抗人T细胞猪免疫球蛋白联合艾曲泊帕治疗初发重型再生障碍性贫血疗效分析

宫跃敏; 马永超; 陈小玉; 李瑞鑫; 李悦; 张雅文; 师锦宁; 龙启强; 杨岩; 贾晋松; 林圣云; 何广胜; 李建勇

doi:10.13201/j.issn.1004-2806.2023.07.006

抗人T细胞猪免疫球蛋白联合艾曲泊帕治疗初发重型再生障碍性贫血疗效分析

- 1.
  南京医科大学第一附属医院江苏省人民医院血液科(南京，210029)
- 2.
  南京医科大学附属江宁医院血液内科
- 3.
  南京市第二医院南京中医药大学附属南京医院血液科
- 4.
  吉林大学第一医院血液肿瘤中心
- 5.
  北京大学人民医院血液科
- 6.
  浙江省中医院血液科
基金项目:
国家自然科学基金(No：81900109)；南京医科大学附属江宁医院免疫细胞转化研究中心开放课题(No：JNYYZXKY202214)

详细信息

通讯作者: 何广胜，E-mail：heguangsheng1972@sina.com

中图分类号: R556.5

收稿日期: 2022-10-22

修回日期: 2023-04-12

刊出日期: 2023-07-01

Anti-human T-cell porcine immunoglobin combined with eltrombopag in patients with severe aplastic anemia

- 1.
  Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, 210029, China
- 2.
  Department of Hematology, the Affiliated Jiangning Hospital of Nanjing Medical University
- 3.
  Department of Hematology, Second Hospital of Nanjing, the Affiliated Nanjing Hospital of Nanjing Traditional Chinese Medical University
- 4.
  The Hematology & Tumor Center of the First Hospital of Jilin University
- 5.
  Department of Hematology, People's Hospital of Peking University
- 6.
  Department of Hematology, Zhejiang Traditional Chinese Medicine Hospital

More Information

Corresponding author: HE Guangsheng, E-mail: heguangsheng1972@sina.com

Received Date: 22 October 2022

Revised Date: 12 April 2023

Publish Date: 01 July 2023

摘要

摘要: 目的研究抗人T细胞猪免疫球蛋白(anti-human T lymphocyte porcine immunoglobulin，p-ATG)，环孢素A(Cyclosporin A，CsA)组成的强化免疫抑制治疗(intensive immunosuppressive therapy，IST)联合艾曲泊帕在重型再生障碍性贫血(severe aplastic anemia，SAA)患者的疗效及影响因素。方法前瞻性登记纳入2020年4月—2022年8月25例初发SAA患者，接受p-ATG为基础的IST联合艾曲泊帕治疗。主要终点是6个月完全反应(complete response，CR)率和总体反应率(overall response rate，ORR)。次要终点是生存率、复发率及克隆演变风险。结果治疗后6个月CR率和ORR分别为19.05%、71.43%。中位获得反应时间为3.00(0.10~11.80)个月，中位获得CR时间为14.40(0.90~20.00)个月，多因素分析显示疾病严重程度对获得反应时间有显著影响。中位随访时间11.30(0.70~26.40)个月，总生存率96.00%，中位无事件生存期为12.70(1.40~18.90)个月。1例于治疗后10个月出现克隆性造血。≥3级不良反应：感染8例，1例死亡；肝肾功能损害1例和牙周病2例。结论 p-ATG为基础的IST联合艾曲泊帕治疗SAA可获得较为满意的血液学反应率和反应速度，耐受性和安全性良好。
- 重型再生障碍性贫血 /
- 抗人T细胞免疫球蛋白 /
- 艾曲泊帕
Abstract: Objective To evaluate the efficacy and safety of anti-human T-cell porcine immunoglobin(p-ATG) based intensive immunosuppressive therapy(IST) combined with eltrombopag in patients with severe aplastic anemia(SAA).Methods From April 2020 to August 2022, 25 newly-diagnosed SAA patients enrolled in a prospective cohort registry study were treated by p-ATG plus eltrombopag. The primary outcome was complete response(CR) and overall response rate(ORR) at 6 months. Secondary end points included survival, relapse, and clonal evolution.Results CR and ORR at 6 months were 19.05% and 71.43%, respectively. The median time to first response was 3.00(0.10-11.80) months. The median time to achieve complete response was 14.40(0.90-20.00) months. Severity (vSAA vs SAA) was associated with the time to get first response. The median follow-up was 11.30(0.70-26.40) months, the over survival rate was 96.00%. The median event-free survival time was 12.70(1.40-18.90) months. Clonal hematopoiesis was found in one patient 10 months after initiation of treatment. Adverse events above grade 3 occurred in 8 cases of infection, including one death; 1 case of abnormal liver and renal functions, and 2 cases of parodontopathy, which were relieved by adjusting concentration of CsA.Conclusion The addition of EPAG to p-ATG based IST was well tolerant and associated with high rates of hematologic response among previously untreated patients with SAA.
- severe aplastic anemia /
- antithymocyte globulin /
- eltrombopag

