Risk Analysis of Cytokine Release Syndrome, Immune Effector Cell- Associated Neurotoxicity Syndrome, and Immune Effector Cell- Associated Hemophagocytic Lymphohistiocytosis-like Syndrome in BiTE Therapy Vs CAR-T Therapy Using Real World Data

Background Bispecific T-cell engagers (BiTEs) are novel immunotherapies comprising of two linked antibodies that simultaneously bind T-cells and tumor cells, facilitating targeted cancer cell destruction. BiTEs have been approved for various hematologic malignancies, including multiple myeloma, diffuse large B-cell lymphoma and follicular lymphoma. However, BiTE therapy is associated with potential adverse events, notably cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and immune effector cell-associated hemophagocytic lymphocytosis-like syndrome (IEC-HS). These toxicities are also observed in chimeric antigen receptor T-cell (CAR-T) therapy, another immunotherapeutic approach for hematologic malignancies. This study aims to evaluate the real-world risk of CRS, ICANS, and IEC-HS associated with BiTE therapy using pharmacovigilance data and compare it to the risk profile of CAR-T therapy. Methods The FDA Adverse Event Reporting System (FAERS) is a database that records adverse events and medication errors reported to the FDA for drugs and biological products. This study analyzed five BiTE therapies (epcoritamab, glofitamab, mosunetuzumab, teclistamab, and talquetamab) documented in the FAERS database from 2019 to February 2024. We assessed the risk of CRS, HLS, and ICANS associated with these therapies. Statistical analysis was performed in R using a disproportionality analysis by calculating the reported odds ratio (ROR) from FAERS database and standardized proportional mortality (SPM) ratio from the literature. Results The FAERS database analysis revealed 3,010 reported cases of BiTE therapy, distributed across five agents: epcoritamab (n=1,198), teclistamab (n=817), glofitamab (n=502), mosunetuzumab (n=326), and talquetamab (n=183). Among these, 843 cases involved immune system disorder events. The median age of 67 years, with 52% male (n=434), 33% female (n=278), and 16% unspecified (n=131). The primary indications included B-cell lymphoma for epcoritamab (n=344), glofitamab (n=194), and mosunetuzumab (n=65), while multiple myeloma was the primary indication for teclistamab (n=115) and talquetamab (n=23). Immune-related adverse events were categorized as follows: CRS (753 events, 89.3%), IEC-HS (14 events, 1.6%), combined CRS and ICANS (46 events, 5.5%), combined CRS and IEC-HS (3 events, 0.4%), combined CRS, ICANS, and IEC-HS (1 event, 0.1%), and other immunologic events (26 events, 3.1%). Teclistamab was associated with the strongest risk of CRS (ROR=111.07, p-value < 0.00001), followed by mosunetuzumab (ROR=20.01, p-value=0.00001), talquetamab (ROR=19.05, p-value= 0.00001), epcoritamab (ROR=13.31, p-value= 0.00001), and glofitamab (ROR= 11.40, p-value= 0.00002). Teclistamab also had the highest ROR (1.274) for ICANS, although it was not statistically significant (p-value= 0.315). Mosunetuzumab and talquetamab had the lowest associated risk for ICANS with ROR values of 0.300 (p-value= 0.009) and 0.388 (p-value= 0.018), respectively. For CRS events, the calculated SPM values for all BiTE products were not significant, as all values were lower than 1, indicating lower incidence of CRS compared to CAR-T reference population. For ICANS, only teclistamab had an SPM value greater than 1 (SPM= 1.2), suggesting a higher incidence of ICANS comparable to CAR-T. The other four BiTEs had SPM values below 1. Conclusion This analysis reveals crucial differences in the risk profiles of CRS, ICANS, and IEC-HS across five BiTE therapies. Notably, teclistamab demonstrates the highest risk for CRS, while the other four BiTEs (epcoritamab, glofitamab, mosunetuzumab, and talquetamab) show comparatively lower incidences. These findings underscore the importance of pharmacovigilance strategies for patients undergoing BiTE therapy and have significant clinical implications. Clinicians should consider the unique risk profile of each BiTE therapy when selecting treatment options, implement stringent monitoring protocols (particularly for teclistamab patients), and educate patients about potential risks. Healthcare facilities should ensure adequate resources and staff training for managing adverse events, especially when administering higher-risk therapies, leading to safer, and effective BiTE therapies. Additional analysis regarding IEC-HS will be provided at the annual meeting.