Smoldering myocarditis following immune checkpoint blockade

Abstract

BackgroundSevere myocarditis associated with electrical conduction abnormalities and occasionally heart failure has been well documented following treatment with immune checkpoint blockade with an estimated incidence of less than 1%. However, the incidence, early detection, and management of less severe immune-related myocarditis are unknown since most immunotherapy trials have not included routine cardiac monitoring. Herein, we provide the first description of subclinical or smoldering myocarditis with minimal signs and symptoms following immune checkpoint blockade with a single dose of ipilimumab and nivolumab.Case presentationOur patient was diagnosed with immune checkpoint blockade-induced myocarditis based upon an acute rise in serum cardiac troponin I beginning 2 weeks after the initial dose of ipilimumab/nivolumab consistent with the reported median onset of clinical myocarditis at 17 days, as well as a lack of other causes despite extensive cardiac evaluation. The patient initially presented with intractable nausea with no known gastrointestinal etiology. High dose glucocorticoid therapy led to rapid resolution of nausea and a four-fold decrease in troponin I over 4 days. Serum troponin I spiked again following a steroid taper to 13 times the upper limit of normal with endomyocardial biopsy revealing collagen fibrosis and lymphocytic inflammation predominantly comprised of CD8+ T cells consistent with chronic smoldering myocarditis. Serum anti-striated muscle antibodies were also detected with no evidence of rhabdomyolysis. Serum cardiac troponin I levels as an indicator of ongoing myocyte damage gradually improved with chronic prednisone at 10 mg daily. Late addition of intravenous immunoglobulin was associated with rapid normalization of creatine kinase-myocardial band.ConclusionsThis case demonstrates that subclinical, smoldering myocarditis may occur following immune checkpoint blockade, with evidence of both humoral and cell-mediated immunity responsive to corticosteroid therapy. This experience supports early monitoring for myocarditis with serial electrocardiograms and serum troponin I determinations in large, prospective cohorts of patients receiving combination immune checkpoint blockade as early detection and initiation of immunosuppression may forestall fulminant presentation of this disease and limit myocardial damage.

Myocarditis Associated with Immune Checkpoint Inhibitors: An Expert Consensus on Data Gaps and a Call to Action

“…The first specific report of myocarditis during treatment with a PD‐1/PD‐L1 inhibitor was published in 2014 [27], and a number of cases of ICI‐associated myocarditis have been described since . In an early analysis of more than 20,000 patients treated with ICIs, either alone or in combination, the incidence of myocarditis was 0.09%; the incidence of fatal myocarditis in this sample was 0.03% .…”

“…Additional standard imaging methods that have been used for the assessment and diagnosis of ICI‐associated myocarditis include echocardiography and cardiac magnetic resonance imaging, which may reveal left‐ventricular ejection fraction abnormalities, wall motion abnormalities, myocardial edema, and fibrosis. Even endomyocardial biopsy, currently considered the gold‐standard method for diagnosis, has its limitations, as ICI‐associated myocarditis may occur as a patchy distribution of T‐cell‐predominant lymphocytic infiltrate within or adjacent to regions of myocardial necrosis , similar to histologic findings in patients with cardiac transplant rejection . Therefore, proper diagnosis of ICI‐associated myocarditis may involve a combination of high clinical acumen, biomarkers, cardiac imaging, and endomyocardial biopsy.…”

“…Like most irAEs, which typically emerge early in the course of treatment , preliminary observations suggest ICI‐associated myocarditis generally occurs within 3 months of treatment initiation . Management of ICI‐associated myocarditis varies in published reports but frequently includes administration of corticosteroids , with outcomes ranging from complete resolution to the occurrence of major adverse cardiac events and/or death.…”

Serial Troponin for Early Detection of Nivolumab Cardiotoxicity in Advanced Non-Small Cell Lung Cancer Patients

“…In an attempt to detect cardiovascular complications early, the authors of this article report their practice of performing weekly testing of troponin levels during weeks 1–3 of treatment, but they do not go into details in how to deal with troponin positivity. Most recently, Norwood et al provided the first description of subclinical or smoldering myocarditis with mild symptoms following immune checkpoint blockade with a single dose of ipilimumab and nivolumab . They performed a troponin testing as additional workup in a 49‐year‐old woman with metastatic melanoma and no cardiac risk factors who developed nausea unresponsive to treatment 14 days after the first dose of ipilimumab and nivolumab.…”

“…Available data appear to indicate a low sensitivity of cardiac MRI for detecting immune checkpoint blockade‐induced myocarditis , but further studies should clarify the role of this technique. Endomyocardial biopsy, the underused diagnostic gold standard for myocarditis , should be performed when is suspected that it would influence therapy.…”