Emerging Concerns in Cardio-Oncology: Immune Checkpoint Inhibitor Cardiotoxicity
The use of immune checkpoint inhibitors (ICIs) in cancer management has significantly increased in recent years. The remarkable efficacy of these agents as anti-neoplastic therapies is shadowed by their potential for inducing autoimmune or inflammatory side effects, collectively termed immune-related adverse events. Cardiovascular immune-related adverse events, particularly myocarditis, are increasingly recognized. The prevalence of myocarditis has been reported between 0.06% and 2.4%, with a higher risk in combination immunotherapy.1-3 Based on recent data, ICI-induced myocarditis can no longer be considered a rare immune-related adverse event.4 Other manifestations include pericardial disease,6 vasculitis,5 Takotsubo syndrome,7 destabilization of atherosclerotic lesions,8 venous thromboembolism,9 or conduction abnormalities,4 but epidemiological data are sparse. Here we summarize the current approach to the diagnosis and management of ICI-associated myocarditis.
Mechanism of ICI Cardiotoxicity
The therapeutic mechanisms of the most commonly used ICIs are based on blocking either the cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) or programmed cell death protein-1 (PD-1) pathways. CTLA-4 and PD-1 serve as immune response inhibitors by normally suppressing the T-cell response in order to prevent autoimmunity and maintain T-cell tolerance.10,11 Concomitant use of CTLA-4 and PD-1 antagonists leads to a synergistic effect, providing a dual blockade of T-lymphocyte inhibition.11 Cardiac immune-related adverse events appear more frequently in patients treated with CTLA-4 antagonists compared with PD-1 inhibitors,12 and the risk increases with combination therapy.3,13,14 The development of cardiac immune-related adverse events in patients treated with combination therapy leads to ICI discontinuation in up to 50% of patients.13,14
CTLA-4 is expressed predominantly on T-cells, and PD-1 may also be expressed on human hearts.15 CTLA-4 and PD-1-deficient mice develop autoimmune myocarditis or dilated cardiomyopathy, eventually leading to death due to heart failure.15,16 However, the mechanism of ICI-induced myocarditis is still unclear. It has been hypothesized that it occurs due to a loss of the inhibitors of T-cell inactivation, leading to an autoimmune reaction secondary to the release of cardiac antigens (e.g., troponin)17 and T-cell infiltration of the myocardium. Similar T-cell clones were identified in other tissues and organs of patients treated with ICIs, generating a shared antigen hypothesis.3 As such, patients with comorbid autoimmune diseases are at increased risk,18,19 as are those with diabetes mellitus or pre-existing cardiovascular disease.2,18
Diagnosis of ICI-Associated Myocarditis
The onset of ICI-associated myocarditis is within 3 months of treatment initiation in 81% of cases,2,3 with a median time of 17-65 days after the first dose of ICI.20 Symptoms are non-specific and may include dyspnea, chest pain, fatigue, myalgia, palpitations, syncope, dizziness, or altered mental status. Subclinical myocarditis has also been described, posing management challenges.21 It is unclear whether screening for myocarditis is warranted because currently available imaging modalities are normal in the majority of patients.12 Almost all patients will have increased serum troponin, which should immediately prompt suspicion of ICI-associated myocarditis. An electrocardiogram (ECG) should be performed to rule out an acute coronary syndrome, but findings are non-specific. It is unclear whether baseline ECG or troponins predict ICI-associated myocarditis or modify management/outcomes. Echocardiography is useful for determining cardiac function, but the definitive imaging modality is cardiac magnetic resonance (CMR), which allows for better tissue characterization. T1- and T2-weighted sequences, as well as late gadolinium enhancement sequence, may reveal myocardial inflammation or necrosis. Endomyocardial biopsy (EMB) remains the gold standard for diagnosing myocarditis. The false-negative rate for EMB remains high due to the patchy infiltration of T-cells within the myocardium; at least six samples should be collected from different endomyocardial regions, and results should be interpreted in conjunction with the results from CMR. Various T-cell phenotypes have been observed on EMB in cases of ICI-associated myocarditis. It is unclear whether outcomes differ based on these phenotypes. Further research in immune profiling may identify certain inflammation patterns and pave the way toward individualized management.
