Let's get started. We are so excited to have you all here today. I know people are trickling in and we have a bunch of, we have over 200 people that signed up for this webinar so I'm sure people will trickle in. Hi, I'm Michelle bloom I am the director of cardio oncology at NYU Langone health here in Manhattan, New York, and I am joined by on a Barack who needs no introduction but I will let her introduce herself as well. So Michelle, I'm on a Barack I'm a cardiologist with the Nova short horn vascular in northern Virginia. And on this call I have a true joy and honor and privilege to have co chaired the HFSA scientific statement on cardio oncology. And we are joined by a fabulous writing group members who've also volunteered to put practical cases and how do we apply this document in real life practice of a heart failure cardiologist. Welcome. So just take us to the next set of slides, or. Yeah, I was just going to say very quickly a couple housekeeping things you can actually scroll forward I was going to tell the audience there's a q amp a on the bottom of the screen. If you have burning questions that you want our panelists to answer. Please feel free to put them in the chat I will monitor the q amp a for the entirety of the webinar, whatever we don't get to we'll do our best afterwards to get to those questions and perhaps the HFSA will help us even send out some of those answers for you. So feel free to put your questions in the chat and if we can get to them we will. Excellent. I think this is a good moment to introduce we are showing the, the cover or the, the front page of the statement. And I would like our panelists to introduce themselves and we'll start with Dr Polaska. Good morning. Pleasure to be here. My name is Nick Polaska, I am a cardiologist associate professor at MD Anderson Cancer Center in Houston, Texas, and I'm our deputy chair of clinical research and cardiology. Thank you. Wonderful. Next on the screen I have Dr Alana Ferrari. Hi everyone it's an honor to be here today. I am a hematology oncology pharmacist, with a specialty in lymphoma and myeloma and cellular therapies, and I'm glad to be on the panel today with everyone. And I'm, I practice at the University of Virginia. Yes. We have next on the screen Dr Richard Chang. Hey everyone, it's great to be here today and see so many friends online. So I'm the current section head of heart failure transplant MCS and Cardio Oncology at the University of Washington, and I look forward to this wonderful discussion. Right. Dr Dan Lenihan. Thank you so much. Great honor to be here with all my great friends and I'm Dan Lenihan I've been involved in cardiology, cardio oncology for many years now, getting, getting close to 30, and was a founder of the International Cardio Oncology Society, and have been essentially a career member of the HFSA so I'm currently director of Cardio Oncology Center of Excellence at Cape Girardeau in Missouri. Wonderful. It should have said that you started in kindergarten. And then we have Dr Anne Blase, our oncology champion. Hi, thanks for having me. Anne Blase, I'm a medical oncologist and hematologist at the University of Minnesota. I'm also the division director there and the co-director of our screening prevention etiology and cancer survivorship program within the Masonic Cancer Center. Thanks for having me. A lot of this document is about multidisciplinary care and one of our goals was to illustrate that and feature that through these cases. You can see that not all the members could join. Whoa, spot on time straight from the clinic Dr Anju Noria. Hello, introduce yourself Anju. Hi, I'm Anju Noria, I'm a heart failure specialist, and the director of Cardio Oncology at Brigham and Women's at Dana-Farber in Boston and I'm very excited to be part of this webinar. Wonderful. Perfect timing. I was going to say that we have many other authors, they all send regards and we'll dive into the cases. Before we go into cases, we just wanted to show top takeaways, which you're going to hear today. These are sort of messages from the paper. So starting with bullet point number one, that heart failure and cancer share common pathophysiological mechanisms and that we now have evidence of bidirectional link between cancer and heart failure. A second point beyond anthracycline and HER2-targeted monoclonal antibodies, very few cancer therapeutics have standardized cardiac imaging surveillance recommendations. And through our cases, we will demonstrate how we in practice deal with that lack of standardized guidance, because you will see this in the document. We will also illustrate the concept of permissive toxicity through at least two of our cases. One case will feature cardiogenic shock in cancer patients, which can arise from various causes, including LV dysfunction due to cancer therapies, acute coronary syndrome, stress cardiomyopathy, and then as well as immune checkpoint inhibitor-associated myocarditis. We will discuss the approach of left ventricular assist devices and their feasibility, and how do we think through them in patients with stage 3 heart failure. Finally, one important take point from our document is that for candidates who have history of cancer, we need careful and individualized risk assessment in collaboration with oncology specialists when we discuss eligibility for heart transplantation. And finally, the comment about ICI-associated myocarditis, which is an increasing entity relevant to heart failure specialists, we will discuss how to approach it and how to utilize multidisciplinary care. With that, I think we are ready to start with the first case. And we'll be advancing the slides, and we'll have our panelists present individual cases. Dr. Lenehan, this is yours. Thanks, Ana and Michelle, in particular, and all the other colleagues, again, for having me to be part of this. So I'm going to talk about lung cancer treated with targeted therapy and EGFR tyrosine kinase inhibitor-induced cardiomyopathy. And I put that as a question mark, as you'll see from the case. Those are my relevant disclosures. So we recently published sort of a large retrospective analysis, you know, on the rate of major adverse cardiac events that occur after a cancer diagnosis. And if you look from this cumulative incidence curve, you can see that the highest rate of MACE is actually associated with lung cancer. And it's really by quite a long distance that patients with lung cancer will have a higher rate of cardiac events than many of the other cancers that we see very commonly. And just as a point of reference, at roughly four years, 26% of patients will have had a major adverse cardiac event. And when you contrast that with breast cancer, it's 2.7-fold higher risk. And so, you know, we talk a lot about breast cancer, and we'll even talk about it today, because it's a common cancer, but so is lung cancer. And the rate of MACE is so much higher that we really need to sort of put our best minds forward. How do we manage this? So next slide. So I want to highlight a basic case. And honestly, you could say that I just saw this case last week because this is so common. But a 75-year-old with metastatic non-small cell lung cancer that was adenocarcinoma. And he was on osimertinib. He had a history of hypertension, diabetes, hyperlipidemia, actually had a previous stent placed about five years ago, and also had been a longtime smoker, but he quit at the time of his stenting. He was then diagnosed with metastatic left lower lobe adenocarcinoma that was EGFR exon 19 positive and started on osimertinib at 80 milligrams daily, which is a pretty standard dose. And a point of reference is that there was no recent cardiovascular assessment at the time of diagnosis or initiating therapy. After about six months of being on therapy, he reported progressive shortness of breath, 15-pound weight gain, orthognia, and PND over the past month. His blood pressure was slightly elevated, 140 over 90, EKG not particularly remarkable, in sinus rhythm with sort of a borderline QT interval. His medicines are listed there. Some are OK and others are not so good, but that's sort of a typical clinic patient for most of us, I would imagine. And then looking at his PET scan, which formed the basis of his treatment, actually, he, at six months after initiating therapy, there was a dramatic improvement in his FDG avid mass in the left lower lobe. And then also improved FDG avidity in the various lymph nodes that were associated with the cancer. As it turns out, he had an echo done at that time because of his shortness of breath. And his EF was 38%, had a dilated IVC, borderline elevations of the pulmonary artery systolic pressure estimate at 38 millimeters of mercury, and a dilated left atrium. Pretty typical echo for most patients that have heart failure that we see. And this scan is the baseline PET image, or basically a CT image, from his initial diagnosis. And you can see the measurements there was a 5 by 3 centimeter mass. And after six months of therapy, it's almost completely gone. There was a little bit of pleural effusion still left, but nearly a complete resolution after six months of treatment. Next slide. And I did want to point out from the document that Ana and Michelle were co-chairs for, this sort of central figure, I guess that's what you call it, but sort of main figure from the paper, to me is really outstanding. It's