Immune Checkpoint Inhibitor-Related Myocarditis: A Case Series and Literature Review

Abbreviations

AV, Atrioventricular

CD, Cluster of differentiation

CMR, Cardiac magnetic resonance imaging

ECG, Electrocardiograph

EMB, Endomyocardial biopsy

H&E, Hematoxylin and eosin

ICIs, Immune checkpoint inhibitors

IHC, Immunohistochemical

irAE, Immune-related adverse event

PD-L1, Programmed cell death ligand 1

INTRODUCTION

Immune checkpoint inhibitors (ICIs) are novel anticancer agents widely used by oncologists to treat various tumor types. However, the immune system might also misrecognize and attack normal cells. This uncontrolled immune response is an immune-related adverse event (irAE). IrAEs may involve organs — mainly the gastrointestinal tract, endocrine glands, skin, and liver.¹ Although cardiotoxicity induced by ICIs is rare, it can be fatal and can occur early after the initiation of therapy.^2,3 Herein, we introduce the treatment experience of three patients diagnosed with ICI-related myocarditis.

CASES

Three patients were treated consecutively between September 2018 and December 2022. The patients received anti-programmed cell death ligand 1 (PD-L1) antibody as anticancer therapy (two patients received nivolumab, and one patient received pembrolizumab). The median time from the first ICI dose to myocarditis presentation was 31 days (12-42). The patients’ clinical courses and treatments are listed in Figure 1 and Table 1.

Figure 1.

Serial electrocardiographs (ECGs), clinical courses, and treatment responses in immune checkpoint inhibitor (ICI)-related myocarditis. The diagnosis of myocarditis was based on Bonaca criteria as definite, probable, and possible. The severity of myocarditis was defined as fulminant, non-fulminant, and steroidrefractory based on current ESC 2022 cardio-oncology guidelines. (A) Case 1 patient developed atrial fibrillation with marked bradycardia as initial presentation of ICI-related myocarditis. Serial ECGs showed atrial fibrillation with severely low ventricular rate and alternating bundle branch block. Low ventricular rate subsided after steroid therapy. Patient did not exhibit pacing dependency during 4-year follow-up after steroid treatment. This patient was categorized as having possible and fulminant ICI-related myocarditis with complete recovery. (B) Case 2 patient experienced congestive heart failure and ventricular tachycardia (VT) caused by ICI related cardiomyopathy. Serial ECGs showed optimal response to pulse therapy with gradual reduction of ST elevation. After steroid treatment, echocardiography showed left ventricular systolic function recovery but right heart dilatation with right ventricular systolic dysfunction. No further VT occurred. This patient was categorized as having definite and fulminant ICI-related myocarditis with complete recovery. (C) Case 3 patient reported generalized blanching maculopapular skin rash after immunotherapy. Serial ECGs showed progressive ST elevation at leads II, II, and V1-V5 and deep Q wave formation in the anterior wall. Subsequently, patient exhibited rapid onset of cardiogenic shock, marked sinus bradycardia, and VT attacks despite steroid treatment. Finally, patient died of cardiogenic shock. This patient was categorized as having definite, fulminant and steroid refractory ICI-related myocarditis.

Table 1. Clinical characteristics and prognosis.

	Patient 1	Patient 2	Patient 3
Age (years)	65	67	63
Sex	Male	Male	Female
Underlying malignancy	Oropharynx SCC, cT2N3M1, stage IVC	HCC, T2N0M0, stage II	Lung adenocarcinoma, cT4N0M1a, stage IVA
Immunotherapy drug	Nivolumab	Nivolumab	Pembrolizumab
Doses received	Two	Two	One
Days after 1st dose of ICI before myocarditis onset	34	48	12
irAEs	Myocarditis	Myocarditis	Myocarditis
	Hepatitis		Rhabdomyolysis
			Skin rash
ECG changes	Atrial fibrillation with complete AV block	ST elevation in leads II, III, aVF, V1-V6	ST elevation in leads II, III, V1-V5
Clinical symptoms	Fatigue and dizziness	Chest pain and dyspnea on exertion	Itchy skin rash, dyspnea
Use of mechanical ventilation	No	No	Yes
Use of inotropic agents	No	No	Yes
CAG findings	Not checked	Patent coronary artery	Patent coronary artery
Peak hsTnI (ng/mL)	0.68	16.096	26.607
Peak NT-pro BNP (pg/mL)	Not checked	6426	2575
LVEF	56.4%	34.3%	65.1% (initial presentation)
Lethal ventricular arrhythmia	No	Yes	Yes
Steroid dose (methylprednisolone)	1 mg/kg/day for 8 days, then tapered	1 g/day for 3 days, then tapered	0.6 mg/kg/day for 3 days, then titrated to 1.2 mg/kg/day
Outcomes
Follow-up time	3 years	1.5 year	Nil
Prognosis	Survived, AV block recovery after steroid treatment, died from cancer metastasis	Survived	Died of cardiogenic shock 16 days after presentation

