Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jun 9;44(22):2029-2042.
doi: 10.1093/eurheartj/ehad117.

Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients

Syed S Mahmood  1   2 , Peter A Riedell  3 , Stephanie Feldman  2 , Gina George  4 , Stephen A Sansoterra  4 , Thomas Althaus  3 , Mahin Rehman  2 , Elena Mead  5 , Jennifer E Liu  2 , Richard B Devereux  1 , Jonathan W Weinsaft  1 , Jiwon Kim  1 , Lauren Balkan  6 , Tarek Barbar  6 , Katherine Lee Chuy  2 , Bhisham Harchandani  2 , Miguel-Angel Perales  7   6 , Mark B Geyer  8   6 , Jae H Park  8   6 , M Lia Palomba  9   6 , Roni Shouval  7   6 , Ana A Tomas  7 , Gunjan L Shah  7   6 , Eric H Yang  10 , Daria L Gaut  11 , Michael V Rothberg  12 , Evelyn M Horn  1 , John P Leonard  13 , Koen Van Besien  13 , Matthew J Frigault  14   15 , Zhengming Chen  16 , Bhoomi Mehrotra  17 , Tomas G Neilan  18 , Richard M Steingart  2
Affiliations

Biomarkers and cardiovascular outcomes in chimeric antigen receptor T-cell therapy recipients

Syed S Mahmood et al. Eur Heart J. .

Abstract

Aims: Chimeric antigen receptor T-cell therapy (CAR-T) harnesses a patient's immune system to target cancer. There are sparse existing data characterizing death outcomes after CAR-T-related cardiotoxicity. This study examines the association between CAR-T-related severe cardiovascular events (SCE) and mortality.

Methods and results: From a multi-centre registry of 202 patients receiving anti-CD19 CAR-T, covariates including standard baseline cardiovascular and cancer parameters and biomarkers were collected. Severe cardiovascular events were defined as a composite of heart failure, cardiogenic shock, or myocardial infarction. Thirty-three patients experienced SCE, and 108 patients died during a median follow-up of 297 (interquartile range 104-647) days. Those that did and did not die after CAR-T were similar in age, sex, and prior anthracycline use. Those who died had higher peak interleukin (IL)-6 and ferritin levels after CAR-T infusion, and those who experienced SCE had higher peak IL-6, C-reactive protein (CRP), ferritin, and troponin levels. The day-100 and 1-year Kaplan-Meier overall mortality estimates were 18% and 43%, respectively, while the non-relapse mortality (NRM) cumulative incidence rates were 3.5% and 6.7%, respectively. In a Cox model, SCE occurrence following CAR-T was independently associated with increased overall mortality risk [hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.6-4.7] after adjusting for age, cancer type and burden, anthracycline use, cytokine release syndrome grade ≥ 2, pre-existing heart failure, hypertension, and African American ancestry; SCEs were independently associated with increased NRM (HR 3.5, 95% CI 1.4-8.8) after adjusting for cancer burden.

Conclusion: Chimeric antigen receptor T-cell therapy recipients who experience SCE have higher overall mortality and NRM and higher peak levels of IL-6, CRP, ferritin, and troponin.

