Cardiovascular Toxicities: Management of irAEs Guideline (Part 11)
An interview with Dr. Pauline Funchain from Cleveland Clinic, author on “Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.” She reviews the recommendations for cardiovascular toxicities in patients receiving ICPis, including overall cardiac toxicities (i.e., myocarditis, pericarditis & arrhythmias), and VTE in Part 11 of this 13-part series. For more information visit www.asco.org/supportive-care-guidelines
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BRITTANY HARVEY: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts.
My name is Brittany Harvey, and today we're continuing our series on the management of immune related adverse events. I am joined by Dr. Pauline Fontaine from the Cleveland Clinic in Cleveland, Ohio, author on "Management of Immune Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy, ASCO Guideline Update," and Management of Immune Related Adverse Events in Patients Treated with Chimeric Antigen Receptor T Cell Therapy, ASCO Guideline."
And today we're focusing on the cardiovascular toxicities in patients treated with immune checkpoint inhibitor therapy. Thank you for being here, Dr. Fontaine.
PAULINE FONTAINE: Thank you, Brittany, for the invitation.
BRITTANY HARVEY: First, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guidelines in the Journal of Clinical Oncology. Dr. Fontaine, do you have any relevant disclosures that are directly related to these guidelines?
PAULINE FONTAINE: So I do. My institution receives research funding from Pfizer and Bristol Myers Squibb for clinical trials where I'm a primary investigator. And I have done some consultation work with Eisai.
BRITTANY HARVEY: OK. thank you for those disclosures.
Then talking about the content of this guideline, what are the immune related cardiovascular toxicities addressed in this guideline?
PAULINE FONTAINE: So there are two major categories. One is an overall cardiovascular category. That includes myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, and vasculitis. That's overall. And there's a second category of venous thromboembolism.
BRITTANY HARVEY: Great. Then starting with that overall category, what are the key recommendations for identification, evaluation, and management of myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure, and vasculitis?
PAULINE FONTAINE: So in that overall category, I think it's important to recognize that there are symptoms that are a little bit more general. They may be cardiovascular. They may be pulmonary. But we have to be aware that some of these can be cardiovascular.
So that would include worsening fatigue, progressive or acute dyspnea. I think they're generally going to be other things, but you really have to recognize a potential cardiac IRE, as those can have major medical consequences.
I mean there are other things that are more obviously cardiac, like chest pain, arrhythmia, palpitations, acute onset peripheral edema. And it is important to note that they can, like every other IRE, happen at any time. In the literature, the median time to onset is 6 weeks, but the range is somewhere between 1.4 to 54, and we know that it can be all over the place with IREs in terms of presentation.
Then next would be evaluation. So with evaluation, whenever you see this type of side effect, fatigue, dyspnea, chest pain, it's natural to want to get an EKG troponin. I think that's a great place to start. And I think if there's more concern for cardiac type of IRE, then an echocardiogram, a chest X-ray, I think, are probably the next easiest evaluations to assess for cardiac IRE.
One of the important things to note is that cardiac IREs, especially myocarditis, tend to happen along with concurrent myocytis, so it's important to check a CPK to rule that in or rule that out. And typically, then if people need more evaluation, the cardiac MRI is the next step, but things like cardiac catheterization may be involved.
And so that's where I think it's really important with management to have cardiology involved early. I mentioned this briefly before, but it's really important to know that myocarditis has a very high fatality rate, up to about 50% in published series. I think as we get better at recognizing myocarditis, that fatality rate will likely go down, but catching a cardiac IRE late can have some very serious implications for our patients.
So immediately recognizing that a cardiac workup is necessary, and referring early to cardiology is really important, no matter what grade of cardiac IRE we see.
And I do think that with cardiac IREs, it's really, is it an inpatient workup? Does it require immediate cardiac consultation and workup? If there are elevated troponins that are going up, or conduction abnormalities, does that patient need to be in a cardiac unit? I think those are the major things to keep in mind with management.
Another thing, I think, that is really important because of the high fatality rate: starting corticosteroids early. So like our other IREs, you can start corticosteroids that 1 to 2 mgs per kg per day. And doing that early has the potential to quickly improve cardiac inflammation, keep people from the very serious and potentially fatal side effects for cardiac IREs. And it really doesn't have that much of a consequence in the short term.