an excellent figure. You kind of have to dig into the details about the colors and that sort of thing, but you can see my blue arrow where this patient would fit. So if you look at the ESC guideline consensus statement from 2022, that's the sort of middle area. This patient at this point would be diagnosed with symptomatic CTR-CD of at least a moderate degree because he was very symptomatic and certainly needed intensification of heart failure-based therapy. So at least moderate symptomatic CTR-CD is how he would be classified. When you look at the CTC-AE version 5 definition, it's difficult to say where he would fit. And for those oncology representatives on the call, that's what you're used to grading. You're used to putting in some designation for how severe the CTC-AE might be. And then if you go to the classic ACCHA, HFSA heart failure guidelines, he would certainly fall in the stage C or symptomatic heart failure category. So please go to the next slide. So when we think about this patient, you have a patient who was started on cancer therapy for lung cancer, osomertinib, and after six months had a dramatic cancer response. And at the same time, within the last few weeks has developed symptomatic heart failure. So what is our plan? Obviously, for any group that represents the HFSA, we're obviously going to want to give optimal heart failure therapy in a classic manner. And in this case, I would especially emphasize an SGLT2 inhibitor. You don't need to go back, but if you looked at his medications, he was on metformin and insulin. And could we have done better on those medications at the outset? But certainly at this point in time with significant heart failure, we're going to want to switch to SGLT2. And then, of course, aspirin and statin would be basic therapy for somebody who's got known coronary disease and multiple risk factors. So then to really dig into this case, what about his cancer therapy? So he's got a great response, and he's now developed symptoms. Does that mean we need to stop his cancer therapy permanently or consider restarting at a lower dose? And I would like to hear some opinions from our group here. I know, Richard, you're sort of overseeing this particular case. What are your thoughts about this? Yeah, I know that. I think that's a good question. I mean, I think I'm curious to hear what others think. But one of my first thoughts is in terms of adjudicating the case and actual ideology, how certain are we that this is due to the tyrosine kinase inhibitor? Because, you know, previously you stated that this individual has multiple cardiac risk factors, as well as histiocoronary artery disease. So it makes me question a little bit in terms of whether this is actually a direct crotoxic effect from a TKI, although we do recognize it as a side effect that's not very common. And I'm curious whether you did additional testing to really determine whether this was due to the TKI. Because I feel like it's almost a diagnosis of exclusion, even though temporarily it lines up. Yeah, well, so you bring up sort of an essential point, obviously. But if you go back in time and you talk about Herceptin or some other drug, if you didn't do an accurate baseline assessment and a patient develops some symptoms and then you do a test and it shows moderate LV dysfunction, you have to assign that moderate LV dysfunction to the drug. I mean, because that's the way clinical trials are done. But the key point here is just what you said. If you had reassessed his cardiac status before you initiated therapy, maybe his LVEF would have been 37 at baseline, and here it's 38. And maybe he's got a few more symptoms, but certainly there may not have been any significant change in his EF. We just don't know the answer. But if you go to CTCAE criteria at this point, you would say he's at least sort of grade 3, maybe grade 4 heart failure according to those criteria. So that right there is usually a stop indication for any oncology treatment trial. And so that goes to this last question here. Is this truly CTRCD or just newly discovered heart failure? Or I guess I should add one more thing. Previous heart failure that got a little bit worse. And so those are all different questions. Because, you know, if he had heart failure at baseline, we would have wanted to improve the treatments that he was on. So I don't know. Ana or Michelle, what would you say to all of that? Well, actually, first, a very quick housekeeping thing, because I have to be the annoying person that keeps everyone on time today. Ana gave me that job. I will say for every single one of these cases, we could probably talk for an hour and a half, but we won't. And so we're just about at the end of time. I do want to say very quickly, I think you'll find, and a lot of people on here obviously are not cardio-oncology-specific practitioners, but are heart failure people, that a theme that will come up over and over is if we don't have a good baseline assessment and we don't have a good handle on risk factor modification, then you often find yourself in this pickle where a patient develops a toxicity and you don't know if it's the drug or you don't know if they started with that and maybe it just exacerbated something else. And I also think it's really important, common things being common, you still have to go about the same evaluation that you would do with any other patient. You would go through an ischemic evaluation, figure out if you need to do a stress test or a cap, figure out what low-hanging fruit you have in terms of adding or subtracting medicines. I'd take off the calcium channel blocker, I'd add heart failure therapy and all of those things, and then you sort of get yourself into a question of, well, do I really need to permanently stop this therapy or can I manage the heart failure, get them clinically stabilized, and then have a conversation with the oncologist about restarting, maybe at a lower dose or maybe, you know, if absolutely necessary, a different therapy. But you really hate, as the cardiologist or the heart failure doctor on the case, to be the person who has to permanently discontinue a lifesaving therapy that they had such great response to. That's kind of my thought. Yeah, so Ana, can you go forward one slide? Of course. And then- And as I know, I would comment- Yeah, to follow up on what Michelle said, though, just imagine you were the patient and you looked at your CT at baseline and then now the one at six months, and you go, oh, wow, that drug really made a big difference. I want to continue that. You know, any patient, any doctor who's dealing with this patient is going to be saying, oh, wow, you know, what a response. We need to figure out a way to continue that lifesaving therapy. Yeah. So, Dan, these are excellent points. And I will say that if you look into a package insert for osimertinib, it does recommend baseline, both EKG and echocardiogram. So, I think that's one of the lessons for us as- and I feel our group will, for anyone listening, if you work, I would make sure that the patients who are receiving osimertinib do get the baseline echocardiogram. Because not only it's there not to prevent the patient from getting osimertinib, but rather to- we would have- and you don't need to see low EF. You would have recognized that this patient, if it was referred, the therapy almost certainly would be changed. Whether we would have prevented this or not, it's hard to tell. But I think certainly that baseline assessment will help you attribute and help sort of predict. You would know that the patient was at risk because of the existing risk factors in addition of osimertinib. One thing that often comes up as a question, so why are these huge differences in the guidelines? And we'll tackle that a little later. They are- because they are developed with different perspective. ASCO guidelines really focused only on the evidence-based, which we had at the time only for anthracyclines and trastuzumab. And it specifically says that it does not address any kinase inhibitors overall, because there is no level 3 guidance for prevention of cardiac dysfunction there. We live in that intersect where we have a package insert that tells you that the patient might be at risk, and we have then try, I think ESC guidelines which were developed together with ICOS was an attempt of bringing that package insert into real-life practice. There is no data to say, well, if you do it every three versus every six months, but I think we will all agree that baseline assessment is necessary and then you personalize to the patient. Yeah, you could probably go forward one slide. These are just summary points. Obviously, the baseline assessment is absolutely critical, especially in a group like patients with lung cancer that have known coronary disease or known complications of heart disease in one form or another. They have the highest rate of MACE of any cancer group that you could study. To not do a baseline cardiovascular assessment, it's just unacceptable. I think that has to be our message going forward. Then obviously, optimal therapy for heart failure is absolute key, but including vascular disease and arrhythmia, we didn't talk about those things, but they're certainly present. Then truly, prevention and early detection of cardiovascular issues are essential to allow ongoing cancer therapy, especially when a drug is so