Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy.

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, always causing an underestimate of rare but fatal toxicities. Here, we systematically analyzed CAR-T-associated hematologic AEs using the Food and Drug Administration Adverse Event Reporting System between January 2017 and December 2021. Disproportionality analyzes were performed using reporting odds ratios (ROR) and information component (IC), and 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, 5112 CAR-T-related hematotoxicity reports were identified. We found 23 significant over-reporting hematologic AEs (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), B cell aplasia (n = 98 [1.9%], ROR025 = 118.16, all IC025 > 0) were highly underreported AEs 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 AEs were identified using LASSO regression analysis. These findings could help clinicians early alert those rarely reported but lethal hematologic AEs, thus reducing the risk of severe toxicities for CAR-T recipients.