ABCB1 C3435T基因多态性与成熟B细胞淋巴瘤患儿大剂量甲氨蝶呤血药浓度和不良反应的相关性研究

doi:10.19803/j.1672-8629.20220680

摘要/Abstract

摘要： 目的探讨成熟B细胞淋巴瘤患儿ABCB1 C3435T（CC型、CT型和TT型）基因多态性与大剂量甲氨蝶呤（HD-MTX）化疗后血药浓度和药品不良反应（ADR）的相关性。方法回顾性收集本院2019年10月1日至2022年10月1日收治的行HD-MTX化疗且检测ABCB1 C3435T基因型并测定MTX血药浓度的成熟B细胞淋巴瘤患儿的病历资料,分析基因多态性与MTX血药浓度和ADR的关系。结果共收集66例患者,其中男52例,女14例,平均年龄（7.46±3.09）岁（1.9~15.0岁）。HD-MTX化疗后常见ADR为中性粒细胞减少（98.48%）、贫血（89.39%）、血小板减少（77.27%）和黏膜损伤（53.03%）等。ABCB1 C3435T TT型比CC型的MTX 44 h血药浓度更高（P<0.05）。CT和TT型比CC型的黏膜损伤、呕吐和肝损伤发生率更高（P<0.05）。结论 ABCB1 C3435T基因多态性与成熟B细胞淋巴瘤患儿HD-MTX血药浓度水平及ADR（黏膜损伤、呕吐和肝损伤）可能有关。

关键词: ABCB1 C3435T基因多态性, 大剂量甲氨蝶呤, 药品不良反应, 成熟B细胞淋巴瘤, 儿童

Abstract: Objective To investigate the correlations between polymorphisms of ABCB1 C3435T genes（CC, CT and TT）, blood drug concentrations and adverse drug reactions (ADR) during high-dose methotrexate (HD-MTX) chemotherapy in children with mature B-cell lymphoma. Methods The medical data of children with mature B-cell lymphoma who had received HD-MTX chemotherapy and had had their MTX concentrations after administration determined and polymorphisms of ABCB1 C3435T detected was retrospectively collected from Oct, 2019 to Oct, 2022. The relationships between ABCB1 C3435T gene polymorphisms, MTX plasma concentrations and ADR were analyzed. Results A total of 66 patients, including 52 males and 14 females with an average age of 7.46±3.09 years (1.9~15.0 years), were enrolled. The most common ADR associated with HD-MTX were neutropenia (98.48%), anemia (89.39%), thrombocytopenia (77.27%) and mucosal injury (53.03%). The MTX 44 h blood concentration of the ABCB1 C3435T TT type was higher than that of the CC type (P<0.05). Compared with the ABCB1 C3435T CC type, CT and TT types had higher incidence of mucosal injury, vomiting and liver function damage (P<0.05). Conclusion ABCB1 C3435T gene polymorphisms may be associated with serum levels of HD-MTX and adverse reactions (mucosal injury, vomiting and liver function damage) in children with mature B-cell lymphoma.

Key words: ABCB1 C3435T genetic polymorphism, high-dose methotrexate, adverse drug reaction, mature B-cell lymphoma, pediatric

中图分类号:

R994.11

罗芳梅, 吴攀, 李静, 王婷, 王方杰. ABCB1 C3435T基因多态性与成熟B细胞淋巴瘤患儿大剂量甲氨蝶呤血药浓度和不良反应的相关性研究[J]. 中国药物警戒, 2023, 20(6): 675-679.

LUO Fangmei, WU Pan, LI Jing, WANG Ting, WANG Fangjie. Correlations of ABCB1 C3435T genetic polymorphism with serum concentrations and adverse reactions of high-dose methotrexate in children with mature B-cell lymphoma[J]. Chinese Journal of Pharmacovigilance, 2023, 20(6): 675-679.

