托法替布治疗激素抵抗型免疫检查点抑制剂相关心肌炎的临床研究

许宇辰; 张健; 王妍; 林瑾仪; 周宇红; 程蕾蕾; 葛均波

doi:10.19401/j.cnki.1007-3639.2024.04.007

您当前的位置：

首页 >

文章列表页 >

托法替布治疗激素抵抗型免疫检查点抑制剂相关心肌炎的临床研究

论著 | 更新时间：2025-12-31

- 托法替布治疗激素抵抗型免疫检查点抑制剂相关心肌炎的临床研究
- Therapeutic effects of tofacitinib on steroid-resistant immune checkpoint inhibitor-associated myocarditis
- 中国癌症杂志 2024年34卷第4期页码：400-408
- 作者机构：
  
  1. 复旦大学附属中山医院心血管内科，上海 200032
  2. 上海市心血管病研究所，上海 200032
  3. 复旦大学附属中山医院肿瘤内科，上海 200032
  4. 复旦大学附属中山医院心脏超声诊断科，上海 200032
  5. 上海市影像医学研究所，上海 200032
- 作者简介：
  
  [ "许宇辰（ORCID: 0000-0001-7910-693X），博士。" ]
  葛均波（ORCID: 0000-0002-9360-7332），中国科学院院士。
- 基金信息：
  
  国家自然科学基金(82170359);放射与治疗临床医学研究中心项目(19MC1910300)
- DOI：10.19401/j.cnki.1007-3639.2024.04.007
  中图分类号： R730.6
- 收稿：2024-01-18，
  
  修回：2024-04-09，
  
  纸质出版：2024-04-30
- 稿件说明：
移动端阅览
许宇辰, 张健, 王妍, 等. 托法替布治疗激素抵抗型免疫检查点抑制剂相关心肌炎的临床研究[J]. 中国癌症杂志, 2024,34(4):400-408.

Yuchen XU, Jian ZHANG, Yan WANG, et al. Therapeutic effects of tofacitinib on steroid-resistant immune checkpoint inhibitor-associated myocarditis[J]. China Oncology, 2024, 34(4): 400-408.
许宇辰, 张健, 王妍, 等. 托法替布治疗激素抵抗型免疫检查点抑制剂相关心肌炎的临床研究[J]. 中国癌症杂志, 2024,34(4):400-408. DOI： 10.19401/j.cnki.1007-3639.2024.04.007.

Yuchen XU, Jian ZHANG, Yan WANG, et al. Therapeutic effects of tofacitinib on steroid-resistant immune checkpoint inhibitor-associated myocarditis[J]. China Oncology, 2024, 34(4): 400-408. DOI： 10.19401/j.cnki.1007-3639.2024.04.007.

摘要

背景与目的：

激素抵抗型免疫检查点抑制剂相关心肌炎（steroid-resistant immune checkpoint inhibitor-associated myocarditis，srICIAM）是一种在接受免疫治疗后出现的心脏相关不良反应，患者总体预后较差。既往研究显示，包含Janus激酶（Janus kinase，JAK）抑制剂托法替布在内的免疫强化抑制治疗可能对srICIAM具有一定疗效。然而，由于缺乏足够的临床数据，其治疗效果及对于肿瘤病情的影响尚不明确。本研究旨在探讨托法替布对srICIAM的治疗效果。

方法：

本项回顾性病例对照研究连续纳入了2019年7月—2022年5月在复旦大学附属中山医院接受免疫检查点抑制剂治疗且出现srICIAM的36例恶性肿瘤患者。接受糖皮质激素联合托法替布治疗的患者被分配至托法替布组（

= 19），未使用托法替布治疗的患者被分配至对照组（

= 17）。比较两组患者在临床特征、检验指标、影像学检查结果等方面的数据。同时对这些患者进行随访以监测心血管终点事件的发生。研究方案经过复旦大学附属中山医院伦理委员会批准（批准号：

