Oncologists play key role in diagnosing immune checkpoint inhibitor-induced myocarditis
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Results of a pooled meta-analysis presented at last year’s ASCO Annual Meeting and published in Journal of Clinical Oncology showed that among 6,925 participants in cancer clinical trials, only 0.6% developed an immune checkpoint inhibitor (ICI)-related major adverse cardiac event, with less than half (45%) of those cases being myocarditis.
However, when myocarditis occurs it presents a substantial mortality risk — results of the same meta-analysis showed a myocarditis-related death rate of 22.5%.
“As more people receive immunotherapy, more people will be at risk for developing myocarditis,” Namrata (Neena) Vijayvergia, MD, assistant chief of gastrointestinal medical oncology at Fox Chase Cancer Center, told Healio | HemOnc Today.
Heart-related issues should not be taken lightly, she said, adding that early recognition is the most important factor in successful outcomes when treating ICI-induced myocarditis.
“I bring a cardio-oncologist on board right away whenever I have a concern about myocarditis,” Vijayvergia said. “I would want that for myself if it were my health.”
No standardized method exists for diagnosing and treating ICI-induced myocarditis, but a multidisciplinary approach can lead to prompt diagnosis, rapid intervention and positive outcomes, according to experts.
Healio | HemOnc Today spoke with cardio-oncologists and others in the field about how physicians can identify patients at risk for ICI-induced myocarditis and approaches they can take to minimize the effects of this condition.
Multidisciplinary care
The relatively low incidence of ICI-induced myocarditis matters does not make it less of a concern to Abdul Rafeh Naqash, MD, assistant professor in the early phase division of Stephenson Cancer Center at University of Oklahoma.
Small numbers simply minimize the large risks for myocarditis or any other cardiac toxicity, he said.
“The potential for some of these events getting worse is very high,” he told Healio | HemOnc Today. “Cardiac toxicities are big red flags.”
The issue is not just cardiac damage, but oncologists will often lose their ability to rechallenge patients with typically effective ICIs, which increases the risk for cancer mortality.
“The problems associated with identifying cardiac toxicities is significantly high, and early intervention is very important,” he said.
Early intervention requires a multidisciplinary approach, according to Naqash. This includes timely collaboration with a cardiologist or cardio-oncologist if a patient with cancer has baseline cardiac comorbidities and ICIs are the recommended treatment, he noted.
“Multidisciplinary care in this setting is extremely important,” Naqash said. “Full cardiac workups are not necessary for all patients who receive ICIs, but treatment of high-risk patients should involve multidisciplinary teams. It’s all about being cognizant that something like [myocarditis] can happen and then triaging patients appropriately based on their baseline risk factors.”
The pathophysiology of ICI-induced myocarditis
If the immune system were an engine, administration of an ICI would be like taking your foot off the brake and putting it on the accelerator, according to Joe‐Elie Salem, MD, PhD, full professor at Sorbonne Université and director of Clinical Investigation Center Paris Est.
“Autoreactive T cells that normally are turned down are completely unleashed by immune checkpoint inhibitors,” he told Healio | HemOnc Today.
ICI-induced myocarditis is thought to occur because those autoreactive T cells target antigens shared with heart muscle.
However, Salem referred to the condition as “myotoxicity” rather than “myocarditis” because the autoreactive T cells attack more than just the myocardium and are activated against antigens on muscle cells that affect respiratory function.
This can lead to hypercapnia because dysfunctional respiratory muscles — including the diaphragm — allow for the accumulation of too much carbon dioxide in the blood, Salem noted.
“Cardiologists call it myocarditis, while internists or rheumatologists call it myositis,” Salem said. “Neurologists call it myasthenia gravis, but at the end of the day this is the result of the same autoreactive T cells attacking all of the muscles with shared antigens — the heart being the most critical among them.”
Exactly how ICI-induced myocarditis occurs and which antigens are involved is still a matter of debate, according to Javid Moslehi, MD, associate professor in residence in the department of medicine and chief of the cardio-oncology and immunology program at University of California, San Francisco.
Moslehi was part of a group of investigators who conducted a preclinical analysis aiming to understand the pathogenesis of ICI-associated myocarditis. The results suggested ICI-induced myocarditis is an “antigen-driven, cytotoxic T cell-mediated toxicity,” the researchers wrote in a 2022 study published in Nature.
Using a mouse model that mimicked features of ICI-induced myocarditis, the group identified the cardiac-specific protein alpha-myosin as an antigen source responsible for the development of inflammation leading to myocarditis.
The study also identified alpha-myosin-expanded T-cell receptors (TCRs) that overlapped with TCRs found in a separate investigation of the heart and skeletal muscle of three patients with ICI-induced myocarditis.
“Although the presence of shared clones is insufficient to establish causality, these data suggest that alpha-myosin may be an important autoantigen in immune checkpoint inhibitor-induced myocarditis,” the researchers wrote.
Preclinical mouse models require more robust validation because they do not always accurately reflect the course of ICI-related toxicity seen in humans, Moslehi noted.
