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Open Access 03-10-2023 | Myocarditis

Cardiovascular Magnetic Resonance Assessment of Immunotherapy Cardiotoxicity

Authors: Marilia B. Voigt, Dmitrij Kravchenko, Alexander Isaak, Annkristin Heine, Tobias A. W. Holderried, Julian A. Luetkens

Published in: Current Cardiovascular Imaging Reports | Issue 12/2023

Abstract

Purpose of Review

To review the current and future role of cardiovascular magnetic resonance (CMR) assessment of immunotherapy cardiotoxicity.

Recent Findings

In patients who suffer from immune checkpoint inhibitor (ICI) myocarditis, pathologic CMR findings, including myocardial edema, reduced left ventricular ejection fraction (LVEF), late gadolinium enhancement (i.e., fibrosis and/or necrosis), and myocardial strain, are mostly subtle, but fulminant courses have been described. Individual cases of cardiotoxicity in chimeric antigen receptor (CAR) T cell therapy have also already been documented, but there are currently no studies addressing the role of CMR in CAR T cell therapy. There are also classes of immunotherapies for which no cases of cardiotoxicity are known yet, such as cytokines or adjuvants.

Summary

Together with patient symptoms, laboratory markers, electrocardiogram, and echocardiography, CMR is of high value in the diagnostic workup of immunotherapy-associated myocarditis in hemodynamically stable patients, according to recent guidelines. Additionally, quantitative strain analysis and T1 relaxation times with CMR can aid in assessing disease severity, prognosis, and patient outcomes with ICI-associated myocarditis. Future CMR studies on cardiotoxicity in CAR T cell therapy are needed.

Tan S, Li D, Zhu X. Cancer immunotherapy: pros, cons and beyond. Biomed Pharmacother. 2020;124. https://doi.org/10.1016/j.biopha.2020.109821.

Choi J, Lee SY. Clinical characteristics and treatment of immune-related adverse events of immune checkpoint inhibitors. Immune Netw. 2020;20(1):e9. https://doi.org/10.4110/IN.2020.20.E9.CrossRefPubMedPubMedCentral

Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377:1345–56. https://doi.org/10.1056/NEJMOA1709684.CrossRefPubMedPubMedCentral

Patel RP, Parikh R, Gunturu KS, et al. Cardiotoxicity of immune checkpoint inhibitors. 2021;23:79. https://doi.org/10.1007/s11912-021-01070-6.CrossRef

Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol. 2018;71:1755–64. https://doi.org/10.1016/J.JACC.2018.02.037.CrossRefPubMedPubMedCentral

• Zhang L, Awadalla M, Mahmood SS, et al. Cardiovascular magnetic resonance in immune checkpoint inhibitor-associated myocarditis. Eur Heart J. 2020;41:1733–43. https://doi.org/10.1093/EURHEARTJ/EHAA051. This scientific paper represents relevant literature from the last three years on the role of MRI in ICI myocarditis.CrossRefPubMedPubMedCentral

Lyon AR, Yousaf N, Battisti NML, et al. Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol. 2018;19:e447–58. https://doi.org/10.1016/S1470-2045(18)30457-1.CrossRefPubMed

Lefebvre B, Kang Y, Smith AM, et al. Cardiovascular effects of CAR T cell therapy: a retrospective study. JACC CardioOncol. 2020;2:193–203. https://doi.org/10.1016/J.JACCAO.2020.04.012.CrossRefPubMedPubMedCentral

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

10.

Qi K, Yan Z, Cheng H, et al. An analysis of cardiac disorders associated with chimeric antigen receptor T cell therapy in 126 patients: a single-centre retrospective study. Front Oncol. 2021;11. https://doi.org/10.3389/fonc.2021.691064.

11.

Palaskas N, Lopez-Mattei J, Durand JB, et al. Immune checkpoint inhibitor myocarditis: pathophysiological characteristics, diagnosis, and treatment. J Am Heart Assoc. 2020;9. https://doi.org/10.1161/JAHA.119.013757/FORMAT/EPUB.

12.

Suresh A, Martens P, Tang WHW. Biomarkers for myocarditis and inflammatory cardiomyopathy. Curr Heart Fail Rep. 2022;19:346–55. https://doi.org/10.1007/S11897-022-00569-8.CrossRefPubMedPubMedCentral

13.

