嵌合抗原受体T细胞治疗血液肿瘤所致凝血障碍及相关因素分析*

doi:10.3969/j.issn.1671-2587.2021.03.016

临床输血与检验 ›› 2021, Vol. 23 ›› Issue (3): 364-370.DOI: 10.3969/j.issn.1671-2587.2021.03.016

嵌合抗原受体T细胞治疗血液肿瘤所致凝血障碍及相关因素分析^*

许倩文, 薛磊, 汪敏, 强萍, 王丽, 徐慧, 张旭晗, 许汉英, 刘欣, 朱薇波, 蔡晓燕, 刘会兰, 孙自敏, 杨林, 王兴兵

230001 合肥,安徽医科大学附属省立医院（许倩文,王兴兵）; 中国科学技术大学附属第一医院（安徽省立医院）血液科（王兴兵,薛磊,强萍,王丽,徐慧,张旭晗,刘欣,朱薇波,蔡晓燕,刘会兰,孙自敏）; 博生吉安科细胞技术有限公司（汪敏,许汉英,杨林）

收稿日期:2021-01-11 出版日期:2021-06-20 发布日期:2021-06-22
通讯作者: 王兴兵,男,主任医师,博士,主要从事内科血液病的临床和基础工作,（E-mail）wangxingbing@ustc.edu.cn。
作者简介:许倩文（1996-）,女,硕士研究生在读,主要从事内科学（血液病学）研究,（E-mail）18225883016@163.com。
基金资助:
*本课题受安徽省科技重大专项（No.18030801126）、安徽省科技攻关项目（No.1604a0802071）资助

Coagulation Disorder and Relevant Factors Analysis after Chimeric Antigen Receptor T Cell Therapy in Hematological Malignancies

XU Qian-wen, XUE Lei, WANG Min, et al

Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001

Received:2021-01-11 Online:2021-06-20 Published:2021-06-22

摘要/Abstract

摘要： 目的研究复发难治B细胞血液系统恶性肿瘤患者接受靶向CD19的嵌合抗原受体T细胞（chimeric antigen receptor T cell,CAR-T）治疗后出现的凝血功能变化情况及相关因素分析。方法评估2016年10月~2020年1月46例复发难治B细胞血液系统恶性肿瘤患者接受靶向CD19 CAR-T治疗后凝血功能变化及其相关因素分析。结果 46例患者凝血功能异常为37例（80.4%）,包括D-二聚体>5 mg/L（31/46, 67.4%）、凝血酶原时间延长超过正常值>3 s（7/46, 15.2%）、部分凝血活酶时间延长超过正常值>10 s（25/46, 54.3%）、凝血酶时间延长（19/46, 41.3%）、纤维蛋白原<1.5 g/L（22/46, 47.8%）以及纤维蛋白原降解产物>20 mg/L（12/18, 66.7%）。相关因素分析提示凝血指标的变化与回输方式、输注后的炎症因子水平及输注后出现的细胞因子释放综合征（cytokine release syndrome, CRS）严重程度相关。结论 CAR-T治疗可影响患者凝血功能,逐步递增分次回输可以减轻输注后的凝血功能异常,CRS的严重程度与凝血功能异常密切相关。

关键词: 血液肿瘤, 嵌合抗原受体, CD19, 细胞因子释放综合征, 凝血功能异常

Abstract: Objective To explore coagulation disorder and relevant factors in patients with B cell hematological malignancies after CD19 targeted chimeric antigen receptor (CAR)-T cell therapy. Methods We retrospectively enrolled 46 patients with relapsed/refractory (R/R) B cell hematological malignancies from October 2016 to January 2020, and the changes of coagulation parameters after CAR-T therapy were collected and analyzed. Results Among 46 patients, 37 (80.4%) patients occurred coagulation disorders, including elevated D-dimer [ (>5 mg/L) (31/46, 67.4%)], prolonged APTT [ (> 10s) (25/46, 54.3%)], prolonged TT (19/46, 41.3%), decreased fibrinogen concentration [(<1.5 g/L) (22/46, 47.8%)], prolonged PT [ (>3s) (7/46, 15.2% )], and elevated FDP [ (> 20 mg/L (12/18, 66.7%)). Correlation analysis showed that coagulation disorder were associated with dose escalation, the level of inflammatory factors after infusion, and the severity of cytokine release syndrome (CRS) after infusion. Conclusion Coagulation disorder is a common adverse event after CAR-T therapy. Dose escalation infusion can reduce the risk of coagulopathy, and the severity of CRS is significantly associated with coagulopathy.

Key words: Hematological malignancies, Chimeric antigen receptor, CD19, Cytokine release syndrome Coagulopathy

中图分类号:

R331.1⁺43

许倩文, 薛磊, 汪敏, 强萍, 王丽, 徐慧, 张旭晗, 许汉英, 刘欣, 朱薇波, 蔡晓燕, 刘会兰, 孙自敏, 杨林, 王兴兵. 嵌合抗原受体T细胞治疗血液肿瘤所致凝血障碍及相关因素分析^*[J]. 临床输血与检验, 2021, 23(3): 364-370.

XU Qian-wen, XUE Lei, WANG Min, et al. Coagulation Disorder and Relevant Factors Analysis after Chimeric Antigen Receptor T Cell Therapy in Hematological Malignancies[J]. JOURNAL OF CLINICAL TRANSFUSION AND LABORATORY MEDICINE, 2021, 23(3): 364-370.

