Immune-Related Fulminant Myocarditis in a Patient Receiving Ipilimumab Therapy for Relapsed Chronic Myelomonocytic Leukaemia

A 66-year-old man with chronic myelomonocytic leukaemia (CMML) presented with myalgias and acute-onset shortness of breath, profound orthopnoea, and bilateral pedal oedema of 1 day's duration. He had been diagnosed with CMML a year and half before presentation, and after an inadequate response to four cycles of decitabine chemotherapy, he underwent a matched unrelated donor allogeneic haematopoietic stem cell transplant 7 months before presentation. Six months after his transplant, he developed recurrent anaemia and thrombocytopenia, and bone marrow biopsy confirmed relapsed CMML. He was enrolled in an experimental protocol of ipilimumab, a monoclonal antibody (IgG1) that blocks the checkpoint protein cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), to promote anti-tumour immunity. One week after receiving his first infusion, he was admitted to the hospital with abdominal pain and diarrhoea, and was found to have colitis involving the descending and sigmoid colon. He underwent flexible sigmoidoscopy and biopsy of the inflamed tissue showed focal active colitis and ulceration with no diagnostic features of cytomegalovirus infection or graft-vs.-host disease. A diagnosis of ipilimumab-related colitis was made, and he was treated with a 7-day taper of dexamethasone. His presenting cardiopulmonary symptoms began on the day after he completed corticosteroid treatment. At presentation, his temperature was 36.8 °C, pulse was 108 b.p.m., blood pressure was 116/59 mmHg, respiratory rate was 24/min, and oxygen saturation was 92% on room air. His breathing was laboured and he was unable to lie flat. His jugular venous pressure was elevated at 12 cmH2O. Auscultation of the heart and lungs revealed a rapid and regular heart rate, an S4 gallop, and audible crackles at the bases of both lung fields. His extremities were warm and he had 2+ bilateral symmetric pitting pedal oedema. His complete blood count was near his recent baseline with a white blood cell count of 33 × 103 cells/mm3 (with 44% monocytes), haematocrit was 28.9%, and platelet count was 7000/µL. Other laboratories measurements of note included a serum sodium of 132 mmol/L, alanine aminotransferase 268 U/L, aspartate aminotransferase 189 U/L, lactate 2.9 mmol/L, troponin-T 1.99 ng/mL (reference range <0.01 ng/mL), creatine kinase 1172 U/L (reference range 39–308 U/L), creatine kinase MB isoenzyme 168.5 ng/ml (reference range 0.0–7.7 mg/ml), and N-terminal-pro-B-type natriuretic peptide 2155 pg/ml (reference range <900 pg/ml). His electrocardiogram showed low voltage, sinus rhythm, and a new right bundle branch block (Figure 1), and chest radiography revealed mild interstitial oedema and small bilateral pleural effusions. Computed tomography angiography of the chest showed no evidence of pulmonary embolism. Transthoracic echocardiography demonstrated preserved left ventricular systolic function (ejection fraction 70%) with evidence of diastolic dysfunction, normal right ventricular size and function, and no significant valvular lesions. He was given intravenous furosemide for decongestion and admitted to the cardiac intensive care unit for closer monitoring. It was recommended that a pulmonary artery catheter be placed for closer haemodynamic assessment; however, the patient declined invasive monitoring. Within hours of presentation, he developed progressive hypotension requiring the initiation of dopamine as well as progressive high-grade atrioventricular block and ultimately complete heart block with a wide ventricular escape (Figure 1). He was started on empirical high-dose methylprednisolone (1000 mg daily), and was offered temporary transvenous pacing and right heart catheterization with endomyocardial biopsy, but again declined all invasive measures. Following extensive discussion between the patient, the treating oncologist, and the intensive care unit team, the patient was transitioned to comfort measures only given his poor oncological prognosis. He expired within 24 h. Post-mortem examination with microscopic evaluation of skeletal muscle biopsies demonstrated inflammatory myositis, characterized by a predominantly CD3+ T-cell inflammatory infiltrate with associated myocyte necrosis (Figure 2). Microscopic evaluation of cardiac muscle was not performed because of the family's request for a limited post-mortem examination. Immunological checkpoint blockade with monoclonal antibodies targeting the CTLA-4 and programmed cell death protein 1 (PD-1) receptors on activated T lymphocytes has been successful in treating a variety of cancers. As checkpoint proteins are important negative regulators of T-cell activation, inhibiting their function prevents tumour cells from evading the immune system and results in significant antitumor immunity,1 including in patients with haematological malignancies who relapse after allogeneic transplantation.2 Because checkpoint inhibitors may not selectively enhance anti-tumour immune responses, they can cause widespread adverse inflammatory reactions, which have been collectively termed immune-related adverse events. As the clinical experience with these agents builds, a number of recent reports have brought attention to clinically apparent cardiotoxicity as a suspected complication of checkpoint inhibitor therapy. We describe a case of fulminant myocarditis resulting in the death of the patient despite treatment with high-dose corticosteroids. The skeletal muscle at autopsy revealed fulminant T-cell infiltration and muscle necrosis, correlating with the clinical symptoms of myalgias and weakness. Microscopic evaluation of the cardiac muscle was not performed, limiting our ability to definitively diagnose myocarditis; however, it is noteworthy that other case reports of checkpoint inhibitor-related cardiotoxicity describe coincident myositis.3 Although direct viral polymerase chain reaction analyses were not performed, his lack of antecedent upper