基于美国FDA不良事件报告系统数据库CAR⁃T细胞疗法brexucabtagene autoleucel神经系统不良事件风险分析

Risk analysis of neurological adverse events related to CAR T‑cell therapy with brexucabtagene autoleucel based on the US FDA Adverse Event Reporting System

目的了解brexucabtagene autoleucel(brexu⁃cel)相关的神经系统不良事件(AE)及其发生风险。方法收集美国食品药品管理局不良事件报告系统(FAERS)数据库中2020年7月1日至2022年9月31日报告的有关brexu⁃cel的神经系统AE报告,采用国际医学用语词典(MedDRA)24.1版的系统器官分类(SOC)和首选术语(PT)对AE进行分类统计,采用信息成分(IC)法及报告比值比(ROR)法进行信号挖掘。报告数≥3,IC的95%置信区间(CI)下限>0或ROR的95%CI下限>1的AE被定义为阳性风险信号。统计分析发生brexu⁃cel相关神经系统AE后出现死亡不良结局的患者比例。结果共收集到1960例brexu⁃cel相关神经系统AE报告,涉及559例患者,22个PT。采用IC法和ROR法进行信号挖掘,共检测出15个阳性信号(PT)。AE报告数排前5位的PT为免疫效应细胞相关性神经毒性综合征(153例)、意识模糊状态(32例)、脑病(29例)、震颤(27例)、失语(25例);信号强度居前5位的为免疫效应细胞相关性神经毒性综合征(IC=7.81,ROR=235.74)、脑病(IC=4.74,ROR=26.96)、失语(IC=4.28,ROR=19.58)、脑水肿(IC=3.35,ROR=10.24)、失禁(IC=3.04,ROR=8.22)。失禁(报告数6,IC=3.04,ROR=8.22)在说明书中未见记载。22个PT中有17个PT所涉及的患者出现死亡不良结局,其中,免疫效应细胞相关性神经毒性综合征的死亡比例为18%(28/153);死亡结局患者比例>50%的PT为刺激反应消失(80%,4/5)、脑水肿(75%,6/8)、脑血管意外(67%,2/3)、困倦(60%,3/5)、惊厥发作(57%,4/7)。结论CAR⁃T细胞疗法brexu⁃cel相关的神经系统AE较常见,其中失禁尚未被说明书记载;部分AE(刺激反应消失,脑水肿,困倦)临床结局较差,应提高警惕,并采取早期干预措施。

Objective To explore the neurological adverse events(AE)associated to brexucabta⁃gene autoleucel(brexu⁃cel)and their risk of occurrence.Methods Neurological AE reports related to brexu⁃cel were collected through the US FDA Adverse Event Reporting System database from July 1,2020 to September 31,2022.The AEs were classified and counted according to the system organ class(SOC)and preferred term(PT)of Medical Dictionary for Regulatory Activities(MedDRA)24.1.The information compo⁃nent(IC)method and the reporting odds ratio(ROR)method were used to perform signal mining.AEs with≥3 reports and a lower limit of 95%confidence interval(CI)for IC>0 or that for ROR>1 were defined as positive risk signals.The proportion of patients who suffered fatal outcomes after experiencing neurological AEs related to brexu⁃cel was analyzed.Results A total of 1960 neurological AE reports related to brexu⁃cel were collected,involving 559 patients and 22 PTs.Fifteen positive signals(PT)were detected by using the IC and ROR methods.The top 5 PTs in the number of AE reports were immune effector cell⁃associated neurotoxicity syndrome(153 reports),altered mental status(32 reports),encephalopathy(29 reports),tremor(27 reports),and aphasia(25 reports);the top 5 PTs with the high signal intensity were immune effector cell⁃associated neurotoxicity syndrome(IC=7.81,ROR=235.74),encephalopathy(IC=4.74,ROR=26.96),aphasia(IC=4.28,ROR=19.58),cerebral edema(IC=3.35,ROR=10.24),and incontinence(IC=3.04,ROR=8.22);incontinence(6 cases,IC=3.04,ROR=8.22)was not recorded in the drug instruction.Patients involved in 17 PTs,out of the 22 PTs,had fatal outcomes,and the proportion of deaths from immune effector cell⁃associated neurotoxicity syndrome was 18%(28/153).The PTs with a proportion of patient deaths>50%were unresponsive to stimuli(80%,4/5),brain oedema(75%,6/8),cerebrovascular accident(67%,2/3),lethargy(60%,3/5),and seizure(57%,4/7).Conclusions Neurological AEs related to brexu⁃cel are common,of which inconti⁃nence is not yet recorded in the drug instruction.The clinical outcomes of some AEs(unrespontive to stimulus,brain oedema,and lethargy)are poor and should be closely monitored.