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Case Media – immune checkpoint inhibitor myocarditis

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Episode Schematics & Teaching

Pearls – immune checkpoint inhibitor myocarditis

1. ICI-associated myocarditis has a high mortality rate necessitating a high degree of clinical suspicion. When in doubt, check it out! The initial 4 diagnostic pillars include EKG, troponin, BNP and TTE. Cardiac MRI and endomyocardial biopsy help to confirm the diagnosis.
2. Left ventricular function is normal in 50% of these patients with ICI-associated myocarditis, so the ejection fraction is not a sensitive test for ruling this out.
3. Endomyocardial biopsy should be considered in patients with a high clinical suspicion but negative or ambiguous non-invasive imaging.
4. Early initiation of corticosteroids within 24 hours of presentation is associated with better outcomes.
5. ICIs should be discontinued indefinitely in those with Grade 3 or 4 disease.

Notes – immune checkpoint inhibitor myocarditis

1. Immune checkpoint inhibitors – What are they and why should we as cardiologists know about them?

• Immune checkpoint inhibitors (ICI) boost the host immune response against tumor cells by inhibiting the intrinsic brakes of the immune response.
• There are currently 7 FDA approved drugs in this group: one CTLA-4-blocking antibody called ipilimumab; three PD-1-blocking antibodies [nivolumab, pembrolizumab, and cemiplimab]; and three PD-L1-blocking antibodies [atezolizumab, avelumab, and durvalumab].
• Like a car, T-cells have an ignition switch, gas pedals, and brakes.
• T-cells become activated when receptors on the surface of the T-cell bind to an antigen on the surface of the invading cells like cancer cells.
• Think of the T-cell receptor as the ignition switch and the antigen as the key.
• Antigen presenting cells patrol the body and pick up evidence of foreign antigens like cancer which they present to T-cells in the lymph nodes via the T-cell receptor.
• Like gas pedals, there are co-stimulatory signals like CD 28 which interact with proteins on the antigen presenting cells. With these “gas pedal” stimuli, T-cells get activated, multiply, and hunt for the cancer and finally kill the cancer cells.
• The T-cells also have “breaks” or “checkpoints” to down-regulate the immune response.
• The Cytotoxic T-lymphocyte antigen 4, also called the CTLA-4, acts to slow down the activation of T-cells.
• Further down the line, there is another checkpoint called the Programmed cell death 1 or PD-1. PD-1 is a molecule on the surface of T-cells which acts as another set of brakes.
• When a T cell with PD-1 on its surface interacts with another cell which has a PD-1 ligand (PD-L1), the T-cell activity is down-regulated.
• Many cancer cells overexpress PD-L1 to fight back against the T cells, by putting a “brake” on their immune response.
• By removing these brakes, we can augment the T-cells’ immune response against cancer cells.
• But if the T-cells mount an exaggerated response against normal host cells, then an autoimmune process ensues leading to “immune-related adverse events” (irAEs) like ICI-associated myocarditis.

2. Who are at risk of developing ICI-associated myocarditis?

• Anti-CTLA 4 therapy is associated with a higher prevalence of cardiotoxicity than the PD-1 and PD-L1 inhibitors.
• Combination therapy (i.e., when 2 or more ICIs are given together) increase the risk of irAEs.
• Preexisting diabetes, obesity, and autoimmune disease have been found to be independent risk factors.
• An association of preexisting cardiovascular risk factors like hypertension and smoking with the development of ICI-induced myocarditis has been suggested.

3. What are the prevalence and prognosis of ICI-associated myocarditis?

• Immune checkpoint inhibitors have various forms of cardiotoxicities, but ICI-associated myocarditis is the most feared complication.
• The overall prevalence is 1.2% to 2.4% when using combination ICI therapy. However, the estimated rate of mortality in ICI associated myocarditis is 38 to 46%.
• Approximately 50% of these patients with myocarditis may develop heart failure, cardiogenic shock, complete heart block, cardiac arrest, and ventricular arrhythmias.

