CAR T-cell therapy linked to cardiovascular, pulmonary adverse effects
Chimeric antigen receptor T-cell therapy appeared associated with various cardiovascular and pulmonary adverse events, according to results of a retrospective pharmacovigilance study.
The analysis — published in Journal of the American College of Cardiology — revealed overreporting of tachyarrhythmias, cardiomyopathy, pleural disorders, pericardial diseases and venous-thromboembolic events relative to background incidence across the FDA Adverse Event Reporting System database.
“[Although] the true incidence of cardiovascular complications cannot be directly deduced from the FDA Adverse Event Reporting System, we estimate that over 10% of patients experience them,” Roni Shouval, MD, PhD, attending physician in the department of medicine and member of the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center, told Healio.
Researchers used the FDA Adverse Event Reporting System database to characterize treatment-related cardiovascular and pulmonary toxicities among 2,657 patients who underwent CD19-directed CAR T-cell therapy with axicabtagene ciloleucel (Yescarta; Kite Pharma/Gilead Sciences) or tisagenlecleucel (Kymriah, Novartis) between July 1, 2014, and June 30, 2020. The majority (83.7%) of patients had non-Hodgkin lymphoma.
Investigators identified 546 cardiovascular and pulmonary adverse events (CPAEs) in this group.
CPAEs overlapped with cytokine release syndrome in 68.3% of reports, making CRS the most widely reported adverse effect of CAR-T recipients in the database, with a fatality rate of 17.4%.
“The early timing of CPAE reports and the overlap with CRS timing further support the potential mechanistic link between CRS and CPAEs,” Shouval and colleagues wrote. “Vigilant monitoring of vital signs and electrocardiography is appropriate [for] patients treated with CAR-T, especially among those who develop CRS.”
Excluding hypotension, the most common overreported CPAEs were tachyarrhythmias (adjusted reporting OR = 2.78; 95% CI, 2.21-3.51) and cardiomyopathy (adjusted reporting OR = 3.51; 95% CI, 2.42-5.09). Researchers characterized corresponding fatality rates as “substantial” (36.5% for tachyarrhythmias and 36.9% for cardiomyopathy).
Researchers reported a 30.9% fatality rate with the CPAEs assessed. Overreported CPAEs associated with the highest fatality rates were cardiogenic shock (80.9%) and respiratory failure (66.2%).
When investigators stratified by CAR-T product, they observed what they called “a significant overreporting signal of VTE” after axicabtagene ciloleucel therapy (adjusted reporting OR = 1.8; 95% CI, 1.24-2.62).
An age- and sex-adjusted comparison of the two CD19-directed CAR-T products showed axicabtagene ciloleucel was associated with higher reporting of CRS (adjusted reporting OR = 1.4; 95% CI, 1.04-1.9), tachyarrhythmias (adjusted reporting OR = 1.82; 95% CI, 1.04-3.18) and VTE (adjusted reporting OR = 2.86; 95% CI, 1.18-6.93) than tisagenlecleucel.
Results showed similar reporting of composite severe cardiovascular adverse events between treatment groups.
“This post-marketing surveillance study suggests that CPAEs represent a meaningful challenge in the care of CAR-T recipients,” Shouval told Healio. “The strong link with CRS and increased mortality signal related to cardiovascular and pulmonary toxicity should prompt early interventions to mitigate CRS in early stages, especially [among] patients with cardiovascular risk factors. Importantly, more research is needed to define the mechanisms of cardiac complications in CAR-T recipients.”