A Case Study of Myopericarditis due to Immune Checkpoint Inhibitor Therapy: Proposed Surveillance and Management

Abstract

Immune checkpoint inhibitor (ICI) therapy is a treatment modality used in many types of cancer. Immune related adverse events are relatively common. Cardiovascular adverse events are uncommon, but carry a high mortality rate of 25–50%. They require cessation of therapy. There is currently no universal screening prior to initiation of ICI therapy to identify patients with cardiovascular risk. There is also no ongoing screening to identify myocarditis and is driven by symptoms.

This article provides a case study of a patient who developed myopericarditis and the patient’s clinical course. Furthermore, it proposes surveillance for patients before and during therapy with ICI therapy to swiftly identify potential cases of myocarditis.

There is currently no universal baseline screening for cardiovascular risk in patients planned for ICI therapy. A proposed baseline cardiac evaluation, as well as scheduled surveillance therapy is outlined in this article. With further education and training, immune related cardiac adverse events may be more promptly detected, leading to better patient outcomes.

Immunotherapies (ICI) have emerged as front-line treatments where past treatments have been ineffective. (Murciano-Goroff et al, 2020) They represent a major advancement in the cancer battle. Their autoimmune effects, however, can target organs other than those involved in cancer treatment causing edema, inflammation, and organ failure. (Murciano-Goroff et al, 2020) “The incidence of myocarditis in patients treated with ICI therapy is 0.04%–1.14%, but it carries a high mortality rate of 25%–50%. A baseline cardiac evaluation and scheduled surveillance throughout therapy is recommended, particularly for patients with cardiovascular risk factors.” (Kuhnly & Coviello, 2022) This case study will illustrate a patient with ICI related myocarditis, the importance of early recognition of sometimes asymptomatic cardiac changes, as well as a proposed plan for surveillance that will mitigate overall morbidity and mortality. Oncology nurses are an integral part of the interprofessional team and positioned to recognize and intervene on these early changes since they maintain close therapeutic relationships with patients in the context of treatment.

Case Study

AW is a 75-year-old male with diagnosis of metastatic prostate carcinoma and Stage IVB adenocarcinoma of the left lung. He had a past medical history significant for right bundle branch block and chronic pulmonary embolus secondary to malignancy on Xarelto. He had completed four cycles of carboplatin, pemetrexed and pembrolizumab followed by six cycles of maintenance pemetrexed and pembrolizumab to achieve stable disease. He presented to the emergency department with progressively worsening shortness of breath and weakness. He was subsequently diagnosed with pericardial effusion and decreased left ventricular ejection fraction (LVEF) concerning for pembrolizumab-induced cardiomyopathy. A pericardiocentesis was attempted by interventional cardiology and was unsuccessful. During his hospitalization, AW experienced an episode of supraventricular tachycardia with altered mental status and hypotension. He was successfully converted to normal sinus rhythm using amiodarone and metoprolol. Cardiothoracic surgery was consulted to evaluate the patient as a candidate for a pericardial window, however, subsequent echocardiograms showed resolving pericardial effusion. Cardiac Magnetic Resonance Imaging (CMR) was attempted while AW was inpatient, but it was not completed due to orthopnea experienced by AW. Clinical decision was made to start intravenous Solumedrol (1mg/kg) for presumed Pembrolizumab induced myopericarditis. This was converted to prednisone with plans to taper off the medication in the outpatient setting. He was started on colchicine and ibuprofen to treat the symptoms of pericarditis. In addition, he was started on Bactrim prophylaxis due to high-dose steroid use. He was discharged with plans to follow outpatient oncologist’s instructions to slowly taper prednisone, starting with 90mg daily. Cardiac MRI was successfully completed in the outpatient setting and demonstrated T2 hyperintense signal concerning for myocarditis, with a LVEF of 50%. AW was referred to cardio-oncology and seen in consultation approximately six weeks after the hospitalization for myocarditis. He was tapered down to 50mg of prednisone daily by his oncologist based on his troponin levels. His troponin level was 0.01 while on 60mg of prednisone and he was tapered to 50mg of prednisone with a rise in his troponin to 0.02 the following week. Following his initial visit with cardio-oncology, the prednisone dosing and taper responsibility was transitioned to the specialist and would be communicated to primary oncology team. Cardio-oncology followed AW with weekly troponin levels and appropriate tapering of the prednisone, with successful completion of taper in November 2020, approximately 5 months after the start of his myocarditis. His troponin level was undetectable and has remained undetectable since completion of his high-dose prednisone course. Repeat CMR done about six weeks following prednisone completion demonstrated improved LVEF of 58% and pericardial edema suggestive of subacute/chronic pericarditis.

Diagnosis, Surveillance, and Management

Diagnosis of ICI-related cardiotoxicity is currently made through assessment (signs of heart failure), electrocardiogram (EKG) and Echocardiogram (Echo). CMR may help to rule out myocarditis. Cardiac biomarkers and exclusion of acute coronary syndrome should be included. Recommended treatment includes stopping ICI, initiating prednisone (up 1 gram daily), avoiding QT prolonging medications. In patients with cardiopulmonary complications due to presumed or diagnosed myocarditis, intensive care may be required with mechanical circulatory support. Few studies are available on ICI re-challenge following a course of presumed or diagnosed myocarditis. If re-challenge is attempted, it should be done after recovery of left ventricular function with close cardiac monitoring and collaboration with cardio-oncology. (Ederhy et al, 2021; Lyon et al, 2018)

