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Current Treatment Options in Cardiovascular Medicine

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01-12-2020 | Cardiomyopathy | Cardio-oncology (M Fradley, Section Editor)

Cardiotoxicity of Contemporary Anticancer Immunotherapy

Authors: Natalie Dal’bo, MD, Rushin Patel, MD, Rohan Parikh, MD, Sachin P. Shah, MD, Avirup Guha, MD, Sourbha S. Dani, MD, Sarju Ganatra, MD

Published in: Current Treatment Options in Cardiovascular Medicine | Issue 12/2020

Abstract

Purpose of review

Contemporary anticancer immunotherapy, particularly immune checkpoint inhibitors (ICI) and chimeric antigen receptor (CAR) T cell therapy, has changed the landscape of treatment for patients with a variety of malignancies who historically had a poor prognosis. However, both immune checkpoint inhibitors and CAR T cell therapy are associated with serious cardiovascular adverse effects. As immunotherapy evolves to include high-risk patients with preexisting cardiovascular risk factors and disease, the risk and relevance of its associated cardiotoxicity will be even higher.

Recent findings

ICI can cause myocarditis, which usually occurs early after initiation, can be fulminant, and prompt treatment with high-dose corticosteroids is crucial. CAR T cell therapy frequently leads to cytokine release syndrome, which is associated with cardiomyopathy or arrhythmia development and may also result in circulatory collapse. Supportive treatment, as well as tocilizumab, an anti-interleukin-6 receptor antibody, is the cornerstone of treatment. Recent findings suggest that preexisting cardiovascular risk factors and disease may increase the risk of such cardiotoxicity, and prompt recognition, as well as treatment, may favorably alter the outcomes.

Summary

ICI and CAR T cell therapy have improved cancer-related outcomes; however, they both are associated with potentially therapy-limiting cardiotoxicity. Cardio-oncologists are required to play an important role in patient selection, pretherapy cardiovascular optimization, and prompt recognition and treatment of cardiotoxicity.

Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23. https://doi.org/10.1056/NEJMoa1003466.CrossRefPubMedPubMedCentral

Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26. https://doi.org/10.1056/NEJMoa1104621.CrossRefPubMed

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(5):439–48. https://doi.org/10.1056/NEJMoa1709866.CrossRefPubMedPubMedCentral

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(26):2531–44. https://doi.org/10.1056/NEJMoa1707447.CrossRefPubMedPubMedCentral

Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45–56. https://doi.org/10.1056/NEJMoa1804980.CrossRefPubMed

Ganatra S, Parikh R, Neilan TG. Cardiotoxicity of immune therapy. Cardiol Clin. 2019;37(4):385–97. https://doi.org/10.1016/j.ccl.2019.07.008.CrossRefPubMed

Ganatra S, Neilan TG. Immune checkpoint inhibitor-associated myocarditis. Oncologist. 2018;23:879–86. https://doi.org/10.1634/theoncologist.2018-0130.CrossRefPubMedPubMedCentral

•• Ganatra S, Carver JR, Hayek SS, Ky B, Leja MJ, Lenihan DJ, et al. Chimeric antigen receptor T-cell therapy for cancer and heart: JACC Council perspectives. J Am Coll Cardiol. 2019;74(25):3153–63. https://doi.org/10.1016/j.jacc.2019.10.049 This is an American College of Cardiology (ACC) Cardio-Oncology council perspective on cardiovascular effects of CAR T-cell therapy with proposed pre-CAR T cell therapy workup and management strategies.CrossRefPubMedPubMedCentral

Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158–68. https://doi.org/10.1056/NEJMra1703481.CrossRefPubMed

10.

•• Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol. 2018;71(16):1755–64. https://doi.org/10.1016/j.jacc.2018.02.037 This paper encompasses the data from international ICI-associated myocarditis registry and delineates risk factors, sensitivity, and specificity of various diagnostic tests and treatment strategies.CrossRefPubMedPubMedCentral

11.

