SUMMARY: Bispecific T-cell engager (BTE) therapies are a novel class of targeted immunotherapies with activity against hematologic malignancies. These bispecific antibodies have 2 binding domains, one targeting and binding to CD3 on the T-cell receptor, whereas the other is a modifiable domain designed to bind to specific tumor-associated antigens, which can be CD19, CD20, B-Cell Maturation Antigen (BCMA) or GPRC5D. Blinatumomab (BLINCYTO®) targets the CD19 on B-cells and is approved for the treatment of advanced Acute Lymphoblastic Leukemia (ALL); Mosunetuzumab (LUNSUMIO®), Glofitamab (COLUMVI®), and Epcoritamab (EPKINLY®), target CD20 on B cells and have also been approved for the treatment of Non-Hodgkin lymphoma; Teclistamab (TECVAYLI®), targets BCMA expressed on myeloma cells and is approved for use in relapsed/refractory multiple myeloma; Talquetamab (TALVEY®) targets GPRC5D expressed on myeloma cells and is approved for use in relapsed/refractory multiple myeloma.
Adverse events of BTEs include Cytokine Release Syndrome (CRS), hematological toxicities, and neurotoxicity. Serious CardioVascular Adverse Events (CVAEs) have been reported with certain BTEs. However, this has not been clearly defined. Given that CVAEs have not been observed in a previous pharmacovigilance analysis focused on CAR-T therapy, it appears that the pathophysiology of CVAEs associated with novel T-cell modulatory therapies (BTEs) may be different.
The present study was conducted to examine the CardioVascular Adverse Events (CVAEs) associated with Bispecific T-cell Engager therapies (BTEs). The five BTE products considered for analysis were Blinatumomab, Teclistamab, Mosunetuzumab, Glofitamab, and Epcoritamab. Leveraging the vast repository of the US Food and Drug Administration’s Adverse Events Reporting System (FAERS), researchers embarked on a meticulous analysis, investigating the frequency and association of CVAE reporting with BTE, the prognostic implications of CVAEs in patients receiving BTEs, as well as the extent these adverse events overlap with CRS, spanning from October 2014 to March 2023. The primary objective was to delineate the frequency and fatality rates of CVAEs associated with BTEs, encompassing a spectrum of conditions including bleeding, hypotension or shock, thromboembolic disease, heart failure, and conduction abnormalities, myocarditis, pericarditis, sudden death, and vasculitis.
Utilizing multivariable logistic regression models, adjusted for age, sex, and disease status, the researchers calculated adjusted Reporting Odds Ratios (RORs). These RORs served as a metric to gauge the likelihood of reporting a given adverse event with BTEs compared to reporting the same event with all other drugs in the FAERS database.
Their study examined 3,668 cases of reported adverse events, 73.9% of which involved Blinatumomab and 11.2% involved Teclistamab as the primary suspected drug. Mosunetuzumab, Glofitamab and Epcoritamab accounted for a smaller proportion of events. (7.4%, 5.2% and 2.3%, respectively). The median age of patients was 52.0 years, with individuals from 52 countries represented in this analysis, with 43.2% of cases coming from the U.S. The indication for BTE therapy was leukemia/lymphoma in 88.7% of cases, multiple myeloma in 11.2% of cases, and both in 0.1% of cases.
The results of the study unveiled several significant findings:
1) Of the 3668 BTE-related cases reported to FAERS, 20.4% involved CVAEs.
2) BTEs were associated with disproportionately higher rates of fatal CVAEs, an association mainly driven by Teclistamab. Teclistamab was also associated with a disproportionate risk of myocarditis and shock, whereas Blinatumomab was associated with a disproportionate risk of Disseminated Intravascular Coagulation and hypotension.
3) Majority of these fatal CVAEs (96.7%) occurred in individuals without previously documented cardiovascular comorbidities.
4) CVAEs were more likely to be fatal compared with non-CVAEs (31.1% versus 17.4%).
5) CVAEs were not necessarily a consequence of Cytokine Release Syndrome (CRS), as approximately 85% of CVAE reports did not involve concurrent CRS.
6) In general, CVAEs tended to occur sooner following BTE therapy compared with non-CVAEs (median time to onset 6 days versus17 days; p<0.001).
7) No significant associations with CVAEs were observed with the other three BTE products (Glofitamab, Mosunetuzumab, and Epcoritamab).
8) Compared with CVAEs, neurotoxicity and CRS commonly associated with BTEs were associated with lower mortality. The elevated risk of death following CVAEs was especially noted for myocarditis, heart failure, bleeding, and DIC, with which mortality rates were 2-3 times higher than other AEs.
The researchers concluded that in this first postmarketing pharmacovigilance analysis of BTEs, CVAEs were involved in approximately 1 in 5 Adverse Event reports, and carried a significantly high mortality rate. The researchers cautioned that clinicians must be cognizant of the potential of CVAEs when treating patients with BTEs, and consider either stopping or switching therapies when CVAEs are suspected.
Cardiovascular toxicities associated with bispecific T-cell engager therapy. Sayed A, Munir M, Ghazi SM, et al. J Immunother Cancer. 2024 Feb 21;12(2):e008518. doi: 10.1136/jitc-2023-008518.