Ideally, any patient with known risk factors for cardiotoxicity would be referred prior to cardio-oncology for a cardiovascular pre-treatment assessment. (Spallarossa et al, 2017) These risk factors would include those with autoimmune disease, known coronary artery disease (CAD) or known heart failure. Referral should be considered for those with uncontrolled diabetes or hypertension. Figure 1 outlines the recommendations for baseline screening prior to initiation of ICI therapy. (Kuhnly & Coviello, 2022) A baseline cardiovascular risk assessment as well as baseline EKG, echocardiogram, and labs are necessary prior to starting immunotherapy treatment. Cardiovascular risk factors include CAD, known heart failure, autoimmune disease, diabetes, and hypertension. In those patients with identifiable risk factors, cardiac MRI should be obtained whenever feasible, as well as a referral to cardio-oncology prior to starting therapy. In patients with and without identifiable cardiovascular risk, baseline screening can identify any abnormalities which would warrant further evaluation, including cardio-oncology referral, prior to proceeding with immunotherapy. (Spallarossa et al, 2020)

Figure 1:

Proposed Baseline Screening Recommendations. The proposed recommendations should be done for all patients prior to ICI therapy. As demonstrated above, risk stratification for presence of cardiovascular risk factors determines baseline screening modalities and if a referral to cardio-oncology prior to treatment is recommended.

Management

Once determined that a patient is experiencing ICI-associated cardiotoxicity, there are several actions that can be taken. Based on the NCCN guidelines, the first action to take for expected cardiotoxicity, is to consult cardio-oncology. (Thompson, 2018) The checkpoint inhibitor is discontinued. Steroids are started and titrated to severity up to 1 gram daily. If unresponsive to steroids, other immunosuppressive agents may be used (e.g., Anti-thymocyte globulin (ATG), infliximab, IVIG, Mycophenolate mofetil). (Kuhnly & Coviello, 2022; Upadhrasta et al, 2019) Plasmapheresis may be performed in patients whose cardiotoxicity is steroid refractory. (Kuhnly & Coviello, 2022; Patel et al, 2021) Additional therapies can also help in relieving symptoms such as ACEIs, beta-blockers, aspirin diuretics, antiarrhythmic drugs, pacemaker placement and pericardiocentesis for those with effusion. (Spallarossa et al, 2020) Figure 2 outlines ongoing surveillance for all patients on ICI therapy regimens, regardless of their baseline cardiovascular risk. (Kuhnly & Coviello, 2022) Recommendations include weekly troponin levels and EKG for the first 6 weeks and then every 2 weeks until week 22, followed by monthly surveillance while on treatment. If patients develop symptoms, the recommendation is to stop ICI therapy, repeat troponin, EKG and order cardiac MRI and start prednisone in the outpatient setting if feasible. If the patient requires hospital admission, intravenous steroid therapy is warranted. If patients remain asymptomatic during their treatment and screening remains normal, ICI therapy can be continued. If the patient is asymptomatic and develops asymptomatic troponinemia, recommendations include starting prednisone, consulting cardio-oncology and ordering cardiac MRI. (Kuhnly & Coviello, 2022; Spallarossa et al, 2020)

Figure 2:

Proposed Surveillance on ICI therapy. Close monitoring is recommended for the first twenty-two weeks, followed by monthly ongoing surveillance of troponin levels and electrocardiogram. Proposed surveillance aims to identify early cases of myocarditis in patients who may be asymptomatic.

Pericarditis

Pericardial disease is the second most common cardiac adverse reaction from ICI therapy and often is seen in conjunction with myocarditis. (Ederhy et al, 2021; Salem et al, 2018) When this is the case, it can also be referred to as myopericarditis, with a reported 13% of all cases in analysis of adverse reactions by the World Health Organization. (Upadhrasta et al, 2019)

Pericarditis may be asymptomatic but SOB and pleuritic pain are the most common symptoms. (Upadhrasta et al, 2019) Signs of increasing pericardial effusion, which may or may not be associated with pericarditis, include upper venous congestion and cardiogenic shock as seen in effusion causing tamponade. Physical exam, EKG, echo and cardiac biomarkers help make the diagnosis. CMR is helpful in determining if myocarditis is also involved. Examination of pericardial fluid may assist in differential diagnosis between ICI related and cancer related pericardial disease. When seen in the absence of myocarditis, treatment includes the discontinuation of the ICI, Colchicine and NSAIDS. In more severe cases, pericardiocentesis is indicated in the case of tamponade and 500–1000mg of prednisone daily are used. ICI re-challenge can be considered after recovery. (Kuhnly & Coviello, 2022) As discussed, there is not currently a standard of care for routine surveillance while on ICI therapy. There may be cost implications and difficulty with insurance approval in obtaining the above testing measures, at which point peer-to-peer discussion with insurance companies and discussions with hospital administration and laboratory management may need to be held. It is imperative to minimize financial toxicity when able and this is an important consideration when recommending routine surveillance while on ICI therapy.

Conclusions

Immunotherapy is a great treatment option for several cancers and will continue to grow as new treatments and combination therapies emerge. Though cardiotoxicity secondary to ICI therapy is rare, it carries a high mortality rate. Myocarditis, pericarditis, and myopericarditis are critical diagnoses which must be detected as early as possible. In order to achieve this, baseline screening is recommended, as well as pre-treatment referral to cardio-oncology for those with risk factors. Continued monitoring is important to detect subclinical, or “smoldering” myocarditis and prompt evaluation is essential for quick initiation of treatment. Further research is needed into the pathophysiology of ICI related myocarditis and surveillance protocols will need to be adapted accordingly. Establishing surveillance and treatment protocols will have implications for nurse practitioners and other clinicians to ensure patient safety and follow evidence-based best practice.