Maldini CR, Ellis GI, Riley JL. CAR T cells for infection, autoimmunity and allotransplantation. Nat Rev Immunol. 2018;18(10):605–16. https://doi.org/10.1038/s41577-018-0042-2.CrossRefPubMedPubMedCentral

12.

Alvi RM, Frigault MJ, Fradley MG, Jain MD, Mahmood SS, Awadalla M, et al. Cardiovascular events among adults treated with chimeric antigen receptor T-cells (CAR-T). J Am Coll Cardiol. 2019;74(25):3099–108. https://doi.org/10.1016/j.jacc.2019.10.038.CrossRefPubMedPubMedCentral

13.

Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749–55. https://doi.org/10.1056/NEJMoa1609214.CrossRefPubMedPubMedCentral

14.

Love VA, Grabie N, Duramad P, Stavrakis G, Sharpe A, Lichtman A. CTLA-4 ablation and interleukin-12 driven differentiation synergistically augment cardiac pathogenicity of cytotoxic T lymphocytes. Circ Res. 2007;101(3):248–57. https://doi.org/10.1161/CIRCRESAHA.106.147124.CrossRefPubMed

15.

Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291(5502):319–22. https://doi.org/10.1126/science.291.5502.319.CrossRefPubMed

16.

Okazaki T, Tanaka Y, Nishio R, Mitsuiye T, Mizoguchi A, Wang J, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med. 2003;9(12):1477–83. https://doi.org/10.1038/nm955.CrossRefPubMed

17.

Grabie N, Gotsman I, DaCosta R, Pang H, Stavrakis G, Butte MJ, et al. Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell mediated injury in the heart. Circulation. 2007;116(18):2062–71. https://doi.org/10.1161/CIRCULATIONAHA.107.709360.CrossRefPubMed

18.

Escudier M, Cautela J, Malissen N, Ancedy Y, Orabona M, Pinto J, et al. Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity. Circulation. 2017;136(21):2085–7. https://doi.org/10.1161/CIRCULATIONAHA.117.030571.CrossRefPubMed

19.

Sarocchi M, Grossi F, Arboscello E, Bellodi A, Genova C, Dal Bello MG, et al. Serial troponin for early detection of nivolumab cardiotoxicity in advanced non-small cell lung cancer patients. Oncologist. 2018;23(8):936–42. https://doi.org/10.1634/theoncologist.2017-0452.CrossRefPubMedPubMedCentral

20.

Läubli H, Balmelli C, Kaufmann L, Stanczak M, Syedbasha M, Vogt D, et al. Influenza vaccination of cancer patients during PD-1 blockade induces serological protection but may raise the risk for immune-related adverse events. J Immunother Cancer. 2018;6(1):40. https://doi.org/10.1186/s40425-018-0353-7.CrossRefPubMedPubMedCentral

21.

Awadalla M, Golden DLA, Mahmood SS, Alvi RM, Mercaldo ND, Hassan MZO, et al. Influenza vaccination and myocarditis among patients receiving immune checkpoint inhibitors. J Immunother Cancer. 2019;7(1):53. https://doi.org/10.1186/s40425-019-0535-y.CrossRefPubMedPubMedCentral

22.

Lee C, Zafar A, Drobni ZD, et al. Pre-existing cardiovascular risk factors are associated with the development of immune checkpoint inhibitor myocarditis. AHA Abstract. 2020;Submitted.

23.

Awadalla M, Mahmood SS, Groarke JD, Hassan MZO, Nohria A, Rokicki A, et al. Global longitudinal strain and cardiac events in patients with immune checkpoint inhibitor-related myocarditis. J Am Coll Cardiol. 2020;75(5):467–78. https://doi.org/10.1016/j.jacc.2019.11.049.CrossRefPubMedPubMedCentral

24.

