Checkpoint Inhibitors May Induce Myocarditis

Immune checkpoint inhibitors have revolutionized treatment for some types of melanoma, Hodgkin lymphoma, and other malignancies. However, these immunotherapies can also cause serious, albeit rare, side effects, including myocarditis, or heart inflammation.

Until now, immune checkpoint inhibitor–induced myocarditis, which seems to be more common when the drugs are used in combination, has primarily been studied through anecdotal reports and case studies. “About 2 years ago we recognized patients where, after treatment with immunotherapies, the immune system would attack the heart itself, causing cardiac inflammation,” explains lead author Javid Moslehi, MD, director of the Cardio-Oncology Program at Vanderbilt-Ingram Cancer Center in Nashville, TN, who described two cases in The New England Journal of Medicine in 2016.

In their new Lancet report, Moslehi and colleagues tapped the VigiBase World Health Organization database, identifying 101 cases of myocarditis following treatment with immune checkpoint inhibitors. Patients varied by age, cancer type, and treatment, and 75% were not taking cardiovascular or diabetes medications. Myocarditis occurred alongside musculoskeletal inflammation in 25% of patients and myasthenia gravis in 10% of patients, and was fatal in 46% of cases. In 33 patients for whom data were available, the median onset of myocarditis occurred 27 days after treatment began.

“Myocarditis is still a rare event at the end of the day. However, I think we have to recognize that we're playing with new tools for patients, and sometimes some of these tools can backfire,” Moslehi says. Myocarditis has the same symptoms as other cardiac issues, making it difficult to diagnose, and physicians are still determining the best course of treatment, which is currently steroids.

“The last thing we would want to do is encourage people to avoid transformative, life-saving immunotherapies based on concerns of rare toxicities,” adds senior author Douglas Johnson, MD, MSCI, also of Vanderbilt-Ingram. “The goal is much more to educate and understand so we can manage, prevent, and treat, rather than to do any alarm sounding.”

Johnson hopes a better understanding of toxicities such as myocarditis will not only improve diagnosis and treatment, but also accelerate the development of more multidrug combinations, which have raised concerns about side effects.

To that end, the researchers are using human tissue samples and mouse models to delve into the molecular and biological basis of myocarditis. They have also launched www.cardioonc.org, an effort to share resources and compile incidents of serious cardiac side effects related to immune checkpoint inhibitors.

Michael Postow, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, praises the researchers for using the database to “go beyond anecdotal reports and case series and look for patterns among the much larger communal pool of all the patients that are having this toxicity.”

For Postow, physician awareness of rare side effects is key, especially as immune checkpoint inhibitors become an increasingly common cancer treatment. “These toxicities are too rare for any one individual physician to have a lot of experience in managing tons and tons of cases,” he says. “We need to build systems where we can extend our own clinical experience beyond ourselves, and care for the community of patients that are going to be receiving these drugs in an aggregate way.” –Catherine Caruso