Early myocarditis onset after immunotherapy linked to higher fatality risk

Patients who developed myocarditis within the first month of receiving immune checkpoint inhibitor therapy were more likely to die of myocarditis, and myocarditis-specific fatality was more common in patients who experienced co-occurring myositis and myasthenia gravis, according to results from a study 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 immunotherapies, but on rare occasions, they can cause myocarditis, which can prove more immediately deadly than the cancers the drugs are meant to treat in some cases, explained Hassan M. Abushukair, MD, a postdoctoral researcher at the Oklahoma University Stephenson Cancer Center, who presented the study.

When ICIs cause myocarditis, he added, they can often also cause myositis (autoimmune muscle inflammation) and myasthenia gravis (nerve-muscle communication disruption), which come together to form what researchers term "triple-M overlap syndrome," or TMOS.

TMOS and the conditions that compose it can easily cause fatalities for the subset of ICI-treated patients who develop these side effects. But clinicians need to know who may be at the greatest risk for fatal outcomes, and we do not yet have that level of understanding. Our analysis aimed to identify how we can more systematically approach risk stratification for patients who may develop fatal cardiac and autoimmune side effects from ICI treatment."

Hassan M. Abushukair, MD, postdoctoral researcher, Oklahoma University Stephenson Cancer Center

Abushukair and colleagues identified ICI-induced myocarditis, myositis, and myasthenia gravis in cancer cases within the World Health Organization (WHO) VigiBase pharmacovigilance databases. From this dataset, they formed seven groups of ICI side effects of concern: myocarditis alone; myositis alone; myasthenia gravis alone; myocarditis and myositis; myocarditis and myasthenia gravis; myositis and myasthenia gravis; and TMOS.

Out of 4,950 cases of myocarditis, myositis, and myasthenia gravis identified within the dataset, the researchers identified 2,641 ICI-induced myocarditis cases. Of those instances of myocarditis, 1,911 (72%) were myocarditis alone, and 730 (27.6%) overlapped with myocarditis and/or myasthenia gravis. The most common overlap combination was myocarditis and myositis (364 cases), followed by TMOS (207 cases). An overlap of myocarditis and myasthenia gravis was the least common combination, with 159 cases.

Following the start of ICI therapy, myocarditis had a significantly later median date of onset (60.8 days) than myocarditis and myositis (27 days); myocarditis and myasthenia gravis (27 days); and TMOS (26 days).

After adjusting for age, ICI regimens, cancer type, and co-reactions, the researchers found that myocarditis occurring during the first month of ICI therapy start was associated with a significantly increased likelihood of myocarditis-specific fatality. Patients with ICI-induced myocarditis that began less than a month after starting treatment were 59% more likely to die from myocarditis than those whose myocarditis began one to three months after starting treatment; they were also 56% more likely to die from myocarditis than those whose ICI-induced myocarditis occurred three to 12 months after starting treatment.

Myocarditis-specific fatality was highest in patients with TMOS (38%). Deaths attributable to myocarditis were less frequent in patients with myocarditis alone (21.2%); myocarditis and myositis (22.5%); and myocarditis and myasthenia gravis (25.7%).

The team is also developing an algorithm to predict fatality from ICI-induced myocarditis by using machine learning based on 858 cases of ICI-induced myocarditis with complete data availability. The researchers' tool achieved considerable accuracy in classifying fatal and nonfatal cases.

"Our analysis indicates that the first month of a patient receiving ICI therapy is the crucial period for determining patients' risk of myocarditis fatality. If a patent on ICIs develops myocarditis in those first 30 days, that's a flashing warning light," said Abushukair. "This gives clinicians an actionable timeframe for determining whom ICI therapy may be dangerous for."

Abushukair also spoke to the potential of his team's algorithmic model, which he hopes, following additional training data and validation currently ongoing, might have use on the clinical side for patient monitoring and risk stratification for patients receiving ICI therapy.

"I believe the model we're developing is a great illustration of how even simple clinical data analysis can be used to address fatality in cancer treatment. Ultimately, we envision a helpful bedside tool to rule out high-risk fatality from TMOS and its constituent conditions," he said. "With a greater understanding of the risks that these ICI side effects pose, clinicians and patients alike can be more attuned to which symptoms to be on the lookout 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 that contained considerable heterogeneity for various protocols, thresholds, etc. The WHO dataset also lacked complete treatment information.