MTHFR基因多态性与成人急性淋巴细胞白血病患者大剂量甲氨蝶呤毒性反应及血药浓度关系

doi:10.20223/j.cnki.1000-8535.2025.10.010

摘要/Abstract

摘要： 目的明确亚甲基四氢叶酸还原酶（MTHFR）C677T、A1298C基因多态性与成人患者使用大剂量甲氨蝶呤（MTX）治疗急性淋巴细胞白血病（ALL）毒性反应和24、48、72 h MTX血药浓度关系。方法收集2014年6月—2020年6月就诊于新疆医科大学第一附属医院成人急性淋巴细胞白血病75例患者血样检测MTHFR C677T及A1298C基因多态性,根据抗癌药物常见毒性反应分级标准对毒性反应进行分级,采用非条件Logistic回归分析MTHFR C677T、A1298C基因多态性与HD-MTX毒性反应及血药浓度的关系。结果 MTHFR 677TT型发生贫血风险显著高于CC型（P=0.027,OR=4.694,95%CI：1.195~18.438）;未发现MTHFR C677T与白细胞减少、血小板计数减少、中性粒细胞计数减少、淋巴粒细胞计数减少、骨髓抑制、谷丙转氨酶升高、谷草转氨酶升高、肝功能损伤、急性肾损伤及黏膜损伤、24 h、48 h及72 h MTX血药浓度有相关性（P>0.05）;未发现MTHFR A1298C与HD-MTX毒性反应及血药浓度有相关性（P>0.05）。结论 MTHFR C677T基因多态性与成人急性淋巴细胞白血病患者大剂量MTX化学治疗后血液毒性存在相关性。

关键词: 急性淋巴细胞白血病, 成人, 甲氨蝶呤, 亚甲基四氢叶酸还原酶, 毒性反应, 血药浓度

Abstract: Objective To determine the relationship among C677T and A1298C gene polymorphisms of methyltetrahydrofolate reductase（MTHFR）and adult acute lymphocytic leukemia（ALL）,the relationship between the toxicity of high-dose methotrexate（HD-MTX）after chemotherapy and the MTX blood concentration of 24 h,48 h and 72 h in patients with ALL．Methods Blood samples were collected from 75 adult patients with ALL who were treated at the First Affiliated Hospital of Xinjiang Medical University from June 2014 to June 2020．The samples were used to detect the genetic polymorphisms of MTHFR C677T and A1298C,and the toxic reactions were graded according to the common toxic reaction classification criteria of anti-cancer drugs．Unconditional Logistic regression was used to analyze the relationship between MTHFR C677T and A1298C gene polymorphisms and HD-MTX toxic reactions and blood drug concentration．Results The risk of anemia in MTHFR 677TT was significantly higher than that in CC type（P=0.027,OR=4.694,95% CI：1.195-18.438）．No correlation was found between MTHFR C677T and leukopenia,thrombocytopenia,neutropenia,lymphogranulocytopenia,bone marrow suppression,elevated alanine aminotransferase,elevated aspartate aminotransferase,liver function injury,acute kidney injury and mucosal injury,24 h,48 h and 72 h MTX plasma concentrations（>0.05）．No correlation was found among MTHFR A1298C and HD-MTX toxicity and blood concentration（P>0.05）．Conclusions MTHFR C677T gene polymorphism is associated with hematotoxicity after HD-MTX chemotherapy in adult patients with ALL．

Key words: acute lymphocytic leukemia, adult, methotrexate, methylene tetrahydrofolate reductase, toxicity, blood concentration

徐蕊, 麦吾菊丹·阿力甫, 张瑞, 胡玉, 孙璇, 李静, 陈军辉. MTHFR基因多态性与成人急性淋巴细胞白血病患者大剂量甲氨蝶呤毒性反应及血药浓度关系[J]. 广州医药, 2025, 56(10): 1390-1397.

