Top

Published in:

01-01-2021 | Myocarditis | Original Paper

Re-introducing immunotherapy in patients surviving immune checkpoint inhibitors-mediated myocarditis

Authors: Shira Peleg Hasson, Benjamin Salwen, Ayelet Sivan, Sivan Shamai, Ravit Geva, Ofer Merimsky, Ari Raphael, Haim Shmilovich, Yonatan Moshkovits, livia Kapusta, Zach Rozenbaum, Ido Wolf, Michal Laufer-Perl

Published in: Clinical Research in Cardiology | Issue 1/2021

Abstract

Background

Immune checkpoint inhibitors (ICI) have transformed the standard care of cancer treatment. Recent case reports describe ICI-mediated myocarditis with an atypical presentation and fatal potential which lead to permanent interruption of immunotherapy.

Objectives

To characterize ICI-mediated myocarditis and re-introduction to immunotherapy.

Methods

During 2019, 849 patients were treated with ICI at Tel Aviv Sourasky Medical Center for the diagnosis of lung adenocarcinoma, gastric adenocarcinoma, urothelial carcinoma, and hepatocellular carcinoma. Overall, seven (0.8%) patients were diagnosed with ICI-mediated myocarditis, according to the European Society of Cardiology guidelines of myocarditis 2013. We retrospectively evaluated their presentation, severity, and clinical outcomes.

Results

Among the seven patients, only one had a history of cardiac disease. The majority were diagnosed with lung adenocarcinoma and treated with anti-programmed death-1 antibody. All patients were treated with single-agent ICI. Most patients presented with cardiac symptoms, elevated troponin and typical cardiac magnetic resonance; however, only three had reduced ejection fraction. Overall, three patients were chosen for re-introduction with concomitant low dose steroids and weekly troponin follow-up. Two patients diagnosed with grade I and II renewed therapy successfully with no recurrence of symptoms and improvement in disease burden. The one patient diagnosed with grade III developed worsening of cardiac symptoms after the 1st cycle and, therefore, therapy was interrupted permanently.

Conclusions

ICI-mediated myocarditis is potentially fatal and leads to permanent interruption of life-saving cancer therapy. The current data suggest that re-introduction may be considered in low-grade patients; however, a better definition of the diagnosis and grading is needed.

Graphic abstract

Emens LA, Ascierto PA, Darcy PK et al (2017) Cancer immunotherapy: opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer 81:116–129CrossRef

Chen DS, Mellman I (2013) Oncology meets immunology: the cancer-immunity cycle. Immunity 39:1–10CrossRef

Larkin J, Chiarion-Sileni V, Gonzalez R et al (2015) Combined nivolumab and ipilimumab or monotherapy in untreated Melanoma. N Engl J Med. https://doi.org/10.1056/NEJMoa1504030CrossRefPubMedPubMedCentral

Jazirehi AR, Lim A, Dinh T (2016) PD-1 inhibition and treatment of advanced melanoma-role of pembrolizumab. Am J Cancer Res 6(10):2117–2128PubMedPubMedCentral

Motzer RJ, Escudier B, McDermott DF et al (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. https://doi.org/10.1056/NEJMoa1510665CrossRefPubMedPubMedCentral

Lee CK, Man J, Lord S et al (2017) Checkpoint inhibitors in metastatic egfr-mutated non-small cell lung cancer: a meta-analysis. J Thorac Oncol. https://doi.org/10.1016/j.jtho.2016.10.007CrossRefPubMed

Bellmunt J, De Wit R, Vaughn DJ et al (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. https://doi.org/10.1056/NEJMoa1613683CrossRefPubMedPubMedCentral

Lyon AR, Yousaf N, Battisti NML et al (2018) Immune checkpoint inhibitors and cardiovascular toxicity. Lancet Oncol 19:447–458CrossRef

Guo CW, Alexander M, Dib Y et al (2020) A closer look at immune-mediated myocarditis in the era of combined checkpoint blockade and targeted therapies. Eur J Cancer. https://doi.org/10.1016/j.ejca.2019.09.009CrossRefPubMed

10.

Weber JS, Kähler KC, Hauschild A (2012) Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 30:2691–2697CrossRef

11.

Forde PM, Chaft JE, Smith KN et al (2018) Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. https://doi.org/10.1056/NEJMoa1716078CrossRefPubMedPubMedCentral

12.

Von Minckwitz G, Procter M, De Azambuja E et al (2017) Adjuvant pertuzumab and trastuzumab in early her2-positive breast cancer. N Engl J Med. https://doi.org/10.1056/NEJMoa1703643CrossRef

13.

Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. https://doi.org/10.1056/NEJMoa1200690CrossRefPubMedPubMedCentral

14.

Johnson DB, Balko JM, Compton ML et al (2016) Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. https://doi.org/10.1056/NEJMoa1609214CrossRefPubMedPubMedCentral

15.

Mir H, Alhussein M, Alrashidi S et al (2018) Cardiac complications associated with checkpoint inhibition: a systematic review of the literature in an important emerging area. Can J Cardiol 34:1059–1068CrossRef

16.

Mahmood SS, Fradley MG, Cohen JV et al (2018) Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol. https://doi.org/10.1016/j.jacc.2018.02.037CrossRefPubMedPubMedCentral

17.

Moslehi JJ, Salem JE, Sosman JA et al (2018) Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet 391:933CrossRef

18.

Caforio ALP, Pankuweit S, Arbustini E et al (2013) Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. https://doi.org/10.1093/eurheartj/eht210CrossRefPubMed

19.

Pradhan R, Nautiyal A, Singh S (2019) Diagnosis of immune checkpoint inhibitor-associated myocarditis: a systematic review. Int J Cardiol. https://doi.org/10.1016/j.ijcard.2019.07.025CrossRefPubMed

20.

