Multidisciplinary Management of Cardiovascular Risk in Patients With CLL on BTK Inhibitors
In this expert Q&A, Daniel Lenihan, MD, FACC, FESC, FIC-OS, a cardio-oncologist at Saint Francis Healthcare in Cape Girardeau, Missouri, explores cardiovascular safety considerations for patients with chronic lymphocytic leukemia (CLL) receiving Bruton tyrosine kinase (BTK) inhibitors. Drawing on decades of experience, Dr Lenihan outlines the evolving role of cardio-oncology in improving outcomes for patients treated with agents like ibrutinib and its newer-generation counterparts. He emphasizes the importance of personalized care, vigilance around atrial fibrillation and hypertension, and the critical value of multidisciplinary communication in treatment planning.
Key Highlights:
- First-generation BTK inhibitor ibrutinib is associated with significant cardiovascular risks, including atrial fibrillation, hypertension, and bleeding due to platelet inhibition.
- Newer-generation BTK inhibitors (eg, acalabrutinib, zanubrutinib) offer improved cardiovascular safety profiles and may be better options for patients with preexisting cardiac conditions.
- Multidisciplinary collaboration between cardiology and oncology is essential to optimize treatment outcomes and manage cardiovascular adverse effects during BTK inhibitor therapy.
- Key research gaps remain, including optimal cardiac medication choices, blood pressure targets, and anticoagulation strategies for patients on BTK inhibitors.
Additional Resource:
- Lenihan D, Bloom M, Copeland-Halperin R, et al. Considerations for the practical management of cardiovascular risk With Bruton's tyrosine kinase inhibitors for patients With CLL. Oncologist. 2025:oyaf237. doi:10.1093/oncolo/oyaf237
Daniel Lenihan, MD, FACC, FESC, FIC-OS: I'm Daniel Lenihan. I am a cardio-oncologist at Cape Girardeau, Missouri, and I am a founder and board member for the International Cardio-Oncology Society.
Consultant360: Your study highlights the cardiovascular risks associated with BTK inhibitors, especially the earlier agents. What were the most important differences you found in safety profiles between the first-generation and newer-generation therapies?
Dr Lenihan: Well, I think the first real important point to make is that all of these classes of therapies are essentially a revolution in the treatment of CLL and other B-cell malignancies. And the reason why we're really talking about the consequences of being on those therapies is because they extend the lives of the patients that have those malignancies. So in years past, a patient with CLL might not live 2 to 5 years, but with the BTK inhibitors, they might live 20 or 25 years after their diagnosis—or after their diagnosis requires treatment. So I think that this is the most important point: how effective these therapies are in general.
And then when you start detailing what the consequences are of those therapies, that's where you start noticing some differences. So certainly, in the case of ibrutinib, which was the first-generation BTK inhibitor, it was very clear that there was a certain rate of atrial fibrillation. There was also a certain rate of hypertension that results. And then all of these drugs, including ibrutinib especially, act as a platelet inhibitor. So they make patients more likely to bruise or bleed.
So the consequences of being on those therapies are certainly atrial fibrillation and other arrhythmias, hypertension, and then an increased risk of bleeding.
And then if you do traditional treatment for atrial fibrillation, obviously we're going to be using some sort of anticoagulant, so you're really complicating the matter. You have a drug that may make you more prone to bleeding, and then you're adding a blood thinner to that, so it can get very complex.
C360: So with that in mind, with some of these newer BTK inhibitors showing a better cardiovascular safety profile, how should clinicians factor in a patient's heart health when choosing a treatment approach for CLL?
Dr Lenihan: Well, I mean, this is a really good question.
And, you know, as a cardio-oncologist, I'm not the one making that decision. I think I might be advising my hematology and oncology colleagues about which one I think might be better. But in the end, they're the ones that decide, based on possible side effects but also about efficacy.
So really the decision comes to them, but I would say we definitely want to advise them appropriately to consider that atrial fibrillation or hypertension or some other consequence of those two problems could be an important factor in a particular patient. So more than anything, I would say we want to engage in a conversation to say, for example, yes, this patient had trouble with atrial fibrillation in the past and we had to go to this level to straighten it out, for example. And then if you had a drug choice that would not put them at higher risk for the development of AFib, then that would be an appropriate choice.
C360: And that really brings me to my next question, that discussion around the multidisciplinary care of these patients. Why do you feel it's particularly important to focus on this intersection of cardiology and oncology right now in the management of CLL?
Dr Lenihan: Well, the biggest thing is that we—the collective "we" for cardiology—do have a lot of input, or should have a lot of input, into these decisions, and to say, “You know, this drug is known to cause this problem,” and if we either adjust the dose or adjust the medication to a different one where we’re not likely to encounter that particular problem, then as a result, the patient is on appropriate cancer therapy for a longer period of time.
This same paradigm existed when, for example, trastuzumab was first coming out. There was a high rate of cardiomyopathy or heart failure that resulted, and as it turned out, it was a combination of things that led to that higher rate of heart failure. And it wasn't until we investigated it more and thought about what ways we can avoid this problem that patients now get trastuzumab or any of the variants of HER2-based therapy for many years and don't have—I mean there's still a possibility for cardiomyopathy or heart failure, but it's much lower than it used to be.
So in the end, that whole process led to patients getting best-case-scenario cancer therapy for a longer period of time, resulting in the best cancer outcome. And if we could prevent or detect heart failure or some cardiomyopathy early in its stage, then we could put the appropriate cardiac-based therapy on board so that the patient did not have a consequence of that therapy. So this whole paradigm of managing or preventing heart-related problems allowed for best cancer therapy.