参考文献

[1] TERWILLIGER T,ABDUL-HAY M.Acute lymphoblastic leukemia:a comprehensive review and 2017 update[J].Blood Cancer J,2017,7(6):e577.
[2] MENG X,MIN Q,WANG JY.B cell lymphoma[M].Advances in Experimental Medicine and Biology,2004,9(1):90.
[3] KÖHL U,ARSENIEVA S,HOLZINGER A,et al.CAR T cells in trials:recent achievements and challenges that remain in the production of modified T cells for clinical applications[J].Hum Gene Ther,2018,29(5):559-568.
[4] RIEGLER L L,JONES G P,LEE D W.Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy[J].Ther Clin Risk Manag,2019,15:323-335.
[5] MEI H,JIANG H W,WU Y H,et al.Neurological toxicities and coagulation disorders in the cytokine release syndrome during CAR-T therapy[J].Br J Haematol,2018,181(5):689-692.
[6] WANG Y,QI K M,CHENG H,et al.Coagulation disorders after chimeric antigen receptor T cell therapy:analysis of 100 patients with relapsed and refractory hematologic malignancies[J].Biol Blood Marrow Transplant,2020,26(5):865-875.
[7] LEE D W,SANTOMASSO B D,LOCKE F L,et al.ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells[J].Biol Blood Marrow Transplant,2019,25(4):625-638.
[8] 美国卫生及公共服务部.常见不良反应事件评价标准( CTCAE)[S].2010.
[9] 中华医学会血液学分会血栓与止血学组.弥散性血管内凝血诊断中国专家共识(2017年版)[J].中华血液学杂志,2017,38(5):361-363.
[10] SCHUTTE T,THIJS A,SMULDERS Y M.Never ignore extremely elevated D-dimer levels:they are specific for serious illness[J].Neth J Med,2016,74(10):443-448.
[11] MAUDE S L,FREY N,SHAW P A,et al.Chimeric antigen receptor T cells for sustained remissions in leukemia[J].N Engl J Med,2014,371(16):1507-1517.
[12] KOCHENDERFER J N,SOMERVILLE R P T,LU T,et al.Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels[J].J Clin Oncol,2017,35(16):1803-1813.
[13] TURTLE C J,HANAFI L A,BERGER C,et al.CD19 CAR-T cells of defined CD4+:CD8+composition in adult B cell ALL patients[J].J Clin Invest,2016,126(6):2123-2138.
[14] LEVI M,VAN DER POLL T.Inflammation and coagulation[J].Crit Care Med,2010,38(2 Suppl):S26-S34.
[15] VAN DEVENTER S J,BÜLLER H R,TEN CATE J W,et al.Experimental endotoxemia in humans:analysis of cytokine release and coagulation,fibrinolytic,and complement pathways[J].Blood,1990,76(12):2520-2526.
[16] BOERMEESTER M A,VAN LEEUWEN P A,COYLE S M,et al.Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human Sepsis[J].Arch Surg Chic Ill,1995,130(7):739-748.
[17] VAN DER POLL T,LEVI M,HACK C E,et al.Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees[J].J Exp Med,1994,179(4):1253-1259.
[18] HAY K A,HANAFI L A,LI D,et al.Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy[J].Blood,2017,130(21):2295-2306.
[19] PRIVRATSKY J R,NEWMAN P J.PECAM-1:regulator of endothelial junctional integrity[J].Cell Tissue Res,2014,355(3):607-619.
[20] GOLDBERGER A,MIDDLETON K A,OLIVER J A,et al.Biosynthesis and processing of the cell adhesion molecule PECAM-1 includes production of a soluble form[J].J Biol Chem,1994,269(25):17183-17191.
[21] JIANG H,LIU L,GUO T,et al.Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy[J].Ann Hematol,2019,98(7):1721-1732.
[22] DUAN J C,LIANG S,YU Y,et al.Inflammation-coagulation response and thrombotic effects induced by silica nanoparticles in zebrafish embryos[J].Nanotoxicology,2018,12(5):470-484.
[23] 齐昆明,曹江,程海,等.六例血液系统疾病患者嵌合抗原受体T细胞治疗后并发弥散性血管内凝血临床分析[J].中华血液学杂志,2019,40(5):422-425.
[24] BRENTJENS R J,DAVILA M L,RIVIERE I,et al.CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia[J].Sci Transl Med,2013,5(177):177ra38.
[25] TANAKA T,NARAZAKI M,KISHIMOTO T.Immunotherapeutic implications of IL-6 blockade for cytokine storm[J].Immunotherapy,2016,8(8):959-970.
[26] DASYAM N,GEORGE P,WEINKOVE R.Chimeric antigen receptor T-cell therapies:Optimising the dose[J].Br J Clin Pharmacol,2020,86(9):1678-1689.
[27] BUECHNER J,GRUPP S A,HIRAMATSU H,et al.Practical guidelines for monitoring and management of coagulopathy following tisagenlecleucel CAR T-cell therapy[J].Blood Adv,2021,5(2):593-601.

嵌合抗原受体T细胞治疗血液肿瘤所致凝血障碍及相关因素分析^*

Coagulation Disorder and Relevant Factors Analysis after Chimeric Antigen Receptor T Cell Therapy in Hematological Malignancies

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