ICI-Related Myocarditis Deaths Down With Tailored Non-Corticosteroid Strategy

For immune checkpoint inhibitor (ICI)-associated myocarditis, increased vigilance of respiratory muscle failure and initiation of JAK‐STAT pathway inhibition led to a jump in patient survival at a Paris hospital.

Based on 40 consecutive cancer patients admitted to Assistance Publique-Hôpitaux de Paris with confirmed ICI-associated myocarditis, the incidence of related death dropped from 60% during the era of usual guideline-recommended care to 3.4% after clinicians started screening for and managing concomitant respiratory muscle involvement on top of high-dose abatacept (Orencia) and ruxolitinib (Jakafi) therapy (P<0.0001), reported Joe-Elie Salem, MD, PhD, of Sorbonne Université and Hôpital Pitié‐Salpêtrière in Paris, and colleagues.

Looking only at patients with severe cases of myocarditis, deaths occurred in 80% versus 5%, respectively (P<0.0001). Accounting for other causes of death such as COVID-19 and sepsis, all-cause mortality at 3 months was 60% versus 23% (P=0.03), and 70% versus 30% at 6 months (P=0.03), they noted in Cancer Discovery.

"Early management of respiratory muscle failure using mechanical ventilation and high‐dose abatacept with CD86 receptor occupancy monitoring combined with ruxolitinib may be promising to mitigate high fatality rates in severe ICI myocarditis," Salem and colleagues wrote.

Serial arterial blood gas tests and management of respiratory muscle involvement appeared critical in avoiding life‐threatening hypoventilation from receiving immunotherapy for various cancers in this group with myotoxicity, the group suggested.

"While our study is not a clinical trial, our results may provide a promising platform by which to best treat the growing population that presents with fulminant ICI‐myocarditis, with a mechanism‐based and personalized assessment of drug receptor occupancy," the authors noted.

Their first 10 study participants had received standard treatment with high-dose corticosteroids followed by second-line immunosuppressive agents as needed. Then came the next 30 patients, the center's first cohort to be treated with the new approach along with lower concomitant doses of corticosteroids.

Respiratory muscle involvement, present in over 70% of the overall cohort, was severe and required mechanical ventilation in over a third of patients.

Severe ICI-associated myocarditis was observed in eight of the first 10 patients, and 22 of the subsequent group of 30. Of the latter group, 77% received ruxolitinib and 100% received abatacept.

"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 in a press release. "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."

Myocarditis is diagnosed in approximately 1% of cancer patients receiving ICI treatment, and nonspecific treatment with high-dose corticosteroids leaves this population with a mortality rate between 20% and 60%, according to historical data, the study authors noted.

As such, they sought to find a role for anti-inflammatory agents targeting the autoreactive T-cell activity that can lead to myotoxicity.

Abatacept, approved for the treatment of rheumatoid arthritis since 2005, prevents macrophages from activating T cells and is sometimes used at low doses to help treat ICI-related myocarditis. Ruxolitinib decreases T-cell activation by inhibiting the immune-stimulatory proteins JAK1 and JAK2, and is FDA approved for myelofibrosis unsuited for stem cell transplant. (Its topical formulation Opzelura is marketed for repigmentation in vitiligo and short-term relief for atopic dermatitis.)

"Altogether, our results are promising and should guide further research assessing the question of the optimal drug mix, dosage and duration to be used to preserve ICI therapeutic effect while treating a severe [immune-related adverse event], the subject of further ongoing clinical study," Salem and colleagues wrote.

Their dose-finding ACHLYS trial is scheduled to be completed late next year.

The 40 participants in the current observational study had confirmed ICI-associated myocarditis that manifested in increased troponin-T in all patients and abnormal ECG features in most. Ventricular tachycardias were noted in 30%, and severe conduction disorders were seen in 23%.

Participants had a median age of 72 years, 58% were men, and most had lung, skin, or genitourinary cancers.

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