Kerry Rogers, MD, on BTK Inhibitor Selection and Tolerability in CLL

Selecting and sustaining Bruton tyrosine kinase (BTK) inhibitor therapy for chronic lymphocytic leukemia (CLL) involves more than matching a drug to a diagnosis. In this interview with The American Journal of Managed Care^® (AJMC^®), Kerry Rogers, MD, associate professor at The James—The Ohio State University Comprehensive Cancer Center, walks through how she approaches both ends of that decision: which agent to start with and how to help patients stay on it.

On the selection side, Rogers explains why covalent BTK inhibitors remain the frontline standard, where the noncovalent agent pirtobrutinib may fit for select patients, and why sequencing uncertainty makes that choice complicated for younger, higher-risk patients. On the tolerability side, she turns to adverse effects that rarely make it into treatment algorithms: joint and muscle aches, loose stools, and bruising. Though often dismissed as minor, Rogers argues these quietly shape whether patients stay on therapy at all.

This interview has been lightly edited for clarity.

AJMC: Can you walk us through how you approach your decision on BTK inhibition in CLL and what you think about emerging frontline data on noncovalent BTK inhibitors within that context?

Rogers: When you’re thinking about a BTK inhibitor for someone as an initial therapy, one thing that currently makes the decision really easy is that there’s only FDA approval for covalent BTK inhibitors. While there’s recently been some data with the noncovalent BTK inhibitor pirtobrutinib in the frontline setting for CLL, the drugs that are approved are all covalent BTK inhibitors, with the 2 more preferred options these days being acalabrutinib and zanubrutinib because they have improved cardiovascular safety compared with ibrutinib.

Really, if I’m talking about a standard-of-care treatment for someone, I’m only talking about covalent BTK inhibitors, just because that’s what’s going to be covered by insurance. I do think pirtobrutinib might be suitable for some patients in the frontline setting. There were a lot of data at [the American Society of Hematology] this year, showing that, of course, it had improved progression-free survival [PFS] compared with bendamustine and rituximab. That was kind of an obvious conclusion; otherwise, what have we been doing as a field for the last decade?

But actually showing in the frontline setting, it looks like the PFS is going to be longer than ibrutinib, and while that’s not really compared with the ones we use now, acalabrutinib or zanubrutinib, I do think that the PFS is likely to be at least as good, if not better, than that with those newer covalent BTK inhibitors. And the adverse effect profile is really great, especially because of the noncovalent binding and the selectivity of that agent. So if you’re looking at someone in whom really limiting adverse effects is a huge goal, maybe that would be a better option, especially since the risk of atrial fibrillation and stuff is much lower with pirtobrutinib.

Problems arise because we don’t know if you can use something like acalabrutinib or zanubrutinib after pirtobrutinib, and we certainly know very well that you can use pirtobrutinib after covalent BTK inhibitors; that’s how it was developed initially. I think you'd also have to be thinking about your patient’s lifespan and how many therapies they’re going to get in their natural lifespan. Someone with high-risk disease who’s younger, probably who is healthy and you think has a lifespan that could be decades, probably shouldn’t be getting pirtobrutinib as a first-line therapy at this point because you don’t know how long their lifespan’s going to be otherwise, and certainly [they] could run into problems with drug resistance, CLL resistance to BTK inhibitors in the future. You wouldn’t want to potentially burn that bridge with covalent BTK inhibitors. Maybe we’ll find out that that isn’t important, that you can use them after pirtobrutinib, but based on some of the mutations we’ve seen in pirtobrutinib resistance, I worry that that’s not going to be something that works for everybody.

I think the last aspect of this is, you asked me about noncovalent BTK inhibitors, and I’m really only talking about pirtobrutinib here. But there are other noncovalent BTK inhibitors that don't currently really have frontline data, and if you look at nemtabrutinib, that’s actually the opposite. It’s less selective by quite a bit, and actually has generally more adverse effects. One of the reasons it can work in resistance is that it’s less selective and hits multiple relevant targets, but that’s probably not something you want to move to a frontline setting when it has more adverse effects—unless it’s markedly more effective, at least as a single agent given continuously. Really just thinking about pirtobrutinib, and I think it would be appropriate for select patients where you don’t think they’re going to need many therapies in their lifespan, maybe because they’re older or people who you really think won’t need a BTK inhibitor badly, like venetoclax isn’t going to be an option and won’t tolerate that covalent one.

