SOHO 2026 | Factors influencing BTK inhibitor selection in real-world CLL treatment

When I think about selecting a BTK inhibitor for someone in my routine practice, there’s a couple of factors that really matter. I think one is what treatments have they had previously, because if they’ve had a BTK inhibitor before that the CLL is resistant to, you’re really looking at pirtobrutinib being an option there, or some investigational BTK inhibitors like rocbrutinib, which we’ve had in clinical trials, such as zanubrutinib. I think whether there’s resistance to a BTK inhibitor that they’ve had previously is a major factor. The other one, if they’ve had a BTK inhibitor before, say in a fixed duration combination with venetoclax or that they stopped for intolerance or other health reasons, what their experience was with a prior BTK inhibitor. So if someone has taken a BTK inhibitor that their CLL was still responding to and they stopped taking it, what side effects they had or how it went for them matters. Because I’ve had patients that took ibrutinib in clinical trials. Then when they needed a treatment again, and we discussed that BTK inhibitor is the right option for them, even though we discussed that acalabrutinib and zanubrutinib have fewer cardiovascular side effects, I have some patients that just wanted ibrutinib again. They’re like, I know it. It went great. It worked well. I liked it. I want to do that. So you have some of those patients and some also that have had side effects, like someone that had a bunch of headaches with acalabrutinib that will say, okay, I need a BTK inhibitor again. I want to try a different one because the side effects weren’t really what I was hoping for. So I think that goes into it for people that have had prior BTK inhibitor exposure. For people with no prior BTK inhibitor exposure, I think there’s a variety of options. Ibrutinib is less favored just because of the cardiovascular toxicities. So usually zanubrutinib and acalabrutinib would be the choice. One factor is certainly the administration. I have some patients that just will not take two pills a day. It doesn’t work for them. In which case, zanubrutinib has an approved daily dosing scheme. The other thing that can kind of make a difference is minor side effects. So people that have a lot of headaches might not want to take acalabrutinib. People that had a lot of problems with neutropenia, maybe acalabrutinib would be better. And then I do think the hypertension data looks a little bit better with acalabrutinib. So if someone has hypertension that’s a little difficult to control or is on multiple drugs, I’ll probably lean towards acalabrutinib. But I think that both of those are really excellent choices. There is data in a frontline setting for pirtobrutinib now, with it certainly looking better than bendamustine rituximab chemoimmunotherapy, which is not surprising. But also in the randomized study of pirtobrutinib compared to ibrutinib, there was a group of patients receiving it as a first treatment. And it looks like the efficacy in terms of progression-free survival is looking a little bit better than pirtobrutinib. That’s not the main endpoint to do that kind of subgroup analysis. But I think that’s an excellent option. The problem is we don’t yet know if people’s CLL develops resistance to pirtobrutinib if you can go back and use something like acalabrutinib or zanubrutinib later so I’d probably limit my frontline use of pirtobrutinib currently to people who are really unfit. Pirtobrutinib has the least side effects if you have someone that needs a BTK inhibitor but you worry very much about what’s going to happen and you know their lifespan is probably not 15 years, you know, so you don’t worry about and they don’t have high-risk CLL, you’re not worried about getting four treatments into their natural lifespan, you’re worried about getting one, maybe two. We don’t talk about this a lot when we talk about clinical trial data, but CLL has a lot of patients that are over 85. I see people in their 90s, people with, you know, memory problems, people that live in facilities or supported living environments, people that have a lot of serious comorbidities or are unwell, and I think we could still offer them something to help their CLL. Pirtobrutinib would be an excellent fit even in the front line for those patients where you’re just trying to do the least harm for someone who’s pretty unwell at baseline. I don’t know how degraders are going to play out in the front line setting. I’m sure that will be studied. I think the combinations will probably be best, but that’s not really part of the current discussion.

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