Early View

Bispecific T-cell engagers (BiTEs) are pivotal for hematological malignancies. However, real-world safety assessments often emphasize adverse event (AE) incidence while overlooking severity and fatality rates. Furthermore, toxicity heterogeneity across BiTE targets and their comparative safety against chimeric antigen receptor T-cell (CAR-T) therapy remain incompletely elucidated. To address these gaps, a retrospective pharmacovigilance study using the FAERS and VigiBase databases (2015–2025) employed disproportionality analysis (reporting odds ratios) to identify BiTE-associated high-occurrence (BAHO) and high-fatality (BAHF) AEs. By integrating incidence and fatality data, we developed a clinical risk stratification framework. Time-to-onset kinetics, co-occurrence patterns, and comparative safety versus CAR-T therapies were also evaluated. Analyzing 18,928 reports (9,350 FAERS; 9,578 VigiBase) identified 198 BAHO-AEs and 36 BAHF-AEs. Cytokine release syndrome (CRS) emerged as a central toxicity hub, frequently co-occurring with ICANS and infections. AEs were classified into three risk patterns: BAHO-nonBAHF (e.g., CRS), BAHO-BAHF (e.g., sepsis, ICANS), and an underrecognized nonBAHO-BAHF category (e.g., cardiac failure, pleural effusion). BiTE toxicities showed an early-onset trend, with immune disorders typically manifesting within seven days, whereas infections and respiratory disorders peaked later (28–90 days). Distinct toxicity profiles were observed across CD19, BCMA, GPRC5D, and CD20-directed agents. Additionally, BiTEs showed a stronger fatality signal for ICANS in FAERS than CAR-T therapies, despite CAR-T's higher overall fatal burden. Ultimately, this large-scale analysis comprehensively maps the BiTE safety landscape. The proposed incidence-fatality framework highlights underrecognized severe toxicities, synergistic lethal risks, and distinct temporal dynamics, providing an evidence-based foundation to optimize precision safety management.

Keywords: Bispecific T-cell Engagers | Adverse Events | Pharmacovigilance | FAERS | VigiBase | Clinical Risk Stratification | Time-to-Onset