Abstract
Even if immune checkpoint inhibitors have revolutionized the landscape of cancer therapy, their use may be complicated by immune-related adverse events. Among these, myocarditis is the most severe complication. The clinical suspicion often arises after clinical symptoms onset and increase in cardiac biomarkers or electrocardiographic manifestations. Echocardiography and cardiac magnetic resonance imaging are recommended for each patient. However, since they may be misleadingly normal, endomyocardial biopsy remains the gold standard for establishing the diagnosis. Until now, treatment has been based on glucocorticoids even if increasing interest has risen in other immunosuppressive agents. Although myocarditis currently imposes immunotherapy discontinuation, case reports have suggested a safety rechallenge in low-grade myocarditis paving the way for further studies to respond to this unmet clinical need.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J. Clin. Oncol. 34(23), 2698–2704 (2016).
- 2. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 17(9), 1283–1294 (2016).
- 3. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087. Blood 134(14), 1144–1153 (2019).
- 4. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373(1), 23–34 (2015).
- 5. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med. 372(21), 2006–2017 (2015).
- 6. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372(4), 320–330 (2015).
- 7. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 32(10), 1020–1030 (2014).
- 8. . The evolving immunotherapy landscape and the epidemiology, diagnosis, and management of cardiotoxicity: JACC: CardioOncology primer. JACC CardioOncol. 3(1), 35–47 (2021). •• This is probably the most important paper and bigger casuistry concerning immune checkpoint inhibitor (ICI)-myocarditis.
- 9. Immune checkpoint inhibitor cardiotoxicity: understanding basic mechanisms and clinical characteristics and finding a cure. Annu. Rev. Pharmacol. Toxicol. 61, 113–134 (2021). • This was one of the most important papers that guided our comprehension of the mechanism underlying ICI-related cardiotoxicity.
- 10. Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med. 375(18), 1749–1755 (2016).
- 11. . Cardiotoxicity associated with immune checkpoint inhibitor therapy: a meta-analysis. Eur. J. Heart Fail. 23(10), 1739–1747 (2021). • This well-written metanalysis gave us and the scientific community an accurate photograph of epidemiology concerning this adverse event.
- 12. A genetic mouse model recapitulates immune checkpoint inhibitor-associated myocarditis and supports a mechanism-based therapeutic intervention. Cancer Discov. 11(3), 614–625 (2021).
- 13. Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc. Res. 115(5), 854–868 (2019).
- 14. Cardiovascular toxicity of immune checkpoint inhibitors: clinical risk factors. Curr. Oncol. Rep. 23(2), 13 (2021).
- 15. . A retrospective analysis of cardiovascular adverse events associated with immune checkpoint inhibitors. Cardiooncology 7(1), 19 (2021).
- 16. . Co-inhibitory molecules: controlling the effectors or controlling the controllers? Self/Nonself 1(2), 77–88 (2010).
- 17. Cardiotoxicity of immune checkpoint inhibitors. Curr. Oncol. Rep. 23(7), 79 (2021).
- 19. Myocarditis in patients treated with immune checkpoint inhibitors. J. Am. Coll. Cardiol. 71(16), 1755–1764 (2018).
- 20. . Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet 391(10124), 933 (2018).
- 21. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 19(12), 1579–1589 (2018). •• This pharmacovigilance study helped a deeper comprehension on this fascinating field paving the way to a risk stratification process for patients undergoing to ICI therapy.
- 22. . Reporting of immune checkpoint inhibitor-associated myocarditis. Lancet 392(10145), 382–383 (2018).
- 23. Clinical features, management, and outcomes of immune checkpoint inhibitor-related cardiotoxicity. Circulation 136(21), 2085–2087 (2017).
- 24. . Cardiac toxicity associated with immune checkpoint inhibitors: a systematic review. Cancers (Basel) 13(20), 5218 (2021).
- 25. . Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet 391(10124), 933 (2018).
