Author + information
- Received June 16, 2019
- Revision received September 9, 2019
- Accepted October 1, 2019
- Published online December 16, 2019.
- Raza M. Alvi, MDa,∗,
- Matthew J. Frigault, MDb,∗,
- Michael G. Fradley, MDc,
- Michael D. Jain, MD, PhDd,
- Syed S. Mahmood, MD, MPHe,
- Magid Awadalla, MDa,
- Dae Hyun Lee, MDc,
- Daniel A. Zlotoff, MD, PhDf,
- Lili Zhang, MD, ScMa,
- Zsofia D. Drobni, MDa,
- Malek Z.O. Hassan, MDa,
- Emmanuel Bassily, MDc,
- Isaac Rhea, MDc,
- Roohi Ismail-Khan, MD, MScc,
- Connor P. Mulligan, BAa,
- Dahlia Banerji, MDa,
- Aleksandr Lazaryan, MD, MPH, PhDg,
- Bijal D. Shah, MDg,
- Adam Rokicki, BSa,
- Noopur Raje, MDh,
- Julio C. Chavez, MDg,
- Jeremy Abramson, MDh,
- Frederick L. Locke, MDd,† and
- Tomas G. Neilan, MD, MPHa,f,∗,† (, )@MGHHeartHealth
- aCardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- bCellular Immunotherapy Program, Division of Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- cCardio-Oncology Program, Division of Cardiovascular Medicine, University of South Florida Morsani College of Medicine and Moffitt Cancer Center, Tampa, Florida
- dDepartment of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida
- eDivision of Cardiology, New York-Presbyterian Hospital, Weil Cornell Medical Center, New York, New York
- fCardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- gDepartment of Malignant Hematology, Moffitt Cancer Center, Tampa, Florida
- hDivision of Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Tomas G. Neilan, Cardio-Oncology Program & Cardiovascular Imaging Research Center (CIRC), Massachusetts General Hospital, 165 Cambridge Street, Suite 400, Boston, Massachusetts 02114.
Background Chimeric antigen receptors redirect T cells (CAR-T) to target cancer cells. There are limited data characterizing cardiac toxicity and cardiovascular (CV) events among adults treated with CAR-T.
Objectives The purpose of this study was to evaluate the possible cardiac toxicities of CAR-T.
Methods The registry included 137 patients who received CAR-T. Covariates included the occurrence and grade of cytokine release syndrome (CRS) and the administration of tocilizumab for CRS. Cardiac toxicity was defined as a decrease in the left ventricular ejection fraction or an increase in serum troponin. Cardiovascular events were a composite of arrhythmias, decompensated heart failure, and CV death.
Results The median age was 62 years (interquartile range [IQR]: 54 to 70 years), 67% were male, 88% had lymphoma, and 8% had myeloma. Approximately 50% were treated with commercial CAR-T (Yescarta or Kymriah), and the remainder received noncommercial products. CRS, occurring a median of 5 days (IQR: 2 to 7 days) after CAR-T, occurred in 59%, and 39% were grade ≥2. Tocilizumab was administered to 56 patients (41%) with CRS, at a median of 27 h (IQR: 16 to 48 h) after onset. An elevated troponin occurred in 29 of 53 tested patients (54%), and a decreased left ventricular ejection fraction in 8 of 29 (28%); each occurred only in patients with grade ≥2 CRS. There were 17 CV events (12%, 6 CV deaths, 6 decompensated heart failure, and 5 arrhythmias; median time to event of 21 days), all occurred with grade ≥2 CRS (31% patients with grade ≥2 CRS), and 95% of events occurred after an elevated troponin. The duration between CRS onset and tocilizumab administration was associated with CV events, where the risk increased 1.7-fold with each 12-h delay to tocilizumab.
Conclusions Among adults, cardiac injury and CV events are common post–CAR-T. There was a graded relationship among CRS, elevated troponin, and CV events, and a shorter time from CRS onset to tocilizumab was associated with a lower rate of CV events.
↵∗ The first authors Drs. Alvi and Frigault contributed equally to this work.
↵† The senior authors Drs. Locke and Neilan contributed equally to this work.
This work was supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (T32HL076136 to Dr. Alvi; R01HL137562, R01HL130539, and K24HL113128-06 to Dr. Neilan), and National Cancer Institute (K23 CA201594 and P30 CA076292 to Dr. Locke). Drs. Alvi and Banerji were supported by National Institutes of Health/National Heart, Lung, and Blood Institute grant 5T32HL076136. Dr. Frigault has acted as a scientific advisor for Arcellx and Xenetic Bio; and has served as a consultant for Novartis, Kite/Gilead, and Celgene. Dr. Fradley has served as a consultant for Novartis. Dr. Jain has served as a consultant for Kite/Gilead. Dr. Mahmood has received consulting fees from Medicure, OMR globus, Alpha Detail, and Opinion Research Team; has performed cardiovascular event adjudication for PIVOT-2 clinical trials of anti-cancer therapy; and is supported by the Glorney-Raisbeck Fellowship Award in Cardiovascular Diseases from the New York Academy of Medicine. Dr. Lazaryan has served as a consultant for EUSA Pharma and Kadmon. Dr. Shah has served as a consultant for Celgene/Juno, Gilead/Kite, Novartis, and Adaptive; has received salary support for a pre-clinical grant from Incyte; and has received honoraria (for educational lectures for medical staff) from Gilead/Kite, Pharmacyclics, AstraZeneca, and Spectrum. Dr. Chavez has served as a consultant for Novartis, Kite, Genentech, Bayer, and Karyopharm; and has served on the Speakers Bureau of Genentech and AstraZeneca. Dr. Abramson has served as a consultant for Celgene, Gilead, Juno Therapeutics, Kite Pharma, and Novartis. Dr. Locke has acted as a scientific advisor for Kite/Gilead and Novartis; and has served as a consultant to Cellular BioMedicine Group Inc. Dr. Neilan was supported, in part, through a kind gift from A. Curtis Greer and Pamela Kohlberg; and has acted as a consultant for Parexel, Bristol-Myers Squibb, Aprea Therapeutics, H3 Biomedicine, and Intrinsic Imaging, unrelated to the current research. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received June 16, 2019.
- Revision received September 9, 2019.
- Accepted October 1, 2019.
- 2019 American College of Cardiology Foundation
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