Ferreira VM, Schulz-Menger J, Holmvang G, Kramer CM, Carbone I, Sechtem U, et al. Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations. J Am Coll Cardiol. 2018;72(24):3158–76. https://doi.org/10.1016/j.jacc.2018.09.072.CrossRefPubMed

25.

Zhang L, Awadalla M, Mahmood SS, Nohria A, Hassan MZO, Thuny F, et al. Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis. Eur Heart J. 2020;41(18):1733–43. https://doi.org/10.1093/eurheartj/ehaa051.CrossRefPubMedPubMedCentral

26.

Hauck AJ, Kearney DL, Edwards WD. Evaluation of postmortem endomyocardial biopsy specimens from 38 patients with lymphocytic myocarditis: implications for role of sampling error. Mayo Clin Proc. 1989;64(10):1235–45.CrossRefPubMed

27.

Maisch B, Portig I, Ristic A, Hufnagel G, Pankuweit S. Definition of inflammatory cardiomyopathy (myocarditis): on the way to consensus. A status report. Herz. 2000;25(3):200–9.CrossRefPubMed

28.

•• Zhang L, Zlotoff DA, Awadalla M, Mahmood SS, Nohria A, Hassan MZO, et al. Major adverse cardiovascular events and the timing and dose of corticosteroids in immune checkpoint inhibitor-associated myocarditis. Circulation. 2020;141(24):2031–4. https://doi.org/10.1161/circulationaha.119.044703 This manuscript demonstrates the importance of prompt initiation of high-dose corticosteroids for the treatment of ICI-associated myocarditis.CrossRefPubMedPubMedCentral

29.

Kwon HJ, Cote TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med. 2003;138(10):807–11.CrossRefPubMed

30.

Salem JE, Allenbach Y, Vozy A, Brechot N, Johnson DB, Moslehi JJ, et al. Abatacept for severe immune checkpoint inhibitor-associated myocarditis. N Engl J Med. 2019;380(24):2377–9. https://doi.org/10.1056/NEJMc1901677.CrossRefPubMed

31.

Esfahani K, Buhlaiga N, Thébault P, Lapointe R, Johnson NA, Miller WH. Alemtuzumab for immune-related myocarditis due to PD-1 therapy. N Engl J Med. 2019;380(24):2375–6. https://doi.org/10.1056/NEJMc1903064.CrossRefPubMed

32.

Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391(10124):933. https://doi.org/10.1016/S0140-6736(18)30533-6.CrossRefPubMedPubMedCentral

33.

Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714–68. https://doi.org/10.1200/JCO.2017.77.6385.CrossRefPubMed

34.

Pollack MH, Betof A, Dearden H, Rapazzo K, Valentine I, Brohl AS, et al. Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Ann Oncol. 2018;29(1):250–5. https://doi.org/10.1093/annonc/mdx642.CrossRefPubMed

35.

Sadelain M, Brentjens R, Riviere I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3(4):388–98. https://doi.org/10.1158/2159-8290.CD-12-0548.CrossRefPubMedPubMedCentral

36.

June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379(1):64–73. https://doi.org/10.1056/NEJMra1706169.CrossRefPubMedPubMedCentral

37.

Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726–37. https://doi.org/10.1056/NEJMoa1817226.CrossRefPubMedPubMedCentral

38.

Burstein DS, Maude S, Grupp S, Griffis H, Rossano J, Lin K. Cardiac profile of chimeric antigen receptor T cell therapy in children: a single-institution experience. Biol Blood Marrow Transplant. 2018;24(8):1590–5. https://doi.org/10.1016/j.bbmt.2018.05.014.CrossRefPubMed

39.

Pathan N, Hemingway CA, Alizadeh AA, Stephens AC, Boldrick JC, Oragui EE, et al. Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock. Lancet. 2004;363(9404):203–9. https://doi.org/10.1016/S0140-6736(03)15326-3.CrossRefPubMed

40.