参考文献

[1] The Subspecialty Group of Oncology, the Society of Pediatrics, Chinese Medical Association, the Subspecialty Group of Hematology, the Society of Pediatrics, Chinese Medical Association, Committee of Pediatrics, Chinese Anti-Cancer Association, et al. Experts consensus on current management of children and adolescents with aggressive mature B cell non Hodgkin lymphoma[J]. Chinese Journal of Pediatrics(中华儿科杂志), 2020, 58(10): 790-795.
[2] National Health Commission of the People's Republic of China. Guidelines for diagnosis and treatment of mature B-cell lymphoma in children (2019 edition)[EB/OL]. (2019-09-05)[2022-10-09].http://www.nhc.gov.cn/yzygj/s3593/201909/ 5f1d3329606e4cd2aa6e501603703ee4.shtml.
[3] Chinese Society of Clinical Oncology, Chinese Society of Clinical Oncology Anti-Leukemia Alliance, Chinese Society of Clinical Oncology Anti-Lymphoma Alliance. Expert consensus on high-dose methotrexate and calcium folinate rescue therapy for malignant tumors[J]. Chinese Journal of Clinical Oncology(中国肿瘤临床), 2019, 46(15): 761-767.
[4] AVIVI I, ZUCKERMAN T, KRIVOY N, et al.Genetic polymorphisms predicting methotrexate blood levels and toxicity in adult nonHodgkin lymphoma[J]. Leuk Lymphoma, 2014, 55(3): 565-570.
[5] AMITAI I, ROZOVSKI U, EL-SALEH R, et al.Risk factors for high-dose methotrexate associated acute kidney injury in patients with hematological malignancies[J]. Hematol Oncol, 2020, 38(4):584-588.
[6] MENG C.Effect of of ABCB1 C3435T gene polymorphism on plasma concentration and adverse reactions of high-dose methotrexate in children with acute lymphoblastic leukemia[D]. Shenyang: China Medical University(中国医科大学), 2020.
[7] KATHAWALA RJ, WANG YJ, SHUKLA S, et al.ATP-binding cassette subfamily B member 1 (ABCB1) and subfamily C member 10 (ABCC10) are not primary resistance factors for cabazitaxel[J]. Chin J Cancer, 2015, 34(3): 115-120.
[8] ZHU Y, LOU YC, LIU MM, et al.Effect of ABCB13435C>T genetic polymorphism on plasma concentration and adverse reactions of high-dose methotrexate in acute lymphoblastic leukemia children[J]. China Pharmacist(中国药师), 2017, 20(6): 1058-1061.
[9] SONG Z, HU Y, LIU S, et al.The role of genetic polymorphisms in high-dose methotrexate toxicity and response in hematological malignancies: a systematic review and meta-analysis[J]. Front Pharmacol, 2021, 12: 757464.
[10] MANTADAKIS E, COLE PD, KAMEN BA.High-dose methotrexate in acute lymphoblastic leukemia: Where is the evidence for its continued use?[J]. Pharmacotherapy, 2005, 25(5): 748-755.
[11] National Cancer Institude. Common terminology criteria for adverse events(CTC AE) Version 5.0[EB/OL]. (2017-05-22)[2019-11-12]. https://ctep.Cancer. gov/protocol/Development/electronic_applications/ctc.htm.
[12] PAW CHO SING E, ROBINSON PD, FLANK J, et al. Classification of the acute emetogenicity of chemotherapy in pediatric patients: a clinical practice guideline[J]. Pediatr Blood Cancer, 2019, 66(5): 1-7.
[13] BASCH E, PRESTRUD AA, HESKETH PJ, et al.Antiemetics: American Society of Clinical Oncology clinical practice guideline update[J]. J Clin Oncol, 2011, 29(31): 4189-4198.
[14] JIANG ZP, PENG Q, HE LM, et al.Clinical analysis of adverse drug reasctions of high-dose methotrexate in children with acute lymphoblastic leukemia[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2019, 16(1): 13-17.
[15] MORSY MA, EL-SHEIKH AAK, ABDEL-HAFEZ SMN, et al.Paeonol protects against methotrexate-induced nephrotoxicity via upregulation of p-gp expression and inhibition of TLR4/NF-κB pathway[J]. Front Pharmacol, 2022, 13: 774387.
[16] KIM IW, YUN HY, CHOI B, et al.ABCB1 C3435T genetic polymorphism on population pharmacokinetics of methotrexate after hematopoietic stem cell transplantation in Korean patients: a prospective analysis[J]. Clinical Therapeutics, 2012, 34(8): 1816-1826.
[17] EBID AIM, HOSSAM A, EL GAMMAL MM, et al.High dose methotrexate in adult Egyptian patients with hematological malignancies: impact of ABCB1 3435C>T rs1045642 and MTHFR 677C>T rs1801133 polymorphisms on toxicities and delayed elimination[J]. J Chemother, 2022, 34(6): 381-390.
[18] LI Y, FAN HH, FENG XJ, et al.Association between ABCB1 C3435T polymorphisms and methotrexate-induced toxicity in childhood acute lymphoblastic leukemia: Meta analysis[J]. Chinese Journal of Pharmacovigilance(中国药物警戒), 2022, 19(4): 421-425.
[19] SONG Z, HU Y, LIU S, et al.Medication therapy of high-dose methotrexate: An evidence-based practice guideline of the Division of Therapeutic Drug Monitoring, Chinese Pharmacological Society[J]. Br J Clin Pharmacol, 2022, 88(5): 2456-2472.
[20] SAMARA SA, IRSHAID YM, MUSTAFA KN.Association of MDR1 C3435T and RFC1 G80A polymorphisms with methotrexate toxicity and response in Jordanian rheumatoid arthritis patients[J]. International Journal of Clinical Pharmacology and Therapeutics, 2014, 52(9): 746-755.