AV, atrioventricular; CAG, coronary angiography; ECG, electrocardiograph; HCC, hepatocellular carcinoma; hsTnI, high-sensitivity troponin I; ICI, immune checkpoint inhibitor;irAEs, immune-related adverse effect; LVEF, left ventricular ejection fraction; NT-pro BNP, N terminal pro B type natriuretic peptide; SCC, squamous cell carcinoma; VT, ventricular tachycardia.

Case 1

A 65-year-old man with a history of right renal cell carcinoma, complete remission after partial nephrectomy and left tonsillar squamous carcinoma (cT2N3M1, skin metastasis, proved by excisional biopsy, stage IVC) received two doses of nivolumab as anticancer therapy. Before receiving ICI therapy, he was defined as a progressed disease under concurrent chemoradiotherapy with TPF (Docetaxel, Cisplatin, and Fluorouracil). He presented with progressive fatigue and dizziness 34 days after receiving the first dose of nivolumab. Further study revealed hepatitis and myocarditis. Serial electrocardiographs (ECGs) showed the presence of regularized atrial fibrillation with a severely slow ventricular rate and alternating bundle branch block (Figure 1A). We administered methylprednisolone at a dose of 1 mg/kg/day for 8 days and then gradually reduced the dose. His liver enzyme levels declined after this treatment, and atrial fibrillation with residual right bundle branch block returned after 6 days of steroid therapy. We implanted a permanent pacemaker for backup pacing. We also stopped administering nivolumab, shifted to salvage cetuximab plus paclitaxel, and followed up the patient for 3 years. The patient exhibits no further pacing dependency after treatment (Figure 1A).

Case 2

A 67-year-old man with hypertension and hepatocellular carcinoma (T2N0M0, stage II, BCLC B) received two doses of Nivolumab as anticancer therapy. Before starting immunotherapy, he had received Lenvatinib, but the disease progressed. Subsequently, he received Sorafenib and had to switch to Nivolumab due to hand-foot syndrome. The patient reported chest pain and dyspnea on exertion 48 days after receiving the second dose of Nivolumab. His initial ECG showed V1-5 ST elevation with T wave inversion and QTc prolongation. Coronary angiography revealed patent coronary arteries without stenosis. Sustained ventricular tachycardia occurred 11 days after the onset of chest pain. Additionally, the patient’s left ventricular ejection fraction decreased from 64.2% to 34.3% within 1 week. We administrated pulse therapy with 1 g per day of methylprednisolone for 3 days, and the dose was then tapered to 1 mg/kg/day as a maintenance dose. With pulse therapy, the ST elevation in the ECG gradually remitted (Figure 1B), and cardiac enzyme levels gradually decreased. After steroid treatment, we arranged an electrophysiology study and noninducibility of sustained ventricular tachycardia using programmed stimulation. We also performed an endomyocardial biopsy (EMB). Hematoxylin and eosin (H&E) staining of the myocardial biopsy demonstrated inflammatory infiltration with myocyte destruction (Figure 2). Immunohistochemical (IHC) staining showed infiltration predominantly by a cluster of differentiation (CD) 8-positive T cells as well as PD-L1 expression on injured myocytes (Figure 2). These findings were attributable to ICI-related myocarditis. We gradually tapered the steroid dose and conducted a follow-up for 1 year. Immunotherapy was discontinued, and salvage Sorafenib was administrated again (Figure 1B). Subsequent echocardiography showed left ventricular systolic function recovery but right heart dilatation with right ventricular systolic dysfunction.

Figure 2.

