Adam Goldman1, Elad Maor1, David Bomze2, Jennifer E Liu3, Joerg Herrmann4, Joshua Fein5, Richard M Steingart3, Syed S Mahmood6, Wendy L Schaffer3, Miguel-Angel Perales7, Roni Shouval8. 1. Leviev Heart Center, Chaim Sheba Medical Center, Ramat Gan, Israel; School of Medicine, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 2. School of Medicine, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 3. Cardiology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA; Department of Medicine, Weill Cornell Medical College, New York, New York, USA. 4. Department of Cardiovascular Disease, Mayo Clinic, Rochester, Minnesota, USA. 5. Department of Internal Medicine, UCONN Health, Farmington, Connecticut, USA. 6. Cardiology Division, New York-Presbyterian Hospital, Weill Cornell Medical Center, New York, New York, USA. 7. Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA. 8. Department of Medicine, Weill Cornell Medical College, New York, New York, USA; Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA. Electronic address: shouvalr@mskcc.org.
Abstract
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: This study sought to investigate CPAEs associated with commercial CD19-directed CAR-T therapy. METHODS: In this retrospective, pharmacovigilance study, the authors used the Food and Drug Administration adverse event reporting system to identify CPAEs associated with axicabtagene-ciloleucel and tisagenlecleucel. The authors evaluated disproportionate reporting by the reporting odds ratio (ROR) and the lower bound of the information component 95% credibility interval (IC025 >0 is deemed significant). Significant associations were further adjusted to age and sex (adj.ROR). RESULTS: The authors identified CAR-T reports of 2,657 patients, including 546 CPAEs (20.5%). CPAEs overlapped with cytokine release syndrome in 68.3% (373 of 546) of the reports. Compared with the full database, CAR-T was associated with overreporting 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 tachyarrhythmia, followed by ventricular arrhythmias (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, the authors identified an association between CAR-T and various CPAEs, including tachyarrhythmias, cardiomyopathy, pericardial and pleural disorders, and VTEs. These findings should be considered in the multidisciplinary assessment for and monitoring of CAR-T therapy recipients.
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: This study sought to investigate CPAEs associated with commercial CD19-directed CAR-T therapy. METHODS: In this retrospective, pharmacovigilance study, the authors used the Food and Drug Administration adverse event reporting system to identify CPAEs associated with axicabtagene-ciloleucel and tisagenlecleucel. The authors evaluated disproportionate reporting by the reporting odds ratio (ROR) and the lower bound of the information component 95% credibility interval (IC025 >0 is deemed significant). Significant associations were further adjusted to age and sex (adj.ROR). RESULTS: The authors identified CAR-T reports of 2,657 patients, including 546 CPAEs (20.5%). CPAEs overlapped with cytokine release syndrome in 68.3% (373 of 546) of the reports. Compared with the full database, CAR-T was associated with overreporting 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 tachyarrhythmia, followed by ventricular arrhythmias (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, the authors identified an association between CAR-T and various CPAEs, including tachyarrhythmias, cardiomyopathy, pericardial and pleural disorders, and VTEs. These findings should be considered in the multidisciplinary assessment for and monitoring of CAR-T therapy recipients.
Authors: Stephen J Schuster; Michael R Bishop; Constantine S Tam; Edmund K Waller; Peter Borchmann; Joseph P McGuirk; Ulrich Jäger; Samantha Jaglowski; Charalambos Andreadis; Jason R Westin; Isabelle Fleury; Veronika Bachanova; S Ronan Foley; P Joy Ho; Stephan Mielke; John M Magenau; Harald Holte; Serafino Pantano; Lida B Pacaud; Rakesh Awasthi; Jufen Chu; Özlem Anak; Gilles Salles; Richard T Maziarz Journal: N Engl J Med Date: 2018-12-01 Impact factor: 91.245
Authors: A Bate; M Lindquist; I R Edwards; S Olsson; R Orre; A Lansner; R M De Freitas Journal: Eur J Clin Pharmacol Date: 1998-06 Impact factor: 2.953
Authors: Frederick L Locke; Armin Ghobadi; Caron A Jacobson; David B Miklos; Lazaros J Lekakis; Olalekan O Oluwole; Yi Lin; Ira Braunschweig; Brian T Hill; John M Timmerman; Abhinav Deol; Patrick M Reagan; Patrick Stiff; Ian W Flinn; Umar Farooq; Andre Goy; Peter A McSweeney; Javier Munoz; Tanya Siddiqi; Julio C Chavez; Alex F Herrera; Nancy L Bartlett; Jeffrey S Wiezorek; Lynn Navale; Allen Xue; Yizhou Jiang; Adrian Bot; John M Rossi; Jenny J Kim; William Y Go; Sattva S Neelapu Journal: Lancet Oncol Date: 2018-12-02 Impact factor: 41.316
Authors: Sattva S Neelapu; Frederick L Locke; Nancy L Bartlett; Lazaros J Lekakis; David B Miklos; Caron A Jacobson; Ira Braunschweig; Olalekan O Oluwole; Tanya Siddiqi; Yi Lin; John M Timmerman; Patrick J Stiff; Jonathan W Friedberg; Ian W Flinn; Andre Goy; Brian T Hill; Mitchell R Smith; Abhinav Deol; Umar Farooq; Peter McSweeney; Javier Munoz; Irit Avivi; Januario E Castro; Jason R Westin; Julio C Chavez; Armin Ghobadi; Krishna V Komanduri; Ronald Levy; Eric D Jacobsen; Thomas E Witzig; Patrick Reagan; Adrian Bot; John Rossi; Lynn Navale; Yizhou Jiang; Jeff Aycock; Meg Elias; David Chang; Jeff Wiezorek; William Y Go Journal: N Engl J Med Date: 2017-12-10 Impact factor: 91.245
Authors: Nazima Pathan; Cheryl A Hemingway; Ash A Alizadeh; Alick C Stephens; Jennifer C Boldrick; Emmanuelle E Oragui; Colm McCabe; Steven B Welch; Adeline Whitney; Peter O'Gara; Simon Nadel; David A Relman; Sian E Harding; Michael Levin Journal: Lancet Date: 2004-01-17 Impact factor: 79.321
Authors: Gerald P Linette; Edward A Stadtmauer; Marcela V Maus; Aaron P Rapoport; Bruce L Levine; Lyndsey Emery; Leslie Litzky; Adam Bagg; Beatriz M Carreno; Patrick J Cimino; Gwendolyn K Binder-Scholl; Dominic P Smethurst; Andrew B Gerry; Nick J Pumphrey; Alan D Bennett; Joanna E Brewer; Joseph Dukes; Jane Harper; Helen K Tayton-Martin; Bent K Jakobsen; Namir J Hassan; Michael Kalos; Carl H June Journal: Blood Date: 2013-06-14 Impact factor: 22.113
Authors: L B Silverman; K E Stevenson; J E O'Brien; B L Asselin; R D Barr; L Clavell; P D Cole; K M Kelly; C Laverdiere; B Michon; M A Schorin; C L Schwartz; E W O'Holleran; D S Neuberg; H J Cohen; S E Sallan Journal: Leukemia Date: 2009-12-17 Impact factor: 11.528
Authors: Jutta Bergler-Klein; Peter P Rainer; Markus Wallner; Marc-Michael Zaruba; Jakob Dörler; Armin Böhmer; Tamara Buchacher; Maria Frey; Christopher Adlbrecht; Rupert Bartsch; Mariann Gyöngyösi; Ursula-Maria Fürst Journal: Wien Klin Wochenschr Date: 2022-05-04 Impact factor: 2.275