- 26. . CTLA-4: a moving target in immunotherapy. Blood 131(1), 58–67 (2018).
- 27. The diverse function of PD-1/PD-L pathway beyond cancer. Front. Immunol. 10, 2298 (2019).
- 28. Mechanisms of cardiovascular toxicities associated with immunotherapies. Circ. Res. 128(11), 1780–1801 (2021).
- 29. Programmed cell death-1: programmed cell death - ligand 1 interaction protects human cardiomyocytes against T-cell mediated inflammation and apoptosis response in vitro. Int. J. Mol. Sci. 21(7), 2399 (2020).
- 30. Management of acute myocarditis and chronic inflammatory cardiomyopathy: an expert consensus document. Circ. Heart Fail. 13(11), e007405 (2020).
- 31. Immune checkpoint inhibitor myocarditis: elucidating the spectrum of disease through endomyocardial biopsy. Eur. J. Heart Fail. 23(10), 1725–1735 (2021).
- 32. PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int. Immunol. 22(6), 443–452 (2010).
- 33. . Immune checkpoint inhibitors: cardiotoxicity in pre-clinical models and clinical studies. Front. Cardiovasc. Med. 8, 619650 (2021).
- 34. National Comprehensive Cancer Network. 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(17), 1714–1768 (2018).
- 35. Acute lymphocytic myocarditis with anti-PD-1 antibody nivolumab. Circ. Heart Fail. 9(10), e003514 (2016).
- 36. . Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J. Immunother. Cancer 21, 3–11 (2015).
- 37. Cardiovascular adverse events in immune checkpoint inhibitor clinical trials: a US Food and Drug Administration pooled analysis. J. Clin. Oncol. 9(2), e013757 (2018).
- 38. ESC Scientific Document Group. 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. 43(41), 4229–4361 (2022).
- 39. Myocarditis surveillance in patients with advanced melanoma on combination immune checkpoint inhibitor therapy: the Memorial Sloan Kettering Cancer Center experience. Oncologist 24(5), e196–e197 (2019). • Despite the suggested surveillance protocol's failed in demonstrating to improve early myocarditis detection, the authors underlined that identification of reliable predictors in this setting remains fundamental.
- 40. Myocarditis surveillance with high-sensitivity Troponin I during cancer treatment with immune checkpoint inhibitors. JACC CardioOncol. 23(1), 137–139 (2021).
- 41. Electrocardiographic features of immune checkpoint inhibitor-associated myocarditis. Curr. Probl. Cardiol. 48(2), 101478 (2023).
- 42. . Diagnosis of immune checkpoint inhibitor-associated myocarditis: a systematic review. Int. J. Cardiol. 296, 113–121 (2019).
- 43. Global longitudinal strain and cardiac events in patients with immune checkpoint inhibitor-related myocarditis. J. Am. Coll. Cardiol. 75(5), 467–478 (2020).
- 44. International consensus group on cardiovascular magnetic resonance in myocarditis. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J. Am. Coll. Cardiol. 53(17), 1475–1487 (2009).
- 45. . Diagnostic and prognostic value of cardiac magnetic resonance in acute myocarditis: a systematic review and meta-analysis. Int. J. Cardiovasc. Imaging 35, 2221–2229 (2019).
- 46. Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations. J. Am. Coll. Cardiol. 72(24), 3158–3176 (2018).
- 47. Myocardial T1 and T2 mapping by magnetic resonance in patients with immune checkpoint inhibitor-associated myocarditis. J. Am. Coll. Cardiol. 77(12), 1503–1516 (2021).
- 48. Myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline-based chemotherapy. Am. J. Cardiol. 111(5), 717–722 (2013).
- 49. . Immunotherapy in small-cell lung cancer: from molecular promises to clinical challenges. J. Immunother. Cancer 7(1), 205 (2019).
- 50. 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. 34(33), 2636–2648 (2013).