So I think in discussions about this guideline, we all felt that if a patient has a Grade 2 or higher IRE-- so that's anything that has a cardiac biomarker that's abnormal plus symptoms of any kind-- it's important to keep in mind early steroids and early cardiac consultation.
For very, very severe cases where management with corticosteroids is not improving the patient's status, then we highly recommend considering cardiac transplant rejection doses, which would be methyl pred at 1 gram daily, or adding other immunosuppressants.
So there are not as many studies as we would like, but mycophenolate, infliximab, antithymocyte globulin have all been reported. There have also been case reports on abatacept or alemtuzumab, with good outcomes. So those are things to consider, of course, with cardiology input for severe cases.
BRITTANY HARVEY: Thank you. Those are important notes for clinicians to keep in mind for management and evaluation.
So then, the second category that you mentioned, what are the key recommendations for identification, evaluation, and management of venous thromboembolism?
PAULINE FONTAINE: So for identification, most everyone listening to this podcast knows what a venous thromboembolism looks like. That's extremity swelling, extremity pain, sometimes accompanied by fever, pleuritic pain, cough, dyspnea.
And the evaluation is the same as what you would see in clinic. That would be venous ultrasounds for any suspected deep vein thromboembolisms. And CT, PE for any suspected pulmonary embolism. And of course, a VQ scan if you can't do that type of CT.
And the management is the same as what you would normally do in clinic. So if it's a superficial thrombosis, that would be a grade 1. You would do a warm compress, do supportive care. But importantly, you can continue the immune checkpoint inhibitor per our recommendations.
For grade 2, so a symptomatic thrombosis, a deep vein thrombosis, that would require anticoagulation. But again, once anticoagulation has been started, the recommendation is that it is safe to continue the immune checkpoint inhibitor therapy, because at this point, you're protected. Should be, in theory, protected from future embolic events.
And then, I think the major thing is that for management in general once there is anticoagulation on board, then there isn't necessarily a reason to hold immune checkpoint inhibitor therapy. I think that the major reasons we would recommend to hold it are life threatening consequences, organ damage. So grade 4 embolic event, where you would have to admit the patient. And then it becomes a risk benefit discussion after an admission.
In general, I think the recognition and treatment are the same in terms of venous thromboemboli that are identified in the context of immune checkpoint inhibitor therapy. The major thing is just to know that it exists as a potential side effect, that the incidences appear to be higher, and that there is something about immune checkpoint inhibitor therapy that may put our patients at higher risk for these embolic events.
BRITTANY HARVEY: Definitely. That's key to know, and particularly also when to hold or continue ICPI therapy.
So then in your view, Dr. Fontaine, how will these recommendations for management of cardiovascular toxicities impact both clinicians and patients?
PAULINE FONTAINE: I think the major thing is to know that these exist. The overall cardiac toxicities are less common, so if we're talking about myocarditis, that is a pretty rare event. But it's important to know that this is an event that is potentially fatal, that that fatality happens often, and that myocarditis can occur along with a myositis, and in some cases with myasthenia gravis.
So these are three different rare side effects that can happen together, sometimes in pairs, sometimes in triplets, sometimes just one of them. But any one of these three has a higher risk for fatality.
So I think just to know that it's out there. So that that is just hanging around in the differential for someone who is tired or out of breath. It may be pulmonary, but also keep in mind that it could be cardiac, and that is serious, and that should be worked up early and treated early.
I think that's the major thing that I hope these guidelines do, is put these important but rare side effects out there and potentially save lives.
I will say for VTEs, for venous thromboemboli, again, so PE can happen, and it can be fatal. I think this is not as rare, but of course, it's not rare in our patient population either. So these are things that we already look out for. Just, I think, if this podcast and the guidelines can add to the education that immune checkpoint inhibitors will increase the risk of thromboembolism, I think that those are the important takeaways.
BRITTANY HARVEY: Absolutely. Recognition of these IREs is a common theme across the affected organ sites that we've heard in many of these podcast episodes.
So I want to thank you for your work on these guidelines and for taking the time to speak with me today, Dr. Fontaine.
PAULINE FONTAINE: Thank you for having me.
BRITTANY HARVEY: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. Stay tuned for additional episodes on the management of immune related adverse events.
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