Porcari A, Merlo M, Crosera L et al (2019) Strain analysis reveals subtle systolic dysfunction in confirmed and suspected myocarditis with normal LVEF: a cardiac magnetic resonance study. Clin Res Cardiol. https://doi.org/10.1007/s00392-019-01577-wCrossRefPubMed

21.

Zhang L, Jones-O’Connor M, Awadalla M et al (2019) Cardiotoxicity of Immune Checkpoint Inhibitors. Curr Treat Opt Cardiovasc Med 21:32CrossRef

22.

Brahmer JR, Lacchetti C, Schneider BJ et al (2018) 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 36:1714–1768. https://doi.org/10.1200/JCO.2017.77.6385CrossRefPubMedPubMedCentral

23.

Haanen JBAG, Carbonnel F, Robert C et al (2017) Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. https://doi.org/10.1093/annonc/mdx225CrossRefPubMedPubMedCentral

24.

Bäuml M, Udi J, Klingel K et al (2019) Severe eosinophilic myocarditis associated with modafinil in a patient with normal peripheral eosinophil count. Clin Res Cardiol 108:963–966CrossRef

25.

Heinzerling L, Ott PA, Hodi FS et al (2016) Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy. J Immunother Cancer. https://doi.org/10.1186/s40425-016-0152-yCrossRefPubMedPubMedCentral

26.

Dalen H, Thorstensen A, Aase SA et al (2010) Segmental and global longitudinal strain and strain rate based on echocardiography of 1266 healthy individuals: the HUNT study in Norway. Eur J Echocardiogr. https://doi.org/10.1093/ejechocard/jep194CrossRefPubMed

27.

Hu JR, Florido R, Lipson EJ et al (2019) Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res 115:854–868CrossRef

28.

Salem JE, Manouchehri A, Moey M et al (2018) Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. https://doi.org/10.1016/S1470-2045(18)30608-9CrossRefPubMedPubMedCentral

29.

Varricchi G, Galdiero MR, Marone G et al (2017) Cardiotoxicity of immune checkpoint inhibitors. ESMO Open 2:e000247CrossRef

30.

Wolchok JD, Chiarion-Sileni V, Gonzalez R et al (2017) Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. https://doi.org/10.1056/NEJMoa1709684CrossRefPubMedPubMedCentral

31.

Heymans S, Eriksson U, Lehtonen J, Cooper LT (2016) The quest for new approaches in myocarditis and inflammatory cardiomyopathy. J Am Coll Cardiol 68:2348–2364. https://doi.org/10.1016/J.JACC.2016.09.937CrossRefPubMed

32.

Escudier M, Cautela J, Malissen N et al (2017) Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity. Circulation 136:2085–2087CrossRef

33.

Smith SC, Ladenson JH, Mason JW, Jaffe AS (1997) Elevations of cardiac troponin I associated with myocarditis: experimental and clinical correlates. Circulation. https://doi.org/10.1161/01.CIR.95.1.163CrossRefPubMed

34.

Friedrich MG, Sechtem U, Schulz-Menger J et al (2009) Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol 53:1475–1487CrossRef

35.

Imbriaco M, Nappi C, Puglia M et al (2019) Assessment of acute myocarditis by cardiac magnetic resonance imaging: comparison of qualitative and quantitative analysis methods. J Nucl Cardiol. https://doi.org/10.1007/s12350-017-1109-3CrossRefPubMed

36.

Awadalla M, Mahmood SS, Groarke JD et al (2020) Global longitudinal strain and cardiac events in patients with immune checkpoint inhibitor-related myocarditis. J Am Coll Cardiol. https://doi.org/10.1016/j.jacc.2019.11.049CrossRefPubMed

37.

Desai MY, Jellis CL, Kotecha R et al (2018) Radiation-associated cardiac disease: a practical approach to diagnosis and management. JACC Cardiovasc Imaging 112:1132–1149CrossRef

Title: Re-introducing immunotherapy in patients surviving immune checkpoint inhibitors-mediated myocarditis
Authors: Shira Peleg Hasson
Benjamin Salwen
Ayelet Sivan
Sivan Shamai
Ravit Geva
Ofer Merimsky
Ari Raphael
Haim Shmilovich
Yonatan Moshkovits
livia Kapusta
Zach Rozenbaum
Ido Wolf
Michal Laufer-Perl
Publication date: 01-01-2021
Publisher: Springer Berlin Heidelberg
Keywords: Myocarditis
Checkpoint Inhibitors
Published in: Clinical Research in Cardiology / Issue 1/2021
Print ISSN: 1861-0684
Electronic ISSN: 1861-0692
DOI: https://doi.org/10.1007/s00392-020-01648-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Re-introducing immunotherapy in patients surviving immune checkpoint inhibitors-mediated myocarditis

Abstract

Background

Objectives

Methods

Results

Conclusions

Graphic abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Objectives

Methods

Results

Conclusions

Graphic abstract

Please log in to get access to this content

Other articles of this Issue 1/2021

Midregional pro atrial natriuretic peptide: a novel important biomarker for noise annoyance-induced cardiovascular morbidity and mortality?

Giant coronary aneurysm in a patient with autosomal dominant polycystic kidney disease

Global longitudinal strain by feature tracking for optimized prediction of adverse remodeling after ST-elevation myocardial infarction

Diagnostic value of the novel CMR parameter “myocardial transit-time” (MyoTT) for the assessment of microvascular changes in cardiac amyloidosis and hypertrophic cardiomyopathy

Cardiac sympathetic denervation in patients with nonischemic cardiomyopathy and refractory ventricular arrhythmias: a single-center experience

No adequate evidence indicating hypertension as an independent risk factor for COVID-19 severity