Cardiovascular and Pulmonary Adverse Events Associated with Chimeric Antigen Receptor T-cell Therapy - The 68th Annual Conference of the Israel Heart Society in association with the Israel Society of Cardiothoracic Surgery

Adam Goldman ¹ Elad Maor ^1,2 David Bomze ¹ Jennifer E Liu ^3,4 Joerg Herrmann ⁵ Joshua Fein ⁶ Richard M Steingart ^3,4 Syed S Mahmood ⁷ Wendy L Schaffer ^3,4 Miguel-Angel Perales ^4,8 Roni Shouval ⁸

¹School of Medicine,, Sackler Faculty of Medicine, Tel-Aviv University, Israel
²Leviev Heart Center, Sheba Medical Centᶠer, Israel
³Cardiology Service, Department of Medicine., Memorial Sloan Kettering Cancer Center, New York, New York., USA
⁴Medicine, Weill Cornell Medical College, USA
⁵Department of Cardiovascular Disease, Mayo Clinic, USA
⁶Department of Internal Medicine, UCONN Health, USA
⁷Cardiology Division, New York-Presbyterian Hospital, Weill Cornell Medical Center., USA
⁸Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, USA

Background: Pivotal trials of chimeric antigen receptor T-cell (CAR-T) have identified common toxicities but may have been underpowered to detect cardiovascular and pulmonary adverse events (CPAEs).

Objectives: To investigate CPAEs associated with commercial CD19-directed CAR-T therapy.

Methods: In this retrospective, pharmacovigilance study we used the FDA adverse event reporting system to identify CPAEs associated with axicabtagene-ciloleucel and tisagenlecleucel. We evaluated disproportionate reporting by the reporting odds ratio (ROR) and the lower bound of the Information Component (IC) 95% credibility interval (IC025>0 is deemed significant). Significant associations were further adjusted to age and sex (adj.ROR).

Results: We identified CAR-T reports of 2,657 patients, including 546 (20.5%) CPAEs. CPAEs overlapped with cytokine release syndrome in 68.3% (373/546) of the reports. Compared to the full database, CAR-T was associated with over-reporting of tachyarrhythmias (n=74[2.8%], adj.ROR=2.78 [95% CI, 2.21-3.51]), cardiomyopathy (n=69[2.6%], adj.ROR=3.51 [2.42-5.09]), pleural disorders (n=46[1.7%], adj.ROR=3.91 [2.92-5.23]), and pericardial diseases (n=11[0.4%], adj.ROR=2.26 [1.25-4.09], all IC025>0). Venous-thromboembolic events (VTEs) were associated only with axicabtagene-ciloleucel therapy (n=28[1.6%], adj.ROR= 1.80 [1.24-2.62], IC025>0). Atrial fibrillation (n=55) was the leading tachyarrythmia, followed by ventricular arrythmias (n=14). Tachyarrhythmias and VTEs were reported more often following axicabtagene-ciloleucel than tisagenlecleucel in an age and sex-adjusted model (adj.ROR=1.82 [1.04-3.18] and adj.ROR=2.86 [1.18-6.93], respectively). Finally, the fatality rate of CPAEs was 30.9%.

Conclusions: In this largest post-marketing study to date, we identified an association between CAR-T and various CPAEs, including tachyarrhythmias, cardiomyopathy, pericardial and pleural disorders, and VTEs. Our findings should be considered in the multi-disciplinary assessment for and monitoring recipients after CAR-T therapy.