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图 1 p-ATG为基础的IST联合艾曲泊帕治疗SAA累积疗效曲线和生存曲线

下载: 全尺寸图片幻灯片

表 1 25例SAA患者基线临床资料

基线临床特征	数值
年龄/岁	24(3~77)
性别/例
女	11
男	14
严重程度/例
SAA	16
vSAA	9
诊断至ATG治疗的时间/d	27.00(3.00~639.00)
治疗前感染/例	13
PNH克隆/例	2
铁蛋白/(ng/mL)	885.70(523.82~1 139.59)
HGB/(g/L)	68.00(59.00~72.00)
ANC/(×10⁹/L)	0.30(0.09~0.45)
淋巴细胞计数/(×10⁹/L)	1.31(0.43~1.85)
PLT/(×10⁹/L)	12.00(5.50~15.50)
ARC(×10⁹/L)	10.20(5.55~32.35)
红细胞分布宽度变异系数(RDW-CV)/%	14.80(12.10~16.60)
CD3⁺ T细胞比例/%	72.03(81.46~84.40)
CD4⁺ T细胞/%	47.30(31.40~57.75)
CD8⁺ T细胞/%	24.00(18.55~35.50)
调节性T细胞/%	5.30(4.58~7.06)
髓系肿瘤基因突变/例	4

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表 2 p-ATG联合艾曲泊帕治疗SAA不同时间点疗效

治疗时间	1个月	3个月	6个月	12个月
CR/例	1	3	4	5
PR/例	2	12	11	4
NR/例	22	9	6	4
死亡/例	0	1	1	1
不可评估^*/例	0	1	4	12
ORR/%	12.00(3/25)	62.50(15/24)	71.43(15/21)	69.23(9/13)
CR率/%	4.00(1/25)	12.50(3/24)	19.05(4/21)	38.46(5/13)
^*失访或未达评估时间。

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参考文献(26)