I think the patients have really been driving a lot of the solutions, and I find the best I can do sometimes is discuss these, talk about what might have worked for others, and be supportive of them trying different things.

AJMC: What clinical features most influence your decision to use a BTK inhibitor vs a time-limited regimen in the front-line setting?

Rogers: When you’re picking an initial therapy for patients, I think there are 2 major options now. You’ve got these covalent BTK inhibitors that are given as a monotherapy mostly until progression, and then you’ve got regimens that include venetoclax that are given for a fixed duration. I think there are 2 major drivers for patients that lead to the selection of a continuous BTK inhibitor strategy in an initial setting.

For me, one of them that I really think about is patients with TP53 mutations or deletion 17p in their CLL because we know that outcomes when you give a covalent BTK inhibitor, and I think this would probably be true for [pirtobrutinib]; I just haven’t seen that data to show it’s true yet. When you give a BTK inhibitor in the frontline setting, the PFS is almost as good as patients who don’t have a TP53 alteration. With every other therapy, we’ve seen that PFS is shorter in patients with a TP53 alteration. I think this is a very special circumstance where patients whose CLL has deletion 17p or a TP53 mutation can really maximize the PFS of their first therapy.

That being said, some people want time-limited therapy and their main interest is not maximizing the remission with their first therapy, and that’s okay. But that is one reason that I recommend covalent BTK inhibitors continuously: their opportunity to have an outcome that is statistically the same as people without those features, although I feel like it might be a hair shorter. But still, this is a very good outcome.

The second major driver for selection of a covalent BTK inhibitor in a frontline setting, or continuous BTK inhibitor strategy, is definitely patient preference. These are really easy. Take these pills and go about your business, and that’s very appealing to a lot of people. Sometimes people are working full time and don’t want to take the time away from work to do the ramp up for venetoclax. Sometimes people are retired and don't want to take the time away from golfing to do the venetoclax ramp up or interfere with their RVing around the country or other things they want to do with their lives. Some people aren’t doing anything else but just don’t want to come to my clinic for venetoclax. And that’s okay.

The outcomes with this are actually the best PFS we have in a frontline setting with continuous BTK inhibitors. I think it is completely fine. The main driver of these fixed-duration regimens is, of course, the fact that they’re fixed duration and concerns about future resistance. But if people are in their 80s, they’re not highly concerned about their 40-year outlook. At least I haven’t met many octogenarians who were. A lot of them just pick something that’s a better lifestyle fit for them, and I think that is completely fine.

Those are really the 2 major drivers of this.

A third one that I will throw in there, although I think in most cases this is probably not what drives selection, is that this is the only kind of monotherapy regimen. You can give venetoclax by itself, but usually you don’t. Those fixed-duration regimens are combinations. Sometimes you have people who are just very unwell, and this population is not really captured in clinical trials because these are people who weren’t really fit enough or healthy enough to be in a research study. Even research studies or clinical trials for unfit patients. And you’re like, “Okay, let’s just try to do something the least harmful as possible so that you don’t feel sick from your CLL.”

Although this isn’t really captured in trial populations, I have patients who have dementia who live in memory care facilities or have a lot of health problems other than the CLL that greatly impair their functioning, and you don’t want the CLL to be something that adds to their symptom burden or decreased quality of life. So, you can get away with 1 agent if you do a BTK inhibitor, and it’s better than giving more than 1 agent to someone who’s very unwell just from other things, not from the CLL.

AJMC: What are the most underrecognized toxicities of BTK inhibitors, and how should clinicians better anticipate or manage them?

Rogers: I think when you think about BTK inhibitor toxicities, most of the evidence is with the covalent BTK inhibitors. There are toxicities that worry doctors a lot, like high blood pressure, arrhythmias, things like that. I think what is kind of underrecognized, or at least underemphasized, is some of the stuff that impacts the patients on a daily basis.

I would say probably muscle or joint pain, like arthralgias and myalgias, is a big one. That is a huge dissatisfier for a lot of patients when they wake up feeling achy all the time, and while that’s not usually medically serious, the care team isn’t always really focused on that. That can be a huge deal for patients. I would say the few patients who get problematic loose stools—that can be one, too—that you’re like, “Okay, yeah, so you have loose stools.” It’s not really that big of a deal from your perspective as a physician, but if you’re the one who is having to run to the bathroom more often, even though it’s tolerable to you, it still may be detracting from your enjoyment of your life. Those are really, I think, 2 big ones.

