CAR T细胞治疗后继发第二原发恶性肿瘤的特征：来自FAERS和VigiBase两个全球药物不良反应监测数据库的真实世界洞察
Characterization of second primary malignancies post CAR T-cell therapy: real-world insights from the two global pharmacovigilance databases of FAERS and VigiBase
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影响因子:10
分区:医学1区 Top / 医学：内科1区
发表日期:2024 Jul
作者:
Junyi Shen, Rong Hu, Anqi Lin, Aimin Jiang, Bufu Tang, Zaoqu Liu, Quan Cheng, Kai Miao, Jian Zhang, Peng Luo
DOI:
10.1016/j.eclinm.2024.102684
摘要
FDA关于CAR-T细胞治疗后T细胞淋巴瘤风险的警示引起了全球关注，但关于CAR-T治疗后第二原发恶性肿瘤（SPMs）的全面特征尚缺乏系统报道。我们从FAERS和VigiBase数据库（2017-2023）中提取了明确界定的血液恶性肿瘤（HMs）伴随SPMs的不良事件报告。采用报告比值比（ROR）和调整后ROR进行离散性分析，评估SPMs与CAR-T治疗的关联。时间起点分析探讨影响SPM出现的因素。CAR T细胞治疗后出现的SPMs包括HMs和实体瘤。T细胞淋巴瘤和骨髓发育不良综合征在整体及亚组分析中持续显示为正信号。血液系统SPMs表现为早发，且随着CAR-T治疗后年度发生率上升，而实体瘤表现为延迟出现。CAR-T受试者的SPMs明显早于非受试者。年龄特异性分析显示，儿童、青少年和年轻成人在CAR-T治疗后SPM表现出较早的发生时间。当前SPM特征提示所有CAR-T受试者都需要长期的安全监测，考虑到SPMs的年度增长趋势。针对不同年龄组定制的长期SPM筛查策略，有助于早期检测和干预，最终改善CAR-T受试者的随访预后。该研究由广东省自然科学基金（2018A030313846及2021A1515012593）、广东省科技计划项目（2019A030317020）、国家自然科学基金（81802257、81871859、81772457、82172750、82172811及82260546）、广东基础与应用基础研究基金（粤港合作基金，2022A1515111212）以及广州市科技计划（2023A04J1257）资助。
Abstract
The FDA's alerts regarding the T-cell lymphoma risk post CAR-T therapy has garnered global attention, yet a comprehensive profile of second primary malignancies (SPMs) following CAR-T treatment is lacking.We extracted adverse event reports of hematological malignancies (HMs) patients with clearly definable SPMs from the FAERS and VigiBase databases (2017-2023). Disproportionality analysis using reporting odds ratio (ROR) and adjusted ROR was performed to assess associations between SPMs and CAR-T therapy. Time-to-onset analysis explored factors affecting SPM manifestation.SPMs post CAR T-cell therapy include HMs and solid tumors. T-cell lymphoma and myelodysplastic syndromes were consistently identified as positive signals across the overall and subgroup analyses. Hematological SPMs showed earlier onset with increasing annual incidence post CAR-T therapy, whereas solid tumors exhibit delayed manifestation. SPMs in CAR-T recipients had significantly earlier onset than non-recipients. Furthermore, age-specific characteristics reveal earlier SPM manifestations in pediatric, adolescent, and young adult populations compared to older populations post CAR-T therapy.The current SPM profile highlights the necessity of long-term safety monitoring for all CAR-T recipients given the observed yearly increase of SPMs. Customizing long-term SPM screening across different age groups may enhance early detection and intervention strategies, ultimately improving patient outcomes in the follow-up of CAR-T recipients.This work was supported by grants from the Natural Science Foundation of Guangdong Province (2018A030313846 and 2021A1515012593), the Science and Technology Planning Project of Guangdong Province (2019A030317020), the National Natural Science Foundation of China (81802257, 81871859, 81772457, 82172750, 82172811, and 82260546), the Guangdong Basic and Applied Basic Research Foundation (Guangdong-Guangzhou Joint Funds) (2022A1515111212), and the Science and Technology Program of Guangzhou (2023A04J1257).