Cameron BJ, Gerry AB, Dukes J, Harper JV, Kannan V, Bianchi FC, et al. Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med. 2013;5(197):197ra03. https://doi.org/10.1126/scitranslmed.3006034.CrossRef

41.

Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130(21):2295–306. https://doi.org/10.1182/blood-2017-06-793141.CrossRefPubMedPubMedCentral

42.

Ganatra S, Redd R, Hayek SS, Parikh R, Azam T, Yanik G, et al. Chimeric antigen receptor T-cell therapy associated cardiomyopathy in patients with refractory or relapsed non-Hodgkin lymphoma. Circulation. 2020;In Press.

43.

Lefebvre B, Kang Y, Smith AM, Frey NV, Carver JR, Scherrer-Crosbie M. Cardiovascular effects of CAR T cell therapy. A retrospective study. JACC: CardioOncol. 2020;2(2):193–203. https://doi.org/10.1016/j.jaccao.2020.04.012.CrossRef

44.

Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, et al. FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cell-induced severe or life-threatening cytokine release syndrome. Oncologist. 2018;23(8):943–7. https://doi.org/10.1634/theoncologist.2018-0028.CrossRefPubMedPubMedCentral

45.

Riegler LL, Jones GP, Lee DW. Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther Clin Risk Manag. 2019;15:323–35. https://doi.org/10.2147/TCRM.S150524.CrossRefPubMedPubMedCentral

46.

Locke FL, Neelapu SS, Bartlett NL, Lekakis LJ, Jacobson CA, Braunschweig I, et al. Preliminary results of prophylactic tocilizumab after axicabtageneciloleucel (axi-cel; KTE-C19) treatment for patients with refractory,aggressive non-Hodgkin lymphoma (NHL). Blood. 2017;130(Suppl 1):1547.

47.

Ganatra S, Hammond SP, Nohria A. The novel coronavirus disease (COVID-19) threat for patients with cardiovascular disease and cancer. JACC: CardioOncol. 2020;80:350–5. https://doi.org/10.1016/j.jaccao.2020.03.001.CrossRef

48.

Ganatra S, Dani S, Redd R, Rieger-Christ K, Patel R, Parikh R, et al. Outcomes of the novel coronavirus disease 2019 in patients with a history of cancer and co-morbid cardiovascular disease. J Natl Compr Canc Netw. 2020;In Press.

49.

Ganatra S, Dani SS, Shah S, Asnani A, Neilan TG, Lenihan D, et al. Management of cardiovascular disease during coronavirus disease (COVID-19) pandemic. Trends Cardiovasc Med. 2020;30:315–25. https://doi.org/10.1016/j.tcm.2020.05.004.CrossRefPubMedPubMedCentral

50.

Lenihan D, Carver J, Porter C, Liu JE, Dent S, Thavendiranathan P et al. Cardio-oncology care in the era of the coronavirus (COVID-19) pandemic: an International Cardio-Oncology Society (ICOS) statement on cardiac safety in a new treatment paradigm. CA Cancer J Clin. 2020;In Press.

Title: Cardiotoxicity of Contemporary Anticancer Immunotherapy
Authors: Natalie Dal’bo, MD
Rushin Patel, MD
Rohan Parikh, MD
Sachin P. Shah, MD
Avirup Guha, MD
Sourbha S. Dani, MD
Sarju Ganatra, MD
Publication date: 01-12-2020
Publisher: Springer US
Keywords: Cardiomyopathy
Myocarditis
Tocilizumab
COVID-19
CAR T-Cell Therapy
Cytokines
Checkpoint Inhibitors
Published in: Current Treatment Options in Cardiovascular Medicine / Issue 12/2020
Print ISSN: 1092-8464
Electronic ISSN: 1534-3189
DOI: https://doi.org/10.1007/s11936-020-00867-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Cardiotoxicity of Contemporary Anticancer Immunotherapy

Abstract

Purpose of review

Recent findings

Summary

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose of review

Recent findings

Summary

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