(A) Hematoxylin and eosin staining shows inflammatory infiltration with myocyte destruction. (B) Immunohistochemical (IHC) staining shows infiltration predominantly by cluster of differentiation 8-positive T cells (red arrow, those brown spots are T cells marked by a cluster of differentiation (CD) 8 identifying stain). (C) Specific IHC stains show programmed cell death ligand 1 expression on injured myocyte (red arrow, those light brown spots are myocytes marked by programmed cell death ligand 1 identifying stain).

Case 3

A 63-year-old woman with a history of obesity (body mass index: 30.7 kg/m²) and right upper lobe squamous cell carcinoma with right-side lung and pleural metastasis (cT4N0M1a, stage IVA) received one dose of pembrolizumab as anticancer therapy. After receiving immunotherapy, she presented with a diffuse blanching maculopapular skin rash on her face, limbs, and trunk. The patient experienced acute onset of shortness of breath and general muscle soreness 12 days later. Subsequently, symptoms of cardiogenic shock, sinus bradycardia, and frequent ventricular premature complexes gradually developed. In this case, the peak of high-sensitive troponin-I was 26.607 ng/mL. Besides, her myoglobin level remained beyond our analytical measurement range (> 10000 ng/mL) during hospitalization, and she was diagnosed with rhabdomyolysis. Coronary angiography revealed patent coronary arteries without stenosis. We placed a temporal pacemaker for backup pacing and initiated treatment with methylprednisolone at 0.6 mg/kg/day. However, nonsustained ventricular tachycardia occurred soon after, and a series of ECGs demonstrated progressive ST elevation at leads II, III, and V1-V5 (Figure 1C). Although we gradually titrated her dose of methylprednisolone to 1.2 mg/kg/day, bradycardia and profound shock developed. She passed away as the result of cardiogenic shock with lactic acidosis and multiple organ failure 16 days after the initial presentation (Figure 1C).

DISCUSSION

ICI-related myocarditis is a rare but fatal disease. Myocarditis-related mortality is 33%-67%,² and conduction abnormality-related mortality is 80%.³ The median time for fatal events after the first programmed cell death protein 1 treatment is 40 days.⁴ Potential mechanisms include myocyte and tumor cells sharing a common antigen, T cells targeting a myocyte antigen that is different from but similar to that of the tumor cell, or the blockage of tumor cell immune checkpoints causing activated T cells to target the antigen of a normal myocyte.⁵

Although ICI-related myocarditis is associated with a high mortality rate, it is usually misdiagnosed or diagnosed late. The cardinal symptoms of ICI-related myocarditis, including chest pain, fatigue, dyspnea, orthopnea, fatal arrhythmias, and heart failure, are usually nonspecific. The clinical presentation of ICI-related myocarditis can vary from the asymptomatic elevation of cardiac biomarkers to severe cardiogenic shock and decompensated heart failure. History of ICI use is thus essential to consider when diagnosing ICI-related myocarditis. A specific indicator of ICI-related myocarditis might be the co-occurrence of other irAEs. Our first patient had concomitant hepatitis, and our third patient had an accompanying skin rash and rhabdomyolysis. ICI-related myasthenia gravis and ICI-related myositis are the irAEs most commonly associated with ICI-related myocarditis.⁵

EMB is considered the gold standard for ICI-related myocarditis testing. The histologic diagnosis of myocarditis is based on the Dallas criteria with two components: inflammatory cell infiltration and myocardial necrosis.⁶ Histopathologic analysis might reveal lymphocyte, histocyte, and macrophage infiltration within the endocardium and conduction system. Myocyte destruction is another common histologic finding.⁷ IHC staining typically demonstrates the presence of the T-cell marker CD3 and the macrophage marker CD63. The infiltrated cells include abundant CD4-positive and CD8-positive T cells.^5,7,8 CD20 (a surface marker of B cells)-positive cells and antibody deposits are not present.^7,8 Our patients’ H&E and IHC staining revealed the aforementioned features, but this was insufficient to support the diagnosis of ICI-related myocarditis. We identified the expression of PD-L1 on myocytes. Increased PD-L1 expression in the injured myocardium is characteristic of ICI-related myocarditis. A cytokine-induced cardioprotective mechanism may upregulate PD-L1 expression on myocytes to protect against the self-targeting immune response, and blocking this pathway by ICIs may trigger ICI-related myocarditis.^7,8 However, EMB is rarely performed because of its high invasiveness and the risk of a rare major complication of perforation, which occurs at a rate of < 1% in experienced centers.⁵ Furthermore, interpreting EMBs is challenging. Cardiac magnetic resonance imaging (CMR) might be an alternative tool for diagnosis. CMR-based diagnosis of myocarditis is primarily based on the Lake Louise Criteria.⁹ Although CMR is useful for diagnosing myocarditis, specific CMR findings indicating ICI-related myocarditis require further research. To solve these dilemmas, Bonaca et al. provided a uniform diagnosis criterion for cancer treatment-related myocarditis. By combining the findings of EMB, CMR, clinical symptoms, serial ECG, echocardiography findings, and biomarkers, clinicians can categorize ICI-related myocarditis as possible, probable, or definite.¹⁰ With this criterion, we could diagnose ICI-related myocarditis in a setting where EMB and CMR are unavailable, enabling the treatment to start earlier.