B2021-275R）。本研究按照《赫尔辛基宣言》的伦理学规范进行。

结果：

与对照组相比，在糖皮质激素累积剂量及持续时间差异无统计学意义（

0.05）的情况下，托法替布组的心肌炎恢复时间更短（中位恢复时间：86.5 d

126.5 d，

= 0.021）。托法替布组的心肌炎相关死亡率显著低于对照组（5%

35%，

= 0.025）。

结论：

托法替布可在一定程度上降低srICIAM患者的死亡率并缩短康复时间，同时对于肿瘤患者的预后未产生不良影响。其可能成为srICIAM的潜在治疗药物之一。

Abstract

Background and purpose:

Outcomes for cancer patients with steroid-resistant immune checkpoint inhibitor-associated myocarditis (srICIAM) are poor. Intensified immunosuppressive therapies

including tofacitinib

a novel Janus kinase (JAK) inhibitor

may have some therapeutic benefits. However

due to the lack of sufficient clinical data

the effectiveness of such treatments and their impact on cardiovascular outcomes remain unclear. This study aimed to investigate the therapeutic effect of tofacitinib on srICIAM.

Methods:

This retrospective case-control study included 36 malignant tumor patients who received immune checkpoint inhibitor treatment at Zhongshan Hospital affiliated to Fudan University from July 2019 to May 2022 and developed srICIAM. Patients receiving corticosteroids in combination with tofacitinib were assigned to the tofacitinib group (

=19)

while those not treated with tofacitinib were allocated to the control group (

=17). The study compared clinical characteristics

laboratory findings

and imaging results between the two groups. Additionally

follow-up was conducted to monitor the incidence of cardiovascular endpoints in these patients. The research plan was approved by the Ethics Committee of Zhongshan Hospital Affiliated to Fudan University (Approval Number: B2021-275R). This study was conducted in accordance with the ethical guidelines of the Helsinki Declaration.

Results:

Compared to the control group

and with no significant difference in the cumulative dose and duratio

n of corticosteroids (

0.05)

the tofacitinib group showed a shorter myocarditis recovery time (median recovery time: 86.5 days

126.5 days

=0.021). The myocarditis-related mortality rate was significantly lower in the tofacitinib group than in the control group (5%

35%

=0.025).

Conclusion:

Tofacitinib may reduce mortality and promote cardiac recovery in srICIAM patients without impeding the anti-tumor effect. It may become one of the potential treatment strategies in the future.

关键词

Keywords

references

YANG K L , LI J R , ZHAO L , et al . Estimating the number of Chinese cancer patients eligible for and benefit from immune checkpoint inhibitors [J ] . Front Med , 2022 , 16 ( 5 ): 773 - 783 .

HASLAM A , PRASAD V . Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs [J ] . JAMA Netw Open , 2019 , 2 ( 5 ): e192535 .

CHHABRA N , KENNEDY J . A review of cancer immunotherapy toxicity: immune checkpoint inhibitors [J ] . J Med Toxicol , 2021 , 17 ( 4 ): 411 - 424 . DOI: 10.1007/s13181-021-00833-8 http://doi.org/10.1007/s13181-021-00833-8

WANG D Y , SALEM J E , COHEN J V , et al . Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis [J ] . JAMA Oncol , 2018 , 4 ( 12 ): 1721 - 1728 . DOI: 10.1001/jamaoncol.2018.3923 http://doi.org/10.1001/jamaoncol.2018.3923

HU J R , FLORIDO R , LIPSON E J , et al . Cardiovascular toxicities associated with immune checkpoint inhibitors [J ] . Cardiovasc Res , 2019 , 115 ( 5 ): 854 - 868 .

WANG C , LIN J Y , WANG Y , et al . Case series of steroid-resistant immune checkpoint inhibitor associated myocarditis: a comparative analysis of corticosteroid and tofacitinib treatment [J ] . Front Pharmacol , 2021 , 12 : 770631 .

