Cardio-Oncology Corner

Fulminant myocarditis related to immunotherapy

A cancer cell’s survival is predicated on its ability to evade the immune system. Cancer cells maintain this cloak of invisibility by manipulating the body’s immune response. Immunotherapy is designed to enhance the ability of the immune system to recognize and remove cancer cells from the body. Immune checkpoint inhibitors, a subset of immunotherapy, inhibit the “breaks” in T lymphocytes, thus harnessing the immune system and have shown efficacy in cancer treatment. Specific pathways, or breaks, involved include cytotoxic T-lymphocyte antigen-4, programmed cell death protein 1, programmed cell death ligand-1 and lymphocyte-activation gene 3.

Wendy Bottinor

Immune checkpoint inhibitors

Immune checkpoint inhibitors include monoclonal antibodies that target cytotoxic T-lymphocyte antigen-4 (CTLA-4; ipilimumab [Yervoy, Bristol-Myers Squibb]), programmed cell death protein 1 (PD-1; nivolumab [Opdivo, Bristol-Myers Squibb] and pembrolizumab [Keytruda, Merck]), programmed cell death ligand-1 (PD-L1; durvalumab [Imfinzi, AstraZeneca], atezolizumab [Tecentriq, Genentech] and avelumab [Bavencio, EMD Serono]) and lymphocyte-activation gene 3 (LAG-3; Bristol-Myers Squibb investigational drug BMS-986016). Immune checkpoint inhibitors have been approved to treat a wide variety of cancers, including lymphoma, melanoma, lung cancer, renal cancer, bladder cancer and others (see Table). They are currently under investigation in most other cancer types.

As the indications for use have broadened, the use of immune checkpoint inhibitors has been on the rise. There is also a trend toward combining immune checkpoint inhibitors for enhanced immunologic response. For example, the combination of ipilimumab and nivolumab is FDA-approved for the treatment of advanced melanoma. In addition, recently, ipilimumab and nivolumab combination therapy has been recommended as standard of care for patients with intermediate- or poor-risk metastatic clear cell renal carcinoma.

Possible adverse events

As treatments using immune checkpoint inhibitors have increased, the potential for immune-related adverse events has come to the forefront, especially when using combination therapy. Cardiac immune-related adverse events, specifically myocarditis, have emerged as a rare but lethal complication after treatment with immune checkpoint inhibitors. Early data suggest that combination therapy (for example, nivolumab and ipilimumab) is a risk factor for myocarditis. Cardiac immune-related adverse events tend to occur early in treatment, generally in the first three cycles. Clinical presentation of cardiac involvement most commonly includes dyspnea, palpitations and evidence of congestive HF. Left ventricular systolic dysfunction occurs in most — but not all — patients. A takotsubo-like syndrome and fulminant myocarditis have also been described. Dysrhythmia, including atrial fibrillation, ventricular tachycardia and complete heart block, can be observed both in isolation and in conjunction with cardiomyopathy. In cases of death, refractory arrhythmia is the most common inciting event, followed by HF as the second most common cause.

It is imperative that clinicians exercise vigilance in assessing for potential cardiac complications related to treatment with immunotherapy. Myocarditis, in particular, requires a high level of suspicion given the variability in presentation, lack of specific markers and often fatal outcome. Screening high-risk patients with a baseline ECG and troponin, and with serial troponins in follow-up, has been proposed in high-risk patients (for example, those being treated with combination therapy). When troponins are elevated, it is recommended that they be followed every 2 to 3 days until normalization. Oncologists should have a low threshold for involving cardiologists or cardio-oncologists in patients who may have evidence of complications. Patients with suspected myocarditis should undergo the necessary diagnostic assessment immediately. Since myocarditis is often a diagnosis of exclusion, appropriate testing must rule out other causes for the cardiac presentation, especially cardiac ischemia. Elevated biomarkers, cardiac imaging and endomyocardial biopsy may all be necessary for proper diagnosis of myocarditis.

Treatment recommendations

Treatment of immune checkpoint inhibitor-related cardiotoxicity is based on the concept that immune cell activation is an integral component to these events. Several cases of immune checkpoint inhibitor-related cardiotoxicity have documented T-cell infiltration of the heart. Therefore, preliminary recommendations for the treatment of patients with myocarditis involve early intervention with high-dose steroids. This first-line therapy and has been associated recovery in some cases. Agents that may be considered in conjunction with steroids include IV immunoglobulin, anti-thymocyte globulin and tacrolimus. In cases of significant myocarditis, collaboration with advanced HF and transplant experts should be considered. Rechallenge with immune checkpoint inhibitors after a cardiac immune-related adverse event has been infrequent, but has been successful in a few reported cases.

This unexpected new issue in cardio-oncology may create a renewed interest in the intersection of the CV and the immune systems. The observations that mice genetically deficient in CTLA-4 and murine models of PD-1 inhibition develop immune system dysfunction may suggest a critical role of immune checkpoint in the heart in normal and pathologic settings. Understanding this interaction better may not only help the growing number of patients treated with cancer immunotherapies and who may be at risk for cardiotoxicity but also other forms of cardiac pathology, such as cardiac transplant rejection and other forms of myocarditis.

Disclosure: Bottinor reports no relevant financial disclosures.

