BTK Inhibitors and Toxicity Management in B-Cell Lymphomas

Harry P. Erba, MD, PhD:Is there any reason to choose between the BTK [Bruton tyrosine kinase] inhibitors based on comorbidities, organ function?

Anthony R. Mato, MD, MSCE:You mean individual ones?

Harry P. Erba, MD, PhD:Yes, like ibrutinib versus acalabrutinib in patients with cardiac disease.

Anthony R. Mato, MD, MSCE:I don’t necessarily think so. I think that what we learned between ASH [the American Society of Hematology meeting] of 2018, and 2017, or 2016, when we saw the early data for acalabrutinib versus more longer-term follow-up—40-plus months median follow up—was that some of the same AEs [adverse events] that were present for ibrutinib were present with acalabrutinib. Again, maybe at less frequency. But I don’t think that you could say to a patient, “I don’t want you to have a fatal bleed. Therefore, I’m going to prescribe acalabrutinib.” Or, “I don’t want you to have AF [atrial fibrillation] or hypertension, therefore I’m going to prescribe acalabrutinib.”

I think from a clinical standpoint, you couldn’t make that argument yet that those AEs are not possible, or not within that particular drug within the subclass. The AEs were there, they just were less than what we would have expected with ibrutinib. But then again, it’s apples to oranges, in terms of patient population. And so, I don’t really know. I’m a little cautious about doing it for that reason.

Harry P. Erba, MD, PhD:That’s a nice segue. Let’s delve deeper into the toxicities that we see with the BTK inhibitors. Let’s talk about ibrutinib first. What can patients expect? What do you warn them about?

Anthony R. Mato, MD, MSCE:We generally spend a lot of time talking about the AE profile of targeted therapies. We have them meet with the pharmacist as well, in case we forget something. The major toxicities with ibrutinib that I think about are arthralgias, myalgias, rash, bleeding, oozing, atrial fibrillation, or other arrhythmia, and infection, and minor GI [gastrointestinal] toxicities. That’s sort of the scope of AEs that we deal with when we’re using that drug.

Harry P. Erba, MD, PhD:OK, so let me go into a little bit more detail about that. I’ve had these patients myself. Your patient is on full-dose ibrutinib and develops atrial fibrillation. It’s ultimately controlled, but still in AF, or they go back into sinus. Can that patient be rechallenged? Do you stop the ibrutinib? Do you rechallenge? Do you lower the dose? What are we supposed to do?

Anthony R. Mato, MD, MSCE:I only stop it if it’s symptomatic AF. If you’re in the office and you feel their pulse and you find they have AF, I really think you can manage them or co-manage them with a good internist or a cardiologist or cardio-oncologist, depending on your institution. Very few patients we’ve had to actually stop because of an AF event. It requires management and somebody who has to think about control, but whether rhythm control is warranted, anticoagulation, whether that increases the bleeding risk… I think in the right hands, these patients can be managed. It’s not a reason to give up on a good drug, but it does make the situation more complicated. Probably, the rate of AF is somewhere between 5% and 10%.

Harry P. Erba, MD, PhD:Do you dose reduce based on that type of AE?

Anthony R. Mato, MD, MSCE:We’ve tried that. I can’t tell you there’s any compelling data from my own experience or from the clinical trials or the registries or real-world studies that suggest that there are very many dose-dependent toxicities. I can’t really say AF gets better if you’re at 280 mg versus 420 mg. I can’t say that about rash. Maybe with platelet function, you could argue there’s sort of like an aspirin, and you’re inhibiting platelets based on dose. But I really don’t know whether that does decrease the bleeding risk when you go to a lower dose.

Harry P. Erba, MD, PhD:So, again, people are looking to you for guidance based on your experience here. In patients who develop atrial fibrillation, who are going to be on long-term anticoagulation, clearly the concern with ibrutinib, the BTK inhibitors, is bleeding. Do you use a lower dose of a DOAC [direct oral anticoagulant]? Or what do you use for it?

