Early onset of immune checkpoint inhibitor (ICI)–related myocarditis is associated with increased mortality risk, as is the presence of concurrent major adverse cardiac events, according to results presented in a poster and at a press briefing during the 2026 American Association for Cancer Research (AACR) Annual Meeting.¹

ICIs are broadly used across cancer types based on their immunomodulatory antitumor effects; however, immune-related adverse events such as myocarditis may occur. “While [myocarditis] is not the most frequent, it is the most fatal across different toxicities,” said presenting author Hassan M. Abushukair, MD, Postdoctoral Associate Researcher, Stephenson Cancer Center, the University of Oklahoma, Oklahoma City, noting that some studies have reported fatality rates between 20% and 50% for this event. Also presenting these results, were corresponding authors Abdul Rafeh Naqash, MD, FASCO, Senior Associate Director for AI and Data Science and Tae Gyu Oh, PhD, Assistant Professor, Department of Oncology Science, Stephenson Cancer Center, the University of Oklahoma.

Hassan M. Abushukair, MD

Abdul Rafeh Naqash, MD, FASCO

Tae Gyu Oh, PhD

“Our analysis indicates that the first month of a patient receiving immune checkpoint inhibitor therapy is the crucial period for determining patients’ risk of myocarditis fatality. If a patient…develops myocarditis in those first 30 days, that’s a flashing warning light,” he commented in an AACR press release. “This gives clinicians an actionable time frame for determining for whom [ICI] therapy may be dangerous.”

The analysis also examined triple M overlap syndrome (TMOS)—a rare, often fatal and more severe clinical phenotype combining myocarditis and the neuromuscular immune-related adverse events myositis and myasthenia gravis—which was associated with earlier onset and a higher likelihood of occurring in older patients, men, those with melanoma, and those receiving dual ICI therapy compared with myocarditis alone.

Study Details

Using the World Health Organization (WHO) VigiBase pharmacovigilance database, the researchers gathered cases of ICI–related myocarditis, myositis, and myasthenia gravis in 4,635 patients with cancer. The cases were separated into seven groups: myocarditis alone, myositis alone, myasthenia gravis alone, myocarditis plus myositis, myocarditis plus myasthenia gravis, myositis plus myasthenia gravis, and TMOS.

“In this study, we report the largest clinical series of [TMOS], aimed at delineating clinical features, fatality predictors, and temporal trends,” the researchers wrote in their abstract.

An XGBoost-based machine learning model for fatality prediction was developed using a subset of patients with ICI–related myocarditis who had complete data available (age, sex, co-reactions, cancer and ICI type, and myocarditis timing; n = 822). The cohort was split 80:20 into training and testing sets for model development and evaluation. The researchers also used an external real-world data set of patients with ICI–related myocarditis (n = 37) for independent validation of the model.

TMOS Through a Pharmacovigilance Lens

Among the total cases identified, approximately 2,600 involved ICI–related myocarditis, including 71.3% classified as myocarditis alone and 7.7% as TMOS.

Compared with myocarditis alone, TMOS was associated with older age at myocarditis diagnosis (median, 75 vs 68 years; P < .0001) and male sex (66.2% vs 56.7%; P = .0121), as well as more frequent use of dual ICI therapy (25.1% vs 21.5%) and melanoma (35.7% vs 16.6%). TMOS vs myocarditis alone also showed higher rates of all-cause fatality (37.7% vs 21.4%; P = .0001) and myocarditis-specific fatality (36.8% vs 20.2%; P < .0001).

Among co-occurring immune-related adverse events, hepatitis was more common in TMOS than in myocarditis alone (16.4% vs 3.9%; P < .0001). Myocarditis also occurred earlier after treatment initiation in the TMOS group (≤ 1 month: 80.8% vs 50.1%), consistent with a lower hazard of later onset (hazard ratio = 0.57; P < .0001).

Focus on Fatal Myocarditis

After multivariable adjustment, myocarditis-specific fatality risk was higher with early onset (ie, ≤ 1 month after ICI initiation; 2.6-fold vs 1–3 months, P = .0005; 2.0-fold vs 3–12 months, P = .034), TMOS (2.7-fold vs myocarditis alone, P = .013), age over 75 years (2.2-fold vs ≤ 60 years, P = .018), concurrent non–myocarditis major adverse cardiac events (3.6-fold, P < .0001), and concurrent pneumobronchitis (3.4-fold, P = .0145).

Using clinical data available at the time of myocarditis diagnosis, the fatality machine learning model achieved an area under the curve of 0.76 in the training set, 0.73 in the testing set, and 0.74 in external validation. Early-onset myocarditis and the presence of concurrent cardiac events were identified as the most influential predictors of fatality.

Conclusions and Clinical Implications

In conclusion, the researchers wrote that TMOS represents a uniquely fatal phenotype of ICI–related myocarditis, with an earlier onset and higher tendency in cancers with wider use of such therapy, as well as in older patients, males, and those with melanoma. Regarding myocarditis fatality, they identified timing as a “critical” determinant, particularly within the first month after initiating therapy.

Dr. Abushukair stated in the press release, “Ultimately, we envision a helpful bedside tool to rule out high-risk fatality from TMOS and its constituent conditions.” The study was limited by its retrospective, descriptive design and the heterogeneity of the global data set on which it relied. In addition, the WHO database lacked complete treatment information. 

DISCLOSURE: The study authors reported no conflicts of interest.

REFERENCE

1. Abushukair HM, et al:2026 AACR Meeting. Abstract 5212. April 21, 2026.