Matsuura H, Watanabe N, Shibata Y, Asada Y. Combination of echocardiography and emergency endomyocardial biopsy for suspected myocarditis in the cardiovascular emergency medical care. J Echocardiogr. 2021;19:86–94. https://doi.org/10.1007/S12574-021-00521-0.CrossRefPubMed

14.

Erley J, Beitzen-Heineke A, Tahir E. Cardiooncology-usefulness of cardiac MRI : Inflammation, fibrosis, outcome. Radiologie (Heidelberg, Germany). 2022;62:941–6. https://doi.org/10.1007/S00117-022-01055-X.CrossRefPubMed

15.

Luetkens JA, Petry P, Kuetting D, et al. Left and right ventricular strain in the course of acute myocarditis: a cardiovascular magnetic resonance study. RoFo Fortschr Gebiet Rontgenstrahlen Bildgebenden Verfahren. 2018;190:722–32. https://doi.org/10.1055/a-0585-0271.CrossRef

16.

Luetkens JA, Faron A, Isaak A, et al. Comparison of original and 2018 Lake Louise Criteria for diagnosis of acute myocarditis: results of a validation cohort. Radiol Cardiothorac Imaging. 2019;1(3). https://doi.org/10.1148/ryct.2019190010.

17.

Luetkens JA, Voigt M, Faron A, et al. Influence of hydration status on cardiovascular magnetic resonance myocardial T1 and T2 relaxation time assessment: an intraindividual study in healthy subjects. J Cardiovasc Magn Reson. 2020;22:1–9. https://doi.org/10.1186/S12968-020-00661-9/FIGURES/5.CrossRef

18.

Luetkens JA, Homsi R, Sprinkart AM, et al. Incremental value of quantitative CMR including parametric mapping for the diagnosis of acute myocarditis. Eur Heart J Cardiovasc Imaging. 2016;17:154–61. https://doi.org/10.1093/EHJCI/JEV246.CrossRefPubMed

19.

Luetkens JA, Homsi R, Dabir D, et al. Comprehensive cardiac magnetic resonance for short-term follow-up in acute myocarditis. J Am Heart Assoc. 2016;5:e003603. https://doi.org/10.1161/JAHA.116.003603.

20.

• Faron A, Isaak A, Mesropyan N, et al. Cardiac MRI depicts immune checkpoint inhibitor-induced myocarditis: a prospective study. Radiology. 2021;301:602–9. https://doi.org/10.1148/radiol.2021210814. This scientific paper represents relevant literature from the last three years on the role of MRI in ICI myocarditis.CrossRefPubMed

21.

Thavendiranathan P, Wintersperger BJ, Flamm SD, Marwick TH. Cardiac MRI in the assessment of cardiac injury and toxicity from cancer chemotherapy: a systematic review. Circ Cardiovasc Imaging. 2013;6:1080–91. https://doi.org/10.1161/CIRCIMAGING.113.000899.CrossRefPubMed

22.

Geller MA, Cooley S, Argenta PA, et al. Toll-like receptor-7 agonist administered subcutaneously in a prolonged dosing schedule in heavily pretreated recurrent breast, ovarian, and cervix cancers. Cancer Immunol Immunother. 2010;59:1877–84. https://doi.org/10.1007/s00262-010-0914-1.CrossRefPubMedPubMedCentral

23.

Mantarro S, Rossi M, Bonifazi M, et al. Risk of severe cardiotoxicity following treatment with trastuzumab: a meta-analysis of randomized and cohort studies of 29,000 women with breast cancer. Intern Emerg Med. 2016;11:123–40. https://doi.org/10.1007/S11739-015-1362-X/FIGURES/3.CrossRefPubMed

24.

Pondé NF, Lambertini M, De Azambuja E. Twenty years of anti-HER2 therapy-associated cardiotoxicity. ESMO Open. 2016;1(4):e000073. https://doi.org/10.1136/ESMOOPEN-2016-000073.

25.

Nicolazzi MA, Carnicelli A, Fuorlo M, et al. Anthracycline and trastuzumab-induced cardiotoxicity in breast cancer. 2018;22(7):2175–2185. https://doi.org/10.26355/eurrev_201804_14752.