respiratory tract infection symptoms makes a viral aetiology of myocarditis less compelling. Despite these limitations, our case highlights several salient features of this emerging clinical entity. Previous reports of immune-mediated myocarditis have described patients who have experienced both regional and global left ventricular dysfunction. One patient developed a takotsubo cardiomyopathy-like syndrome with classic left ventricular apical ballooning after receiving ipilimumab for metastatic melanoma.4 Another patient developed acute heart failure following treatment with pembrolizumab, a PD-1 inhibitor, for metastatic melanoma. A transthoracic echocardiogram demonstrated reduced left ventricular systolic function (ejection fraction 30%), and endomyocardial biopsy ultimately revealed a dense lymphocytic infiltrate with predominantly CD8+ T cells.5 Despite presenting with of rapidly progressive fulminant myocarditis, our patient had preserved left ventricular ejection fraction, suggesting that clinically apparent disease may precede the onset of echocardiographically apparent ventricular dysfunction in some cases. As with other cases of fulminant myocarditis, classical signs and symptoms of heart failure appear to be present in many patients with checkpoint inhibitor-related cardiotoxicity. One patient with metastatic melanoma being treated with nivolumab (PD-1 inhibitor) developed fulminant myocarditis and cardiogenic shock requiring prolonged support with inotropes. Endomyocardial biopsy confirmed lymphocytic infiltration with a predominance of CD8+ T-cells, and he ultimately improved with high-dose corticosteroids.6 Two other patients treated with combination ipilimumab and nivolumab for metastatic melanoma developed progressive and refractory conduction system disease and ultimately died.3 Other cases of checkpoint inhibitor-related cardiotoxicity have had subtler presentations. A patient with metastatic melanoma developed left arm pain while undergoing treatment with combination ipilimumab and nivolumab therapy for treatment of metastatic melanoma. Work-up revealed a mildly elevated troponin-T (peak 0.12 ng/mL), which was followed by an echocardiogram showing preserved left ventricular systolic function and a coronary angiogram demonstrating normal coronary arteries. The patient's symptoms resolved with high-dose corticosteroids and discontinuation of combination immunotherapy.7 It is notable that our patient's clinical course was defined by rapidly progressive electrical instability, marked by atrioventricular conduction disease and bradyarrhythmias. Myocarditis related to these immunotherapies may present with or without significant echocardiographic left ventricular dysfunction. As such, routine echocardiography during treatment may miss a proportion of at-risk patients. Markers of myonecrosis appear to be consistently elevated early in the disease course, and thus serve as important biomarkers of cardiac injury during treatment. Given the substantial electrical instability that preceded our patient's death, regular electrocardiograms may be a simple, inexpensive approach to screening for early on-treatment myocardial toxicity. Use of more than one immune therapy may augment risk of cardiotoxicity3, 7 and thus identify a particularly at-risk cohort for this complication. The appropriate intervals and intensity of screening in patients receiving immune checkpoint inhibitors require further investigation. Given the limited global experience with these immune therapies, the overall prognosis of this rare complication is not yet clear. In a phase 3 trial of adjuvant ipilimumab vs. placebo following complete resection of high-risk stage III melanoma, one myocarditis death was reported in the ipilimumab group.8 Novel cardiac biomarkers may ultimately have a role in identifying patients at high risk for adverse outcomes.9 Treatment strategies employed to date include prompt discontinuation of the immunotherapy, high-dose corticosteroids, and standard neurohormonal medical therapies for heart failure. This approach has led to improvement in symptoms and ventricular function in many patients.5, 6 In more severe cases, there may also be a role for more potent immune suppression with anti-thymocyte globulin, intravenous immune globulin, or tumour necrosis factor-alpha inhibitors; however, the relative efficacy of these therapies has not yet been studied. Given the apparent range of clinical presentations from asymptomatic myonecrosis to fulminant heart failure, the extent of immune suppression needs to be determined on a case-by-case basis with the treating cardiologist and oncologist. The use and applications of immunological checkpoint inhibitors are poised to increase in the treatment of a broad spectrum of malignancies. As such, cardiologists should maintain a high clinical suspicion for potential immune-mediated adverse cardiotoxic events related to these agents. The pathophysiology, clinical presentation, and prognosis of immune-related myocarditis appear to be distinct from the experience with previous cardiotoxic chemotherapies, and heightened clinical attention and greater broad-scale surveillance efforts may help to better define this entity. The European Society of Cardiology recently issued a position paper outlining recommendations for the management of cardiovascular complications of several cancer treatments.10 As clinical experience with immunological checkpoint inhibitors builds, future iterations of this document and other position statements should include dedicated sections on immune-related myocarditis. The ultimate goal is to work closely and collaboratively with our oncology colleagues to deliver these highly-effective immune therapies to carefully selected patients, while exercising appropriate caution and surveillance for potential untoward side-effects. Effectively navigating patients through treatment-related cardiotoxicity may facilitate continued therapy and potentially durable oncologic responses. Conflict of interest: none declared.