responsive like in this case. Anyway, I think probably we can move to case 2. Yes, could not agree more. Then we'll come back. It also features the permissive toxicity. I'll present that this is a patient with a metastatic breast cancer that was also complicated by the development of heart failure. This is a 75-year-old woman who presented with pulmonary embolism as initial manifestation of metastatic breast cancer. At the time of diagnosis, she had metastatic disease present in lung, liver, and bone metastases. Her oncology therapy included docetaxel, trastuzumab, and pertuzumab for six cycles. This is conventional chemotherapy, non-containing anthracycline, and trastuzumab and pertuzumab are monoclonal antibodies against HER2, which you can see here that was overexpressed. That's followed by trastuzumab and pertuzumab. Her cardiac assessment and baseline, this was in retrospect gathered, but this was known. She did have a history of cigarette smoking for about 30 pack years, but she stopped two years prior to diagnosis. She did not have history of diabetes, hypertension, or hyperlipidemia, low BMI of 23. She did have a baseline left bundle branch block, and her echocardiogram was done in the community and was reported as LVF of 50-55 percent, and paradoxical septal motion consistent with left bundle. She had normal right ventricular function and no valvular disease. After cycle 5, so she's received five cycles every three weeks, she presented with heart failure symptoms. She had progressive shortness of breath, new onset, worsening fatigue, worse than before, and she had dyspnea with going up the stairs. She was relatively hypotensive and tachycardic on exam. She had mild JVD, a mild bilateral pitting edema, and her labs were consistent with heart failure. This is a B-type nitritic peptide of 5-68 at a time, and again, unchanged left bundle. Her new echo, repeated echocardiogram now shows the LVF of 33 percent. She has mild mitral regurgitation, slightly elevated right ventricular systolic pressure at 35. At that time, cycle 6 was put on hold due to concern for symptomatic heart failure. Following that echo, she had a cardiac MRI, which I'm showing here, which shows very similar findings that were reported on the echo. So you can see here on cine images, she has reduced LV systolic function. She has mitral regurgitation, which looks at least mild here to moderate. We combine this with the echo imaging for more quantitative assessment. She can clearly see nicely that apex moving laterally, that's consistent with the left bundle branch block. Her RV function was also reduced here quantitatively, and that's probably because of the reduced stroke volume coming to the reduced preload. We are seeing here the similar images in the two-chamber and the three-chamber projections. Again, left bundle. Now I'm showing late gadolinium enhancement, which shows nice and black images. So there was no evidence of abnormal gadolinium enhancement. That means that this is not likely to be due to prior impact. So there's no evidence of prior impact, there is no evidence of myocarditis, there's no evidence of infiltrative process. This is how among the differential diagnosis in the setting of non-ischemic cardiomyopathy characterized by absence of late gadolinium enhancement is anthracycline and HER2-targeted therapy-related cardiomyopathy. So when we talk about her clinical diagnosis, going back to that nice slide that Dan showed, this is heart failure with reduced ejection fraction. This is stage C, NYHA class 3, and this would be related to cancer treatment-related cardiac dysfunction. I think then she would be in that same category that you nicely showed, moderate, which she clearly needs not intensification, she needs initiation of heart failure therapy. But regarding to the cause, I think this is likely related to HER2-targeted therapy because we did have assessment upfront whether the treatment was optimized. At that time, she had still preserved ejection fraction, she had low blood pressure. So temporal relationship to trastuzumab and pertuzumab, even though incidence of symptomatic heart failure with these two therapies is low, one could argue that her left bundle branch block might have predisposed her to therapy, but I think it is likely related to therapy. So this is what she was started on. She was started on saccubitril-valsartan twice daily. It was very challenging to have her continue on it. She had symptomatic hypotension, metoprolsuccinate, spironolactone. This was before SGL-2 were initiated, but we did discuss it. It was at the time of the trials. At that time, we deferred ischemia evaluation. In order to prioritize treatment, she had normal TSH and anemia was stable. So I would like at this point just to briefly comment on the SafeHeart trial that we extrapolated on and I'll go to Anne to her question. So SafeHeart trial was designed now years ago to ask the question about the safety of HER2-targeted therapy in patients with HER2-positive breast cancer and compromised heart function. So compromised heart function in the SafeHeart trial meant left ventricular ejection fraction, whether at baseline or during treatment, like in this case, reduced to up to 40 percent and absence of heart failure. So she would not have been part of the SafeHeart study. So it looked into the less sick of a population, but it did because on the package insert in our clinical standards, the HER2-targeted therapy would not have been, if she were on a trial with tristuzumab and pertuzumab, she would have been taken off the trial because we know that in the patients who have even just reduced ejection fraction, let alone symptomatic heart failure, the risk of subsequent toxicity is higher. So in the SafeHeart, again, we asked this question about the safety and the patient would, for example, if she just had a drop in EF on that echocardiogram to, for example, 42 percent no symptoms, she could have been included and SafeHeart trial included about 42 percent patients with metastatic breast cancer. So like her previous anthracyclines, about 50 percent of patients received them. So she did not. This was her first exposure to HER2-targeted therapy, and then she was on pertuzumab and tristuzumab. So she would be a representative from that standpoint. So SafeHeart was designed with a very pragmatic question in mind, said how many patients, the number of patients who complete the planned HER2-targeted oncology therapy without development of cardiac event. I think now this makes it clear why we did not include patients with recent events. We know they are at high risk. We asked the question if you had asymptomatic stage B, or potentially stage C if the patient had a history of heart failure more than one year prior to enrollment. So we enrolled 30 patients, and of those, 27 were able to complete planned oncology therapy. And in her case, that would have meant one year worth of tristuzumab and pertuzumab and optimized cardiac therapy. In SafeHeart, optimized cardiac therapy meant a beta blocker, which was carvedilol, and we did prioritize carvedilol. And in addition to that, again, this was designed before Entresto was approved, the additional therapy was either an ARB or an ACE. And we would typically start with an ARB, but if the patient was previously on ACE and was doing well on it, we would continue it. So it showed reasonable safety, so 27 patients completed the trial. Two of them developed symptomatic heart failure, and one patient developed further decline in EF into the 30s that did not recover after two months, so that patient was taken off trial. We subsequently published a follow-up showing safety. There were no cardiac deaths, and the patients developing heart failure were treated without further adverse outcomes. So I will just go back to the case and conclude so we can have a discussion. In this case, as I showed you, she improved. Therapy was put on hold. We were limited by low blood pressure, and she went pretty quickly within a month or so for resynchronization therapy. That really made a major difference, both leading to improvement in symptoms. And so within six weeks of the presentation and following the implantation of the biventricular pacemaker, and she opted for pacemaker alone. We had a team discussion, and she opted not to have an ICD placed. We discussed with the oncology that it was reasonable to restart therapy. I will have Anne, at that time, we decided to go with TDM1, and I'll have Anne comment on how would that be different today. This was perhaps a couple of years ago. We also discussed how to follow her. We included antiprobium P prior to each infusion in the beginning and then spread it after the three months, and then her follow-up showed stable liver lesions on TDM1 and LVF that stayed stable for one year after the bivy pacemaker. So I will pause here and have Anne tell us a little bit about what would be your approach. Is it different, and how do we implement this? How often do we see this in the oncology world? What would be a good example for the centers to consider when we encounter these patients to continue building on the structure of these multidisciplinary discussions? Yeah, I mean, I think there's a couple important takeaways. In the case, one, patients with metastatic HER2-positive breast cancer, their life expectancy, if you get them on treatment, is years. So this isn't