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. 2024 Feb 21;12(2):e008518.
doi: 10.1136/jitc-2023-008518.

Cardiovascular toxicities associated with bispecific T-cell engager therapy

Ahmed Sayed  1 , Malak Munir  1 , Sanam M Ghazi  2 , Mussammat Ferdousi  2 , Satyam Krishan  3 , Adnan Shaaban  2 , Alma Habib  2 , Onaopepo Kola-Kehinde  2 , Patrick Ruz  2 , Sarah Khan  2 , Sneha Sharma  2 , Alexa Meara  2 , Syed Mahmood  4 , Stephanie Feldman  5 , Eric H Yang  6 , Jiwon Kim  5 , Narendranath Epperla #  2 , Daniel Addison #  7   8   9
Affiliations

Cardiovascular toxicities associated with bispecific T-cell engager therapy

Ahmed Sayed et al. J Immunother Cancer. .

Abstract

Background: Bispecific T-cell engagers (BTEs) are novel agents used to treat hematological malignancies. Early trials were underpowered to define cardiovascular adverse events (CVAE) and no large-scale studies systematically examined the CVAEs associated with BTEs.

Methods: Leveraging the US Food and Drug Administration's Adverse Event Reporting System-(FAERS), we identified the relative frequency of CVAEs after initiation of five BTE products approved by the Food and Drug Administration between 2014 and 2023 for the treatment of hematological malignancies. Adjusted reporting ORs (aROR) were used to identify disproportionate reporting of CVAEs with BTEs compared with background rates in the database. Fatality rates and risk ratios (RRs) for each adverse event (AE) were calculated.

Results: From 3668 BTE-related cases reported to FAERS, 747 (20.4%) involved CVAEs. BTEs as a class were associated with fatal CVAEs (aROR 1.29 (95% CI 1.12 to 1.50)), an association mainly driven by teclistamab (aROR 2.44 (95% CI 1.65 to 3.60)). Teclistamab was also associated with a disproportionate risk of myocarditis (aROR 25.70 (95% CI 9.54 to 69.23)) and shock (aROR 3.63 (95% CI 2.30 to 5.74)), whereas blinatumomab was associated with a disproportionate risk of disseminated intravascular coagulation (aROR 3.02 (95% CI 1.98 to 4.60)) and hypotension (aROR 1.59 (95% CI 1.25 to 2.03)). CVAEs were more fatal compared with non-CVAEs (31.1% vs 17.4%; RR 1.76 (95% CI 1.54 to 2.03)). Most CVAEs (83.3%) did not overlap with cytokine release syndrome.

Conclusion: In the first postmarketing surveillance study of BTEs, CVAEs were involved in approximately one in five AE reports and carried a significant mortality risk.

Keywords: Antibodies, Bispecific; Cytotoxicity, Immunologic.

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Conflict of interest statement

Competing interests: No, there are no competing interests.

Figures

Figure 1
Figure 1
Graphical abstract. Cardiovascular toxicities of bispecific T-cell engagers. CRS, cytokine release syndrome; DIC, disseminated intravascular coagulation; NCVAE, non-CVAE.
Figure 2
Figure 2
Frequency of cardiovascular adverse events reported with bispecific T-cell engagers. Because each case may involve more than one adverse event, these numbers are not mutually exclusive.
Figure 3
Figure 3
Time to onset of adverse events (CVAEs vs NCVAEs) associated with bispecific T-cell engagers. Each line represents the cumulative proportion of adverse events that occurred by a given time point. A cubic root transformation was applied to the x-axis to aid in visualization. CVAE, cytokine release syndromes; NCVAE, non-CVAEs.
Figure 4
Figure 4
Fatality rates of adverse events reported with bispecific T-cell engagers. The black dashed line denotes the average fatality rate of adverse events reported with bispecific T-cell engagers.
Figure 5
Figure 5
Mortality risk ratios of adverse events reported with bispecific T-cell engagers. These values were obtained using logistic regression models with death as the dependent (outcome) variable and age, sex, and a given adverse event as independent (predictor) variables. Average marginal effects were then applied to obtain adjusted mortality rates and risk ratios. CVAE, cardiovascular adverse event.
Figure 6
Figure 6
Rates of overlap between cytokine release syndrome (CRS) and other adverse events reported with bispecific T-cell engagers. CVAE, cardiovascular adverse events.
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