PD-1/PD-L1抑制剂致肝功能异常不良反应的回顾性分析

Retrospective Analysis of the Adverse Drug Reaction of Hepatic Dysfunction Induced by PD-1/PD-L1 Inhibitor

关键词:  程序性死亡蛋白-1  程序性死亡受体-1  免疫相关肝毒性  回顾性分析

Key words:  PD-1  PD-L1  immune mediated hepatitis  retrospective analysis

摘要:

目的 分析程序性死亡蛋白-1/程序性死亡受体-1(programmed death protein 1/programmed death ligand 1,PD-1/PD-L1)抑制剂相关肝脏毒性发生情况,以指导临床合理应用。方法 纳入苏北人民医院2020年7月-2022年3月使用PD-1/PD-L1抑制剂期间出现免疫相关肝脏毒性(immune mediated hepatitis,IMH)的患者共26例,分析患者的年龄、性别、基础疾病、不良反应(adverse drug reactions,ADRs)发生时间、合并用药、临床表现、肝损伤类型、治疗手段和转归情况。结果 26例患者年龄范围为43~80岁,其中男性22例,女性4例; ≥ 3级不良反应中男性3例,女性3例;女性患者 ≥ 3级不良反应比例明显高于男性。发生肝功能异常不良反应的中位时间为27.5 d(2~248 d),其中20例为1~2级不良反应,均为肝脏生化学检查异常;6例为3~4级不良反应,分别为肝细胞损伤型1例、胆汁淤积型2例和混合型3例。停药或对症处理后肝功能恢复时间范围为2~41 d,平均好转时间为(18.45±9.89)d。不良反应恢复后19例患者继续免疫治疗,其中8例患者再次出现肝功能异常。随访22例患者肝功能均预后良好。结论 临床使用PD-1/PD-L1抑制剂需高度警惕IMH,尤其是用药初期和之前发生过IMH的患者。女性患者发生IMH的严重程度可能更高,需及时对症治疗。

Abstract:

OBJECTIVE To analyze the occurrence of hepatic dysfunction induced by programmed death protein 1/programmed death ligand 1 inhibitor(PD-1/PD-L1) for the rational application in clinic. METHODS Twenty six patients with immune mediated hepatitis(IMH) after treatment with PD-1/PD-L1 inhibitor in Northern Jiangsu People's Hospital between July 2020 and March 2022 were enrolled for study. The age, sex, underlying disease, medication time of adverse drug reactions(ADRs), combined medication, clinical manifestations, liver injury types, treatment methods as well as prognosis were analyzed. RESULTS Among the 26 patients, aged 43-80 years, 22 males and 4 females were included. Grade ≥ 3 IMH was observed in 3 males and 3 females, and the incidence of grade ≥ 3 IMH was higher in females. The median time of adverse drug reactions occurrence was 27.5 d(2-248 d) after the medication. The 20 cases of grade 1-2 ADRs were all abnormal liver biochemical examination, while 6 cases of grade 3-4 ADRs were hepatocellular injury type(1/6), cholestasis type(2/6) and mixed type(3/6). After stopping the drug and/or symptomatic treatment, the time for recovery of liver function was 2-41 d, on the average of (18.45±9.89)d. After the recovery of adverse reactions, 19 patients continued immunotherapy, of which 8 patients had abnormal liver function again. The follow-up of 22 patients had a good prognosis of liver function. CONCLUSION Great attention should be paid to IMH induced by PD-1/PD-L1 inhibitor, especially in patients at early course or with prior IMH. Timely symptomatic treatment should be achieved especially for women who would be more likely to suffer severe IMH