Myocarditis is a rare but highly lethal immune-related adverse event that can occur during treatment with checkpoint inhibitors. The optimal management of such myocarditis is as yet unclear; most cases are treated with high-dose steroids.
Successful treatment with novel monoclonal antibody (MAB) products has now been reported for two patients who were not responding to steroids.
In one case, a single dose of the MAB alemtuzumab (Campath, Millennium and ILEX Partners) led to a complete resolution of cardiac symptoms, researchers report in a letter to the New England Journal of Medicine.
This is most likely the first such case worldwide of the use of alemtuzumab in this setting, explained Khashayar Esfahani, MD, of McGill University in Montreal, Canada, who is the corresponding author of the article.
“Alemtuzumab is an extremely powerful drug, and as an analogy, while other MABs are more of a targeted strike, alemtuzumab is like the nuclear bomb,” he told Medscape Medical News. “It wipes out pretty much everything — T cells, B cells, monocytes, natural killer cells, and so on.
“Its use should be limited as a safety net if all other immunosuppression approaches fail,” Esfahani continued. “What it basically does is to ‘reset’ the immune system by wiping out all current cells, then allowing the bone marrow to repopulate the system with fresh new cells.”
The second case, also reported in a letter to the journal, describes how the use of abatacept (Orencia, Bristol-Myers Squibb), a selective T-cell costimulation modulator, led to resolution of severe, glucocorticoid-refractory myocarditis that was also induced by an immune checkpoint inhibitor.
“Abatacept is an agonist specifically targeting the pathways antagonized by immunotherapy for cancer — the immune checkpoint inhibitors,” said lead author Joe-Elie Salem, MD, PhD, associate professor of medicine, Sorbonne University, Paris, France.
Salem believes that abatacept has been used before in this setting for patients with similar complications from immunotherapy and that it could be considered for patients who are experiencing immune-related myocarditis and whose conditions are refractory to the standard of care. “But, of course, this deserves further appropriate evaluation,” he told Medscape Medical News.
Almost Half of Cases Are Fatal
The first cases of fatal myocarditis associated with immunotherapy were reported in 2016. Two patients with melanoma developed lethal myocarditis accompanied by myositis after being treated with a combination of nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb) (N Engl J Med. 2016;375:1749-1755).
In 2017, the number of reports of severe myocarditis following treatment with immunotherapy checkpoint inhibitors increased “substantially,” with 101 cases reported across cancer types. Almost half of all cases (46%) were fatal, even among patients who had received monotherapy.
Response With Alemtuzumab
Alemtuzumab is a recombinant DNA-derived humanized monoclonal antibody that is directed against the 21–28 kD cell surface glycoprotein, CD52. It has been approved for the treatment of B-cell chronic lymphocytic leukemia (as Campath) and for relapsing multiple sclerosis (as Lemtrada).
The patient treated with this product was a 71-year-old woman who was receiving pembrolizumab (Keytruda, Merck &Co) as first-line treatment for stage IV melanoma. The patient developed shortness of breath and ptosis following her second cycle. Laboratory tests showed elevated concentrations of high-sensitivity troponins I and T. Cardiac MRI confirmed the diagnosis of myocarditis. Additionally, she had high levels of creatine kinase, aminotransferases, and acetylcholine-receptor antibodies. Electromyographic results confirmed the presence of the myositis–myasthenia gravis, which has been observed to overlap in about a quarter of patients with myocarditis.
The patient required mechanical ventilation. She was treated with pulse methylprednisolone sodium succinate at a dose of 1 g/day for 3 days, followed by 2 mg/kg daily, then mycophenolate mofetil (CellCept, Genentech) at a dose of 1 g twice daily for the myocarditis. She also underwent daily plasmapheresis for 5 days and received intravenous rituximab weekly at a dose of 375 mg/m2 for the myasthenia gravis.
Her initial response to immunosuppression was promising, but she subsequently developed life-threatening cardiac arrhythmias consisting of sustained and nonsustained ventricular tachycardias and fast paroxysmal atrial fibrillation that alternated with bradycardia. Cardiac pauses developed 18 days later, despite the fact that she continued to receive immunosuppression at maximum dose.
The onset of the cardiac arrhythmias was associated with a worsening of her biochemical variables, “which reflected an overall immunosuppression failure,” the authors note.