[1]	Zhu CY, Lian Y, Wang CC, et al. Single-cell transcriptomics dissects hematopoietic cell destruction and T-cell engagement in aplastic anemia[J]. Blood, 2021, 138(1): 23-33. doi: 10.1182/blood.2020008966
[2]	Young NS. Aplastic Anemia[J]. N Engl J Med, 2018, 379(17): 1643-1656. doi: 10.1056/NEJMra1413485
[3]	Bacigalupo A. How I treat acquired aplastic anemia[J]. Blood, 2017, 129(11): 1428-1436. doi: 10.1182/blood-2016-08-693481
[4]	何广胜. 免疫抑制治疗再生障碍性贫血的选择[J]. 临床血液学杂志, 2016, 29(11): 874-876. doi: 10.13201/j.issn.1004-2806.2016.11.005
[5]	Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia[J]. N Engl J Med, 2011, 365(5): 430-438. doi: 10.1056/NEJMoa1103975
[6]	Marsh JC, Bacigalupo A, Schrezenmeier H, et al. Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party[J]. Blood, 2012, 119(23): 5391-5396. doi: 10.1182/blood-2012-02-407684
[7]	Ghanima W, Cooper N, Rodeghiero F, et al. Thrombopoietin receptor agonists: ten years later[J]. Haematologica, 2019, 104(6): 1112-1123. doi: 10.3324/haematol.2018.212845
[8]	Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immunosuppression for aplastic Anemia[J]. N Engl J Med, 2017, 376(16): 1540-1550. doi: 10.1056/NEJMoa1613878
[9]	Peffault de Latour R, Kulasekararaj A, Iacobelli S, et al. Eltrombopag added to immunosuppression in severe aplastic Anemia[J]. N Engl J Med, 2022, 386(1): 11-23. doi: 10.1056/NEJMoa2109965
[10]	Jin YY, Li RX, Lin SY, et al. A real-word experience of eltrombopag plus rabbit antithymocyte immunoglobulin-based IST in Chinese patients with severe aplastic anemia[J]. Ann Hematol, 2022, 101(11): 2413-2419. doi: 10.1007/s00277-022-04966-w
[11]	李瑞鑫, 金媛媛, 杨岩, 等. 艾曲泊帕联合强化免疫抑制疗法治疗成人重型再生障碍性贫血疗效的预测因素[J]. 临床血液学杂志, 2022, 35(5): 333-337. https://lcxy.whuhzzs.com/article/doi/10.13201/j.issn.1004-2806.2022.05.007
[12]	Killick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosis and management of adult aplastic anaemia[J]. Br J Haematol, 2016, 172(2): 187-207. doi: 10.1111/bjh.13853
[13]	中华医学会血液学分会红细胞疾病(贫血)学组. 再生障碍性贫血诊断与治疗中国指南(2022年版)[J]. 中华血液学杂志, 2022, 43(11): 881-888.
[14]	贾晋松. 重型再生障碍性贫血细胞免疫功能异常与强化免疫抑制治疗的关系[J]. 中国实用内科杂志, 2021, 41(1): 40-44, 49. https://www.cnki.com.cn/Article/CJFDTOTAL-SYNK202101013.htm
[15]	Li RX, Zhou JT, Liu ZY, et al. Predicting response of severe aplastic Anemia to rabbit-antithymocyte immunoglobulin based immunosuppressive therapy combined with eltrombopag[J]. Front Immunol, 2022, 13: 884312. doi: 10.3389/fimmu.2022.884312
[16]	Zaimoku Y, Patel BA, Shalhoub R, et al. Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag[J]. Haematologica, 2022, 107(1): 126-133.
[17]	Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic mutations and clonal hematopoiesis in aplastic Anemia[J]. N Engl J Med, 2015, 373(1): 35-47. doi: 10.1056/NEJMoa1414799
[18]	何广胜. 再生障碍性贫血分型及免疫抑制治疗选择[J]. 中国实用内科杂志, 2021, 41(10): 836-838. https://www.cnki.com.cn/Article/CJFDTOTAL-SYNK202110006.htm
[19]	Huang LF, Li L, Jia JS, et al. Frontline therapy options for adults with newly diagnosed severe aplastic Anemia: intensive immunosuppressive therapy plus eltrombopag or matched sibling donor hematopoietic stem cell transplantation?[J]. Transplant Cell Ther, 2022, 28(9): 586. e1-586. e7.
[20]	井丽萍, 张莉, 周康, 等. 抗人T细胞猪免疫球蛋白治疗重型再生障碍性贫血患者的药物代谢动力学研究[J]. 中华血液学杂志, 2022, 43(4): 300-304.
[21]	Zhu YM, Yang Y, Yang WR, et al. Efficacy and safety of porcine ALG compared to rabbit ATG as first-line treatment for children with acquired aplastic anemia[J]. Eur J Haematol, 2020, 104(6): 562-570.
[22]	Li RX, Wang NL, Chai XX, et al. Prolonged use of eltrombopag in patients with severe aplastic anemia in the real world[J]. Clin Exp Med, 2023. Epub ahead of print.
[23]	Guan J, Sun YY, Fu R, et al. A cohort study of immune and hematopoietic functionality changes in severe aplastic anemia patients treated with immunosuppressive therapy[J]. Medicine(Baltimore), 2019, 98(3): e14149.
[24]	Liu J, Lu XY, Cheng L, et al. Clinical outcomes of immunosuppressive therapy for severe aplastic anemia patients with absolute neutrophil count of zero[J]. Hematology, 2019, 24(1): 492-497.
[25]	张梦露, 陈婉淑, 杨辰, 等. 影响非重型再生障碍性贫血环孢素治疗起效后复发的因素[J]. 临床血液学杂志, 2022, 35(11): 776-781, 787. https://lcxy.whuhzzs.com/article/doi/10.13201/j.issn.1004-2806.2022.11.005
[26]	Patel BA, Groarke EM, Lotter J, et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study[J]. Blood, 2022, 139(1): 34-43.