XU Rui, Maiwujudan·ALIFU, ZHANG Rui, HU Yu, SUN Xuan, LI Jing, CHEN Junhui. Relationship among MTHFR polymorphism and high dose methotrexate toxicity and blood concentration in adult patients with acute lymphoblastic leukemia[J]. Guangzhou Medical Journal, 2025, 56(10): 1390-1397.

参考文献

[1] ALQARNI A M,ZEIDLER M P.How does methotrexate work[J].Biochem Soc Trans,2020,48(2):559-567.
[2] KAPOOR G,SINHA R,ABEDIN S.Experience with high dose methotrexate therapy in childhood acute lymphoblastic leukemia in a tertiary care cancer centre of a developing country[J].Pediatr Blood Cancer,2012,59(3):448-453.
[3] LOPEZ-LOPEZ E,GUTIERREZ-CAMINO A,BILBAO-ALDAITURRIAGA N,et al.Pharmacogenetics of childhood acute lymphoblastic leukemia[J].Pharmacogenomics,2014,15(10):1383-1398.
[4] 周宏灏. 遗传药理学[M].2版.北京:科学出版社,2013:304-305.
[5] WEISBERG I,TRAN P,CHRISTENSEN B,et al.A second genetic polymorphism in methylenetetrahydrofolate reductase(MTHFR)associated with decreased enzyme activity[J].Mol Genet Metab,1998,64(3):169-172.
[6] PUI C H.Genomic and pharmacogenetic studies of childhood acute lymphoblastic leukemia[J].Front Med,2015,9(1):1-9.
[7] PUI C H,CAMPANA D,PEI D,et al.Treating childhood acute lymphoblastic leukemia without cranial irradiation[J].N Engl J Med,2009,360(26):2730-2741.
[8] THOMAS JOHNSTON W,LIGHTFOOT T J,SIMPSON J,et al.Childhood cancer survival:A report from the United Kingdom childhood cancer study[J].Cancer Epidemiol,2010,34(6):659-666.
[9] CHIUSOLO P,REDDICONTO G,FARINA G,et al.MTHFR polymorphisms’influence on outcome and toxicity in acute lymphoblastic leukemia patients[J].Leuk Res,2007,31(12):1669-1674.
[10] EISSA D S,AHMED T M.C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene:Effect on methotrexate-related toxicity in adult acute lymphoblastic leukaemia[J].Blood Coagul Fibrinolysis,2013,24(2):181-188.
[11] AVIVI I,ZUCKERMAN T,KRIVOY N,et al.Genetic polymorphisms predicting methotrexate blood levels and toxicity in adult non-Hodgkin lymphoma[J].Leuk Lymphoma,2014,55(3):565-570.
[12] RUIZ-ARGÜELLES G J,COCONI-LINARES L N,GARCÉS-EISELE J,et al. Methotrexate-induced mucositis in acute leukemia patients is not associated with the MTHFR 677T allele in Mexico[J].Hematology,2007,12(5):387-391.
[13] 刘伟. MTHFR基因多态性对成年恶性血液病患者应用大剂量甲氨蝶呤后排泄延迟等不良反应影响的临床研究[D].扬州:扬州大学,2022.
[14] YAO P,HE X,ZHANG R,et al.The influence of MTHFR genetic polymorphisms on adverse reactions after methotrexate in patients with hematological malignancies:A meta-analysis[J].Hematology,2019,24(1):10-19.
[15] ZHAO M,LIANG L,JI L,et al.MTHFR gene polymorphisms and methotrexate toxicity in adult patients with hematological malignancies:A meta-analysis[J].Pharmacogenomics,2016,17(9):1005-1017.
[16] SABATTINI E,BACCI F,SAGRAMOSO C,et al.WHO classification of tumours of haematopoietic and lymphoid tissues in 2008:An overview[J].Pathologica,2010,102(3):83-87.