somebody that you're thinking about, you know, under one year. So that's as long as you can get them on treatment. So doing everything we can to optimize her cardiac pressure, or her cardiac function, I think is really important. I think the second takeaway I would say is, usually patients respond really well to treatment. We didn't talk about her clinical course, so it would be really easy to say, I'm going to change treatment, given the fact that she developed heart failure and we have other treatment options. Would you use TDM1? So TDM1 was used in SafeHeart, like you mentioned, and so from that perspective, I think there's data to support using it if she was recovering and had an EF in, you know, above 40. Today, we may consider other antibody drug conjugates, such as trastuzumab durextacan. And trastuzumab durextacan can cause pulmonary fibrosis, and she has a history of tobacco use. So given if she was quite tenuous at her age, you may still choose to use TDM1 first. Knowing that we could go on and use that at another time. And on the cardiac side, both of those in clinical trials, it depends on which destiny breast study you look at. The incidence of cardiac dysfunctions under 1%, but I think obviously following them with close biomarkers and imaging, and this is the case you really want to work with cardio-oncology, is important. Thank you. Any other thoughts or comments? Yeah, I just wanted to add one comment. I feel like, you know, this case is so wonderful, and, you know, we see a lot more of these individuals with metastatic cancer that survive long-term, as you were alluding to. I'm curious, you know, right now, most of our data we have within cardio-oncology does not apply to this patient cohort. So I'm wondering, from your perspective, when you would consider continuing treatments. I know we talk about the concept of permissive cardiotoxicity. This patient have falls outside that realm when the patient was in acute heart failure, but given that this patient had metastatic disease and this was the best treatment option, I'm wondering how you would take that into account. So for me, I would tell you, most of them, especially if this is a patient who never had anthracyclines, so sometimes patients develop metastatic disease and they were already treated in the adjuvant setting and received anthracyclines, but if it was de novo metastatic disease or they've never had an anthracycline, she has other risk factors. So you could use different calculators and understand at baseline she's at high risk for it. But your question, you know, most patients who develop heart failure with Herceptin and Proteusamab, they'll actually recover in the four to six week period of time. And our goal is long-term health. Her disease is not going to progress in such a short period of time. So usually I would see these patients and tell them, gosh, at least for the next month, six weeks, we need to optimize your heart failure. And then we'll talk about the timing of when to start therapy again. I will say while Ana is queuing up the next case, because I want to keep us on time, you all may be entertained to know that of the things that kept Ana and I up at night while we were doing this statement, probably the thing that came up the most was that there's so little data in the stage C space, right? Because we know kind of what to do with permissive toxicity in people that have asymptomatic drops in EF, that's easy. I think where it really comes in the nuance and why we wanted to present this case was in people that have symptomatic heart failure, we still want to do our best to get them back on whatever therapy will be lifesaving from the perspective. And so that really, you know, while we were going through this, it really became apparent that we really need trials in this stage C population. Yeah, and just on that note, as you're talking about it, coming back to Dan's original point, you know, this patient has a lot of risk factors for other reasons to develop cardiac heart failure as well. So making sure we're not forgetting that either. Yep, absolutely. And sometimes it's a mute point. Like in this case, we had the baseline EF. It probably tristizomab or tristizomab contributed, but you could have said, even if she didn't receive these therapies, this patient was at risk for heart failure. And we not always can predict it. So what I took away from it, if it's particularly, if it's metastatic, but cancer, think that we would err on the side. The question is, what is the biggest risk to patient help at any given moment? So after getting the patient on therapy, in both instances, it was fine to put the therapy on hold for a brief time, but I feel in metastatic cancer, the question is always going to be when we can restart and which therapy can be restarted. So that was illustrated. Thank you, Michelle, for keeping us on time. Dr. Palaskas, your turn. Hi, thank you so much. So I'm going to jump right into a case on the next slide, talking about a really fulminant presentation of myocarditis. So if you'll advance the slide here. And many of you that are wondering, you're like talking about immunotherapy and prostate cancer. But this doesn't exist in standard of care. And so this patient was on a clinical trial with immunotherapy, okay? So we have a 76 year old man. He has castration resistant metastatic prostate cancer. And to give you an idea of the slowly progressing or indolent nature of his disease, he's been battling this for over 10 years. All right, so this is not a very aggressive cancer, but he's been on several different treatments for it. And most recently he started this clinical trial and it's actually not an immune checkpoint inhibitor. It's a bispecific antibody that attacks two immune checkpoint receptors, CTLA-4 and PD-1, which are some of our classic immune checkpoint inhibitors that have our immune checkpoint receptors that have therapies against them. His comorbidities as is common with many patients with prostate cancer, hypertension, hyperlipidemia and sleep apnea. He started developing this very rapidly progressive shortness of breath, started driving into MD Anderson because that's where his clinical trial is, but felt so bad he pulled over into a parking lot and called ER or EMS who came in, saw him in the parking lot and found him in VTAC, had to shock him twice, one in the parking lot and then one in route on the way to the hospital. He arrived in the ER and then he went back into VTAC where I then again cardioverted him back into sinus rhythm. And you can see the EKGs on the right, his baseline before starting the trial is up on the top. His VTAC, which looks almost like a hyperkalemia, but his potassium was perfectly normal. That was the first thing I thought when I saw that, but potassium was fine. And then after cardioversion, you see his EKG showing ST elevations in V1, V2. We initially thought this is a STEMI. And so while we have a cath lab at MD Anderson, we don't have nursing capability for post stent care. So we transfer him right across the street for what I suspected was gonna be a STEMI. If we go to the next slide, they did his cath and his cath showed normal coronaries. And so before he left our institution, of course we had labs that we sent off and his troponin T, that's the assay we use at our institution. It's the high sensitivity assay, was above 5,000 and he had a baseline troponin because he's on a trial. Most people actually don't get baselines even though they're in the guidelines. His baseline was perfectly normal at 14. The FDA cutoff is 19. Usually what I use before I even consider a diagnosis of myocarditis is above 100. And he was far above that. Now, interestingly, his CK was only 146. So we see a lot of overlap with myocarditis and other immune related adverse events that can affect any organ system, such as myositis or myasthenia gravis. These are skeletal muscles that get affected by the immunotherapy, but his CK was not very high. His echo bedside before he left our institution in the ambulance to get his cath, his EF was severely depressed, less than 20. You may argue, is this acute? Is this post-cardioversion? We don't know, but it remained low at the other institution too. And after they rolled out any stomach, they did a right heart cath and noted that his wedge was elevated. Cardiac index was very low and you can see he's in cardiogenic shock. His blood pressure is nothing here. And so they initially put in a enteric balloon pump at one-to-one. And then we had a discussion with our cancer colleagues and said, how's he doing from a cancer standpoint? He's been battling this for over 10 years. And they said, well, he's been on this trial. And actually, very interestingly, he's been on this trial for nine months. So usually a myocarditis presents very early after immunotherapy. This guy was nine months later. That's part of the reason I wasn't suspecting myocarditis right when he hit the door either, given how he was presenting and how late he was presenting. But they said his metastases are shrinking. He's doing phenomenal on this immunotherapy trial. So they proceeded to put in ECMO. We gave him Pulse-Dosed Steroids, or we guided the other institution to give Pulse-Dosed Steroids and gave him 1,000 milligrams IV methylpred daily for five days. And unfortunately, after about 10 days, I'll talk about the other therapies after some of my questions