非小细胞肺癌和霍奇金淋巴瘤患者信迪利单抗不良反应发生情况分析

Analysis on occurrence of adverse reactions to sintilimab in patients with non‑small cell lung cancer and Hodgkin lymphoma

目的探讨非小细胞肺癌(NSCLC)和霍奇金淋巴瘤(HL)患者使用信迪利单抗后的不良反应发生情况。方法检索医院信息系统,收集2019年1月至2020年8月在解放军总医院第五医学中心住院并使用信迪利单抗的所有NSCLC和HL患者的病历资料,记录患者基本信息(性别、年龄、诊断)、用药情况(信迪利单抗初治或复治,单次用药剂量和累积剂量,联合用药情况)、不良反应发生情况(累及器官或系统、临床表现、发生时间、干预和转归)等,进行回顾性分析。依据药品不良反应报告和监测工作手册和国际肿瘤化疗药物不良反应评价系统进行药物与不良反应的关联性评价和不良反应分级。结果纳入分析的患者共90例,NSCLC 75例,HL 15例;年龄16~81岁,中位年龄63岁。信迪利单抗初治和复治者分别为81和9例,单次剂量为200、100-mg/周期者分别为88和2例,累积剂量为200、>200~1-000、>1-000-mg者分别39、35和16例,单药治疗和联合其他方案治疗者分别为32和58例。90例患者中53例(58.9%)发生不良反应,其中发生1~2级和≥3级不良反应者分别为41例(45.6%)和12例(13.3%),发生时间为用药后1~242 d。53例发生不良反应的患者中男性37例,女性16例;年龄28~80岁;NSCLC 48例,HL 5例,NSCLC患者不良反应发生率明显高于HL患者[64.0%(48/75)比33.3%(5/15),χ^(2)=4.856,P=0.028];信迪利单抗初治、复治者分别为48和5例;单次剂量为200、100-mg/周期者分别为52和1例,累积剂量为200、>200~1-000、>1-000-mg者分别16、26和11例,不同累积剂量患者间不良反应发生率差异有统计学意义(χ^(2)=9.21,P=0.01);信迪利单抗单药治疗者14例,联合其他方案治疗者39例,联合其他方案治疗者不良反应发生率明显高于单药治疗者[66.1%(39/58)比43.8%(14/32),χ^(2)=4.701,P=0.03]。53例患者共发生信迪利单抗不良反应101例次(发生1、2、3、4、5种不良反应者分别为24、16、9、2、2例),52例次病历中有记载,49例次通过复核实验室和辅助检查结果发现;关联性评价为肯定、很可能和可能者分别为1、3和97例次;1~2级不良反应89例次(88.1%),≥3级12例次(11.9%)。不良反应涉及血液、肝胆、胃肠道、内分泌、呼吸、皮肤及附件、心脏、骨骼肌和结缔组织、泌尿、神经等多个系统或器官,以血液、肝胆、胃肠道、内分泌、呼吸系统不良反应发生率居前5位,分别为24.4%(22/90)、15.6%(14/90)、14.4%(13/90)、12.2%(11/90)和11.1%(10/90)。12例患者因不良反应停用信迪利单抗;4例仅密切观察无特殊治疗,49例接受对症治疗(1 d~7个月);治愈8例,好转29例,未好转6例,不详9例,死亡1例。结论信迪利单抗可导致NSCLC和HL患者发生血液、肝胆、胃肠道、内分泌、呼吸、皮肤及附件等多个系统或器官的不良反应,不良反应发生率和程度均低于该药说明书记载,未发现新的不良反应。

