Abatacept/Ruxolitinib and Screening for Concomitant Respiratory Muscle Failure to Mitigate Fatality of Immune-Checkpoint Inhibitor Myocarditis

Abstract

Immune-checkpoint-inhibitor (ICI)-associated myotoxicity involves the heart (myocarditis) and skeletal muscles (myositis), which frequently occur concurrently and is highly fatal. We report the results of a strategy that included identification of individuals with severe ICI-myocarditis by also screening for and managing concomitant respiratory muscle involvement with mechanical ventilation, as well as treatment with CTLA4-fusion protein abatacept and the Janus-kinase inhibitor ruxolitinib. Forty cases with definite ICI-myocarditis were included with pathological confirmation of concomitant myositis in the majority of patients. In the first 10 patients, using recommended guidelines, myotoxicity-related fatality occurred in 60%, consistent with historical controls. In the subsequent 30 cases, we instituted systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib and abatacept. Abatacept dose was adjusted using CD86-receptor occupancy on circulating monocytes. Myotoxicity-related fatality rate was 3.4%(1/30) in these 30 patients vs.60% in 1st quartile(p<0.0001). These clinical results are hypothesis-generating and need further evaluation.

Combination immunomodulation for immune-checkpoint-inhibitor-associated myocarditis

“…However, others will argue that data from randomized trials are needed to truly validate such a regimen, particularly one with potentially detrimental effects on the antitumour immune response and with substantial financial costs. Even in this well-performed observational study, it is notable that two patients remained ventilator-dependent 6 months after therapy and eight additional patients died of other causes (including COVID-19 and sepsis) 6 , thus providing potential confounders. Although clinicopathological characteristics were relatively well-balanced between the first and second groups, it is possible that earlier diagnostic assessment for myocarditis (owing to better awareness) or other factors contributed to the improved outcomes in the latter group.…”

“…Furthermore, intensive monitoring of respiratory status was initiated for these 30 patients, with prompt elective ventilatory support provided for those with early signs of respiratory failure ( n = 8). Impressively, only 1 patient in this second group died as a result of ICI-associated myotoxicity (3.4%) 6 .…”

“…Abatacept has successfully been used for the treatment of ICI-associated myocarditis in individual case reports 8 , whereas ruxolitinib has less supporting evidence for this indication. The combination has at least a plausible complementary mechanistic rationale, as noted by Salem et al 6 , given that abatacept might have slower-onset and more T-cell-specific effects, whereas ruxolitinib has more rapid activity and also modulates innate immune function. The authors further provided preclinical support using a well-described Ctla4 +/− Pdcd1 −/− mouse model of ICI-associated myocarditis 9 ; RNA-sequencing data demonstrated that JAK2 and the JAK–STAT signalling pathway more broadly are substantially upregulated in cardiac tissue from these mice relative to unaffected Ctla4 +/+ Pdcd1 −/− control mice 6 .…”

“…The combination has at least a plausible complementary mechanistic rationale, as noted by Salem et al 6 , given that abatacept might have slower-onset and more T-cell-specific effects, whereas ruxolitinib has more rapid activity and also modulates innate immune function. The authors further provided preclinical support using a well-described Ctla4 +/− Pdcd1 −/− mouse model of ICI-associated myocarditis 9 ; RNA-sequencing data demonstrated that JAK2 and the JAK–STAT signalling pathway more broadly are substantially upregulated in cardiac tissue from these mice relative to unaffected Ctla4 +/+ Pdcd1 −/− control mice 6 . JAK2 was also found to be overexpressed in endomyocardial biopsies samples from an independent group of patients with ICI‐associated myocarditis ( n = 9), compared with ICI‐treated patients without myocarditis ( n = 4) 6 .…”

“…Within this context, Salem et al 6 recently published their experience in treating 40 consecutive patients who were admitted to a single cardio-oncology unit (at Hôpital Pitié‐Salpétrière, Paris, France) for ICI-associated myocarditis using various therapeutic strategies. The initial 10 patients received guideline-based care between mid-2018 and early 2020, with high-dose steroids and — in most patients — additional second-line therapies, including fixed-dose abatacept (10 mg/kg every 2 weeks; n = 7), plasmapheresis ( n = 8) and/or mycophenolate mofetil ( n = 4).…”