LYON A R , LÓPEZ-FERNÁNDEZ T , COUCH L S , et al . 2022 ESC guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS) [J ] . Eur Heart J , 2022 , 43 ( 41 ): 4229 - 4361 . DOI: 10.1093/eurheartj/ehac244 http://doi.org/10.1093/eurheartj/ehac244

NGUYEN L S , BRETAGNE M , ARRONDEAU J , et al . Reversal of immune-checkpoint inhibitor fulminant myocarditis using personalized-dose-adjusted abatacept and ruxolitinib: proof of concept [J ] . J Immunother Cancer , 2022 , 10 ( 4 ): e004699 .

KADOKAWA Y , TAKAGI M , YOSHIDA T , et al . Efficacy and safety of Infliximab for steroid-resistant immune-related adverse events: a retrospective study [J ] . Mol Clin Oncol , 2021 , 14 ( 4 ): 65 . DOI: 10.3892/mco.2021.2227 http://doi.org/10.3892/mco.2021.2227

ZHANG R S , PADEGIMAS A , MURPHY K M , et al . Treatment of corticosteroid refractory immune checkpoint inhibitor myocarditis with Infliximab: a case series [J ] . Cardiooncology , 2021 , 7 ( 1 ): 13 . DOI: 10.1186/s40959-021-00095-x http://doi.org/10.1186/s40959-021-00095-x

XING Q , ZHANG Z W , ZHU B , et al . Case report: treatment for steroid-refractory immune-related myocarditis with tofacitinib [J ] . Front Immunol , 2022 , 13 : 944013 .

YOGASUNDARAM H , ALHUMAID W , CHEN J W , et al . Plasma exchange for immune checkpoint inhibitor-induced myocarditis [J ] . CJC Open , 2021 , 3 ( 3 ): 379 - 382 . DOI: 10.1016/j.cjco.2020.11.004 http://doi.org/10.1016/j.cjco.2020.11.004

IRVING P M , LEUNG Y , DUBINSKY M C . Review article: guide to tofacitinib dosing in patients with ulcerative colitis [J ] . Aliment Pharmacol Ther , 2022 , 56 ( 7 ): 1131 - 1145 .

DHILLON S . Tofacitinib: a review in rheumatoid arthritis [J ] . Drugs , 2017 , 77 ( 18 ): 1987 - 2001 . DOI: 10.1007/s40265-017-0835-9 http://doi.org/10.1007/s40265-017-0835-9

PANÉS J , GISBERT J P . Efficacy of tofacitinib treatment in ulcerative colitis [J ] . Gastroenterol Hepatol , 2019 , 42 ( 6 ): 403 - 412 . DOI: S0210-5705(19)30094-9 http://doi.org/S0210-5705(19)30094-9

OZDEDE A , YAZICI H . Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis [J ] . N Engl J Med , 2022 , 386 ( 18 ): 1766 - 1768 .

BONACA M P , OLENCHOCK B A , SALEM J E , et al . Myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology [J ] . Circulation , 2019 , 140 ( 2 ): 80 - 91 .

EISENHAUER E A , THERASSE P , BOGAERTS J , et al . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) [J ] . Eur J Cancer , 2009 , 45 ( 2 ): 228 - 247 . DOI: 10.1016/j.ejca.2008.10.026 http://doi.org/10.1016/j.ejca.2008.10.026

SCHNEIDER B J , NAIDOO J , SANTOMASSO B D , et al . Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update [J ] . J Clin Oncol , 2021 , 39 ( 36 ): 4073 - 4126 .

FRIEDRICH M G , SECHTEM U , SCHULZ-MENGER J , et al . Cardiovascular magnetic resonance in myocarditis: a JACC White Paper [J ] . J Am Coll Cardiol , 2009 , 53 ( 17 ): 1475 - 1487 . DOI: 10.1016/j.jacc.2009.02.007 http://doi.org/10.1016/j.jacc.2009.02.007

ARETZ H T . Myocarditis: the Dallas criteria [J ] . Hum Pathol , 1987 , 18 ( 6 ): 619 - 624 .

