Wang Li, Li Xiaolin, Zhao Bin, Mei Dan, Jiang Jiandong, Duan Jingli
Department of Pharmacy, Peking University International Hospital, Beijing, China.
Department of Pharmacy, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Front Pharmacol. 2021 Sep 23;12:679207. doi: 10.3389/fphar.2021.679207. eCollection 2021.
Immune checkpoint inhibitors (ICIs) have substantially improved the clinical outcomes of various malignancies. However, the adverse event of tumor lysis syndrome (TLS) has not been included in the National Comprehensive Cancer Network guidelines or drug inserts. In this study, we aimed to establish the relationship between ICI therapies and TLS events using data from a real-world pharmacovigilance database. The MedDRA terms of TLS and both generic and brand names of ICIs were retrieved from the FDA Adverse Event Reporting System. Four frequentist algorithms were employed to confirm the association between the TLS and the ICI regimens, involving anti-cytotoxic T lymphocyte antigen-4 (anti-CTLA-4), anti-programmed death receptor-1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1), and anti-(CTLA-4 + PD-1). A descriptive and statistical analysis was performed according to the case information. One hundred sixty-four TLS cases, where patients underwent anti-CTLA-4 ( = 14), anti-(PD-1)/(PD-L1) ( = 113), or anti-(CTLA-4 + PD-1) ( = 37) therapies, were collected between the first quarter of 2004 and the fourth quarter of 2020. The most coverage-reporting year, age-group, sex, reporter, region, country, and indication were 2020 ( = 62), 60-74 years ( = 65), males ( = 105), physician ( = 66), Asia ( = 80), Japan ( = 67), and lung and thymus malignancies ( = 40), respectively. The median TLS onset time associated with anti-CTLA-4, anti-(PD-1)/(PD-L1), and anti-(CTLA-4 + PD-1) therapies was 6 (IQR: 2-39.5), 9 (IQR: 2-40), and 20 (IQR: 7.5-37.75) days, respectively. Mortality distribution of 71 reported death outcomes among three groups was statistically significant. All four algorithm signal values of anti-(CTLA-4 + PD-1) were higher than those of anti-CTLA-4 and anti-(PD-1)/(PD-L1). Elderly male patients with lung and thymus malignancies are frequently predisposed to TLS. ICI therapies could induce TLS in both solid and hematological malignancies. The rapid onset time and poor outcomes of patients prompt caution from health-care professionals.
免疫检查点抑制剂（ICIs）已显著改善了各种恶性肿瘤的临床结局。然而，肿瘤溶解综合征（TLS）这一不良事件尚未被纳入美国国立综合癌症网络指南或药品说明书中。在本研究中，我们旨在利用来自真实世界药物警戒数据库的数据，确立ICI治疗与TLS事件之间的关系。从美国食品药品监督管理局不良事件报告系统中检索出TLS的医学术语词典（MedDRA）术语以及ICIs的通用名和商品名。采用四种频率论算法来确认TLS与ICI治疗方案之间的关联，这些方案包括抗细胞毒性T淋巴细胞抗原4（抗CTLA-4）、抗程序性死亡受体1（PD-1）/程序性死亡1配体1（PD-L1）以及抗（CTLA-4 + PD-1）。根据病例信息进行描述性和统计分析。在2004年第一季度至2020年第四季度期间，收集了164例TLS病例，其中患者接受了抗CTLA-4（n = 14）、抗（PD-1）/（PD-L1）（n = 113）或抗（CTLA-4 + PD-1）（n = 37）治疗。覆盖报告最多的年份、年龄组、性别、报告者、地区、国家和适应症分别为2020年（n = 62）、60 - 74岁（n = 65）、男性（n = 105）、医生（n = 66）、亚洲（n = 80）、日本（n = 67）以及肺和胸腺恶性肿瘤（n = 40）。与抗CTLA-4、抗（PD-1）/（PD-L1）和抗（CTLA-4 + PD-1）治疗相关的TLS中位发病时间分别为6天（四分位间距：2 - 39.5）、9天（四分位间距：2 - 40）和20天（四分位间距：7.5 - 37.75）。三组中报告的71例死亡结局的死亡率分布具有统计学意义。抗（CTLA-4 + PD-1）的所有四种算法信号值均高于抗CTLA-4和抗（PD-1）/（PD-L1）。患有肺和胸腺恶性肿瘤的老年男性患者常易发生TLS。ICI治疗可在实体恶性肿瘤和血液系统恶性肿瘤中诱发TLS。患者发病时间快且预后差，这促使医护人员提高警惕。