Objective To explore the adverse reactions to sintilimab in patients with non-small cell lung cancer(NSCLC)and Hodgkin lymphoma(HL).Methods The clinical data of all NSCLC and HL patients who were treated with sintilimab during hospitalization in the Fifth Medical Center of the PLA General Hospital from January 2019 to August 2020 were collected by searching Hospital Information System.The clinical data including patients′basic information(gender,age,diagnosis),medication(initial treatment or retreatment with sintilimab,single and cumulative dose,combined medication),and occurrence of adverse reactions(involved organs or systems,clinical manifestations,occurrence time,intervention and outcome)were recorded and analyzed retrospectively.The correlation between sintilimab and adverse reactions and the grade of adverse reactions were evaluated according to Hand Book of Adverse Drug Reaction Reporting and Monitoring in China and the International Adverse Reaction Evaluation System of Cancer Chemotherapy Drugs.Results A total of 90 patients were enrolled in the analysis,including 75 NSCLC patients and 15 HL patients,aged from 16 to 81 years with the median age of 63 years;81 patients were initially treated with sintilimab and 9 were retreated.Eighty-eight patients received sintilimab 200-mg per cycle and 2 patient received 100-mg per cycle.The cumulative dose was 200,>200-1-000,and>1-000-mg in 39,35,and 16 cases,respectively;32 patients were treated with sintilimab alone and 58 were treated with sintilimab combined with other regimens.Fifty-three(58.9%)patients had adverse reactions,among which,41(45.6%)and 12 cases(13.3%)had grade 1-2 and≥grade 3 adverse reactions,respectively.The occurrence time was 1-242 days after treatment.Among the 53 patients,37 were male and 16 were female,aged 28-80 years;48 were with NSCLC and 5 with HL.The incidence of adverse reactions in NSCLC patients was significantly higher than that in HL patients[64.0%(48/75)vs.33.3%(5/15),χ^(2)=4.856,P=0.028].Forty-eight patients were initially treated and 5 were retreated.Fifty-two patients received sintilimab 200-mg per cycle and 1 patient received 100-mg per cycle.The cumulative dose was 200,>200-1000,and>1000-mg in 16,26,and 11 cases,respectively.The difference in the incidences of adverse reactions among patients with different cumulative doses was significant(χ^(2)=9.21,P=0.01).Fourteen patients were treated with sintilimab alone and 39 patients were treated with sintilimab combined with other therapeutic regimens;the incidence of adverse reactions in patients with sintilimab combined with other therapeutic regimens was higher than that in patients with sintilimab monotherapy,and the difference was statistically significant[66.1%(39/58)vs.43.8%(14/32),χ^(2)=4.701,P=0.03].A total of 101 times of adverse reactions to sintilimab occurred in 53 patients(1,2,3,4 and 5 kinds of adverse reactions occurred in 24,16,9,2,and 2 patients,respectively),52 times of them were recorded in the medical records,and 49 times were found by rechecking the results of laboratory and auxiliary tests;1,3,and 97 times of adverse reactions were evaluated as“certainly”,“probably”,and“possibly”,respectively.Eighty-nine times(88.1%)of adverse reactions were grade 1-2 and 12 times(11.9%)were equal to or greater than grade 3.Multiple systems or organs were involved in the adverse reactions including blood,hepatobiliary,gastrointestinal,endocrine,respiratory,skin and appendix,heart,skeletal muscle and connective tissue,urinary,and nervous systems,and those with the top 5 incidence rates were blood,hepatobiliary,gastrointestinal,endocrine,and respiratory system adverse reactions[24.4%(22/90),15.6%(14/90),14.4%(13/90),12.2%(11/90),and 11.1%(10/90)].Twelve patients stopped sintilimab due to adverse reactions,4 were only closely monitored without special treatment,and 49 received one day to seven months of symptomatic treatments.Among the 53 patients,8 were cured,29 were improved,6 were not improved,9 were unknown,and 1 died.Conclusions Sintilimab could lead to adverse reactions in multiple systems or organs in patients with NSCLC and HL,such as blood,hepatobiliary,gastrointestinal,endocrine,respiratory,and skin and appendages.The incidence and grade of adverse reactions were lower than those documented in the drug label,and no new adverse reactions were detected.