And so applying that principle to CLL is really the essence. So we want to be helpful in advising the hematology/oncology community: in this particular patient, we think that the problem of atrial fibrillation is going to lead to heart failure, is going to be a problem, and you will have to stop your therapy. If we do this or do that, we can prevent this problem, and therefore get best cancer therapy. So this is the whole reason for a multidisciplinary approach.
C360: And to jump off of a point that you just made, what would your top recommendations be for clinicians managing patients on BTK inhibitors who develop new or worsening cardiovascular symptoms? When is it appropriate to pause or switch therapies?
Dr Lenihan: That's a very complex decision, and you have to personalize it. So there could be an instance where, say, for example, a patient was placed on ibrutinib and they had a good response from a cancer perspective, and they went along for a while on that therapy, and their cancer was, you know, felt to be in remission or undetected, and they developed atrial fibrillation.
And we can manage that atrial fibrillation in a variety of ways, including possible cardioversion or an ablation procedure or intensify their medications or any of those decisions in combination. And then we are able to return that patient to sinus rhythm and they're stable. That could either restart that therapy at a lower dose, for example, or in that situation, if you knew there was a difference between a first-generation and a second-generation therapy, you might say, “Okay, if you feel that the CLL requires additional therapy, then use a second-generation or third-generation medication,” because we know it's a little less likely to develop AFib.
And then, on the cardiology side, we would say, “Okay, we want to manage their high blood pressure optimally,” make sure that we're monitoring it and then treating it with the best preventive medicines that we could offer. And so those are not any blood pressure medicine—I mean, you have to be very careful about which medicine you choose and you want to personalize it. So I think that's where there has to be communication and a conversation between the providers there.
C360: What key questions remain unanswered about cardiovascular risk in CLL patients, and what types of research or trials do you feel are still needed to fill those gaps?
Dr. Lenihan: Well, there's always the general belief that—you started off with ibrutinib, and that was a very effective drug for the treatment of CLL and other B-cell malignancies. And then you ran into issues with possible cardiovascular adverse events. And then they developed new drugs for which you might be able to notice a difference in one complication or another.
And, you know, the general argument is, “Okay, well, we'll go with the second- or third-generation drug.” That's certainly the way things go clinically. But one thing that we don't know—and I don't know if we'll ever know this—is whether one drug, either a second- or third-generation, is better than another. There will be very unlikely that there's ever a head-to-head comparison between those newer-generation drugs because there's very little impetus from a drug manufacturer to go head-to-head against their direct competitor. So that's unlikely to happen.
And then the other consideration is that you're basically saying that the newer drugs are better than the older drug. And most people accept that argument. But the real question is, is one of those newer drugs better than the other? We're not going to know that question.
The biggest cardio-oncology question that I think remains—well, actually, there are several. But the first would be, what cardiac medications would be most effective at preventing those problems? That we don't know. We sort of say clinically, okay, a beta blocker would be a better choice here because there's less drug-drug interactions. There are a lot of beta blockers, so each one has its own little characteristic. So is one beta blocker better than another? That's always a cardiology-based question.
And then the other is, you know, if we manage the high blood pressure to a certain goal, is that better than traditional blood pressure goals? So we see that principle in other trials, looking at, you know, if your target goal for blood pressure control is less than 130 over 80 versus less than 140 over 90—so you have two different goals there—is one better than the other? And this is a question that I don't know if we'll ever get answered either, but it's certainly an idea.
And then of course the other issues involve anticoagulation and bleeding. You know, what is our best strategy? And the way cardiology has gone in the last decade or more is instead of aspirin or Plavix or other antiplatelet medications or Coumadin, for example—an old school anticoagulant—pretty much everything goes toward the newer DOACs or other factor inhibitors that are being developed.
So the whole world of anticoagulation has really changed in cardiology in the past 10 years or more. And now we're just starting to understand the dose might matter greatly—traditional dose versus lower dose—and so these details are still out there. And we have to make clinical decisions without a lot of data to back up our decisions.
One thing I would obviously emphasize would be the multidisciplinary discussion. This is something that really has to happen. If you make a decision as a cardiologist in the absence of any direct understanding from the hematology/oncology world, then I don't think you're making the best decisions. So you need to reach out and have a good line of communication among your colleagues there.
And actually, I find that to be one of my most rewarding interactions that occur on a day-to-day basis. I'm really learning a lot from the hematology/oncology world about what the newer drugs are, how effective they are, how you can adjust the dose, or whatever. And that's an area that I just don't know that. And then on the other hand, I would imagine they would say the same thing. They're not familiar with the latest version of how to manage high blood pressure to prevent the development of AFib, which drugs are better than others. How do we manage AFib if it does occur? Do we do an ablation procedure? Do we put in a left atrial occlusion device?
There are various complex decisions that cardiology does that I'm sure hematology is not very aware of. And so having that multidisciplinary discussion is a must. And then a corollary to that piece is that I think cardiology in general—if I asked my colleagues, do they know what ibrutinib is or acalabrutinib or zanubrutinib?—they would say no, have no idea. That we have no idea what the consequences of those medicines are. And so I think it's incumbent on us in the cardiology space to not only engage our own colleagues but help guide them in terms of: yes, these decisions are important, and we can help manage the patient issues in a more proactive way that is going to be a great benefit. So it's on us to engage our own cardiology colleagues and to be active in their practice situations.