Introduction

Over recent years, oncologic utilization of immune checkpoint inhibitors (ICIs) has expanded with concomitant description of unique immune-related adverse events (irAEs). Of the irAEs, diagnosing and defining the clinical spectrum of ICI-associated myocarditis is particularly challenging owing to the low incidence and high mortality rates of approximately 1% and 50%, respectively.⁴ We utilize individual patient cases to highlight the continuum of clinical presentations and diagnostic challenges to heighten awareness of ICI-associated myocarditis.

Case Presentations

Mild Case: 86-year-old man with urothelial carcinoma who presented for routine pre-infusion appointment, 3 weeks after initiating pembrolizumab, was found to have elevated liver enzymes with concurrent myocardial injury and myositis with high-sensitivity troponin (HST) of 1,451pg/ml and creatinine phosphokinase (CPK) of 2,172U/L. During admission, an electrocardiogram (ECG), transthoracic echocardiogram (TTE), and cardiac magnetic resonance imaging (CMR) were unremarkable. He was treated with prednisone and abatacept for ongoing myocardial injury.

Fulminant Case: 65-year-old woman with renal cell carcinoma presented to the emergency department with acute dyspnea, weakness, and fatigue after initiation of ipilimumab and nivolumab 4 weeks prior. Investigations included an HST of 3,647pg/ml and brain natriuretic peptide (BNP) of 1,153pg/ml with ECG demonstrating sinus rhythm with interventricular conduction delay, frequent premature ventricular contractions, and ST-segment elevations in the anteroseptal leads. A TTE demonstrated a globally hypokinetic left ventricle and ejection fraction of 25%. Left heart catheterization (LHC) revealed angiographically normal coronary arteries. Her course was complicated by complete heart block and fulminant cardiogenic shock requiring mechanical circulatory support, and despite treatment with methylprednisolone, ruxolitinib, and abatacept she succumbed to her illness.

False-Positive Case: 68-year-old woman with non-ischemic cardiomyopathy and urothelial carcinoma presented to the emergency department, 4 weeks after initiating pembrolizumab, for acute chest pain and myocardial injury with an HST of 546 pg/ml and BNP of 1,085 pg/ml, without concurrent hepatitis or myositis. An ECG was unremarkable and TTE unchanged from prior. LHC demonstrated angiographically normal coronary arteries and CMR revealed late gadolinium enhancement of the anterior and inferior ventricular walls. The HST peaked at 1,331 pg/ml with rapid improvement to 111 pg/ml over 96 hours. Initially attributed to ICI-associated myocarditis, her presenting symptoms, rapid rise and fall of HST, and cardiomyopathy-attributable CMR changes, favor a diagnosis of type 1 myocardial infarction with spontaneous recanalization.

Conclusion

The diagnosis of ICI-associated myocarditis is variable and elusive necessitating synthesis of clinical data lacking both sensitivity and specificity.¹ The majority of cases occur within 3 months of ICI initiation and has been associated with dual ICI therapy.^1,2 While myocardial injury is definitive, precedent multisystem irAEs are nearly ubiquitous at presentation, particularly myositis, occurring in approximately 90% of cases.^1,3 Therefore, a screening algorithm of bi-weekly CPK and liver enzyme measurement, during the first 3 months of ICI therapy, identifies an at-risk cohort prompting evaluation for myocardial injury.¹ Once identified, marked elevations in presenting HST and CPK are predictors of a fulminant course, whereas ECG and TTE findings are less reliable.^1,3,4 Therapeutics include withdrawal of ICI therapy, severity-driven corticosteroid dosing, and adjunctive immunomodulatory agents for steroid refractory disease.⁵

References

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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. Vasbinder A, Chen Y, Procureur A, et al. Biomarker Trends, Incidence, and Outcomes of Immune Checkpoint Inhibitor–Induced Myocarditis. JACC CardioOncol. 2022;4(5):689-700. doi:10.1016/j.jaccao.2022.11.004

4. Puzanov I, Subramanian P, Yatsynovich YV, et al. Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis. J Immunother Cancer. 2021;9(6):e002553. doi:10.1136/jitc-2021-002553

5. Palaskas N, Lopez‐Mattei J, Durand JB, Iliescu C, Deswal A. Immune Checkpoint Inhibitor Myocarditis: Pathophysiological Characteristics, Diagnosis, and Treatment. JAHA. 2020;9(2):e013757. doi:10.1161/JAHA.119.013757