MTHFRC677T基因多态性对儿童成熟B细胞淋巴瘤患者大剂量甲氨蝶呤治疗相关毒性的影响

Influence of Methylenetetrahydrofolate Reductase C677T Polymorphism on High-Dose Methotrexate Toxicity in Pediatric Mature B-cell lymphoma Patients

目的:探讨MTHFR C677T(rs1801133)基因多态性对成熟B细胞淋巴瘤患儿甲氨蝶呤(MTX)相关毒性的影响。方法:纳入2014年8月至2021年12月在中山大学肿瘤防治中心接受MTX 5 g/m^(2)(24 h静脉滴注)治疗的58例中国18岁以下成熟B细胞淋巴瘤中危及高危的患儿,监测并分析患儿的毒副反应。结果:58例患儿中,MTHFR C677T野生型33例,杂合型19例,纯合型6例。共统计了101个疗程,其中35个疗程观察到MTX输注后48 h血药浓度>0.2μmol/L,66个疗程≤0.2μmol/L。组间比较发现,输注后48 h血浆MTX水平>0.2μmol/L可增加发生口腔黏膜炎的风险(P<0.05)。相比野生型患儿,突变型(杂合型+纯合型)患儿更容易发生骨髓抑制,表现为贫血、白细胞减少、中性粒细胞减少和血小板减少。48 h血浆MTX水平与MTHFR C677T基因多态性无关。结论:成熟B细胞淋巴瘤患儿口腔黏膜炎发生风险与血浆MTX浓度相关。MTHFR C677T基因多态性与成熟B细胞淋巴瘤患儿血浆MTX浓度无关,与III-IV级血液学毒性相关。

Objective:To investigate the effect of genetic polymorphism of MTHFR C677T(rs1801133)on methotrexate(MTX)related toxicity in pediatric mature B-cell lymphoma patients.Methods:Fifty-eight intermediate and high risk patients under 18 years of age with mature B-cell lymphoma who received 5 g/m^(2) MTX(24 h intravenous infusion)in Sun Yat-sen University Cancer Center from August 2014 to December 2021 were included,and their toxicity of high-dose MTX(HD-MTX)were monitored and analyzed.Results:Among the 58 pediatric patients,the number of CC,CT,and TT genotypes for MTHFR C677T was 33,19 and 6,respectively.A total of 101 courses of HD-MTX therapy were counted,of which plasma MTX level>0.2μmol/L at 48 h post-MTX infusion were observed in 35 courses,≤0.2μmol/L in 66 courses.Inter-group comparison showed that plasma MTX level>0.2μmol/L at 48 h post-MTX infusion increased the risk of developing oral mucositis(P<0.05).Compared with wild-type(CC genotype),patients in the mutant group(CT+TT genotype)were more likely to develop myelosuppression,manifested as anemia,leucopenia,neutropenia and thrombocytopenia.However,plasma MTX level at 48 h was not associated with MTHFR C677T gene polymorphism.Conclusion:The risk of developing oral mucositis in children with mature B-cell lymphoma is associated with plasma MTX concentration.Polymorphism of MTHFR C677T gene is not related to plasma MTX concentration in children with mature B-cell lymphoma,but is related to grade III to IV hematological toxicity.