4. What is the differential diagnose for ICI-associated myocarditis?

• The differential diagnoses are acute coronary syndrome, stress cardiomyopathy, other forms of myocarditis, pericarditis, pneumonitis, viral myocarditis, endocrinopathies, cardiac sarcoidosis and other causes of cardiomyopathy and heart failure including prior cardiotoxic therapy.

5. What are the initial investigations to be done for ICI-associated myocarditis?

• EKG, troponin, BNP, and TTE (as needed) are the basic 4 pillars of testing in patients with suspected ICI induced myocarditis.
• Nearly all patients with myocarditis have an abnormal EKG. These are however non-specific findings like sinus tachycardia, QRS or QT prolongation, conduction abnormalities, diffuse T-wave inversion, abnormal Q waves, atrial or ventricular arrhythmias, local or diffuse ST elevation.
• Troponins are elevated in most cases, up to 94% in one study. The implications of the level of troponin elevation are not completely clear but there is data that suggests that higher levels of troponin elevation are associated with worse cardiovascular outcomes.
• BNP can be elevated if the patient is in heart failure or volume overloaded. However, it lacks sensitivity and specificity for ICI associated myocarditis and is not always helpful.
• Even patients with fulminant myocarditis can present with a normal left ventricular function. Around 50% of patients with ICI induced myocarditis have been found to have a normal LV function. Also, among those who had major adverse cardiac events, 38% had a normal EF.

6. How do you grade severity?

The American Society of Clinical Oncology broadly categorized the intensity of disease into 4 groups:

• G1 – Mildly abnormal screening tests and no symptoms
• G2 – Abnormal screening tests with mild symptoms
• G3 – Moderately abnormal screening tests (arrhythmia, cardiac biomarker > upper limits of normal and significant echocardiographic findings) and symptoms with mild activity.
• G4 – Moderate to severe decompensation, hemodynamic instability, cardiac biomarker > 3 upper limit of normal, requiring intravenous medications or interventions.

To summarize, G1 and G2 are considered stable and minimally symptomatic and G3 and G4 are very symptomatic or unstable patients and will need to be admitted.                    

7. What are the treatment options?

• Prompt initiation of immunosuppressive therapy is critical for these patients.
• The first line agents are corticosteroids.
• Start with high dose corticosteroids within 24 hours of presentation. Typically, we start with intravenous methylprednisolone 1000 mg daily for 3 days, followed by oral prednisone 1 mg/kg/day.
• The steroids should then be tapered slowly over at least 4–6 weeks only after resolution of symptoms, normalization of LVEF or stabilization of arrhythmias.
• If unresponsive to steroids, tacrolimus, mycophenolate mofetil, anti-thymocyte globulin, iv gamma globulin and plasmapheresis are alternative therapies.

8. Is it safe to restart ICIs after treatment?

• The current recommendation is a definite discontinuation of ICI in case of grade 3 (severe) or life threatening (grade 4) immune related adverse events.
• May consider re-challenge in those with milder disease and complete cardiac recovery – individualized and multidisciplinary team approach.

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References

1. Patel RP, Parikh R, Gunturu KS, et al. Cardiotoxicity of Immune Checkpoint Inhibitors. Curr Oncol Rep. 2021;23(7):79. Published 2021 May 3. doi:10.1007/s11912-021-01070-6
2. Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in Patients Treated With Immune Checkpoint Inhibitors. J Am Coll Cardiol. 2018;71(16):1755-1764. doi:10.1016/j.jacc.2018.02.037
3. Ganatra S, Neilan TG. Immune checkpoint inhibitor-associated myocarditis. Oncologist. 2018;23(8):879–86. https://doi.org/10. 1634/theoncologist.2018-0130
4. 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 inhibitorassociated myocarditis. Circulation. 2020;141(24):2031–4. https:// doi.org/10.1161/CIRCULATIONAHA.119.044703
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(17):1714-1768. doi:10.1200/JCO.2017.77.6385

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