26.

Hansel TT, Kropshofer H, Singer T, et al. The safety and side effects of monoclonal antibodies. Nat Rev Drug Discov. 2010;9(4):325–38. https://doi.org/10.1038/nrd3003.CrossRefPubMed

27.

Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33:1974. https://doi.org/10.1200/JCO.2014.59.4358.CrossRefPubMedPubMedCentral

28.

Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol. 2021;16:223–49. https://doi.org/10.1146/annurev-pathol-042020-042741.CrossRef

29.

Sharma P, Siddiqui BA, Anandhan S, et al. The next decade of immune checkpoint therapy. Cancer Discov. 2021;11:838–57. https://doi.org/10.1158/2159-8290.CD-20-1680.CrossRefPubMed

30.

Varricchi G, Galdiero MR, Marone G, et al. Cardiotoxicity of immune checkpoint inhibitors. ESMO Open. 2017;2(4):e000247. https://doi.org/10.1136/ESMOOPEN-2017-000247.

31.

Cau R, Solinas C, De Silva P, et al. Role of cardiac MRI in the diagnosis of immune checkpoint inhibitor-associated myocarditis. Int J Cancer. 2022;151(11):1860–73. https://doi.org/10.1002/ijc.34169.CrossRefPubMed

32.

Russo A, Maurea N, Farmakis D, Giordano A. Cardio-oncology: Management of Toxicities in the Era of Immunotherapy. Springer Nature. 2022.

33.

Wang DY, Salem JE, Cohen JV, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4:1721–8. https://doi.org/10.1001/JAMAONCOL.2018.3923/.CrossRefPubMedPubMedCentral

34.

Moslehi J, Salem JE. Immune checkpoint inhibitor myocarditis treatment strategies and future directions. JACC CardioOncol. 2022;4:704–7. https://doi.org/10.1016/J.JACCAO.2022.11.005.CrossRefPubMedPubMedCentral

35.

Zito C, Manganaro R, Ciappina G, et al. Cardiotoxicity induced by immune checkpoint inhibitors: what a cardio-oncology team should know and do. Cancers (Basel). 2022;2022:5403. https://doi.org/10.3390/cancers14215403.CrossRef

36.

Hu C, Zhao L, Zhou C, et al. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block. Open Med (Wars). 2022;17:2109–16. https://doi.org/10.1515/MED-2022-0611.CrossRefPubMed

37.

Li X, Peng W, Wu J, et al. Advances in immune checkpoint inhibitors induced-cardiotoxicity. Front Immunol. 2023;14:1130438. https://doi.org/10.3389/FIMMU.2023.1130438.CrossRefPubMedPubMedCentral

38.

Khan NAJ, Pacioles T, Alsharedi M. Atypical Takotsubo cardiomyopathy secondary to combination of chemo-immunotherapy in a patient with non-small cell lung cancer. Cureus. 2020;12(7):e9429. https://doi.org/10.7759/CUREUS.9429.

39.

Airò G, Maffezzoli M, Lazzarin A, et al. Takotsubo syndrome in a patient with metastatic renal cell carcinoma treated with pembrolizumab plus axitinib. Immunotherapy. 2022;14:1297–305. https://doi.org/10.2217/IMT-2022-0013.CrossRefPubMed

40.

Carbone A, Bottino R, Russo V, et al. Takotsubo cardiomyopathy as epiphenomenon of cardiotoxicity in patients with cancer: a meta-summary of case reports. J Cardiovasc Pharmacol. 2021;78:e20–9. https://doi.org/10.1097/FJC.0000000000001026.CrossRefPubMed

41.

Ball S, Ghosh RK, Wongsaengsak S, et al. Cardiovascular toxicities of immune checkpoint inhibitors: JACC review topic of the week. J Am Coll Cardiol. 2019;74:1714–27. https://doi.org/10.1016/J.JACC.2019.07.079.CrossRefPubMed

42.

Lyon AR, López-Fernández T, Couch LS, et al. 2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS). Eur Heart J. 2022;43:4229–361. https://doi.org/10.1093/EURHEARTJ/EHAC244.CrossRefPubMed

43.