A single dose of alemtuzumab 30 mg was administered to induce rapid cytolytic immunosuppression. The result was a rapid depletion of T cells. Her arrhythmia resolved, and biochemical values normalized. The patient was gradually weaned off the other medications during a 4-week period without recurrence of any cardiac events.
“Given the extreme rarity of this condition, I do not expect this drug to be studied in further clinical trials,” said Esfahani. “However, what is reassuring is that the drug has extensively been used in the organ transplant setting to both prevent rejection and acutely resolve it. Similarly, you can think of immune myocarditis from checkpoint inhibitor as organ rejection without transplantation.”
More Cases Can Be Expected
Approached for comment, Tomas G. Neilan, MD, MPH, director, Cardio-Oncology Program, Massachusetts General Hospital, Boston, pointed out that the use of immune checkpoint inhibitors will continue to increase, and with that, the number of myocarditis cases will also rise.
“Based on projections, about 600,000 patients a year will be eligible for an immune checkpoint inhibitor by 2020–2022,” he said. “If one estimates that 0.5% will get myocarditis, then that is 3000 cases per year.”
There are no data regarding treatments except for steroids, he noted. He said that, to date, there have been case reports of the use of infliximab (Remicade, Janssen), a chimeric IgG1 monoclonal antibody that blocks tumor necrosis factor–alpha; intravenous immunoglobulin; plasmapheresis; mycophenolate mofetil; and antithymocyte globulin, a polyclonal antibody.
Regarding the question of whether alemtuzumab should be considered for certain cases, Neilan said, “I think if a patient fails high-dose steroids and mycophenolate mofetil and is sick, then it is a reasonable consideration.”
Douglas B. Johnson, MD, assistant professor of medicine and clinical director of the Melanoma Research Program, Vanderbilt University, Nashville, Tennessee, who was a coauthor on the abatacept article, said the use of monoclonal antibodies is “a very interesting approach.
“Current treatments largely center around steroids, which are associated with suboptimal outcomes given the high fatality rates, long-term complications in some cases, and unclear effects on the antitumor responses,” he noted.
“Monoclonal antibodies have been used successfully in colitis caused by immune checkpoint inhibitors — specifically, infliximab causes remissions in many cases of colitis that does not respond to steroids,” said Johnson.
Abatacept Resolves Symptoms
The second case involved a 66-year-old woman with metastatic lung cancer who was treated with nivolumab. After receiving three doses, the patient developed ptosis; diplopia; subacute, painful paresis that affected the proximal muscles; and chest pain. Electrocardiographic repolarization abnormalities occurred. Electromyography showed a myogenic disorder without neuromuscular dysfunction. A muscle biopsy revealed myositis.
High-dose intravenous methylprednisolone was administered at a dose of 500 mg per day for 3 days, and plasmapheresis was initiated on day 7. Troponin T levels increased to 5000–6000 ng/L, and premature ventricular contractions (10,000–14,000 per day with triplets) developed.
On day 17 following her admission, abatacept 500 mg was administered intravenously. The patient continued to receive abatacept every 2 weeks for a total of five doses. Her troponin level dropped quickly, and ventricular hyperexcitability resolved during the next 3 weeks. The ejection fraction remained normal, and arrythmias and myositis began to resolve. The patient was discharged 7.5 weeks after admission. Imaging carried out after she received her first dose of abatacept showed no tumor progression.
“I think both of these cases are very intriguing, and we need better options for treating immune checkpoint inhibitor–associated myocarditis,” said Javid J. Moslehi, MD, assistant professor of medicine and director of the Cardio-Oncology Program at Vanderbilt University Medical Center, who is coauthor of the abatacept article.
Johnson agrees. “I think alemtuzumab or abatacept are promising approaches and should be considered as an option in steroid-refractory and/or life-threatening myocarditis,” he said.
Esfahani has received personal fees from Brtistol-Myers Squibb outside the submitted work. Several coauthors disclosed relationships with industry. Johnson has relationships with several pharmaceutical companies outside the submitted work. Moslehi received grants and personal fees from Pfizer and Bristol-Myers Squibb and personal fees from Novartis, Takeda, Deciphera, Myokardia, Audentes, and Ipsen during the conduct of the study. Moslehi has a patent pending.