next that we gave him also, but after 10 days, him and his spouse decided to withdraw care. And the pathology slides you're looking at are actually from an autopsy. It's a really unfortunate case of a fulminant myocarditis. So the questions from this case that I think will bring a lot of discussion are, first of all, when and which other immunomodulator should we use to treat checkpoint inhibitor myocarditis? All right, there's really not a role for these in viral myocarditis. I mean, all the studies have been pretty negative from that standpoint. But in checkpoint inhibitor myocarditis, we're seeing more and more use of these and more and more use early in the course of the disease, especially in fulminant cases like this, which the guidelines are supporting. Is there a role for mechanical circulatory support in patients with cancer? This is always a shared decision-making process, and I'd love to hear some of the panelists' discussion of this. And what's the role of biopsy? Obviously, this patient was crashing and burning. We knew what the diagnosis was. There wasn't time to do a biopsy. There wasn't time to do it. He wasn't stable enough for a cardiac MRI. After ruling out coronary disease, you're pretty sure that this is likely myocarditis, which was shown on the autopsy later. But let's tackle that first question. And I put on this slide here some different buckets of optional therapies. Other ones have been used. There's no head-to-head trials, and there's no large clinical trial data to suggest which is the best, but there's plenty of case reports and case series for each of these. In that bucket on the right, biologics, they're kind of our waste bin bucket. They don't really fit in these other categories, and that's why I put them in that right one. So if anyone on the panel wants to discuss what other immunomodulators they go to or what their thoughts are on this. So I would say, as a community, we've started using abatacept because it is a CTLA-4 agonist, and therefore mechanistically makes the most sense in terms of reversing the biology. In people who have accompanying myositis and or myasthenia, we tend to add ruxolitinib because those people tend to have respiratory compromise that can be quite serious. But in someone like this, where you've gone to VA ECMO, I would say that ATG, even though it's not used very commonly in the cardio-oncology community, is a well-proven therapy for severe transplant rejection, grade three rejection, and the biology of ICI myocarditis is very similar. And in the few cases where we have had fulminant myocarditis, where we've accelerated care to requiring MCS, we have used ATG successfully to reverse the myocarditic process, although often these patients will then succumb to infection and or tumor progression, which is a risk that you have to take, because at that time, the priority becomes saving them from their cardiac compromise without having to worry about whether they will survive long enough to live through their cancer. So abatacept, steroids, ruxolitinib are probably better tolerated in patients who are less severely sick, but in these patients, I would still go for ATG, especially where you're going to mechanical circulatory support. So that's a great point. And just for our audience, ATG has a lot of T cell activity. And so the predominant driver of disease in checkpoint inhibitor myocarditis are CD8 cytotoxic T cells. And so that makes a lot of mechanistic sense. And as Anju had mentioned, the abatacept, think of it as a CTLA-4 agonist, as opposed to the CTLA-4 inhibition that is being caused by the CTLA-4 inhibitor that the patient received. The problem with abatacept is it's supposed to take about seven to 10 days before you really have any effect. And so if you look at the paper out of Sorbonne, where they did a retrospective paper looking at 30 patients compared to historical controls, the way they used abatacept is they gave it in combination with ruxolitinib, a JAK kinase pathway inhibitor, so that the ruxolitinib would tide patients over until the effect of abatacept was really seen. So those are all really great points. In a patient crashing and burning like this, will abatacept work that quickly? And probably not. Although I've seen very good responses in my anecdotal cases. Yeah, I think that this is a, would be a highly controversial area and everybody probably has some positive or negative experience with each one of these things. But I would say, and this is, this basically comes from the publication that Anju was the senior author for about a year ago, looking at different patients, depending on whether they were classified as definitely having myocarditis or maybe having myocarditis or not having any clear indication of myocarditis. So when you have those three categories, the bottom line is, is that the life expectancy wasn't so good for any of those categories. So I would say that when you're in this game, it's pretty serious business. So what you choose to kind of pull them out of a nosedive, I think you kind of give it your best shot, but it's a serious problem. And if you're dealing with these patients and they're crashing and burning, then you're in a major world of hurt. And discussing sort of goals of care, to me, is probably one of the most important pieces. I also just say, Nick, to your second question, because we're, of course, we're out of time, but the whole issue of MCS, I mean, obviously all of us have totally been there, but try being on a shock call with a surgeon and you have a patient with metastatic cancer and you look at the chart and for all intents and purposes, everyone looking at the chart is saying, are you out of your mind that you're even suggesting ECMO? And when you're even contemplating ECMO, it's not like you have the luxury of time to really delve in and decide what the prognosis is and certainly not to get the oncologist on the phone. So I think that these discussions are so hard and there's never a right and a wrong answer. I find this to be very, very difficult to navigate. Yeah, I'll just add from the oncology perspective, like you mentioned, they oftentimes happen very fast. And so everyone is kind of scrambling and trying to do everything they can. From an oncology perspective, you mentioned, this is a patient that for a long time has actually done well, but also has known they've had metastatic cancer. I don't think, I think in a situation where things are very fast and furious, providing all the support for them and then engaging the family is not necessarily a bad thing either in the respect that, and I hear what you're saying, Michelle, but it does give the family time to call other people as you are also calling them. And that can be really helpful for them in their grieving process, so. These are excellent points. I love the Andrew's comment about ATG because sometimes unless your institution has a well-established pathway, it could be very difficult to get a Batacept on a whim at midnight when you call pharmacy. And for this group, for our audience, HFSA members, there many might be very familiar and you can easily get ATG because if you're having transplant patients, you will have that available and probably a protocol for it. So I think it's a very helpful comment. I think also in that list, the one drug that I would say you should not use in this patient is infliximab, right? Because there is data- Exactly. The trial suggesting that it is harmful in people with heart failure. So of all the drugs that you would not use, infliximab would be the only one that I would say is contraindicated. Exactly. It comes from the oncology guidelines because they put together guidelines for the entire universe of immune-related adverse events. And it's mostly, I think, I find it mostly recommended by the GI cancer because, well, by the GI specialists because it's used preferentially for colitis, but it's spot on. Yeah. Sorry. I was just gonna say, we have to move on, but you see here on the screen, Nick helped us with these charts when we were doing the statement and they are phenomenal and they really bring together all the different society guidelines for diagnosis and treatment. So I really, I would encourage all of you listening to go back and look at this because I think it's a really high yield charts that will kind of take you through these really hard cases. Yes. And also discusses these are existing controversies, high steroids, when, yes, if it's severe, but is it severe? So I think that you will have to, if you haven't done it before, you'll have to call a friend. But I think that this, hopefully this discussion, helps with the conversations that will happen. And this is a wonderful paper by Nick in European Heart Journal. When you talk to your pathologist about severity of myocarditis on biopsy, this is the paper you can refer to. And this is the experience from Abatacept and Ruxolitinib. We'll move on to Dr. Ferrari and the case of CLL and Ibrutinib. Yes. I was just entering a little bit in the chat about some of those medications, but I'll enter that later. So thank you. This is a case of cardiomyopathy associated with Ibrutinib use. That being said, I did want to provide a few background slides on Ibrutinib. So if you were to look at some of the early studies with Ibrutinib and some of the trials that led to Ibrutinib's approval, you will not see heart failure