MCDONAGH T A , METRA M , ADAMO M , et al . 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC [J ] . Eur J Heart Fail , 2022 , 24 ( 1 ): 4 - 131 . DOI: 10.1002/ejhf.2333 http://doi.org/10.1002/ejhf.2333

SALEM J E , BRETAGNE M , ABBAR B , et al . Abatacept/ruxolitinib and screening for concomitant respiratory muscle failure to mitigate fatality of immune-checkpoint inhibitor myocarditis [J ] . Cancer Discov , 2023 , 13 ( 5 ): 1100 - 1115 .

FINKE D , HECKMANN M B , SALATZKI J , et al . Comparative transcriptomics of immune checkpoint inhibitor myocarditis identifies guanylate binding protein 5 and 6 dysregulation [J ] . Cancers , 2021 , 13 ( 10 ): 2498 .

PHILIPS R L , WANG Y X , CHEON H , et al . The JAK-STAT pathway at 30: much learned, much more to do [J ] . Cell , 2022 , 185 ( 21 ): 3857 - 3876 . DOI: 10.1016/j.cell.2022.09.023 http://doi.org/10.1016/j.cell.2022.09.023

TANAKA Y , LUO Y M , O’SHEA J J , et al . Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach [J ] . Nat Rev Rheumatol , 2022 , 18 ( 3 ): 133 - 145 . DOI: 10.1038/s41584-021-00726-8 http://doi.org/10.1038/s41584-021-00726-8

SANDBORN W J , SU C , SANDS B E , et al . Tofacitinib as induction and maintenance therapy for ulcerative colitis [J ] . N Engl J Med , 2017 , 376 ( 18 ): 1723 - 1736 .

AXELROD M L , MEIJERS W C , SCREEVER E M , et al . T cells specific for α-myosin drive immunotherapy-related myocarditis [J ] . Nature , 2022 , 611 ( 7937 ): 818 - 826 .

CHAPMAN N M , BOOTHBY M R , CHI H B . Metabolic coordination of T cell quiescence and activation [J ] . Nat Rev Immunol , 2020 , 20 ( 1 ): 55 - 70 . DOI: 10.1038/s41577-019-0203-y http://doi.org/10.1038/s41577-019-0203-y

DUSTIN M L . T-cell activation through immunological synapses and kinapses [J ] . Immunol Rev , 2008 , 221 : 77 - 89 . DOI: 10.1111/j.1600-065X.2008.00589.x http://doi.org/10.1111/j.1600-065X.2008.00589.x

HEINE A , HELD S A , DAECKE S N , et al . The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo [J ] . Blood , 2013 , 122 ( 7 ): 1192 - 1202 .

KUBO S , YAMAOKA K , KONDO M , et al . The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells [J ] . Ann Rheum Dis , 2014 , 73 ( 12 ): 2192 - 2198 . DOI: 10.1136/annrheumdis-2013-203756 http://doi.org/10.1136/annrheumdis-2013-203756

ZHANG H , LIN J Y , SHEN Y H , et al . Protective effect of crocin on immune checkpoint inhibitors-related myocarditis through inhibiting NLRP3 mediated pyroptosis in cardiomyocytes via NF-κB pathway [J ] . J Inflamm Res , 2022 , 15 : 1653 - 1666 . DOI: 10.2147/JIR.S348464 http://doi.org/10.2147/JIR.S348464

浏览量

2362

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

免疫相关不良事件中糖皮质激素及免疫抑制剂管理策略对患者生存结局的影响：系统评价与Meta分析

抗EGFR单抗联合免疫检查点抑制剂治疗头颈部鳞状细胞癌专家共识（2025年版）

免疫检查点抑制剂治疗相关胸腔积液的研究进展

复发/转移性头颈部鳞癌免疫检查点抑制剂治疗专家共识（2024年版）

妇科恶性肿瘤免疫治疗中国专家共识（2023年版）