“It’s not straightforward from a methodology standpoint, although our study showed that in the mouse model — and perhaps in humans — there is an antigen involved,” he said. “It's certainly causal in mice, and it appears associative in humans.”
Identifying risk factors
There are a limited number of known risk factors for developing ICI-induced myocarditis, and researchers have not yet been able to “pinpoint the clear cardiac risk factor that drives the ship,” Moslehi said.
“Although clinicians cannot predict who will develop treatment-related myocarditis, combination therapy seems to be the main risk factor,” Moslehi said.
In the pooled analysis presented at last year’s ASCO Annual Meeting, 72% of patients who developed myocarditis had been treated with anti-PD-1/PD-L1-based combination regimens, the most common of which included an anti-CTLA-4 inhibitor (92%).
The role of oncologists on the front line of detecting treatment-related cardiac toxicity will become even more vital as newer drugs are developed, Salem advised.
“The additional risk for myocarditis by combining immune checkpoint inhibitors has been reproduced very consistently in studies,” he said. “We can expect this risk to increase with new combinations upcoming, including novel strategies with LAG-3 inhibitors already being tested.”
On the positive side, the timeframe in which ICI-induced myocarditis occurs is predictable based on clinical experience, Salem said.
From the cardiologist’s perspective, Salem advised that individuals embarking on treatment with ICIs have a baseline cardiac enzyme workup, cautioning that abnormalities will often exist before treatment in up to 20% of patients.
“If there are abnormalities, you need to do a more comprehensive workup that involves cardiology colleagues before starting therapy,” he said. “Then you have monitor it for at least 2 to 3 months after the start of treatment because myocarditis begins within the first few doses of an immune checkpoint inhibitor and is highly unlikely to happen later in the treatment course.”
This typically coincides with the first several doses of a therapeutic regimen, depending on the agents involved, disease stage and indication, Salem said.
After the initial 2- to-3-month period, he advised physicians could be “more lenient in terms of control of the screening strategy.”
Lack of good biomarkers
Developing reliable biomarkers specific to myocarditis is an active area of investigation, according to Moslehi.
“We have biomarkers that are very sensitive [to cardiac toxicity] but lack specificity,” Moslehi said.
“Cardiac troponin, creatine kinase and B-natriuretic peptide levels are all very sensitive to the occurrence of cardiac damage, but they do not rule out other causes, such as a heart attack. Furthermore, common cardiac biomarkers do not confirm the use of ICIs as the pathogenesis for myocarditis,” he added.
An international group of researchers conducted a study of individuals diagnosed with myocarditis after receiving ICIs to determine whether any blood-based biomarkers could be linked to ICI-induced myocarditis.
Results of the observational cohort analysis of 2,606 adults (mean age, 64 ± 13 years; 60.7% men) published in JACC Cardio-Oncology revealed that patients had elevated levels of high-sensitivity troponin T, aspartate aminotransferase, alanine aminotransferase, creatine phosphokinase (CPK) and lactate dehydrogenase.
Moreover, 95% of patients who developed ICI-induced myocarditis had elevations of at least three biomarkers compared with 5% of those who did not have myocarditis.
The investigators observed a significant association between elevated CPK levels — a routinely collected noncardiac blood-based biomarker indicative of muscle damage — and increased risk for ICI-induced myocarditis. Multivariate analysis identified CPK as the only noncardiac-specific biomarker associated with increased hazard of developing ICI-induced myocarditis (HR = 1.83; 95% CI, 1.59-2.1). Meanwhile, CPK elevations had 99% sensitivity and 23% specificity for identifying myocarditis.
The results emphasize the potential benefits of routinely monitoring for immune-related adverse effects using CPK levels, according to the study’s lead author, Salim S. Hayek, MD, medical director of University of Michigan's Frankel Cardiovascular Center.
“If myocardial injury occurs in the absence of a rise in CPK, then immune checkpoint-related myocarditis is highly unlikely,” he told Healio | HemOnc Today. “Diagnosing [ICI]-induced myocarditis is challenging, given there is no single test that can differentiate it from other causes of cardiac injury. These findings arm clinicians with an effective approach to recognize the complication and diagnose with higher confidence.”
Salem, one of the co-authors of the study, told Healio | HemOnc Today he is confident that ongoing research will soon allow physicians to stratify which biomarkers are most sensitive and specific to myocarditis.
He also said the results reinforce the need for oncologists to play an active role in monitoring the development of treatment-related myocarditis.
“Oncologists play a critical role in diagnosing this toxicity through prompt screening of these patients,” he said.
However, as a clinician with experience in both Europe and the United States, he realizes debate exists about whether systematic screening for myocarditis should be conducted prior to initiation of ICIs, given its rareness.
“In Europe, we come from a different perspective because the cost of screening strategies is way cheaper,” he said. “But from my perspective, when you're starting a patient on a drug that is going to cost $100,000 to $150,000 per year, then doing a few ECGs here and a troponin check there is unquestionably the fastest way to diagnosis myocarditis.”
