Findings reveal ‘crucial’ need to manage immune checkpoint inhibitor-induced myocarditis
Click Here to Manage Email Alerts
Key takeaways:
- Individuals with cancer treated with immune checkpoint inhibitors rarely developed cardiovascular adverse events.
- Patients who developed myocarditis had a high mortality rate.
Patients with cancer who received immune checkpoint inhibitors rarely developed cardiovascular adverse events, according to results of a systematic review and meta-analysis.
However, individuals who developed myocarditis following immune checkpoint inhibitor (ICI) therapy exhibited “substantial mortality” risk, researcher Dorte Lisbet Nielsen, MD, DMSc, professor emeritus at University of Copenhagen in Denmark, told Healio.
“Therefore, it is rather crucial for clinicians to be familiar with its symptoms and management,” she added.
Background
ICIs have improved outcomes for people with multiple cancer types; however, they can increase risk for immune-related adverse events, including those that emerge in the cardiovascular system, according to study background.
Cardiovascular events include myocarditis, pericarditis, acute coronary syndrome, heart failure, arrhythmias, conduction abnormalities and cardiac arrest.
“Data on the incidence of cardiotoxicity in the ever-expanding landscape of clinical trials with ICIs and ICI combination therapies are, however, scarce,” Nielsen said. “Therefore, we wanted systematically to collect such data and investigate the evidence for management of ICI-induced side effects — in particular, myocarditis.”
Nielsen and colleagues conducted two separate systematic reviews and meta-analyses of research published through April 4, 2023.
The first study included phase 1 to phase 4 trials of adults with malignant neoplasms treated with approved ICIs. Incidence of cardiovascular adverse events served as the primary endpoint.
The second study included case reports and retrospective studies on “clinical manifestations and treatment of patients with ICI-induced cardiovascular adverse events,” researchers wrote.
Incidence of cardiovascular events
The first study included data from a combined 83,315 participants enrolled in 589 trials.
The therapies administered in these trials — either as monotherapy or as part of combination therapy — included pembrolizumab (Keytruda, Merck), nivolumab (Opdivo, Bristol Myers Squibb), cemiplimab (Libtayo, Regeneron Pharmaceuticals), atezolizumab (Tecentriq; Genentech, Roche), durvalumab (Imfinzi, AstraZeneca), avelumab (Bavencio, EMD Serono), ipilimumab (Yervoy, Bristol Myers Squibb).
Fewer than 1% of those treated with anti-PD-1 or anti-PD-L1 therapies developed cardiovascular events (0.8%; 95% CI, 0-1.66)
Researchers observed no difference between therapies with the exception of cemiplimab, which appeared associated with a higher risk for high-grade cardiovascular adverse events (2.91% for cemiplimab vs. 0.69% overall).
Results showed 0.24% (95% CI, 0.08-0.4) of patients developed any-grade myocarditis, and 0.2% (95% CI, 0.03-0.36) developed high-grade myocarditis.
Incidence of cardiovascular adverse events did not differ significantly between trial participants who received dual ICI therapy, ICI therapy in combination with chemotherapy, or ICI therapy with tyrosine kinase inhibitors.
However, researchers reported significantly higher myocarditis incidence after dual ICI therapy compared with other regimens.
Myocarditis outcomes
In the second study, researchers analyzed 223 cases of myocarditis (64.5% men).
Most (70%) had received a PD-1 and/or PD-L1 inhibitor, whereas one-quarter (25.6%) received dual ICIs and 4% received ipilimumab.
A review of cardiac risk factors showed 41.1% had hypertension, 16.3% had diabetes, 46.5% had other risk factors and 20.9% had no risk factors.
An analysis of 220 evaluable patients (median age, 70 years; 64.5% men) with myocarditis showed 37.7% died.
“The mortality rate of myocarditis was much higher than we anticipated,” Nielsen said.
Treatments for myocarditis included:
- High corticosteroid doses (n = 96; 63.5% showed improvement, 26% cardiac mortality, 28.1% all-cause mortality);
- Methylprednisolone 500 to 1,000 mg (n = 85; 43.5% showed improvement, 34.1% cardiac mortality, 43.9% all-cause mortality);
- IV immunoglobulin (n = 63; 58.7% showed improvement, 23.8% cardiac mortality, 36.7% all-cause mortality);
- Plasma exchange (n = 52; 46.2% showed improvement; 26.9% cardiac mortality, 40.7% all-cause mortality);
- Mycophenolate mofetil (n = 45; 64.4% showed improvement, 22.2% cardiac mortality, 28.9% all-cause mortality);
- Influximab (n = 21; 38.1% showed improvement, 38.1% cardiac mortality, 42.9% all-cause mortality); and
- Antithymocyte globulin (n = 17; 35.3% showed improvement, 52.9% cardiac mortality, 52.9% all-cause mortality).
Twelve patients received abatacept (Orencia, Bristol Myers Squibb). Eleven (91.7%) showed improvement and one (8.3%) died due to myocarditis.
“Prospective data from 40 patients with myocarditis indicated that systematic screening for respiratory muscle involvement — coupled with active ventilation, prompt use of abatacept and the addition of ruxolitinib [Jakafi, Incyte] — may decrease the mortality rate,” researchers wrote.
However, questions still remain.
“Any management strategy of myocarditis is empirical and it is, at present, impossible to determine which strategy is most efficient,” Nielsen told Healio.
Researchers acknowledged study limitations, including lack of patient-level meta-analyses, which limits insights about the potential role of comorbidities or age. Also, most studies did not prospectively examine cardiac parameters — instead reporting data on immune-related adverse events or treatment-related adverse events — meaning the systematic review and meta-analysis may have underestimated incidence of cardiovascular adverse events.
“Without question, further research and prospective clinical studies are highly warranted. However, it is unrealistic to expect many of such studies,” Nielsen said. “We, therefore, suggest putting more focus on standardizing diagnostic and therapeutic approaches, as well as to establish an international multicenter registry across assorted cancer diagnoses.”
For more information:
Dorte Lisbet Nielsen, MD, DMSc, can be reached at dorte.nielsen.01@regionh.dk.
Collapse
Click Here to Manage Email Alerts