肿瘤细胞治疗研究
英文原题：Safety assessment of anti-B cell maturation antigen chimeric antigen receptor T cell therapy: a real-world study based on the FDA adverse event reporting system database.
Safety assessment of anti-B cell maturation antigen chimeric antigen receptor T cell therapy: a real-world study based on the FDA adverse event reporting system database.
本研究为理解CAR-T细胞疗法的安全性特征提供了基础，特别是与继发性恶性肿瘤出现相关的方面。这些见解有助于临床决策以及这些治疗药物的安全有效使用。
2024年4月18日，美国食品药品监督管理局正式要求更新所有CAR-T 细胞疗法的T细胞恶性肿瘤“黑框警告”。鉴于这些疗法的临床意义，严格的安全性评估至关重要。然而，对于新上市的靶向B细胞成熟抗原的CAR-T产品idecabtagene vicleucel（ide-cel）和ciltacabtagene autoleucel（cilta-cel），尤其是关于继发性恶性肿瘤的风险，尚缺乏全面的真实世界安全性研究。因此，我们旨在深入分析FDA不良事件报告系统（FAERS）数据库中的不良事件（AEs）信息，以全面了解ide-cel和cilta-cel的安全风险。
我们从FAERS数据库（https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html）中提取了2019年1月1日至2023年12月31日期间与ide-cel和cilta-cel相关的AE报告。采用不相称性分析和贝叶斯分析识别各亚组及特定病例（包括死亡和继发性恶性肿瘤）中的风险信号。采用Weibull分布分析确定AE发生时间。
FAERS 数据库中总共纳入了 695 份 ide-cel 的 AE 报告和 848 份 cilta-cel 的 AE 报告。该分析确定了 ide-cel 的 81 个阳性信号和 cilta-cel 的 74 个阳性信号。值得注意的是，与药物标签的比较揭示了“非预期信号”，包括 ide-cel 的发热性骨髓再生障碍（报告比值比=69.10；置信区间 39.12-122.03）和浆细胞骨髓瘤（12.45；8.18-18.95），以及 cilta-cel 的血清铁蛋白升高（24.98；8.0-77.58）和结肠穿孔（18.57；5.98-57.69）。两种药物在男性受者和 65 岁患者中均显示出更高的 AE 发生率，尽管女性受者面临更大的风险。大多数 AE 发生在给药早期阶段。然而，两种药物均检测到继发性恶性肿瘤，主要发生在给药后一年。
BACKGROUND: On April 18, 2024, the U.S. Food and Drug Administration officially required updating of the "boxed warning" for T cell malignancies for all chimeric antigen receptor T cell (CAR-T) therapies. Given the clinical significance of these therapies, a rigorous safety assessment is paramount. However, comprehensive real-world safety studies have been lacking for the newly marketed CAR-T products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which target B cell maturation antigen, especially regarding the risk of secondary malignancies. Therefore, we aimed to thoroughly analyze the adverse events (AEs) information in the FDA Adverse Event Reporting System (FAERS) database to comprehensively understand the safety risks of ide-cel and cilta-cel. METHODS: We extracted AE reports related to ide-cel and cilta-cel from the FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.) from January 1, 2019 to December 31, 2023. Disproportionality analysis and Bayesian analysis were used to identify risk signals across subgroups and specific cases (including for death and secondary malignancies). Weibull distribution analysis was employed to determine the time to AE onset. RESULTS: A total of 695 AE reports for ide-cel and 848 for cilta-cel were included in the FAERS database. This analysis identified 81 positive signals for ide-cel and 74 for cilta-cel. Notably, comparisons with the drug labels revealed "unexpected signals," including febrile bone marrow aplasia (reporting odds ratio=69.10; confidence interval 39.12-122.03) and plasma cell myeloma (12.45; 8.18-18.95) for ide-cel, and increased serum ferritin (24.98; 8.0-77.58) and large intestine perforation (18.57; 5.98-57.69) for cilta-cel. Both drugs showed a higher AE incidence among male recipients and patients aged 65 years, although female recipients faced a greater risk. Most AEs occurred at the early stage of administration. However, secondary malignancies were detected for both drugs, primarily occurring one-year post-administration. CONCLUSION: This study provides a foundation for understanding the safety profile of CAR-T cell therapy, particularly in relation to the emergence of secondary malignancies. Such insights are helpful for clinical decision-making and the safe and effective utilization of these therapeutic agents.
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