The histological characteristic of ICI-related myocarditis is the infiltration of lymphocytes and macrophages in the affected myocardium and the conduction system. The likelihood of all-cause mortality within 30 days is higher among patients with ICI-related myocarditis who develop complete heart block or life-threatening ventricular arrhythmias.¹¹ Although adverse cardiac events tend to occur in the early phase of treatment, lethal arrhythmias can occur at any time.³ In our two cases involving ventricular tachycardia, it occurred in the second week after presentation. The appearance of frequent ventricular premature complexes also indicates the possibility of subsequent ventricular arrhythmias. Changes in waveform patterns in serial ECGs reflect the effectiveness of treatment. Therefore, we suggest continuous ECG monitoring to monitor for new atrioventricular (AV) block or arrhythmias during the acute phase in all patients with symptomatic ICI-related myocarditis.¹² We also recommend measuring cardiac enzymes daily to assess the treatment efficacy of steroids.

The severity of myocarditis was defined as fulminant, non-fulminant, and steroid-refractory based on current ESC 2022 cardio-oncology guidelines.¹² High-dose intravenous methylprednisolone with 500-1000 mg once for 3-5 days is the first-line therapy. A patient should be defined as having steroid-refractory disease if the troponin level does not reduce by more than 50% from its peak and/or AV block, ventricular arrhythmias, or left ventricular dysfunction persist after three days of intravenous methylprednisolone treatment. If steroid-refractory disease is suspected, a second-line immunosuppression regimen and multidisciplinary team discussion are recommended.¹²

Except for immunotherapy, all patients should undergo a comprehensive risk assessment before starting anticancer therapy. Cardiovascular toxicity resulting from anticancer treatment is often fatal and complicated. Based on current guidelines, we recommend using the Heart Failure Association-International Society of Cardio-Oncology (HFA-ICOS) risk score for evaluation.⁶ A cardiovascular referral is strongly advised if a patient is categorized as high-risk. Once ICI-related myocarditis occurs, there is an urgent need to adopt a multidisciplinary approach to develop a personalized, guideline-based treatment plan, considering the patient’s cancer status, prognosis, and comorbidities. Further immunotherapy should be discussed cautiously based on the cancer prognosis, severity of ICI-related myocarditis, and alternative treatment options available after recovery from ICI-related myocarditis.

LEARNING POINTS

The diagnosis of ICI-related myocarditis mainly relies on a patient’s history of ICI use and increased expression of PD-L1 on myocytes, as shown by IHC staining. Although CMR and EMB may be useful for diagnosis, specific CMR indicators of ICI-related myocarditis require further study. EMB is rarely performed because of its high invasiveness. The treatment response for ICI-related myocarditis can be evaluated by monitoring morphological changes in ECGs and cardiac enzyme levels. Additionally, the emergence of complete AV block and ventricular arrhythmia may be prognostic indicators of poor outcomes. Therefore, intensive ECG and cardiac enzyme monitoring in patients with cardiac symptoms can aid physicians in adjusting treatment strategies.

DECLARATION OF CONFLICT OF INTEREST

The authors declare no conflicts of interest relevant to this article.

ETHICS DECLARATION

This study followed the ethical principles of the Declaration of Helsinki. This study was approved by the Ethical Review Board of China Medical University Hospital in Taiwan with the approval code CMUH112-REC2-033. The requirement to obtain informed consent was waived because of the retrospective nature of the study.

AUTHOR CONTRIBUTION

CC: Management of data collection and manuscript writing. HYL and MYL: Consultation and manuscript revision. HPW: Provided case data and final approval.