[17] 中国抗癌协会血液肿瘤专业委员会,中华医学会血液学分会白血病淋巴瘤学组.中国成人急性淋巴细胞白血病诊断与治疗指南(2016年版)[J].中华血液学杂志,2016,37(10):837-845.
[18] National Cancer Institute.Common Terminology Criteria for Adverse Events(CTCAE)v4.0[S].May 28,2009(v4.03:June 14,2010).
[19] 刘晶霞,陈洁平,谭文,等.亚甲基四氢叶酸还原酶基因多态性与急性淋巴细胞白血病患者甲氨蝶呤化疗毒副反应的研究[J].中国实验血液学杂志,2008,16(3):488-492.
[20] WIDEMANN B C,BALIS F M,KIM A,et al.Glucarpidase,leucovorin,and thymidine for high-dose methotrexate-induced renal dysfunction:Clinical and pharmacologic factors affecting outcome[J].J Clin Onco,2010,28(25):3979-3986.
[21] ONGARO A,de MATTEI M,DELLA PORTA M G,et al.Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia:Effects on methotrexate-related toxicity and survival[J].Haematologica,2009,94(10):1391-1398.
[22] ACKLAND S P,SCHILSKY R L.High-dose methotrexate:A critical reappraisal[J].J Clin Oncol,1987,5(12):2017-2031.
[23] YANG B,LIU Y,LI Y,et al.Geographical distribution of MTHFR C677T,A1298C and MTRR A66G gene polymorphisms in China:Findings from 15357 adults of Han nationality[J].PLoS One,2013,8(3):e57917.
[24] CHOI Y J,PARK H,LEE J S,et al.Methotrexate elimination and toxicity:MTHFR 677C>T polymorphism in patients with primary CNS lymphoma treated with high-dose methotrexate[J].Hematol Oncol,2017,35(4):504-509.
[25] CWIKLINSKA M,CZOGALA M,KWIECINSKA K,et al.Polymorphisms of SLC19A1 80 G>A,MTHFR 677 C>T,and tandem TS repeats influence pharmacokinetics,acute liver toxicity,and vomiting in children with acute lymphoblastic leukemia treated with high doses of methotrexate[J].Front Pediatr,2020(8):307.
[26] ESMAILI M A, KAZEMI A, FARANOUSH M,et al.Polymorphisms within methotrexate pathway genes:Relationship between plasma methotrexate levels, toxicity experienced and outcome in pediatric acute lymphoblastic leukemia[J].Iran J Basic Med Sci,2020,23(6):800-809.
[27] 白小红,牛佳慧,倪美艳,等.MTHFR基因多态性与大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病的临床疗效及药物不良反应的相关性分析[J].中国临床药理学杂志,2021,37(22):3056-3059.
[28] XU M,WU S,WANG Y,et al.Association between high-dose methotrexate-induced toxicity and polymorphisms within methotrexate pathway genes in acute lymphoblastic leukemia[J].Front Pharmacol,2022(13):1003812.
[29] KANTAR M,KOSOVAB B,CETINGULA N,et al.Methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms and therapy-related toxicity in children treated for acute lymphoblastic leukemia and non-Hodgkin lymphoma[J].Leuk Lymphoma,2009,50(6):912-917.
[30] 郑苗苗,岳丽杰,陈小文,等.急性淋巴细胞白血病患儿MTHFR基因多态性与大剂量甲氨蝶呤毒副反应的关系[J].中国当代儿科杂志,2013,15(3):201-206.
[31] 马乐,韩佳,吕冬梅.MTHFR与ABCB1基因多态性对血液系统恶性肿瘤患者大剂量甲氨蝶呤排泄延迟和肝肾毒性的影响[J].中国药业,2021,30(6):40-43.
[32] 朱婷婷,赵宇蕾,封利颖,等.大剂量甲氨蝶呤化疗后消除延迟的影响因素和发生机制的研究进展[J].药学与临床研究,2017,25(1):49-54.
[33] 李静,王捷,郁长治,等.亚甲基四氢叶酸还原酶基因多态性与急性淋巴细胞白血病患者甲氨蝶呤化疗药物不良反应的相关性研究[J].中国临床药理学杂志,2017,33(17):1634-1636,1650.