- 51. State-of-the-art of endomyocardial biopsy on acute myocarditis and chronic inflammatory cardiomyopathy. Curr. Cardiol. Rep. 24(5), 597–609 (2022).
- 52. . Histopathologic characterization of myocarditis associated with immune checkpoint inhibitor therapy. Arch. Pathol. Lab. Med. 144(11), 1392–1396 (2020).
- 53. Immune checkpoint inhibitor-induced myositis, the earliest and most lethal complication among rheumatic and musculoskeletal toxicities. Autoimmun. Rev. 19(8), 102586 (2020).
- 54. . Acute autoimmune myocarditis and hepatitis due to ipilimumab monotherapy for malignant melanoma. J. Oncol. Pharm. Pract. 25(4), 966–968 (2019).
- 55. Major adverse cardiovascular events and the timing and dose of corticosteroids in immune checkpoint inhibitor-associated myocarditis. Circulation 141(24), 2031–2034 (2020).
- 56. Case series of steroid-resistant immune-checkpoint inhibitor associated myocarditis: a comparative analysis of corticosteroid and tofacitinib treatment. Front. Pharmacol. 12, 770631 (2021).
- 57. Reversal of immune-checkpoint inhibitor fulminant myocarditis using personalized-dose-adjusted abatacept and ruxolitinib: proof of concept. J. Immunother. Cancer 10, e004699 (2022).
- 58. Survival after fulminant myocarditis induced by immune-checkpoint inhibitors. Ann. Intern. Med. 167(9), 683–684 (2017).
- 59. Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy. Br. J. Cancer 117(7), 921–924 (2017).
- 60. American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology. Recognition and initial management of fulminant myocarditis: a scientific statement from the American Heart Association. Circulation 141(6), e69–e92 (2020).
- 61. Immune checkpoint inhibitor-associated myocarditis: a new challenge for cardiologists. Can. J. Cardiol. 34(1), 92.e1–92.e3 (2018).
- 62. Abatacept for severe immune checkpoint inhibitor-associated myocarditis. N. Engl. J. Med. 380(24), 2377–2379 (2019).
- 63. . Alemtuzumab for immune-related myocarditis due to PD-1 therapy. N. Engl. J. Med. 380(24), 2375–2376 (2019).
- 64. Clinical pharmacology and interplay of immune checkpoint agents: a yin-yang balance. Annu. Rev. Pharmacol. Toxicol. 61, 85–112 (2021).
- 65. . Tocilizumab for refractory severe immune checkpoint inhibitor-associated myocarditis. Ann. Oncol. 31(9), 1273–1275 (2020).
- 66. Association of steroids use with survival in patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Cancers 12(3), 546 (2020).
- 67. ESC Scientific Document Group, 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 42(36), 3599–3726 (2021).
- 68. ESC Scientific Document Group, 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur. Heart J. 43(40), 3997–4126 (2022).
- 69. Abatacept/ruxolitinib and screening for concomitant respiratory muscle failure to mitigate fatality of immune-checkpoint inhibitor myocarditis. Cancer Discov.
doi: 10.1158/2159-8290.CD-22-1180 (2023). - 70. Immune checkpoint inhibitor rechallenge after immune-related adverse events in patients with cancer. JAMA Oncol. 6(6), 865–871 (2020).
- 71. Biomarker trends, incidence, and outcomes of immune checkpoint inhibitor-induced myocarditis. JACC CardioOncol. 4(5), 689–700 (2022).
- 72. 68Ga-DOTATOC PET/CT to detect immune checkpoint inhibitor-related myocarditis. J. Immunother. Cancer 9(10), e003594 (2021).
- 73. Inflammatory myositis in cancer patients receiving immune checkpoint inhibitors. Arthritis Rheumatol. 73, 866–874 (2021).
- 74. Clinical strategy for the diagnosis and treatment of immune checkpoint inhibitor-associated myocarditis: a narrative review. JAMA Cardiol. 6, 1329–1337 (2021).