reported in a high incidence at all. However, longer-term follow-up studies, as well as retrospective assessments over the years have actually demonstrated a particularly increasing risk of heart failure with Ibrutinib over time. So I've put two pictures here. One was from a Vigibase assessment demonstrating just an increased reporting of heart failure associated with Ibrutinib over the years, as well as another study that actually looked back at patients and stratified them by either prior history of atrial fibrillation or no prior history of atrial fibrillation. As you can see, regardless of whether they had prior AFib or not, patients were at risk of developing heart failure over time while on Ibrutinib therapy. So it is an evolving area of risk concern. Next slide. Thank you. One of the potential mechanisms that have been hypothesized to be the reason why Ibrutinib may be associated with a heart failure development is due to some of its off-target effects. So Ibrutinib has, as a tyrosine kinase inhibitor, it has a lot of off-target effects. That being said, it does inhibit the PI3K-AKT pathway, which is a very important pathway within the myocardium and in cardiomyocytes, especially during times of stress and reparative processes. That being said, by inhibiting the PI3K-AKT pathway, Ibrutinib may cause or may help lead to development of fibrosis and myocyte death from its use and by inhibiting this pathway. Next slide. All right. So here is our case. This is a 62-year-old female when she initially presented with her CLL disease. So her past medical history was significant for hypertension, for which she was only on hydrochlorothiazide, type 2 diabetes, for which she attempted to take metformin, but it upset her stomach. So she ultimately was not compliant with her metformin therapy that her primary care physician had initiated. And she did have a history of squamous cell carcinoma, which was just resected. She did not receive any type of systemic therapy for that. In terms of her oncologic history, when she was first diagnosed with CLL, it was Rye stage 1. She had unmutated IgVH, a normal karyotype, and FISH, and she was TP53 wild type. That being said, she was started on Ibrutinib in 2017 as a single agent, and she did develop intermittent AFib at that time. She was ultimately managed with metoprolol tartrate, which was then converted to metoprolol succinate. And because of her CHADS-VASc score, she was started on apixaban at that time. However, after a number of years with intermittent AFib, the patient decided that she would rather not take Ibrutinib any longer. However, it was fairly controlled with her metoprolol therapy, and she was actually able to be switched to acalabrutinib at this time. So in January of 2021, she was switched to acalabrutinib. That being said, and this was somewhat surprising, over the next couple of months, she developed bruising that occurred sporadically, as well as some hematomas. Now, that being said, BTK inhibitors do inhibit the function of platelets as an off-target effect. And it was quite surprising because this did not happen with her Ibrutinib therapy, but it did happen with her acalabrutinib. Of note at this time, during these couple of months, she was trialed off of metoprolol succinate, and she also, there was something just to, and apixaban, of course, because the AFib seemed to be under better control off of Ibrutinib. And I think what is really important here to also note is there was no clinical concern for acquired ITP from her underlying CLL. So just want to make that unknown. So that being said, because of these bruising and bleed risk to the patient, she actually had requested to switch back to the Ibrutinib that she had been on before. Because of the prior atrial fibrillation, we decided to initiate a stepwise titration onto her Ibrutinib dosing and started her at a low dose and worked up to the goal 420 milligram daily dose of Ibrutinib. During this time, she was monitored very frequently for EKGs. All of them actually demonstrated normal sinus rhythm even after we were able to up titrate her and she wasn't having palpitations at home and the patient overall actually felt quite well. That being said, about six months after she was restarted on Ibrutinib, she presented to the hospital, she called a clinic and we told her to go to the hospital, with three-day history of some shortness of breath, especially while walking to the mailbox and also to her car in the parking lots. She described some lower extremity edema and she did check her blood pressure at home and her blood pressure was fairly elevated from her baseline. That being said, in the emergency room and then later during her admission, an echo was retrieved and demonstrated a reduced global systolic function with an estimated ejection fraction between 30 to 35% and her right ventricle was mildly dilated. She did have some pulmonary edema at that time. Her biomarkers are listed there, so her high sensitivity troponin was elevated but only very slightly and trending it was non-significant and her BMP of course was elevated there as well. At this time, the decision was made to hold a burn-in and diuresis was initiated primarily with furosemide and she responded quite well to that from a fluid balance perspective and her pulmonary edema. Lisinopril was added on and dopagliflozin was also initiated a few days prior to discharge. In the outpatient setting, she was started on metoprolol again and plans were to start Entresto within a few days. Or after some time being discharged. That being said, I have a few questions for the panel and that is what could have been done to better monitor this patient as well as to potentially gather a better baseline cardiovascular risk for this patient? So I think it's important to state that the major side effects associated with Bruton tyrosine kinase inhibitors like Ibrutinib, Acalabrutinib, and Pertibrutinib are really hypertension and AFib. And usually when you see heart failure, it's in the context of poorly controlled AFib or poorly controlled hypertension. This case is rather unusual in that the patient is presenting with heart failure without having persistent AFib and poorly controlled hypertension. So in this situation, I'm not sure that anything else could have been done to better manage the patient because she was being or he was being evaluated with serial EKGs and presumably they were being seen and their blood pressure was well controlled. So I think that this patient was fairly well monitored in my opinion. I would agree. And this brings up, I think, several of these. CLL is a chronic disease. And I think what you nicely illustrated, if you don't see a lot of these patients, sometimes providers, it's really challenging. It's a chronic disease like diabetes. So it's not unusual to have the patient say, well, bruising would be an indication to consider other therapy because whenever she has side effects, which are interfering even with quality of life, this is not uncommon that the patients, so a calabrutinib is a second generation, be tried. And I think that the second point that was brought up, the question is like, would this heart failure, which is developing essentially several years after she initially started a brutinib, is it really fully related to a brutinib? I think the temporal relationship would suggest that might have provoked or helped develop, but we always are left with that, like could this have happened without a brutinib. Now with the question of re-challenge, go ahead. I was going to say the same thing to Anju's point, which is again, and I said this before that you have to remember common things being common, that it's not always the cancer drug. And this person had a lot of risk factors. And so maybe the abrutinib didn't help, but it may not have been the cause, particularly in the absence of fib or marked hypertension. So I think we still have to be careful to go about it the same way. We'd always have a differential diagnosis for something like this. And we use, we would use cardiac MRI to also exclude some other causes of heart failure. Abrutinib does not have known late gadolinium enhancement. So it would be falling that group of absence of gadolinium enhancement. So I'm not saying that we have a MRI signature of abrutinib related heart failure, but it does help you exclude other things. We had a case of patient presenting with myocarditis and we said, well, this is not abrutinib related because mechanistically abrutinib would not give you myocarditis. So excluding other things would be helpful. I will move to the next. So these are some slides, I think, Alana, that you wanted to comment on what's recommended. Yes, absolutely. So I think when we're thinking about these brutant tyrosine, or brutin, excuse me, brutin kinase inhibitors, you can see how these, there's different guidance that's available. In terms of the European Society of Cardiology and their consensus statement, again, with multiple other organizations, they do recommend for patients who are at high risk to actually retrieve a baseline echo. So this patient, she did not have a baseline echo that was done. I think at that time, it was 2017, at least, when she was first started on Ibrutinib, there wasn't as much additional data that we now have, you know, years later with some of these increasing incidence reports of Ibrutinib, maybe being