Background Bispecific T-cell engagers (BTEs) have transformed the treatment of hematologic malignancies. The most recently approved BTEs include mosunetuzumab for relapsed/refractory (R/R) follicular lymphoma, glofitamab for R/R diffuse large B-cell lymphoma, and epcoritamab for both indications. While clinical trials reported remarkable efficacy, their cardiovascular safety profile is incompletely understood. Given the initial cardiotoxicity signals of older BTEs and CAR-T therapies, we conducted a comprehensive pharmacovigilance analysis to identify cardiovascular safety signals.

Methods We performed a retrospective analysis of all adverse events (AEs) reported to the FDA Adverse Event Reporting System from December 2022 to June 2025. Reports involving novel BTE therapies (mosunetuzumab, glofitamab, and epcoritamab) were identified and compared to all other drug reports. Cardiovascular adverse events (CVAEs) were systematically classified using Medical Dictionary for Regulatory Activities terms. CVAEs included cardiac (heart failure, myocarditis, coronary disease, myocardial infarction, supraventricular tachycardia, atrial fibrillation, ventricular tachyarrhythmias, bradyarrhythmias, QT prolongation, sudden death, pericardial disorders) and vascular (hypertension, hypotension, thromboembolic disease, bleeding, cerebrovascular events, shock, disseminated intravascular coagulation, vasculitis) disorders. Additional outcomes included cytokine release syndrome. We reported adjusted reporting odds ratios (aRORs) using multivariable logistic regression models, controlling for age, sex, underlying disease (diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, unclassified), and concomitant use of potentially cardiotoxic agents (anthracyclines and BTK inhibitors).

Results Our analysis included 222,268 FAERS AE reports, with 1,785 involving BTE therapies (300 mosunetuzumab, 529 glofitamab, 956 epcoritamab). Cardiovascular adverse events occurred in 17.3% of BTE patients.

Not unsurprisingly, the indication for BTE therapy varied by drug. Glofitamab and epcoritamab were the predominant BTE therapies in patients with DLBCL. Mosunetuzumab was the most commonly used BTE therapy in patients with follicular lymphoma. A substantial proportion of cases across all drugs (22.3% for mosunetuzumab, 30.6% for glofitamab, and 56.3% for epcoritamab) did not specify a B-cell lymphoma subtype.

Overall, novel BTEs were associated with increased reporting odds of hypotension (aROR 1.70, 95% CI: 1.20-2.41, P = 0.003) with 48 cases (2.7% of BTE AEs). Individual BTE therapies had distinct cardiovascular profiles. For hypotension, epcoritamab had the strongest signal (aROR 2.04, 95% CI: 1.40-3.00, P <0.001). Additionally, mosunetuzumab showed increased reporting of multiple cardiac arrhythmias including atrial fibrillation/flutter (aROR 2.57, 95% CI: 1.23-5.36, P = 0.01), supraventricular tachycardia (aROR 2.50, 95% CI: 1.25-5.00, P = 0.01), and tachyarrhythmias (aROR 2.36, 95% CI: 1.26-4.44, P = 0.01).

Cytokine release syndrome occurred in 33.7% of BTE AEs, with rates varying by drug: epcoritamab (41.2%), glofitamab (26.8%), and mosunetuzumab (21.7%). Hypotension co-occurred with CRS in 56.2% of cases. Among mosunetuzumab patients with arrhythmias, supraventricular tachycardia co-occurred with CRS in 46.9% of cases, atrial fibrillation/flutter in 22.2% of cases, and tachyarrhythmias in 16.7% of cases.

Fatality rates of cardiovascular events were high, with shock (69.8%) and heart failure (69.6%) showing the highest rates. Other notable fatality rates include bleeding (61.5%), thromboembolic disease (27.9%), and hypotension (23.9%). As a class, novel BTEs showed increased reporting of fatal vascular events (aROR 1.11, 95% CI: 1.03-1.19, P = 0.004) but not fatal cardiac events (aROR 1.06, 95% CI: 0.98-1.14, P = 0.16).

Conclusion Novel BTE therapies are effective, but are linked with cardiovascular events, with hypotension as the primary safety signal associated with the drug class, often occurring alongside CRS and most strongly associated with epcoritamab. Cardiac arrhythmias were specifically associated with mosunetuzumab. Vascular events showed increased mortality signals compared to cardiac events. Given the frequent co-occurrence with CRS and potential vascular implications, increased cardiovascular vigilance may be warranted during cytokine release syndrome episodes.

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2025
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