New Regimen May Protect Cancer Patients from Rare Heart Damage Resulting From Immunotherapy
Drugs and mechanical ventilation appear to be effective in preventing potentially fatal damage to cardiovascular muscles, including those in the heart, after immune system is stimulated by immune checkpoint inhibitors.
Doctors in France have developed a new treatment regimen to protect cancer patients from rare but potentially fatal side heart damage from the immunotherapy used to treat their cancer, dropping the mortality rate from this condition from 60 percent to 3.3 percent in their study cohort, according to a study published in Cancer Discovery, a journal of the American Association for Cancer Research (AACR).
“Immunotherapy wakes up the immune system, but it sometimes wakes up autoreactive T cells that destroy your own body,” said Joe-Elie Salem, MD, PhD, senior author of the study, a professor at Sorbonne Université, and executive assistant director of one of France’s Clinical Investigation Centers focused on cardio-metabolism. “The heart is at the top of the list of organs you don’t want to harm.”
Immunotherapies known as immune checkpoint inhibitors (ICI) are very effective in treating some cases of cancer, but in rare cases they trigger the immune system to attack muscle cells in the cardiovascular system. This type of muscle damage is known as myotoxicity, or myocarditis when it involves the heart muscle.
Patients undergoing ICI treatment are routinely monitored for myocarditis, which occurs in approximately 1 percent of patients receiving ICI therapy. If signs of myocarditis develop, patients are typically given high-dose corticosteroids. This relatively nonspecific strategy can be too little treatment for some patients and too much treatment for others, Salem said, leading to a mortality rate between 20 and 60 percent.
Salem’s study of cancer patients who developed cardiotoxicity after ICI treatment indicated that those treated with abatacept (Orencia), ruxolitinib, and/or mechanical ventilation as needed, had a significantly lower mortality rate than those treated with corticosteroids.
Abatacept, approved for the treatment of rheumatoid arthritis, prevents macrophages from activating T cells and is sometimes used at low doses to help treat ICI-related myocarditis. Ruxolitinib inhibits the immune-stimulatory proteins JAK1 and JAK2, thereby also decreasing T-cell activation.
While abatacept can take several weeks to reach optimal efficacy, making it a durable, long-lasting treatment, ruxolitinib has a short half-life and begins working almost immediately. Salem and colleagues hypothesized that the two could form a powerful combination in patients with severe myotoxicity.
Forty consecutive cancer patients admitted to Assistance Publique–Hôpitaux de Paris with confirmed ICI-related myocarditis were evaluated in this study. The first 10 were treated according to the standard of care, including high-dose corticosteroids and, in the event of resistance, other immune suppressants as determined by the care team. The subsequent 30 patients were treated according to their disease severity and the extent of myotoxicity.
Twenty-six eligible patients in the experimental group received low-dose corticosteroids and three infusions of high-dose (20 mg/kg) abatacept. Twenty-two of the patients in this group had severe (grade 3+) myocarditis, and 17 of them were given ruxolitinib in addition to abatacept.
All patients in the experimental treatment group were regularly monitored for the spread of myotoxicity to the respiratory muscles to determine eligibility for a ventilator, if necessary. Ten patients met the criteria for elective ventilation, and eight were placed on a ventilator.
The rate of myotoxicity-related mortality was 60 percent among patients in the standard-of-care group and 3.3 percent among patients in the experimental treatment group; the one myotoxicity-related death in the experimental treatment group occurred in a patient who refused elective ventilation.
For patients in the standard-of-care group, the overall survival rate was 40 percent at 3 months and 20 percent at 6 months post-treatment. For patients in the experimental treatment group, the overall survival rate was 77 percent at 3 months and 70 percent at 6 months post-treatment.
“While this is not a randomized clinical trial, the significant improvement in outcomes when patients are treated with targeted therapies is very suggestive that this regimen is helpful,” Salem said.
He further emphasized that the personalized medicine aspect of this new regimen to manage myotoxicity is equally as important as the treatments themselves.
“We have to acknowledge that not all patients need the whole package; you may need all of it for the severe cases and only some of it for intermediate cases, or even none of it for persistently asymptomatic cases,” Salem said. “Even if it’s debated in the literature whether we should screen for and monitor the severity of every patient, for me, there’s no question.”
Limitations of this study include a small sample size, which prevented subgroup analyses based on patient demographics and the type of ICI treatment received. This study was not a randomized clinical trial.