associated with heart failure development. But I also think it's important to recognize that she had multiple cardiovascular risk factors that perhaps maybe could have been better controlled and monitored. So when I think about this too, we could have also gotten an echo when she started developing afib, intermittent afib during that period of time. You know, fortunately, we were monitoring her EKGs very frequently when she was reinitiated on Ibrutinib, so we were doing that, but we did not have any echo, you know, to compare her change in cardiac function too. Additionally, I think, you know, blood pressure monitoring. So something that I think we could have done and what I do recommend now is blood pressure monitoring for her at home as well. So have her have a, you know, blood pressure log, monitor it. We could also provide recommendations and, you know, escalate her care to her cardiologist, you know, if we started seeing more, you know, bigger changes in her blood pressure at that time as well. And also trying to optimize her diabetes control as well, out of good measure for cardiovascular risk factors. And I think here from our Heart Failure Society of America statement, you can see we do recommend, you know, optimizing cardiovascular risk factors and thinking about baseline risk for our patients and trying to optimize as much as possible and potentially based on your patient's baseline risk, you know, optimizing monitoring strategies across multiple different risk factor, you know, categories. So for instance, her blood pressure among others, right, and her EKG is monitoring along those lines. So in terms of whether or not she could restart the BTK inhibitor, so I think this is the big question, right, is would you recommend she stop the BTK inhibitor entirely, switch mechanisms for disease control, or possibly switch to a different BTK inhibitor? So in some ways, we sort of tried this a little bit. Now, we didn't have this situation with regards to her heart failure at the time that we trialed the calibrutinib. We did that for the intermittent AFib that she was experiencing. But based off of some guidance within the oncology community, and much of this is expert opinion, but you can see in patients who develop grade three, which is symptomatic heart failure, that they can, you can consider permanently discontinuing the BTK inhibitor and choosing an alternative treatment. Ultimately, that is what we decided to do. So we switched her to venetoclax after she developed the heart failure, because we could not rule out, while there is a potential mixed ideology, we could not rule out entirely that the brutinib wasn't contributing, especially temporally related to when we reinitiated her brutinib. So we did change her to venetoclax, for instance, but just something to think about. It's a chronic disease you want to treat and the availability of venetoclax is certainly, one needs to watch with venetoclax, I learned, because of the large, I think it's given with a significant volume. So that's a, that's, that is a great point. So in patients at high risk, now this depends on their lymphocyte count, and their total white blood cell count, but in patients that are at high risk of tumor lysis syndrome, they are recommended to be hospitalized with fluids. And so, yes, they're, you know, fluids, your allopurinol, all of that. There are some patients, though, if they're not at a very high risk of TLS, you could potentially manage them in a stepwise titration to get them to their goal venetoclax dose on the outpatient side with frequent lab monitoring and doing weekly titrations. And you can avoid, you know, some of that volume load. And again, that all depends on the risk of their CLL, their TLS risk from their CLL. And I want to mention, I think this is in the table two that you helped put together, because venetoclax, it's a very different mechanism, but if it's given with, in this patient, we would be worried about getting a liter of normal saline shortly following this diagnosis. I will move in the sake of time to the last, but not the least, most challenging case, perhaps. Dr. Nouria, the floor is yours. Thank you. So this is a case of someone with a recent malignancy who came to consideration for advanced heart failure therapies. So this is a 48-year-old female with high grade triple negative right-sided breast cancer that was diagnosed in 2019. She got neoadjuvant chemotherapy with carboplatin and paclitaxel, both of which are not largely cardiotoxic. And then she received anthracyclines, namely doxorubicin and cyclophosphamide followed by bilateral mastectomies. Both doxorubicin, as you know, can cause cardiomyopathy and cyclophosphamide can also cause an acute hemorrhagic myopericarditis. She completed her therapy successfully in November of 2019. Her cumulative anthracycline exposure was 240 milligrams per meter squared, which is considered relatively low dose. Anything above 250 milligrams per meter squared is considered high dose and is associated with a higher risk of developing cardiotoxicity. She was BRCA2 positive, and this gave her an increased lifetime risk of developing ovarian cancer, somewhere in the order of 16 to 27 percent. And her oncologist advised that she undergo prophylactic bilateral salpingo-oophorectomy, but the patient declined. And in December of 2019, her scans showed no evidence of disease. Unfortunately, she presented six months later with 10 days of progressive dyspnea and lightheadedness. Next slide. If you could just, yeah. So this is her echo. As you can see, the images are done both with and without contrast. The contrast image, you can see there is actually a device in place. But in the first image, she has biventricular dysfunction. Both the LV and RV function are quite compromised. Her LVEF was estimated at 15 percent. She had mild LV dilatation with an end-diastolic dimension of 56 millimeters, suggesting that the process was going on for a little bit. Her RV fractional area change was 24 percent, and her TAPC was also reduced at 11. Next slide. Also known as ventricle not moving. So she had a right heart cath, which showed an RA of eight, pulmonary artery pressure of 50 over 22 with a mean of 34, a wedge of 20, and a severely reduced cardiac index of 1.3. Based on these numbers, she was initiated on milrinone, and a balloon pump was inserted. She was transferred to our hospital from the outside facility for consideration of advanced therapies. Luckily, we were able to diurese her and keep her on the milrinone and take her off the balloon pump. A subsequent MRI showed that her LVEF remained approximately 17 percent. Her LV was mildly dilated. Her RVEF was also 17 percent. She had no late gadolinium enhancement and no extracellular edema. A repeat right heart cath, once she has been adequately optimized, showed an RA of three, PF 26 over 15 with a mean of 20, a wedge of 14, and a cardiac index of 1.8 with a PAPI of 3.7 on milrinone at 0.5 mics per kilograms per minute. So at this point, this is her echo once she had been optimized. And as you can see, she continues to have significant biventricular dysfunction, although her RV looks a little bit better than her initial echo if we were to hallucinate appropriately. So next slide. You need to imagine a lot. And she has probably a swan. Yeah, she had a swan in place. In the right ventricle. So move to the next slide. So in summary, this is a 48-year-old woman with breast cancer within the last year who now presents with anthracycline-induced biventricular dysfunction with marginal hemodynamics despite high-dose inotropic support. So if you click on the next. So the first question is, is she a candidate for advanced heart failure therapies given her recent history of breast cancer? If not, why not? And if she is, what kind of advanced heart failure therapy would you consider in this patient? So moving to the first question, if you look at the ISHLT guidelines, they basically say that in heart transplant candidates with a history of malignancy collaboration with the oncology specialist is recommended for individualized risk stratification to assess the malignancy-related survival and the risk of recurrence in the context of immunosuppression before deciding if they're candidates. Furthermore, in patients with a history of malignancy, heart transplant is usually recommended when the malignancy-related survival would not impact post-transplant survival and the risk of recurrence is low based on tumor type, response to therapy, and a negative metastatic evaluation. So this patient had early-stage breast cancer. She really did not have any evidence of metastatic disease, but that being said, she was not even one year out from a diagnosis of breast cancer. Traditionally, we always waited approximately five years after a diagnosis of cancer to list anybody for transplant, but now we're realizing that there are several malignancies where the rate of recurrence is so low, such as prostate cancer that's treated surgically or early-stage renal cell cancer that may be treated surgically. Skin malignancies tend to be relatively benign. So in all of these situations, we have been lowering that five-year mark. So we talked with oncology about this patient, and basically they said that she has about a 5% five-year risk of recurrent breast cancer, and if she does not undergo a bilateral salpingo-oophorectomy given her BRCA2 