Keywords: CAR-T cells; Cancer; Cardio-oncology; Cardiovascular events; Chimeric antigen receptor; Mortality.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest S.S.M. has received consulting fees from Nektar Therapeutics, Health & Wellness Partners, Medicure. P.A.R. has received consulting fees from AbbVie, BMS, Janssen, Novartis, BeiGene, Kite/Gilead, Intellia Therapeutics, Sana Biotechnology, CVS Caremark, Genmab, Pharmacyclics, Takeda, Karyopharm, Nektar Therapeutics, Nurix Therapeutics, and ADC Therapeutics. M.A.P. reports consulting fees from Adicet, Allovir, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Syncopation, VectivBio AG, and Vor Biopharma, is participating in DSMB of Cidara Therapeutics, Medigene, and Sellas Life Sciences, and is on the scientific advisory board of NexImmune and Omeros. M.B.G. has received institutional grant funding from Sanofi, Amgen, and Actinium and consulting fees from Sanofi, Novartis, and Allogene. M.L.P. has received royalties from Juno and Sers and consulting fees from Novartis, Cellectar, Synthekine, Kite, Seres, Magenta, WindMIL, Rheos, Nektar, Notch, Priothera, Ceramedix, Lygenesis, and Pluto. R.S. has received consulting fees from Mudexus and MyBiotics. G.S. has received research funding from Janssen, Amgen, Beyond Spring, and BMS and is on DSMB of ArcellX. E.H.Y. has received institutional grand funding from CSL Behring, Boehringer Ingelheim, BMS and Eli and Lilly and consulting fees from Pfizer. J.P.L. has received institutional grants from Genentech, Janssen, and Epizyme and consulting fees from Abbvie, Astellas, AstraZeneca, Bayer, Beigene, BMS, Calithera, Constellation, Caribou Biosciences, Eisai, Lilly, Epizyme, Genmab, Grail, Incyte, Jansssen, MEI Pharma, Merck, Mustang Bio, Novartis, Pfizer, Roche/Genentech, Seagen, Second Genome, Sutro, ADC Therapeutics, Miltenyi, and Karyopharm. T.G.N. has received consulting fees from BMS, Genentech, Abbvie, Roche, CRO Oncology, and Sanofi and participates in DSMB of Genentech and received research grant funding from AstraZeneca and BMS.

Figures

Structured Graphical Abstract
Structured Graphical Abstract
Cancer patients treated with chimeric antigen receptor T-cell therapy (CAR-T) who experience severe cardiovascular events have higher overall mortality and non-relapse mortality and higher peak levels of IL-6, CRP, ferritin, and troponin. The overall survival was graphed as the Simon—Makuch curve. Non-relapse mortality was graphed as cumulative incidence. IL-6, interleukin-6; CRP, C-reactive protein; HR, hazard ratio; CI, confidence interval. *P-value is from the score test provided by the univariable time-dependent Cox model.
Figure 1
Figure 1
Boxplots for peak biomarker levels after CAR-T infusion stratified by (A) SCE and (B) overall mortality. SCE, severe cardiovascular events; CRP, C-reactive protein; IL-6, interleukin-6; TNF-α, tumour necrosis factor alpha.
Figure 2
Figure 2
(A) Simon–Makuch curve plotting overall survival and (B) cumulative incidence of non-relapse mortality, from time of CAR-T infusion as stratified by SCE. SCE, severe cardiovascular events. *P-value is from the score test provided by an univariable time-dependent Cox model.
Figure 3
Figure 3
Association with overall mortality determined using multi-variate Cox proportional hazards regression analysis. SCE, severe cardiovascular events; CRS, cytokine release syndrome; HR, hazard ratio; CI, confidence interval.
See this image and copyright information in PMC

Comment in

References

    1. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. . Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 2017;377:2531–2544. 10.1056/NEJMoa1707447 - DOI - PMC - PubMed
    1. Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, et al. . Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 2020;396:839–852. 10.1016/s0140-6736(20)31366-0 - DOI - PubMed
    1. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. . Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 2018;378:439–448. 10.1056/NEJMoa1709866 - DOI - PMC - PubMed
    1. Totzeck M, Michel L, Lin Y, Herrmann J, Rassaf T. Cardiotoxicity from chimeric antigen receptor-T cell therapy for advanced malignancies. Eur Heart J 2022;43:1928–1940. 10.1093/eurheartj/ehac106 - DOI - PMC - PubMed
    1. Melenhorst JJ, Chen GM, Wang M, Porter DL, Chen C, Collins MA, et al. . Decade-long leukaemia remissions with persistence of CD4+ CAR T cells. Nature 2022;602:503–509. 10.1038/s41586-021-04390-6 - DOI - PMC - PubMed

Publication types