Anthony R. Mato, MD, MSCE:Generally not. We often then partner with our cardiologist partners to do it. But you know, the risk is stroke, and I feel like making compromises when the outcome is one that’s so serious, without any data to do that, is probably not a great thing for patients. So I really can’t tell them what the risk of stroke is on ibrutinib plus a low-dose anticoagulant. We try to manage the problems independently, if we can. And if it’s not tolerated one way or the other, then it’s time to switch to an alternative drug that doesn’t have that same toxicity profile.

Harry P. Erba, MD, PhD:OK, so what I heard you say then is, the major toxicities that I think of with ibrutinib are atrial fibrillation and bleeding. That’s personally what I think.

Anthony R. Mato, MD, MSCE:Those are the most life-threatening toxicities.

Harry P. Erba, MD, PhD:Most life-threatening. So what I hear you say is those can be managed.

Anthony R. Mato, MD, MSCE:Well, if you have a life-threatening bleed, then I don’t think that there’s a very strong rationale to rechallenge somebody with the same drug.

Harry P. Erba, MD, PhD:OK.

Anthony R. Mato, MD, MSCE:But I think atrial fibrillation could be managed medically, particularly if it’s not causing symptoms when it’s discovered or if there are minimal symptoms when it’s discovered, like they’re not in rapid AF and hypotensive. But if a patient has a life-threatening bleed on ibrutinib with or without anticoagulation, I’m a bit hesitant to try it again. You know, life-threatening to me means just that.

So then I do think about another drug, a PI3K inhibitor, venetoclax, something that doesn’t have as much of a bleeding signal.

Harry P. Erba, MD, PhD:OK, I think that’s very helpful guidance. You also mentioned maybe a lower dose of a BTK inhibitor might have less platelet dysfunction?

Anthony R. Mato, MD, MSCE:Maybe, but we don’t know. I haven’t seen aggregometry to support that. But I do think with some of the other AEs that are more bothersome but less life-threatening, like arthralgias, we do sometimes stop it. Actually, arthralgias are an area where there’s still some confusion. I’m not sure that they are all arthralgias. I think early on, sometimes it may be that we’re just inducing gout in these people, and that a break in steroids or rechallenging them with steroids gets them through it, or starting at a lower dose gets them through it. I do think that later on it’s probably not a gout flare, but it may be the immunological effects of the drug on joints that were injured previously. And there, sometimes, we do different tricks, either lowering the dose or taking a break and then rechallenging. Some people try glucosamine, for example. I’ve seen everything reported at least once through these sort of case reports or case series, but I don’t think we have a standard of care. Stopping statins is another thing I’ve heard people do. They all probably work once.

Harry P. Erba, MD, PhD:So CLL [chronic lymphocytic leukemia] doctors are becoming like CML [chronic myeloid leukemia] doctors. Ten years ago, with the advent of oral inhibitors that have chronic low-grade toxicities, or more serious ones, we were trying to figure out how to manage those toxicities. This is important. Otherwise, it leads to discontinuation.

Anthony R. Mato, MD, MSCE:Correct.

Harry P. Erba, MD, PhD:And I think you published on this?

Anthony R. Mato, MD, MSCE:Yes. And I also think probably one of the most underrecognized toxicities within the class is hypertension. People don’t feel sick unless they’re very hypertensive. And you can have people who have 30%, 40% incidence of hypertension or exacerbation of an underlying hypertension. It’s easy to ignore that. You look at the vitals. They’re 148 over 50s, or 62. Well, that could be ignored for months. What we don’t know is, a), what drugs work best on this BTK-induced hypertension, which is real because we know this from the randomized trial.

And b), oftentimes oncologists are hesitant to manage it. We say, “Go back to your primary doctor.” We don’t know if that actually happens. And so, the long-term vascular, coronary disease, stroke, peripheral vascular disease consequences of hypertension are unknown at this time. That’s an area where it’s a chronic toxicity but no one feels sick from it. And so, that’s one of the biggest areas that we’re focusing on now.

Transcript edited for clarity.