status, she has about a 0.5% per year or 20% lifetime risk of ovarian cancer. And the guidelines actually do touch upon this specifically, where they say that if you have a patient with a history of breast or ovarian cancer, they should be checked for BRCA mutations, and consideration should be given to prophylactic surgery, such as mastectomies or oophorectomies in patients who are BRCA1 or BRCA2 positive. So I guess we could ask Anne, and if this was your patient and she is so sick, what would you say about going ahead with transplant so early after her cancer diagnosis and with massive immunosuppression that she would be getting at least for the first six months to a year? Yeah, these are always really challenging cases, and I think you alluded, Anju, to sort of the limitations of what we have. On top of that, this is a triple negative breast cancer, so it makes all of us very nervous, but yet at the same time, when you think about her heart failure, I would tell you looking at this patient, she's much more likely to have to frankly die from her heart failure in this situation than she is from her breast cancer. There's a few things, you know, as an oncologist, if she was treated in the neoadjuvant setting, I would probably look for other things, such as did she have a complete response or did she have residual disease. The patients who had a complete response do exceptionally well, in which case I would say go ahead with the transplant, and on the BRCA part of it, you don't have time right now to do a prophylactic surgery, at least as a non-heart failure or surgeon, that's what I would say, and her workup thus far has been negative. Ultimately, we would recommend that, but I don't know that I would preclude that from her being listed for transplant, and I don't know that the immune suppression is going to increase that risk so much, so I think it's a joint decision. I usually outline numbers just as you did when we work with our heart failure specialists and the transplant surgeons, and then ultimately, it's left kind of up to them. All right, so next slide. So, again, go ahead. Sorry, back. Oh, sorry. I just want to say, you know, I think at the end of the day, it's all about competing risk of the cancer versus the cardiovascular outcomes. I did want to say, you know, Andrew, I completely agree with you and Anne. One other thing, too, is that mercantile transplant has answer-specific guidelines in terms of the cancer site as well as the stage of disease regarding how long they recommend waiting before solid organ transplant, which was reproduced in the ISHLT guidelines, which were modified specific for heart transplant. So, these questions come up, not infrequently, but there is specific guidance based on the cancer type and stage that's available from AJT as well as ISHLT. Yeah, I think like Andrew mentioned, you know, the guidelines would tell you to wait in a patient with triple negative breast cancer until they are farther out. That's different than somebody who has an early stage hormone receptor positive breast cancer. I think Nick wanted to say something as well. Yes, and just to go for the hypothetical here, because this is a triple negative, so say this patient did get a heart transplant, and sorry to bring it back to immunotherapy, but I love immunotherapy, because they're triple negative in the keynote trial, would you give them checkpoint inhibitors after? We don't really have data on the risk of rejection with checkpoint inhibitors, although from other sites like the kidney, we have data that shows there's increased rejection in transplanted kidneys of patients who get checkpoint inhibitors. So, I think it's an area where you don't have any data, and very interesting to see if she had recurrence after a transplant, would we even consider or how the patient would do with checkpoint inhibitors? So, we have not given it to people with melanoma and other diseases where there are fewer other alternatives, and who might need checkpoint inhibitors, primarily because of the fear of rejection with those agents. But given the interest of time, I'm going to move forward with this case. The guidelines do say that you can consider MCS in these patients where you might be worried about cancer recurrence after transplant. She had biventricular dysfunction, and even though her hemodynamic indices of RV function were not bad, her RA was only three, her PAPI was three and a half, we were worried that she would have post-LVAD RV dysfunction. So, she underwent a HERCMA 3-LVAD with an upfront Protec Duo-RVAD. Eventually, we were able to wean her from the RVAD onto IV milrinone, but she could not be weaned off IV milrinone. And therefore, the decision was made that we should try to list her for transplant. Her cancer was gone, as far as we could tell. She underwent a prophylactic bilateral salpingo-oophorectomy on the VAD and was then listed and ultimately underwent a transplant two years later because she was fairly sensitized as well. So, the second question is, what are the concerns post-transplant in cancer survivors and do they require any special surveillance? If you could go to the next slide. In the interest of time, I'll just tell you this was a study that was done from the ISHLT database of patients who had undergone a cardiac transplant and had a pre-transplant history of malignancy. Majority were solid organ malignancies, but about 25% at hematologic malignancies. And as you can see, the number of patients with prior malignancies who are undergoing transplants is gradually increasing. Interestingly, if you have a history of a solid malignancy, your post-transplant survival is no different than someone who's never had a malignancy. Patients with a heme malignancy tend to have a poor outcome for the first year after transplant, but if they survive that first year, their subsequent mortality is the same as someone who never had a malignancy. So, a prior history of a malignancy alone is not a contraindication to undergoing transplant. These patients do have an increased risk of post-transplant malignancies, and it has been shown that mTOR inhibitors like everolimus reduce this risk, but there's no guidelines on the routine use of these agents as immunosuppressants in post-transplant patients who have a prior history of cancer. And currently, the guidelines do not recommend any special surveillance for secondary cancers and just recommend age-appropriate surveillance. But again, depending on your patient, so our patient, for instance, we have been doing closer surveillance with the oncology team to look for recurrent breast cancer only because she's so early after her original diagnosis. And with that, I'll leave you three minutes to summarize this session. Wow, I do, I think this is most, and thank you, well, first of all, thank you all for phenomenal presentations. I think, I'm thinking of the audience that's listening to this, and I'll put a personal, and I think group, pledge that I think we've opened and touched on a number of areas where we, the reason why we illustrated cases where there was no trials, we all are aware that there will never be randomized trials for many of the instances that we presented. How can we collect, can we conduct pragmatic trials? What are the good ways of asking these questions? And last question that came from Nick, I think we all, at least every two months, run that question, hey, Andrew, hey, Rich, have you challenged the patient? I have a patient who really needs immune checkpoint inhibitor because our population of heart transplant survivors is growing, thanks to everybody who is listening to the, on the call. And as you just showed, they do have a higher risk of malignancies in general. So I think that question will continue to be asked, which therapies, and specifically immune therapy, can it be given if there is no good alternative? So I'll thank everyone in pause here, and I'll leave it to Michelle, and I want to ask if anybody else has more comments. No, I was just going to say this was, we're leaving with one minute to go. For a person with anxiety that was in charge of the time, we're ending right on time. But I think we have highlighted the fact that there is so much that we still don't know. We could easily do this for another hour and a half and still run out of time. But really, thank you so much to our writers for all the work with the writing of the document, and also for joining us and putting together these cases. And I really hope you all got a lot out of it, and I think this really highlights how much we still need to learn. So I hope this sparks your interest in reading the statement and also collaborating with us to get this data, so that we know what to do with our patients. Yes. Oh, I have a question. How can we keep in touch with this team? Maybe we can charge Cynthia. I'm sure you might get some post-webinar questions, and we'll work with Cynthia. I think one could envision activities within HFSA. I think it's wonderful to see the enthusiasm, so we'll get that information back to you. Thank you all. All right. Wonderful. Thank you again. Take care. Thank you. Goodbye.

cardio-oncology

heart failure

cancer treatments

EGFR tyrosine kinase inhibitor

HER2-targeted therapies

fulminant myocarditis

immunotherapy

Ibrutinib

chronic lymphocytic leukemia

atrial fibrillation

heart transplantation

collaborative guidelines