免疫检查点抑制剂相关严重肝损伤后重启免疫治疗的临床及文献病例分析

Clinical and literature case analysis on resumption of immunotherapy following severe liver injury related to immune checkpoint inhibitors

目的探讨发生≥3级免疫检查点抑制剂(ICI)相关免疫性肝损伤(IMH)后患者重启免疫治疗的安全性。方法报道首都医科大学附属北京佑安医院(我院)收治的1例发生4级IMH患者重启免疫治疗临床病例的诊治经过,并对该例及检索PubMed、Embase、Cochrane Library和中国知网、万方数据库(截至2023年11月)收集到的国内外报道相关病例的主要临床资料,从研究类型、初始免疫治疗药物、肝脏毒性严重程度、重启免疫治疗药物、重启后IMH复发率等5个方面进行统计分析。结果共收集相关文献17篇,其中13篇回顾性病例系列研究,1篇前瞻性研究,3篇病例报道。提取到111例发生≥3级IMH后重启ICI治疗的患者,加上我院报告的1例共112例。重启ICI治疗后IMH复发率为22.3%(25/112);ICI治疗方案中含细胞毒性T淋巴细胞相关抗原4(CTLA-4)抑制剂者的复发率(30.0%,6/20)高于不含CTLA-4抑制剂者(21.1%,19/90),差异无统计学意义(χ^(2)=0.736,P=0.279);重启原治疗方案者IMH复发率(22.2%,6/27)高于调整治疗方案者(17.4%,8/46),差异无统计学意义(χ^(2)=0.256,P=0.613)。结论ICI相关≥3级IMH患者在权衡利弊后重启ICI治疗可能会使部分患者获益。

Objective To explore the safety of restarting immunotherapy in patients with≥grade 3 immune checkpoint inhibitor-related immune mediated hepatitis(IMH).Methods The diagnosis and treatment of a patient with grade 4 IMH and restarting immunotherapy who was admitted to Beijing Youan Hospital,Capital Medical University was reported,and the main clinical data of the patient and related cases collected from PubMed,Embase,Cochrane Library,CNKI,and Wanfang databases(as of November 2023)were analyzed statistically from 5 aspects such as the study type,initial immunotherapy,severity of liver toxicity,resumption of immunotherapy,and recurrence rate of IMH after restarting immunotherapy.Results A total of 17 relevant literature were collected,including 13 retrospective case series studies,1 prospective study,and 3 case reports.One hundred and eleven patients who experienced≥grade 3 IMH and restarted treatment with immune checkpoint inhibitors(ICIs)were extracted.Along with one case reported by our hospital,there were totally 112 cases.After restarting ICIs treatment,the recurrence rate of IMH was 22.3%(25/112).The recurrence rate in patients with cytotoxic T lymphocyte associated antigen 4(CTLA-4)inhibitors in the ICIs treatment regimen was higher than those without CTLA-4 inhibitors,and the difference were not statistically significant[30.0%(6/20)vs.21.1%(19/90),χ^(2)=0.736,P=0.279].The recurrence rate of IMH in patients with original treatment regimen was higher than those with adjusted treatments,and the difference were not statistically significant[22.2%(6/27)vs.17.4%(8/46),χ^(2)=0.256,P=0.613].Conclusion Restarting ICIs treatment in patients with≥grade 3 ICI-related IMH after weighing the pros and cons may benefit some patients.