In just a few years, immunotherapy has risen to become a pillar of cancer care, leading to significantly improved response rates and even cures in previously intractable diseases. Leveraging the immune system to treat cancer, however, also increases the potential for serious off-target effects.
During the 2021 American College of Cardiology (ACC) virtual conference on Advancing the Cardiovascular Care of the Oncology Patient, Tomas G. Neilan, MD, MPH, FACC, of the Cardio-Oncology Program, Massachusetts General Hospital, Harvard Medical School, discussed the cardiovascular risks associated with immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapies.1
“It’s up to us as a community to recognize the potential for immunotherapies to lead to cardiovascular injury and long-term cardiovascular sequelae,” said Dr. Neilan. “Whether they are combined with targeted therapy or traditional cytotoxics, the complexity of the use of immune checkpoint inhibitors is going to increase, and, as it does, the role for cardiovascular care among oncology patients will increase as well.”
Tomas G. Neilan, MD, MPH, FACC
Immune-Related Adverse Events
Dr. Neilan reported that, in 2020, an estimated 36% of patients with cancer were eligible for immune checkpoint inhibitors. These drugs block PD-1 and PD-L1 and remove the “blinders” that prevent T cells from recognizing cells as cancerous. Although this opens the door for the immune system to treat cancer, said Dr. Neilan, the immune system can potentially target any organ system in the body.
The incidence of myocarditis in patients treated with immune checkpoint inhibitors is not clearly known but likely ranges from 0.5% to 1%, and the case fatality rate is between 20% and 30%, compared with 2% to 4% for myocarditis with other etiologies.2 In addition, there is significant morbidity, including cardiogenic shock, cardiac arrest, ventricular tachycardia, and complete heart block.
Myocarditis: Detection Strategies and Assessment
Biomarker analysis of patients who develop myocarditis related to immune checkpoint inhibition has shown that nearly all cases had a troponin elevation (94%) and most had a B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) elevation (66%).3 The left-ventricular ejection fraction (LVEF) is normal in approximately 55% to 60% of cases.
Thus, “the presence of a normal ejection fraction does not exclude the presence of myocarditis,” said Dr. Neilan. Data suggest that global longitudinal strain is also decreased among patients who develop myocarditis, he added.
Magnetic resonance imaging (MRI) with parametric mapping is another useful tool for detection of myocarditis. Preliminary data on 86 patients with immune checkpoint inhibitor–associated myocarditis have shown that, when the modified Lake Louise criteria were applied, 95% of patients met the “nonischemic myocardial injury criteria,” 53% met the “myocardial edema” criteria, and 48% met both these main criteria. Of note, said Dr. Neilan, at least one of the main modified Lake Louise criteria for myocarditis was present in 100% of patients.
Suggested Treatment of Myocarditis
According to Dr. Neilan, every guideline suggests admitting the patient to an in-patient unit with telemetry, stopping immune checkpoint inhibition and initiating corticosteroids as first-line treatment for myocarditis, but there are differences as well. For instance, ASCO guidelines recommend starting with 1 to 2 mg/kg of prednisone, whereas the Society for Immunotherapy of Cancer (SITC) recommends the addition of an additional/alternative immunosuppressant if no improvement in 2 to 3 days is observed following the initial starting dose of prednisone. The European Society for Medical Oncology (ESMO), on the other hand, recommends high-dose corticosteroids without a specific dose guidance. The National Comprehensive Cancer Network® (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®) lists methylprednisolone pulse dosing at 1 g/d for 3 to 5 days as a therapeutic option.
High doses of corticosteroids, however, may also adversely impact cancer outcomes. “We may be winning the battle but losing the war,” said Dr. Neilan. “The data are mixed but suggest that lower-dose corticosteroids may not impact cancer outcomes compared with high doses.”
If corticosteroids are not effective, the NCCN Guidelines mention consideration of escalation to other immunosuppressive drugs, such as infliximab. According to Dr. Neilan, however, recent data suggest that chances of death are potentially 10-fold higher in patients treated with infliximab who have immune checkpoint inhibitor–associated myocarditis.
“We’ve started to move away from the use of infliximab,” said Dr. Neilan, who noted a block box warning in patients with reduced ejection fraction. “Beyond current guidelines, abatacept and alemtuzumab are being explored for immune-related myocarditis and have shown promise in animal studies.”
According to Dr. Neilan, every patient should undergo baseline electrocardiography and troponin assessment prior to receiving immune checkpoint inhibitors. Whether patients should have these tests routinely repeated while on treatment is unclear, and routine surveillance should first be tested in a clinical study before recommendations are made.
CAR T-Cell Therapy and the Heart
There are also cardiovascular risks associated with CAR T-cell therapy. As Dr. Neilan reported, data have shown a 15% incidence of heart failure at a median of 11 days after infusion, and overall cardiac toxicities are reported at rates between 20% and 39%.4 In addition, cardiac injury (evidenced by an increase in serum troponin) was documented in at least 21% of patients.5
Guidelines from the SITC state that prior to CAR T-cell therapy in adults, baseline cardiac testing should include transthoracic echocardiography, serum troponin, and BNP or NT-proBNP. Furthermore, said Dr. Neilan, patients with an increased burden of cardiovascular risk factors, a prior cardiac insult, significant valvular disease, a low ejection fraction or cardiomyopathy, a history of heart failure or significant cardiac arrhythmia, or a history of cardiac toxicity from prior therapies should undergo additional cardiac evaluation. Antiplatelet agents such as aspirin and clopidogrel should also be discontinued prior to CAR T-cell therapy.
After CAR T-cell infusion, Dr. Neilan noted that the measurement of serum troponin and LVEF should be considered in patients with any grade of cytokine-release syndrome when additional risk stratification is needed. Evidence of cardiac toxicity, elevated troponin, decrease in LVEF, or significant arrhythmia should prompt consideration of earlier intervention with interleukin-6 blockade and/or steroids or escalation of current treatment. Patients deemed to be at high cardiac risk at baseline might need earlier intervention with tocilizumab and/or steroids at the onset of cytokine-release syndrome.
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DISCLOSURE: Dr. Neilan has served as a consultant or advisor to AbbVie, Bristol Myers Squibb, H3 Biomedicine, Intrinsic Imaging, and Parexel; and has received research funding from AstraZeneca.
REFERENCES
1. Neilan TG: Immune therapy and cardiovascular risk. 2021 ACC Conference on Advancing the Cardiovascular Care of the Oncology Patient. Plenary Session. Presented February 6, 2021.
2. Wang DY, Salem JE, Cohen JV, et al: Fatal toxic effects associated with immune checkpoint inhibitors: A systematic review and meta-analysis. JAMA Oncol 4:1721-1728, 2018.
3. Mahmood SS, Fradley MG, Cohen JV, et al: Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol 71:1755-1764, 2018.
4. Lefebvre B, Kang Y, Smith AM, et al: Cardiovascular effects of CAR T cell therapy: A retrospective study. JACC CardioOncol 2:193-203, 2020.
5. Alvi RM, Frigault MJ, Fradley MG, et al: Cardiovascular events among adults treated with chimeric antigen receptor T-cells (CAR-T). J Am Coll Cardiol 74:3099-3108, 2019.