Treating symptomatic patients
There is no cure for myocarditis, only treatment to reduce its severity until it, hopefully, resolves, according to Naqash.
The best chance for a nonfatal outcome begins with early detection.
“Early interventions that involve routine echocardiograms and monitoring for symptoms are important because by the time myocarditis fully manifests it has a very high mortality,” Naqash said. “Even if the patient survives, myocarditis often leads to discontinuation of what would otherwise be a very important and effective therapy option.”
“Once a patient exhibits symptoms of cardiac abnormalities, oncologists need to consult a cardiologist,” Moslehi said. “Get the cardiologists involved early.”
Vijayvergia — who recently treated a patient who developed ICI-induced myocarditis — agreed and said catching the condition in its earliest stages requires proactive surveillance.
“Myocarditis is very rare, but until you look for it, you will not find it,” she said.
Detection begins with the simplest of steps, she added, including educating patients about ICI-induced myocarditis and symptoms they should report.
“Every visit to my practice, I ask patients about worsening shortness of breath,” Vijayvergia said. “This is to monitor for pneumonitis, which often occurs in patients who receive immune checkpoint inhibitors but is also one of the first signs of worsening cardiac function.”
Next, she determines if the patient has any fluid in the lungs or swelling in the legs, which could indicate congestive heart failure.
Vijayvergia’s patient had new-onset swelling in her legs while receiving an ICI for a gastrointestinal cancer indication. A comprehensive evaluation also revealed the patient had gained 14 pounds in 2 weeks.
“It's difficult to gain weight when you are receiving cancer treatment,” she said. “That was the biggest red flag.”
Withholding further ICI therapy was the first step Vijayvergia took before handing over the cardiac portion of the patient’s care to a cardio-oncologist colleague.
She said stopping therapy immediately to assess whether it caused cardiac issues is paramount because there is lag time while the agent continues to exert its effects throughout the body.
“If a patient skips one dose after a few doses of immunotherapy, it really doesn’t affect the benefit because the drug is already working,” she said. “That also holds true for the damage because if you withhold the drug, it's not going to stop the damage immediately.”
If caught early enough, this type of intervention in tandem with steroids may be sufficient to resolve ICI-related myocarditis without any long-term issues, Vijayvergia said. More severe cases will require more aggressive approaches to prevent further cardiac events.
A novel treatment strategy
Although Salem advocated for a more liberal approach to screening, treatment of ICI-induced myocarditis beyond initial steroids may only be needed in severe cases.
“I don't recommend overtreating anyone,” he told Healio | HemOnc Today.
His approach after diagnosis is to stratify patients based on risk and determine who can benefit from traditional interventions vs. who requires “a more full package of treatment options,” he said.
Along with Moslehi, Salem and a group of investigators from France published a study in Cancer Discovery detailing a novel treatment approach to prevent fatalities once patients with ICI-induced myocarditis become symptomatic.
The motivation for the approach came after many of the first several patients Salem’s center treated for the condition died.
“The patients were dramatically sick, and mortality was 60%,” he said. “As a doctor, it’s hard to have half of your patients die quickly like that in your hands, and nothing we did worked.”
What the researchers needed was a way to “put the brakes on the immune checkpoint inhibitor accelerator,” Salem said.
The answer was systematic screening for respiratory muscle involvement coupled with active ventilation and treatment using ruxolitinib (Jakafi, Incyte) — a Janus kinase inhibitor — and abatacept (Orencia, Bristol Myers Squibb).
The results showed a stark difference in outcomes: the first 10 patients treated with guidelines-based care had a mortality rate of 60% due to myotoxicity, compared with just 3.4% among the next 30 patients treated with the experimental regimen.
“This is a game-changer, despite the study’s small sample size and nonrandomized nature,” Moslehi said. “We have been able to provide these highly symptomatic patients with strong immunosuppressives that seem to have worked well. This [research] may completely change the rules of the game in terms of how we approach treatment for this condition.”
References:
- Axelrod ML, et al. Nature. 2022;doi:10.1038/s41586-022-05432-3.
- Naqash AR, et al. Abstract 2508. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
- Naqash AR, et al. J Clin Oncol. 2022;doi:10.1200/JCO.22.00369.
- Salem JE, et al. Cancer Disc. 2023;doi:10.1158/2159-8290.CD-22-1180.
- Vasbinder A, et al. JACC CardioOncol. 2022;doi:10.1016/j.jaccao.2022.11.004.
For more information:
Salim S. Hayek, MD, can be reached at shayek@med.umich.edu; Twitter: @salimhayek.
Javid Moslehi, MD, can be reached at javid.moslehi@ucsf.edu; Twitter: @CardioOncology.
Abdul Rafeh Naqash, MD, can be reached at abdulrafeh-naqash@ouhsc.edu; Twitter: @thenasheffect.
Joe‐Elie Salem, MD, PhD, can be reached at joe-elie.salem@aphp.fr; Twitter: @DrJESalem.
Neena Vijayvergia, MD, can be reached at namrata.vijayvergia@fccc.edu; Twitter: @NVijayvergiaMD.
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