on the relationship between High-Dose methotrexate (HD-MTX) toxicity and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genes have drawn different conclusions. This study aimed to investigate the relationship between the polymorphism of C677T and A1298C genes and the toxicity responses of MTX.
The C677T and A1298C genotypes of 271 children with ALL who received HD-MTX chemotherapy in southern China from September 2017 to June 2021 were analyzed, and the toxicity of HD-MTX was evaluated and analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0.
The C677T and A1298C gene polymorphisms were not correlated with the 48-hour MTX blood concentrations (P>0.05). Unconditional logistic regression model analysis also revealed that the risk of liver function impairment [odds ratio (OR) =1.656, 95% confidence interval (CI): 1.179-2.324, P<0.05] and mucosal damage (OR =1.508, 95% CI: 1.042-2.183, P<0.05) were 1.656 and 1.508 times higher for the heterozygous mutant (CT), and homozygous mutant (TT) mutant type than for the wild-type (CC), wild-type, respectively. The risk of neutropenia and liver function impairment were 0.498 (OR =0.498, 95% CI: 0.251-0.989, P<0.05) and 6.067 (OR =6.067, 95% CI: 1.183-31.102, P<0.05) times higher in low-risk children with CT+TT mutant genotypes than in those with CC wild genotypes, respectively. Furthermore, the risk of mucosal damage was 1.906 times higher in high-risk children with the CT+TT genotype than in those with the CC genotype (OR =1.906, 95% CI: 1.033-3.518, P<0.05). The A1298C genotypes differed in the incidence of liver function damage and gastrointestinal toxic reactions in children with ALL. Nonetheless, no increased risk of liver function impairment nor gastrointestinal reactions in children with the heterozygous mutant (AC)+CC mutation was observed.
Advancements in genotype testing in children with ALL and the introduction of personalised treatments based on genotype results during HD-MTX chemotherapy will help to predict, prevent, and reduce the occurrence of adverse MTX-related toxic reactions.
急性淋巴细胞白血病（ALL）是儿童最常见的恶性肿瘤，甲氨蝶呤（MTX）是治疗ALL的关键药物。关于大剂量甲氨蝶呤（HD-MTX）毒性与亚甲基四氢叶酸还原酶（MTHFR）C677T和A1298C基因之间关系的研究得出了不同结论。本研究旨在探讨C677T和A1298C基因多态性与MTX毒性反应之间的关系。
分析了2017年9月至2021年6月在中国南方接受HD-MTX化疗的271例ALL患儿的C677T和A1298C基因型，并根据不良事件通用术语标准（CTCAE）5.0对HD-MTX的毒性进行评估和分析。
C677T和A1298C基因多态性与48小时MTX血药浓度无关（P>0.05）。无条件逻辑回归模型分析还显示，杂合突变型（CT）和纯合突变型（TT）的肝功能损害风险[比值比（OR）=1.656，95%置信区间（CI）：1.179-2.324，P<0.05]和黏膜损伤风险（OR =1.508，95%CI：1.042-2.183，P<0.05）分别是野生型（CC）的1.656倍和1.508倍。CT+TT突变基因型的低危患儿中性粒细胞减少和肝功能损害风险分别是CC野生基因型患儿的0.498倍（OR =0.498，95%CI：0.251-0.989，P<0.05）和6.067倍（OR =6.067，95%CI：1.183-31.102，P<0.05）。此外，CT+TT基因型的高危患儿黏膜损伤风险是CC基因型患儿的1.906倍（OR =1.906，95%CI：1.033-3.518，P<0.05）。ALL患儿中，A1298C基因型在肝功能损害和胃肠道毒性反应发生率方面存在差异。然而，未观察到杂合突变型（AC）+CC突变患儿肝功能损害风险和胃肠道反应增加。
ALL患儿基因型检测的进展以及在HD-MTX化疗期间根据基因型结果引入个性化治疗将有助于预测、预防和减少与MTX相关的不良毒性反应的发生。