Wang G, Lee SE, Yang Q, et al. Multicenter study on the diagnostic performance of native-T1 cardiac magnetic resonance of chronic myocardial infarctions at 3T. Circ Cardiovasc Imaging. 2020;13:E009894. https://doi.org/10.1161/CIRCIMAGING.119.009894.CrossRefPubMedPubMedCentral

44.

Arcari L, Tini G, Camastra G, et al. Cardiac magnetic resonance imaging in immune check-point inhibitor myocarditis: a systematic review. J Imaging. 2022;8(4):99. https://doi.org/10.3390/jimaging8040099.CrossRefPubMedPubMedCentral

45.

• Thavendiranathan P, Zhang L, Zafar A, et al. Myocardial T1 and T2 mapping by magnetic resonance in patients with immune checkpoint inhibitor–associated myocarditis. J Am Coll Cardiol. 2021;77:1503–16. https://doi.org/10.1016/j.jacc.2021.01.050. This scientific paper represents relevant literature from the last three years on the role of MRI in ICI myocarditis.CrossRefPubMedPubMedCentral

46.

• Wintersperger BJ, Calvillo-Argü Elles O, Lheureux S, et al. Immune checkpoint inhibitor-related myocarditis: an illustrative case series of applying the updated Cardiovascular Magnetic Resonance Lake Louise Criteria. Eur Heart J Case Rep. 2022;6(1):ytab478. https://doi.org/10.1093/ehjcr/ytab478. This scientific paper represents relevant literature from the last three years on the role of MRI in ICI myocarditis.

47.

• Zhao Sh, Yun H, Chen Cz, et al. The prognostic value of global myocardium strain by CMR-feature tracking in immune checkpoint inhibitor-associated myocarditis. Eur Radiol. 2022;32:7657–67. https://doi.org/10.1007/S00330-022-08844-X. This scientific paper represents relevant literature from the last three years on the role of MRI in ICI myocarditis.CrossRefPubMed

48.

• Liu J, Cao Y, Zhu K, et al. Early evaluation of subclinical cardiotoxicity in patients with lung cancer receiving immune checkpoint inhibitors by cardiovascular magnetic resonance: a prospective observational study. Quant Imaging Med Surg. 2022;12:4771–85. https://doi.org/10.21037/QIMS-22-41/COIF. This scientific paper represents relevant literature from the last three years on the role of MRI in ICI myocarditis.CrossRefPubMedPubMedCentral

49.

• Cadour F, Cautela J, Rapacchi S, et al. Cardiac MRI features and prognostic value in immune checkpoint inhibitor–induced myocarditis. Radiology. 2022;303:512–21. https://doi.org/10.1148/radiol.211765. This scientific paper represents relevant literature from the last three years on the role of MRI in ICI myocarditis.CrossRefPubMed

50.

• Higgins AY, Arbune A, Soufer A, et al. Left ventricular myocardial strain and tissue characterization by cardiac magnetic resonance imaging in immune checkpoint inhibitor associated cardiotoxicity. PLoS One. 2021;16(2):e0246764. https://doi.org/10.1371/journal.pone.0246764. This scientific paper represents relevant literature from the last three years on the role of MRI in ICI myocarditis.

51.

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

52.

Faubry C, Faure M, Toublanc AC, et al. A prospective study to detect immune checkpoint inhibitors associated with myocarditis among patients treated for lung cancer. Front Cardiovasc Med. 2022;9:878211. https://doi.org/10.3389/FCVM.2022.878211/FULL.CrossRefPubMedPubMedCentral

53.

Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):69. https://doi.org/10.1038/S41408-021-00459-7.CrossRefPubMedPubMedCentral

54.

Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625–38. https://doi.org/10.1016/J.BBMT.2018.12.758.CrossRefPubMed

55.

Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531–44. https://doi.org/10.1056/NEJMOA1707447.CrossRefPubMedPubMedCentral

56.

Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377:2545–54. https://doi.org/10.1056/NEJMOA1708566/SUPPL_FILE/NEJMOA1708566_DISCLOSURES.PDF.CrossRefPubMedPubMedCentral

57.

Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nat Rev Clin Oncol. 2017;15(1):47–62. https://doi.org/10.1038/nrclinonc.2017.148.CrossRefPubMedPubMedCentral

58.

Linette GP, Stadtmauer EA, Maus MV, et al. Cardiovascular toxicity and titin cross-reactivity of affinity-enhanced T cells in myeloma and melanoma. Blood. 2013;122:863. https://doi.org/10.1182/BLOOD-2013-03-490565.CrossRefPubMedPubMedCentral

59.

Ganatra S, Redd R, Hayek SS, et al. Chimeric antigen receptor T-cell therapy-associated cardiomyopathy in patients with refractory or relapsed non-Hodgkin lymphoma. Circulation. 2020;142:1687–90. https://doi.org/10.1161/CIRCULATIONAHA.120.048100.CrossRefPubMed

60.

Steiner RE, Banchs J, Koutroumpakis E, et al. Cardiovascular events in patients treated with chimeric antigen receptor T-cell therapy for aggressive B-cell lymphoma. Haematologica. 2022;107:1555–66.CrossRefPubMed

61.

Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–95. https://doi.org/10.1182/BLOOD-2014-05-552729.CrossRefPubMedPubMedCentral

62.

Lydell CP, Vermes E, Childs HC, et al. Relationship of troponin T to cardiac MRI criteria for acute myocarditis. J Cardiovasc Magn Reson. 2011;13(1):1–1. https://doi.org/10.1186/1532-429X-13-S1-P271.CrossRef

63.

Cobb DA, Lee DW. Cytokine release syndrome biology and management. Cancer J. 2021;27:119–25. https://doi.org/10.1097/PPO.0000000000000515.CrossRefPubMed

64.

Luetkens JA, Isaak A, Öztürk C, et al. Cardiac MRI in suspected acute COVID-19 myocarditis. Radiol Cardiothorac Imaging. 2021;3(2):e200628. https://doi.org/10.1148/RYCT.2021200628.

65.

Luetkens JA, Doerner J, Thomas DK, et al. Acute myocarditis: multiparametric cardiac MR imaging. Radiology. 2014;273:383–92. https://doi.org/10.1148/RADIOL.14132540.CrossRefPubMed

66.

Luetkens JA, Doerner J, Schwarze-Zander C, et al. Cardiac magnetic resonance reveals signs of subclinical myocardial inflammation in asymptomatic HIV-infected patients. Circ Cardiovasc Imaging. 2016;9(3):e004091. https://doi.org/10.1161/CIRCIMAGING.115.004091.

67.

Kravchenko D, Isaak A, Zimmer S, et al. Cardiac MRI in patients with prolonged cardiorespiratory symptoms after mild to moderate COVID-19. Radiology. 2021;301:E419–25. https://doi.org/10.1148/RADIOL.2021211162.CrossRefPubMed

68.

Liu Y, Wu W. Cardiovascular immune-related adverse events: evaluation, diagnosis and management. Asia Pac J Clin Oncol. 2020;16:232–40. https://doi.org/10.1111/AJCO.13326.CrossRefPubMedPubMedCentral

69.

Stein-Merlob AF, Rothberg MV, Holman P, Yang EH. Immunotherapy-associated cardiotoxicity of immune checkpoint inhibitors and chimeric antigen receptor T cell therapy: diagnostic and management challenges and strategies. Curr Cardiol Rep. 2021;23:1–11. https://doi.org/10.1007/S11886-021-01440-3/TABLES/2.CrossRef

Title: Cardiovascular Magnetic Resonance Assessment of Immunotherapy Cardiotoxicity
Authors: Marilia B. Voigt
Dmitrij Kravchenko
Alexander Isaak
Annkristin Heine
Tobias A. W. Holderried
Julian A. Luetkens
Publication date: 03-10-2023
Publisher: Springer US
Keywords: Myocarditis
CAR T-Cell Therapy
Checkpoint Inhibitors
Published in: Current Cardiovascular Imaging Reports / Issue 12/2023
Print ISSN: 1941-9066
Electronic ISSN: 1941-9074
DOI: https://doi.org/10.1007/s12410-023-09584-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Cardiovascular Magnetic Resonance Assessment of Immunotherapy Cardiotoxicity

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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