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Immune checkpoint inhibitors linked to myocarditis
Reports of severe myocarditis among patients treated with immune checkpoint inhibitors have been increasing, according to a study of WHO case safety reports.
Among the reported cases of severe myocarditis, almost half of the patients died.
“We have always been concerned about the potential for off-target immune responses to these new immunotherapies, and this study is the first to track the growing number of reports of myocarditis and other serious events with the use of single agents or combination therapies,” Javid J. Moslehi, MD, assistant professor of medicine and director of the cardio-oncology program at Vanderbilt University Medical Center, said in a press release.
Moslehi and colleagues used data from WHO’s VigiBase of individual safety case reports to identify 101 patients (median age, 69 years; range, 20-90) with severe myocarditis following treatment with immune checkpoint inhibitors. Cancer types ranged widely, the most common of which included melanoma and lung cancer.
Of the 101 incidents of myocarditis, 57% of patients were treated with anti-PD-1 therapy and 27% were treated with combination therapy of anti-PD-1/PD-L1 and anti-CTLA-4.
Forty-six percent of patients died.
Among patients taking combination anti-PD-1/PD-L1 and anti-CTLA-4, 67% died compared with 36% of patients taking anti-PD-1/PD-L1 alone (P = .008).
Three of five patients treated with ipilimumab who developed myocarditis died.
“We have been tracking these cases of severe myocarditis and deaths for the past year to gain a better understanding of the frequency of these events and the speed of myocarditis onset following the initial exposure to immune checkpoint inhibitors,” Moslehi said.
Fifty-nine patients had available dosing information. Among those, 64% received one or two doses before developing myocarditis.
Among the 33 patients with data on precise timing of myocarditis onset, the median onset was 27 days (range, 5-155). Most cases (76%) occurred during the first 6 weeks of treatment.
The researchers were unable to assess for comorbidities; however, few assessed patients reported receipt of concurrent cardiovascular or diabetes medications.
“It was interesting to note that three-fourths of these patients were not receiving other cardiovascular or diabetes medications at the time of treatment, which suggests that these patients did not have an underlying diagnosed cardiac or diabetes-related condition,” Moslehi said.
Forty-two percent of patients also experienced high-grade immune-related adverse events, including myositis (25%) and myasthenia gravis (11%).
During the study period, the researchers observed a 76% increased in incidence reporting, possibly due to increased use of immune checkpoint inhibitor therapy.
“Myocarditis was observed across immune checkpoint inhibitor regimens, although it remains too early to determine whether the incidence differs between use of anti-PD-1 and anti-PD-L1 drugs,” the researchers wrote. “Furthermore, this condition occurs early on during therapy and across cancer types.” – by Cassie Homer
Disclosures: Moslehi reports consulting roles with Bristol-Myers Squibb, Daiichi Sankyo, Heart Biologics, Novartis, Regeneron, Pfizer and Pharmacyclics. Please see the full study for all other authors’ relevant financial disclosures.
Perspective
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Ever since the first reports of myocarditis associated with immune checkpoint inhibitors — including a very detailed description of two deaths that two members of this research group published in 2016 in The New England Journal of Medicine — clinicians have had a responsibility to discuss with their patients the rare but severe side effects that are possible following treatment with immune checkpoint inhibitors and emphasize the need to be vigilant about these effects.
Both patients and physicians have welcomed this new class of anticancer therapeutic agents, given the substantial and long-lasting beneficial effects that have been observed in the treatment of patients with a variety of tumor types. Physicians should be cautious, however, not to downplay this type of therapy as producing few side effects or as being easier to tolerate than chemotherapy. The side effects are just different and, in many cases, unpredictable.
Myocarditis appears to present early in the administration, and it is associated with myositis and generalized muscle weakness. T-cell infiltrates appear to be the culprit for myositis and myocarditis, which also can affect the heart electrical system, producing heart block and other dysrhythmias. Of note, mouse models of PD-1 deficiency predicted these types of side effects many years ago, as PD-L1 was shown to regulate T-cell-mediated injury in the heart.
In this study, Moslehi and colleagues discussed the observation of increased reporting of fatal immune checkpoint inhibitor-related myocarditis. Using WHO’s database of individual case safety reports, the authors identified 101 cases of severe myocarditis following immune checkpoint inhibitor treatment. More than half (57%) of these patients were receiving anti-PD-1 monotherapy.
It is extremely concerning that myocarditis developed after only one or two doses on average, and that the death rate for severe myocarditis was high (46%). The reporting rate appeared increased in 2017 compared with prior years, possibly due to the increasing use of this agent, but also possibly pointing toward increased recognition of the casual relationship for these events. Unfortunately, at this point, there is not a clear algorithm to recognize ahead of time the patients most predisposed to develop myocarditis or to identify it early enough to make a clinical difference.
It has been suggested that patients with previous myocardial infarction may have increased PD-1 expression, as reperfusion healing may increase lymphocytes infiltration. Obtaining a baseline ECG — with follow-up ECG for atypical symptoms — and possibly following with troponin for a couple weeks after the first administration may prove valuable in the early identification of this toxicity.
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