15例帕博利珠单抗致免疫相关性心肌炎的病例分析

Case Analysis of 15 Cases of Immune-related Myocarditis Induced by Pembrolizumab

目的:了解帕博利珠单抗致免疫相关性心肌炎发生的规律和特点,为临床合理用药提供参考。方法:以"帕博利珠单抗/可瑞达"和"心肌炎""心脏毒性","Pembrolizumab/Keytruda"和"Cardiac toxicity""Myocarditis""Cardiotoxity""Cardiotoxicity"等为中英文检索词,检索中国生物医学文献数据库、维普网、中国知网、万方数据、PubMed、Wiley Online Library、Embase等数据库中收录的帕博利珠单抗致免疫相关性心肌炎的个案报道,检索时限从建库起至2020年8月。剔除疑似病例文献和重复文献后,对纳入文献中患者性别、年龄、用药原因、既往病史、联合用药、用药剂量、不良反应(ADR)发生时间、临床表现、干预措施与转归等信息进行分析。结果与结论:共纳入15篇文献,其中英文13篇、中文2篇;涉及15例患者,其中男性12例、女性3例,平均年龄为71.35岁;临床诊断非小细胞肺癌4例,黑色素瘤4例,膀胱癌2例,尿路上皮癌、多发性骨髓瘤、胃癌、胸腺癌、鼻咽癌各1例;有6例患者记录了既往病史,其中5例无心脏疾病史,1例既往患有高血压、高血脂;有9例患者记录了联合用药情况;有12例患者详细记录了帕博利珠单抗的用药剂量和频次。93.3%患者的免疫性心肌炎出现在应用帕博利珠单抗第1~2周期用药后,平均发生时间为末次用药后15.5天;最常见临床症状为呼吸困难、乏力、头晕或晕厥等;9例患者心电图检查显示心脏传导阻滞;所有患者都使用了糖皮质激素处理;5例患者经住院治疗后死亡,其中1例患者在心肌炎控制后重启帕博利珠单抗治疗1周期,心肌炎复发并最终死于该ADR。结论:在患者使用帕博利珠单抗免疫治疗时,建议做好心脏功能相关基线检查和常规监测,一旦怀疑出现免疫相关性心肌炎,应及时完善心电图等心功能相关检查,并尽早使用大剂量糖皮质激素治疗,同时应警惕再次用药后心肌炎复发致死的风险。

OBJECTIVE:To investigate the rules and characteristics of pembrolizumab-induced immune-related myocarditis,and to provide reference for rational drug use in clinic.METHODS:Using"pembrolizumab/keytruda""myocarditis""cardiotoxicity""Pembrolizumab/Keytruda""Cardiac toxicity""Myocarditis""Cardiotoxity""Cardiotoxicity"as Chinese and English retrieval words,CBM,VIP,CNKI,Wanfang database,PubMed,Wiley Online Library and Embase database were searched on the case reports of pembrolizumab-induced immune-related myocarditis during the inception to Aug.2020.After eliminating the suspected case literature and repetitive literature,gender,age,medication cause,medical history,drug combination,drug dosage,occurrence time of ADR,clinical manifestation,intervention measure and outcome of patients in the included literature were analyzed.RESULTS&CONCLUSIONS:A total of 15 literatures were included,involving 13 English literatures and 2 Chinese literatures.Totally 15 patients were involved,including 12 males and 3 females,with an average age of 71.35 years.There were 4 cases of non-small cell lung cancer,4 cases of melanoma,2 cases of bladder cancer,1 case of urothelial cancer,1 case of multiple osteosarcomas,1 case of gastric cancer,1 case of thymic cancer,1 case of nasopharyngeal carcinoma.There were 6 patients with previous medical history,of which 5 had no history of heart disease and 1 had hypertension and hyperlipidemia;there were 9 patients recorded the combined use of drugs;the dosage and frequency of pembrolizumab were recorded in 12 patients.Immunological myocarditis of 93.3%patients occurred after the first to second cycle of pembrolizumab administration,and the average occurrence time was 15.5 days after the last administration.The most common clinical symptoms were dyspnea,fatigue,dizziness or syncope.9 patients showed cardiac block on electrocardiogram.All patients were treated with glucocorticoids when they developed immune-associated myocarditis,and 5 patients died after hospitalization;another one patient was restarted with pembrolizumab for one cycle after control of immune-related myocarditis,but developed a recurrence of myocarditis and died of myocarditis ADR.It is suggested that baseline examination and routine monitoring of cardiac function should be done well when patients are treated with pembrolizumab.Once the patient is suspected to have immune-related myocarditis,they should timely improve the cardiograms and other cardiac function-related tests,and start the treatment of high-dose glucocorticoids as soon as possible,and are alert to the risk of death due to recurrence of myocarditis after readministration.