Management of ICI-Associated Myocarditis
The American Society of Clinical Oncology recently issued a practice guideline for the management of ICI-associated myocarditis.9 Baseline ECG and serum troponins are recommended. In all cases suspected of ICI-induced cardiotoxicity, ICI therapy should be withheld. Serum high-sensitivity cardiac troponin T (hs-cTnT) and brain natriuretic peptide should be measured. An ECG and a transthoracic echocardiogram should be performed. Further management is guided by symptoms and serum troponin levels, but patients should be admitted. In symptomatic cases, CMR and cardiac catheterization with EMB are warranted. In asymptomatic cases, we recommend CMR if hs-cTnT is >100 ng/L with no other identifiable cause; cardiac catheterization with EMB should be added if hs-cTnT is >250 ng/L based on the institutional agreed practice at The University of Texas MD Anderson Cancer Center. Ongoing research is validating this approach. If myocarditis is confirmed, serum erythrocyte sedimentation rate, C-reactive protein, C3, and C4 should be measured to guide immunosuppressive therapy going forward.22
The severity of the myocarditis may be broadly classified into four grades with independent treatment strategies.9 G1 is defined as subclinical myocarditis based on an abnormal test; it is unclear whether this grade warrants specific treatments. Symptomatic but clinically stable cases with abnormal tests may be classified as G2 and G3; treatment should be attempted with 1-2 mg/kg prednisone or methylprednisolone. Decompensated cases are classified as G4 and require more aggressive immunosuppressive regimens, such as 1-2 mg/kg prednisone + mycophenolate, anti-thymocyte globulin, or infliximab (to be avoided in cases of heart failure). These cases may also require advanced heart failure support. For most immune-related adverse events, cessation of therapy is recommended for only G2 or higher, but for cardiac immune-related adverse events, the consensus statements recommend stopping at G1 due to the high mortality observed in cardiac immune-related adverse events.9
Several important challenges in the management of ICI-associated cardiotoxicity exist. The rates of mortality and major adverse cardiovascular events remain high with current treatment strategies.2 Reports have emerged of therapeutic success with various immunosuppressive regimens, such as with intravenous immunoglobulins, but no clinical trials comparing the efficiency of these regimens currently exist.2 Further research is warranted to evaluate response to increased doses of glucocorticoids and varying immunosuppression regimens. The benefit of EMB on all patients with suspicion of ICI-associated cardiotoxicity in cases with negative CMR is not currently well-established. Furthermore, the risks versus benefits of cardiac catheterization and EMB in high-risk patients (e.g., with thrombocytopenia) are also unclear. The possibility of ICI resumption after resolution of the myocarditis is currently based on the severity of this immune-related adverse event and perceived risks versus benefits from an oncologic perspective. These challenges highlight the compelling need for clinical vigilance for immune-related adverse events, the collaboration of oncologists and cardiologists when managing these cases, and further research.
- Tajiri K, Ieda M. Cardiac Complications in Immune Checkpoint Inhibition Therapy. Front Cardiovasc Med 2019;6:3.
- Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol 2018;71:1755-64.
- Johnson DB, Balko JM, Compton ML, et al. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med 2016;375:1749-55.
- Reddy N, Moudgil R, Lopez-Mattei JC, et al. Progressive and Reversible Conduction Disease With Checkpoint Inhibitors. Can J Cardiol 2017;33:1335.e13-1335.e15.
- Salem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol 2018;19:1579-89.
- Altan M, Toki MI, Gettinger SN, et al. Immune Checkpoint Inhibitor-Associated Pericarditis. J Thorac Oncol 2019;14:1102-8.
- Anderson RD, Brooks M. Apical takotsubo syndrome in a patient with metastatic breast carcinoma on novel immunotherapy. Int J Cardiol 2016;222:760-1.
- Tomita Y, Sueta D, Kakiuchi Y, et al. Acute coronary syndrome as a possible immune-related adverse event in a lung cancer patient achieving a complete response to anti-PD-1 immune checkpoint antibody. Ann Oncol 2017;28:2893-5.
- Brahmer JR, Lacchetti C, Schneider BJ, 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;36:1714-68.
- Ni L, Dong C. New checkpoints in cancer immunotherapy. Immunol Rev 2017;276:52-65.
- Varricchi G, Galdiero MR, Marone G, et al. Cardiotoxicity of immune checkpoint inhibitors. ESMO Open 2017;2:e000247.
- Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54.
- Tawbi HA, Forsyth PA, Algazi A, et al. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N Engl J Med 2018;379:722-30.
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015;373:23-34.
- Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 2001;291:319-22.
- Okazaki T, Tanaka Y, Nishio R, et al. Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 2003;9:1477-83.
- Mir H, Alhussein M, Alrashidi S, et al. Cardiac Complications Associated With Checkpoint Inhibition: A Systematic Review of the Literature in an Important Emerging Area. Can J Cardiol 2018;34:1059-68.
- Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med 2018;378:158-68.
- Johnson DB, Sullivan RJ, Menzies AM. Immune checkpoint inhibitors in challenging populations. Cancer 2017;123:1904-11.
- Ganatra S, Neilan TG. Immune Checkpoint Inhibitor-Associated Myocarditis. Oncologist 2018;23:879-86.
- Norwood TG, Westbrook BC, Johnson DB, et al. Smoldering myocarditis following immune checkpoint blockade. J Immunother Cancer 2017;5:91.
- Caforio AL, Pankuweit S, Arbustini E, et al. 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 2013;34:2636-48.
Keywords: Cardiotoxicity, Cardiotoxins, Acute Coronary Syndrome, Antilymphocyte Serum, Autoimmunity, Cardiac Catheterization, Biopsy, Blood Sedimentation, Cardiomyopathy, Dilated, Apoptosis Regulatory Proteins, Chest Pain, Consensus, C-Reactive Protein, CTLA-4 Antigen, Diabetes Mellitus, Dizziness, Echocardiography, Dyspnea, Electrocardiography, Gadolinium, Glucocorticoids, Heart Failure, Immunoglobulins, Intravenous, Immunosuppression, Immunosuppressive Agents, Immunotherapy, Inflammation, Magnetic Resonance Spectroscopy, Medical Oncology, Methylprednisolone, Myalgia, Myocardium, Myocarditis, Natriuretic Peptide, Brain, Neoplasms, Phenotype, Prednisone, Syncope, Takotsubo Cardiomyopathy, Thrombocytopenia, T-Lymphocytes, Cytotoxic, Troponin, Troponin T, Vasculitis, Venous Thromboembolism
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