Department of Hematology, Institute of Hematology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433.
Department of Cardiology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200443.
Haematologica. 2023 Aug 1;108(8):2067-2079. doi: 10.3324/haematol.2022.281455.
Hematotoxicity is the most common long-term adverse event (AE) after chimeric antigen receptor T-cell (CAR T) therapy. However, patients who receive CAR T therapy in pivotal clinical trials are subjected to restrictive selection criteria, and this means that rare but fatal toxicities are underestimated. Here, we systematically analyzed CAR T-associated hematologic AE using the US Food and Drug Administration Adverse Event Reporting System (FAERS) between January 2017 and December 2021. Disproportionality analyses were performed using reporting odds ratios (ROR) and information component (IC); the lower limit of the ROR and IC 95% confidence interval (CI) (ROR025 and IC025) exceeding one and zero was considered significant, respectively. Among the 105,087,611 reports in FAERS, 5,112 CAR T-related hematotoxicity reports were identified. We found 23 significant over-reporting hematologic AE (ROR025 >1) compared to the full database, of which hemophagocytic lymphohistiocytosis (HLH; n=136 [2.7%], ROR025 = 21.06), coagulopathy (n=128 [2.5%], ROR025 = 10.43), bone marrow failure (n=112 [2.2%], ROR025 = 4.88), disseminated intravascular coagulation (DIC; n=99 [1.9%], ROR025 = 9.64), and B-cell aplasia (n=98 [1.9%], ROR025 = 118.16, all IC025 > 0) were highly under-reported AE in clinical trials. Importantly, HLH and DIC led to mortality rates of 69.9% and 59.6%, respectively. Lastly, hematotoxicity-related mortality was 41.43%, and 22 death-related hematologic AE were identified using LASSO regression analysis. These findings could help clinicians in the early detection of those rarely reported but lethal hematologic AE, thus reducing the risk of severe toxicities for CAR T recipients.
血液毒性是嵌合抗原受体 T 细胞(CAR T)治疗后最常见的长期不良事件(AE)。然而,接受关键临床试验中 CAR T 治疗的患者受到严格的选择标准限制,这意味着罕见但致命的毒性被低估了。在这里,我们使用美国食品和药物管理局不良事件报告系统(FAERS)系统地分析了 2017 年 1 月至 2021 年 12 月期间与 CAR T 相关的血液学 AE。使用报告比值比(ROR)和信息成分(IC)进行了不相称性分析;ROR025 和 IC025 的下限 95%置信区间(ROR025 和 IC025)超过 1 和 0 分别被认为是显著的。在 FAERS 的 105,087,611 份报告中,确定了 5,112 份与 CAR T 相关的血液毒性报告。我们发现与整个数据库相比,有 23 种显著的血液学 AE 过度报告(ROR025>1),其中噬血细胞性淋巴组织细胞增生症(HLH;n=136 [2.7%],ROR025=21.06)、凝血障碍(n=128 [2.5%],ROR025=10.43)、骨髓衰竭(n=112 [2.2%],ROR025=4.88)、弥散性血管内凝血(DIC;n=99 [1.9%],ROR025=9.64)和 B 细胞发育不全(n=98 [1.9%],ROR025=118.16,所有 IC025>0)在临床试验中是高度未报告的 AE。重要的是,HLH 和 DIC 导致的死亡率分别为 69.9%和 59.6%。最后,与血液毒性相关的死亡率为 41.43%,使用 LASSO 回归分析确定了 22 种与死亡相关的血液学 AE。这些发现可以帮助临床医生早期发现那些罕见但致命的血液学 AE,从而降低 CAR T 受者发生严重毒性的风险。
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