I will say probably the other one that is not necessarily underascertained but kind of underemphasized is the bruising, because it’s not medically serious. Yes, there is a risk of severe bleeding with the BTK inhibitors, but the risk of bruising is experienced by way more people than severe bleeding. People get these extensor surface bruises on their arms, which the formal word for that is called senile purpura. These are older patients, and the skin is thinner there, and so this happens. This will worsen when people are taking these drugs or start to appear for the first time when people are taking these drugs. As a physician, you’re like, “Oh, this is a harmless condition. This isn’t going to hurt you. It’s not going to impair your functioning. It’s not going to cause me to worry about changing your treatment or order a workup for something. This is fine. It’s not like blood in your stool, big bruises on your trunk, bleeding somewhere problematic.”

But to patients, this can be very, very difficult to live with, and I think we don’t discuss that enough in our clinics because it’s a cosmetic problem. Like, “Why is my arm always like this? I have to wear long sleeves on the golf course, and I don’t want to.” Or, “If I wear a polo shirt because it’s summer, then people ask me why I’m bruised, or I feel embarrassed by this.” I think both men and women don’t like the appearance of that. I think those are some of the underemphasized. How do you deal with it?

The last thing I was talking about, which is bruising, I know of no effective therapies to decrease the bruising. If people are also on aspirin or something like apixaban (Eliquis; Bristol Myers Squibb), which is an anticoagulant, if that can be stopped, that will help. But most of the time, that’s not a reality for people because they need that. And so just discussing it, normalizing it, letting them know that sometimes people, even not on blood thinners, will get bruises here, letting them know it’s not harmful. I can’t do anything about the cosmetic nature, but sometimes just making sure even before they start the treatment that they can expect that, and so kind of mentally think about that being different.

The myalgias, actually, I think the advanced practice providers, the nurse practitioners, the physician assistant in my clinic have the best strategies for those. They’ve tried a variety of things. Tonic water. There’s a magnesium-calcium electrolyte pill they’ve been recommending. I think it can be very variable what helps patients with that. One thing that I think is probably underused is ibuprofen, because ibuprofen can inhibit platelet function, so everyone’s like, “Don't take ibuprofen ever.” I really think if people are taking it, maybe don’t take it when you start the BTK inhibitor just to make sure you’re not having severe bleeding, because people get more or less bleeding, and you find out in the first couple weeks.

But if people really aren’t bruising a lot—some people don’t—and they really want ibuprofen, including when they stop taking it for their knee arthritis, where it was working well, take the ibuprofen. It’s fine. I do think it makes sense to figure out how much bruising you’re going to have or bleeding and kind of how that plays out with the BTK inhibitor before restarting it. But I’ve seen people avoid ibuprofen that could be really improving their quality of life for years just because someone told them at the beginning not to do it, and they never brought it up, and I didn’t think to ask about it.

Sometimes people say exercise, stretching, taking the pill at a different time of day helps, and I find it very hard to counsel people on which thing to try because there’s not one that works for everybody. Then actually the diarrhea, I find, or looser stools. Again, you offer people therapies like Imodium or things that could help on the medical side. Most of them are like, “Nah, it’s not worth it to take another pill for this.” But I have seen people have some dietary changes that they’ve found very helpful, but I’m also at a complete loss for telling them what it is.

I had one person that’s like, “Oh yeah, if I eat wheat toast every morning, I get no loose stools.” I’m like, “Fantastic.” Someone else is like, “Oh, if I eat wheat toast, I get horrible loose stools with this drug.” So, it’s really specific. But sometimes I tell patients to think about it, consider trying something from a dietary perspective.

Some people have tried probiotics and said it was helpful. Those are, of course, a crapshoot, a bit as an unregulated supplement. You don’t know what you’re getting, and also they can be very different. And even you have to find the one that works for you, so the one that works for your neighbor might not be the one that works for you.

I think the patients have really been driving a lot of the solutions, and I find the best I can do sometimes is discuss these, talk about what might have worked for others, and be supportive of them trying different things.