A new approach to treating myocarditis that develops in patients taking immune checkpoint inhibitors (ICI) could improve survival, say French researchers.
Immunotherapy-induced myocarditis is rare, occurring in about 1% of patients with cancer being treated with ICIs, but it can be severe and even fatal.
The usual, guideline-sanctioned approach to treating this adverse event is to administer high-dose glucocorticoids with the addition of immunotherapies based on response.
Instead, the French team has developed a treatment approach that tackles the root cause of the problem, the autoreactive T cells triggered by ICI therapy. They used high-dose abatacept and ruxolitinib, and mechanical ventilation as needed.
The team compared the two approaches in patients who developed myocarditis at their center, the Assistance Publique–Hôpitaux in Paris, France. These patients were being treated with ICI therapy primarily for metastatic melanoma or lung or kidney cancer. They were a median of 72 years old and 58% were men.
The fatality rate was 60% among 10 patients treated the usual way, a rate consistent with past reports.
After the study team switched to their new approach, just one of the next 30 patients died, yielding a fatality rate of 3.33%.
The findings were published recently in Cancer Discovery.
“The significant improvement in outcomes when patients are treated with targeted therapies is very suggestive that this regimen is helpful,” lead investigator Joe-Elie Salem, MD, PhD, a cardio-oncologist at Sorbonne University in Paris, France, said in a press release.
“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,” he commented.
However, “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,” he said.
Approached for comment, Nicolas Palaskas, MD, a cardiologist at MD Anderson Cancer Center, Houston, Texas, called the approach “novel.”
“The current consensus recommendations are to initiate steroids and wait for further immunomodulatory therapy based on response to steroids. However, the upfront use of immunomodulatory therapy is increasingly being explored, as in this study,” to target the underlying cause of ICI myocarditis, “which is still not completely understood,” Palaskas told Medscape Medical News.
The French study is the largest to date to test the approach, but even with the promising results reported in this paper, Palaskas said further studies are needed to “ultimately guide targeted interventions for this uncommon but fatal toxicity.”
A Mechanism-Based Approach
Abatacept, which is approved for rheumatoid arthritis, prevents macrophages from activating T cells and is already sometimes used for ICI-related myocarditis, but at lower doses than used by the French team. Ruxolitinib, meanwhile, inhibits the immune-stimulatory proteins JAK1 and JAK2, which also decreases T-cell activation.
In designing their approach, the French team thought the combination would be a good one-two punch because although abatacept effects are potent and durable, they can take several weeks to emerge. Ruxolitinib, on the other hand, has a short half-life and begins to work almost immediately.
In keeping with current guidelines, the first 10 patients in their cohort were treated with high-dose boluses of corticosteroids regardless of symptoms and severity grade. Grade 3 or higher cases were also treated with plasmapheresis, mycophenolate mofetil, and abatacept at 10 mg/kg every 2 weeks.
Treatment of the next 30 patients was based more closely on disease severity and extent of symptoms plus monitoring all patients for concomitant respiratory muscle failure.
Eight patients were ultimately placed on a ventilator. The one myocarditis death in the experimental arm was in a patient who declined ventilation.
Severe cases under the new rubric triggered the prompt initiation of abatacept and ruxolitinib. Corticosteroids were also used in some cases but at lower doses than previously in order to prevent sarcopenia, a steroid side effect that can inhibit respiratory muscle recovery.
Abatacept was dosed at 20 mg/kg with three doses in the first 2 weeks and doses adjusted to ensure strong CD86‐receptor occupancy on circulating monocytes; the goal was 80% or higher occupancy within 72 hours of abatacept initiation.
Patients stayed on abatacept and ruxolitinib for 1-2 months until resolution of severe disease.
There was no difference in myotoxicity severity between the two treatment groups, including peak troponin levels and the presence of severe arrhythmias and heart and respiratory muscle failure.
The investigators noted that it’s unclear to what extent their novel approach altered the anti-cancer effects of ICIs or if it might also be useful for other ICI adverse events.
The work was funded by the Clinical Investigation Center in Paris, France. Several authors had industry disclosures, including Salem, who is an advisor for Bristol Myers Squibb, maker of abatacept, and Novartis, a marketer of ruxolitinib. He also holds patents related to the treatment of ICI-related immune adverse events. Palaskas reports no relevant financial relationships.
Cancer Discovery. Published February 23, 2023. Abstract.
M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected].
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