‘Wake-up call’: Cardiovascular toxicity a concern for patients receiving bispecifics
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Key takeaways:
- Cardiovascular adverse events occurred more frequently in patients who received bispecific T-cell engager therapies.
- Cardiovascular adverse events translated to increased risk for mortality.
More than 20% of reported cases of adverse events following bispecific T-cell engager therapies involved a cardiovascular event, findings reported in Journal for ImmunoTherapy of Cancer showed.
Additionally, those who experienced cardiovascular adverse events (CVAEs) had significantly higher mortality risk compared with other adverse events, according to researchers.
“That result was substantially higher than what we generally expect coming into this based on the limited profile that we have observed in clinical practice and from clinical trials,” Daniel Addison, MD, director of the cardio-oncology program at The Ohio State University, told Healio.
Bispecific T-cell engager (BTE) therapies have produced “impressive and efficacious” results as a treatment option for hematologic malignancies since the approval of the first BTE, blinatumomab (Blincyto, Amgen), in 2014, Addison said.
Common adverse events linked to BTEs include cytokine release syndrome, hematologic toxicities and neurotoxicity, but information regarding their impact on the heart is limited, researchers wrote. Less than 2% of patients in a study cohort in Italy experienced CVAEs, but almost 15% of a cohort in South Korea had them.
“We really didn’t have a clear sense about what the cardiovascular or safety profile of these agents might actually be based on these cancer efficacy-focused studies,” Addison said.
Researchers investigated all five BTEs currently approved for treatment of hematologic malignancies — blinatumomab, teclistamab (Tecvayli, Janssen Biotech), mosunetuzumab (Lunsumio, Genentech), glofitamab (Columvi, Genentech) and epcoritamab (Epkinly; Genmab, AbbVie) — using the FDA’s Adverse Event Reporting System (FAERS) from the last quarter of 2014 to the third quarter of 2023.
Their study examined 3,668 cases of reported adverse events, 73.9% of which involved blinatumomab and 11.2% involved teclistamab.
Reported cases involved BTE recipients with a median age of 52 years (55.6% men). Individuals from 52 countries are represented in the analysis, with 43.2% of cases coming from the U.S.
CVAE cases amounted to 20.4% of the total studied, the most common events being bleeding, thromboembolic events, hypotension, shock and heart failure. One-half of CVAEs occurred within 6 days of receiving a BTE.
Regression models indicated increased risk for myocarditis (reported OR = 2.38; 95% CI, 1.1-5.14), hypotension (reported OR = 1.53; 95% CI, 1.23-1.91) and disseminated intravascular coagulation (reported OR = 3.22; 95% CI, 2.16-4.79) associated with BTE therapy.
“There was a clear pattern wherein these cardiovascular issues that were more prevalent than what we initially thought, and some of which included entities like myocarditis, which was not fully anticipated coming into the analysis,” Addison said.
FAERS did not include patients who received BTEs and did not have any reported adverse events, thus potentially raising the percentage, Addison noted as one of the study’s limitations.
However, CVAEs had a pronounced impact on OS as CVAEs resulted in death in 31.1% of cases vs. 17.4% for non-CVAEs (OR = 1.76; 95 CI, 1.54-2.03). Shock (57.7%), myocarditis (50%) and heart failure (44.2%) had the highest mortality rates.
“This is a general wake-up call,” Addison said. “We have to take it seriously because CVAEs may be a prognostic sign for which the likelihood of success may be dramatically altered based on the development of these events.”
Researchers also discovered individual drugs had different outcomes, with blinatumomab having an association with disseminated intravascular coagulation and hypotension, while teclistamab had links to myocarditis and shock.
Addison did not want to read too deeply into those numbers, however.
“Some of the other bi-cell therapies have literally just been approved in the year 2023,” he said. “If we repeated this analysis in a couple of years, we may see a little bit more balanced signal between the drugs. But at least for now, it’s probably reasonable to consider cardiovascular toxicity if your patient is having myocarditis, potentially either stopping or switching. This should be a consideration for clinicians seeing these patients.”
Addison discussed several areas of future research, including identifying risk factors leading to CVAE, understanding mechanisms that cause them and finding strategies to treat these events.
An unanticipated issue with treatment toxicity currently is that CVAEs did not have a strong association with cytokine release syndrome, “[for] which we know we have effective treatments,” Addison said. “That absence suggests that the strategies that would potentially mitigate or reduce this risk might be different than what we have been using for CAR-T and other therapies where CRS is the primary driver of cardiac and other toxicities.”
For now, clinicians must be cognizant of the potential of CVAEs when it comes to BTEs.
“Great treatment, but we should at least be aware that it can affect your heart, and we shouldn’t ignore these signals,” Addison said. “Someone could have dramatic improvement in their cancer and see an unexpected cardiovascular event. It would be unfortunate if a patient died 30 days or a few months later from heart disease, following what appeared to be successful cancer treatment.”
For more information:
Daniel Addison, MD, can be reached at daniel.addison@osumc.edu.
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