A cancer cell’s survival is predicated on its ability to evade the immune system. Cancer cells maintain this cloak of invisibility by manipulating the body’s immune response. Immunotherapy is designed to enhance the ability of the immune system to recognize and remove cancer cells from the body. Immune checkpoint inhibitors, a subset of immunotherapy, inhibit the “breaks” in T lymphocytes, thus harnessing the immune system and have shown efficacy in cancer treatment. Specific pathways, or breaks, involved include cytotoxic T-lymphocyte antigen-4, programmed cell death protein 1, programmed cell death ligand-1 and lymphocyte-activation gene 3.

Wendy Bottinor

Immune checkpoint inhibitors

Immune checkpoint inhibitors include monoclonal antibodies that target cytotoxic T-lymphocyte antigen-4 (CTLA-4; ipilimumab [Yervoy, Bristol-Myers Squibb]), programmed cell death protein 1 (PD-1; nivolumab [Opdivo, Bristol-Myers Squibb] and pembrolizumab [Keytruda, Merck]), programmed cell death ligand-1 (PD-L1; durvalumab [Imfinzi, AstraZeneca], atezolizumab [Tecentriq, Genentech] and avelumab [Bavencio, EMD Serono]) and lymphocyte-activation gene 3 (LAG-3; Bristol-Myers Squibb investigational drug BMS-986016). Immune checkpoint inhibitors have been approved to treat a wide variety of cancers, including lymphoma, melanoma, lung cancer, renal cancer, bladder cancer and others (see Table). They are currently under investigation in most other cancer types.

As the indications for use have broadened, the use of immune checkpoint inhibitors has been on the rise. There is also a trend toward combining immune checkpoint inhibitors for enhanced immunologic response. For example, the combination of ipilimumab and nivolumab is FDA-approved for the treatment of advanced melanoma. In addition, recently, ipilimumab and nivolumab combination therapy has been recommended as standard of care for patients with intermediate- or poor-risk metastatic clear cell renal carcinoma.

Possible adverse events

As treatments using immune checkpoint inhibitors have increased, the potential for immune-related adverse events has come to the forefront, especially when using combination therapy. Cardiac immune-related adverse events, specifically myocarditis, have emerged as a rare but lethal complication after treatment with immune checkpoint inhibitors. Early data suggest that combination therapy (for example, nivolumab and ipilimumab) is a risk factor for myocarditis. Cardiac immune-related adverse events tend to occur early in treatment, generally in the first three cycles. Clinical presentation of cardiac involvement most commonly includes dyspnea, palpitations and evidence of congestive HF. Left ventricular systolic dysfunction occurs in most — but not all — patients. A takotsubo-like syndrome and fulminant myocarditis have also been described. Dysrhythmia, including atrial fibrillation, ventricular tachycardia and complete heart block, can be observed both in isolation and in conjunction with cardiomyopathy. In cases of death, refractory arrhythmia is the most common inciting event, followed by HF as the second most common cause.

PAGE BREAK

It is imperative that clinicians exercise vigilance in assessing for potential cardiac complications related to treatment with immunotherapy. Myocarditis, in particular, requires a high level of suspicion given the variability in presentation, lack of specific markers and often fatal outcome. Screening high-risk patients with a baseline ECG and troponin, and with serial troponins in follow-up, has been proposed in high-risk patients (for example, those being treated with combination therapy). When troponins are elevated, it is recommended that they be followed every 2 to 3 days until normalization. Oncologists should have a low threshold for involving cardiologists or cardio-oncologists in patients who may have evidence of complications. Patients with suspected myocarditis should undergo the necessary diagnostic assessment immediately. Since myocarditis is often a diagnosis of exclusion, appropriate testing must rule out other causes for the cardiac presentation, especially cardiac ischemia. Elevated biomarkers, cardiac imaging and endomyocardial biopsy may all be necessary for proper diagnosis of myocarditis.

Treatment recommendations

Treatment of immune checkpoint inhibitor-related cardiotoxicity is based on the concept that immune cell activation is an integral component to these events. Several cases of immune checkpoint inhibitor-related cardiotoxicity have documented T-cell infiltration of the heart. Therefore, preliminary recommendations for the treatment of patients with myocarditis involve early intervention with high-dose steroids. This first-line therapy and has been associated recovery in some cases. Agents that may be considered in conjunction with steroids include IV immunoglobulin, anti-thymocyte globulin and tacrolimus. In cases of significant myocarditis, collaboration with advanced HF and transplant experts should be considered. Rechallenge with immune checkpoint inhibitors after a cardiac immune-related adverse event has been infrequent, but has been successful in a few reported cases.

This unexpected new issue in cardio-oncology may create a renewed interest in the intersection of the CV and the immune systems. The observations that mice genetically deficient in CTLA-4 and murine models of PD-1 inhibition develop immune system dysfunction may suggest a critical role of immune checkpoint in the heart in normal and pathologic settings. Understanding this interaction better may not only help the growing number of patients treated with cancer immunotherapies and who may be at risk for cardiotoxicity but also other forms of cardiac pathology, such as cardiac transplant rejection and other forms of myocarditis.

Disclosure: Bottinor reports no relevant financial disclosures.