Comparative analysis of fatal serious adverse events associated with FDA-approved bispecific antibodies in hematologic malignancies Free

Background: Bispecific T-cell engagers (BiTEs) and bispecific antibodies (BiAbs) have transformed the treatment landscape of hematological malignancies by redirecting T cells towards specific tumor antigens, facilitating T-cell-mediated lysis of neoplastic cells. Blinatumomab emerged as the first Food and Drug Administration (FDA) approved BiTE, demonstrating proof-of-concept evidence with its remarkable contribution towards the treatment of Philadelphia chromosome-negative relapsed/refractory acute lymphoblastic leukemia (ALL). A decade later, several BiTEs and BiAbs have now been FDA-approved for a variety of hematological malignancies. Due to the growing body of research into the utility of these drugs in earlier stages, it is of paramount importance to understand their safety and tolerability. The primary adverse events associated with BiAb and BiTE noted in clinical trials include cytokine release syndrome (CRS), infections, hematological toxicity, neurotoxicity, or immune effector cell-associated neurotoxicity syndrome (ICANS). The data on real-world safety signals, especially fatal events, is limited. Hence, here we utilize a real-world post-market surveillance database to analyse the reported Serious Adverse Events (SAEs) with fatal outcome across six approved BiTE/BiAbs for hematologic malignancies.

Methods: Using the FDA Adverse Events Reporting System (FAERS) public dashboard case-listing feature up to Q2 2025, individual reports listings with death as an outcome were extracted for all FDA-approved BsAbs/BiTEs: blinatumomab, glofitamab, epcoritamab, teclistamab, elranatamab, and talquetamab. Reported reactions were grouped into clinical categories: CRS, ICANS, Infectious, Hematologic, Underlying Disease, and Other. Emerging signal categories—Cardiovascular, Rare Neurologic, and Opportunistic Infections—were quantified separately. Frequencies and percentages were calculated across each agent.

Results: Across the six drugs, fatal serious adverse events (SAEs) varied in profile and frequency. CRS-related deaths ranged from 2.9% with blinatumomab to as high as 8.3% with glofitamab, with similarly elevated rates for epcoritamab (8.0%) and talquetamab (5.7%). ICANS was observed most frequently in teclistamab (5.0%) and talquetamab (4.3%). Infectious causes contributed significantly to fatal outcomes, accounting for 9.5% in teclistamab, 8.2% in elranatamab, and 6.9% in epcoritamab. Hematologic toxicities, including cytopenias, comprised a more minor but notable proportion (up to 5.5% in talquetamab). Emerging signals from FAERS included cardiovascular-related deaths (predominantly hypotension), observed in all agents, with the highest burden in epcoritamab (1.63 %). Rare neurologic syndromes such as encephalopathy and cranial nerve palsies, although infrequent, were most frequently associated with blinatumomab. Opportunistic infections, including fungal sepsis and Pneumocystis jirovecii pneumonia, were reported across multiple agents. Underlying disease progression remained a frequent fatal outcome across all agents, ranging from 4.9% to 11.9%.

Conclusion: The FAERS-based analysis aligns with literature on BsAb/BiTEs toxicities: CRS and infections are consistently reported fatal SAEs, with ICANS more notable in BCMA-targeting agents. Notably, our study also reveals underappreciated signals: cardiovascular fatal events, rare neurological syndromes beyond ICANS, and opportunistic infections—which are not prominently featured in the literature but appear in real-world fatal outcomes. These findings highlight both expected and emerging fatal toxicity patterns across FDA-approved BiTEs/BiAbs. While CRS, ICANS, and infections remain prominent, the identification of cardiovascular, neurologic, and opportunistic infection risks may necessitate enhanced surveillance,and tailored supportive care. Further research is needed to confirm and quantify these evolving real-world safety signals.