Patients who developed myocarditis within the first month of treatment with immune checkpoint inhibitors were more likely to die from myocarditis, and death from myocarditis was more common in patients who had both myositis and myasthenia gravis, according to study results presented at the American Association for Cancer Research (AACR) Annual Meeting 2026, held April 17-22.
Immune checkpoint inhibitors (ICIs) have ushered in a new era of cancer immunotherapy, but in rare cases they can cause myocarditis, which in some cases is more likely to cause immediate death than the cancer they are intended to treat, explained Hassan M. Abushcare, MD, a postdoctoral fellow at the University of Oklahoma Stevenson Cancer Center who published the study.
When ICIs cause myocarditis, they can often also cause myositis (autoimmune muscle inflammation) and myasthenia gravis (impaired nerve-to-muscle communication), which together form what researchers call triple M overlap syndrome (TMOS), he added.
TMOS and its constituent symptoms can easily cause death in some ICI-treated patients who develop these side effects. But clinicians need to know who is at greatest risk for fatal outcomes, and we don’t yet have that level of understanding. Our analysis aimed to identify how risk stratification of patients who may develop potentially fatal cardiac and autoimmune side effects from ICI treatment can be approached more systematically. ”
Hassan M. Abusukair, MD, Postdoctoral Researcher, University of Oklahoma Stevenson Cancer Center
Abushukair et al. identified ICI-induced myocarditis, myositis, and myasthenia gravis in cancer cases in the World Health Organization (WHO) VigiBase pharmacovigilance database. From this dataset, they created seven groups of ICI side effects of concern. Myositis only. Myasthenia gravis alone. Myocarditis and myositis. Myocarditis and myasthenia gravis. Myositis and myasthenia gravis. And TMOS.
Of the 4,950 cases of myocarditis, myositis, and myasthenia gravis identified in the dataset, researchers identified 2,641 cases of ICI-induced myocarditis. Of these cases of myocarditis, 1,911 (72%) had myocarditis alone and 730 (27.6%) overlapped with myocarditis and/or myasthenia gravis. The most common duplication combination was myocarditis and myositis (364 cases), followed by TMOS (207 cases). Myocarditis and myasthenia gravis overlap was the least frequent combination, with 159 cases.
After initiation of ICI therapy, the median date of onset of myocarditis (60.8 days) was significantly later than that of myocarditis and myositis (27 days). Myocarditis and myasthenia gravis (27 days). and TMOS (26 days).
After adjusting for age, ICI regimen, cancer type, and co-reactivity, the researchers found that myocarditis occurring during the first month of ICI treatment significantly increased the likelihood of myocarditis-specific death. Patients with ICI-induced myocarditis that began within 1 month of starting treatment were 59% more likely to die from myocarditis than those whose myocarditis began 1 to 3 months after starting treatment. Patients who developed ICI-induced myocarditis 3 to 12 months after starting treatment were also 56% more likely to die from myocarditis.
Myocarditis-specific mortality was highest in TMOS patients (38%). Deaths due to myocarditis were less common in patients with myocarditis alone (21.2%). Myocarditis and myositis (22.5%); myocarditis and myasthenia gravis (25.7%).
The team is also developing an algorithm to predict mortality from ICI-induced myocarditis using machine learning based on 858 cases of ICI-induced myocarditis for which complete data are available. The researchers’ tool achieved considerable accuracy in classifying fatal and non-fatal cases.
“Our analysis shows that the first month after a patient receives ICI treatment is a critical time in determining a patient’s risk of death from myocarditis. If myocarditis develops in the first 30 days due to an ICI patent, that is a flashing warning light,” Abu-Shukair said. “This gives clinicians a workable time frame to determine for whom ICI treatment is risky.”
Abuscare also discussed the potential of his team’s algorithmic model, which, with additional training data and ongoing validation, he hopes could be used clinically for patient monitoring and risk stratification of patients receiving ICI therapy.
“We believe the model we are developing is an excellent example of how even simple clinical data analysis can be used to address mortality in cancer treatment. Ultimately, we envision a useful bedside tool to exclude high-risk mortality from TMOS and its component diseases,” he said. “By better understanding the risks posed by these ICI side effects, clinicians and patients alike will have a better idea of which symptoms to watch out for. Our hope is that this will create a safer paradigm for ICI treatment.”
Limitations of this study include its retrospective, descriptive design and the use of a global dataset containing considerable heterogeneity in different protocols, thresholds, etc. The WHO dataset also lacked complete treatment information.
sauce:
American Association for Cancer Research
