Experts Consider New Data, New BTKi Choices in Frontline CLL

As long-term data with Bruton tyrosine kinase inhibitors (BTKis) continue to mature, clinicians are refining how these agents are used in the frontline management of chronic lymphocytic leukemia (CLL). In a virtual Case-Based Roundtable event, a group of oncologists from Ohio moderated by Catherine Coombs, MD, hematologist and oncologist at UCI Health, discussed patient selection for continuous BTKi therapy and weighed clinical considerations when selecting second-generation BTKis, while also reflecting on how emerging data for newer agents could influence future treatment strategies.

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DISCUSSION QUESTION

• In which patient types do continuous BTKi strategies feel most appropriate in your practice?

Catherine Coombs, MD: Who would like to start with [describing]… a perfect patient where you think [the continuous BTKi strategy] is the way to go, without much discussion?

Samir Abraksia, MD: If the patient is maybe older, [they are] not the best fit for fixed-duration treatment. I believe that a continuous BTKi is very tolerable. So that will be one option. [A continuous BTKi] can overcome the bad mutations and aggressive disease as well. That's the type of patient I would use who is not a candidate for fixed-duration treatment.

Coombs: To push back on the fixed duration—do you think it's difficult for the unfit patients toxicity-wise, or is it more the inconvenience? Because venetoclax [Venclexta]-obinutuzumab [Gazyva] was originally approved, actually, based on a study that [involved] older unfit [patients]..

Kasra Karamlou, MD: I think that…continuous BTK inhibition is appropriate for all patients. I don't think it's something that you can only reserve for a certain group of patients. I think it's something that you discuss with all patients. I think based on the CLL17 [NCT04608318] data, you're not wrong by giving them continuous therapy, honestly.

I think the fixed-duration therapy requires a lot more from the patient. Obviously, there's some niceties to it, because you stop therapy and then there's less cost, less accumulated toxicity, and so forth, but there's some added upfront toxicity, like higher rates of infections and so forth, [that] they have to worry about. And then the inconveniences for the patients coming back and forth are not insignificant.

Coombs: I don't want to speak for you, [Dr Abraksia], but I don't think you were saying only [younger] patients [were a fit for fixed-duration therapy]—but [younger, fitter patients] are maybe the most appropriate?

Abraksia: That’s right.

Coombs: I agree. I think BTKis work for everybody, but maybe there arecertain patients where they are a little bit more attractive. And I think, when someone's older, the inconvenience aspect is a bit more [significant] than maybe a really young, motivated patient. I definitely see what you were saying.

Neeraj Mahajan, MD: My understanding is, for those patients with high-risk features, it’s better for them to be on a continuous treatment. That's why for 17p deletion and unmutated IGHV, we prefer BTK inhibitors over BCL2 inhibitors.

Coombs: I think better is relative; it's probably going to lead to the longest [progression-free survival; PFS], so I would agree with that assessment. But time-limited therapy, I would say, still isn't wrong. It's still listed as preferred in the NCCN Guidelines because they can still get retreated. But that being said, in general, I do more continuous BTKi for the 17p deletion for the reason you say. But if someone has a strong preference to come off therapy, I would say it's not inappropriate to do time-limited treatment.

Mahajan: I think going forward, once we get the combination strategy—BTK and BCL2—and you get more comfortable with those once they are officially approved, just like Europe. That may be the answer for all these patient subtypes or cytogenetics and preferences. Right now, those are still not available on day-to-day clinical practice.

Allison Winter, MD: I think it's a really interesting point that you raise, and [Dr Coombs], I'm glad that you said what you did, because I am on board with you. A lot of CLL specialists will say they prefer a continuous BTKi for 17p-deleted patients, but I don't think that time-limited treatment is wrong for patients just because they have a 17p deletion. And I love the way you've said, PFS is not the only outcome measurement that's important.

Coombs: I've been saying this for a while… There's a lot of people that just worry what's going to happen when they're off therapy, but we don’t see 17p patients early.

Winter: Exactly. Every once in a while, someone does better than you expect.

Coombs: I've been in the minority on that. But again, the NCCN, I think the fact that they're both listed as preferred shows the consensus is that they're okay. Now, I think it's probably the easiest thing to do a BTKi, and I do plenty of that. So again, I just don't think either is wrong.

Winter: If it was wrong, certainly some of the studies that are ongoing would exclude them, and they don't.

Coombs: Yeah. Now, [in] CLL17, the people that are pro-BTKi will say, “The 17p patients, the PFS separates,” but when a patient on time-limited [therapy] progresses, they're still sensitive and they get retreated, whereas [when] someone who progresses on the BTKi, they're done with that class. It’s never a perfect comparison, unless you look at, say, time to venetoclax failure. I don't know; I don't think we're ever going to really know what's truly best.

Ike Onwere, MD: I am already testing. Do you ever use that to actually incorporate whether or not to use fixed-duration therapy?

Coombs: That’s on the greatest hits album of CLL debates. I use it prognostically. I don't use it to prolong therapy, and I've not adapted these [minimal residual disease]-guided strategies, zanubrutinib-venetoclax or acalabrutinib-venetoclax-obinutuzumab yet. I'm not close-minded to it, but I don't know. I don't think the data are necessarily robust enough for me to switch. So, I do it as a prognostic. If a patient is done with venetoclax-obinutuzumab and they’re negative, great. But if they’re positive, that is someone I'm going to watch a little closer in the off-treatment [period], because they'll probably relapse sooner.

DISCUSSION QUESTION

• After reviewing 6-year data from SEQUOIA (NCT03336333)¹ and ELEVATE-TN (NCT02475681),² do you view zanubrutinib (Brukinsa) and acalabrutinib (Calquence) as clinically interchangeable, or are there factors that differentiate them for you?
  • When selecting between zanubrutinib and acalabrutinib, which considerations most influence your decision?

Mahajan: Maybe less cardiac events with zanubrutinib compared [with acalabrutinib affect my decision, but otherwise, [they are] more or less the same. But bleeding and cardiac seems to be less, especially in the elderly patient population.

Mark Knapp, MD: One thing I noticed with acalabrutinib is a little more headache. I bet some patients have to dose-reduce because of that. I haven't seen as much of that with zanubrutinib.

Karamlou: I think they're pretty interchangeable. There are some minor differences. Obviously, they've never been head-to-head compared. There's more hypertension with zanubrutinib than with acalabrutinib. The dosing, obviously, there's more dose flexibility, but I think they're pretty much interchangeable for most.

Arun Sendilnathan, MD: I use both acalabrutinib and zanubrutinib equivalently.

Coombs: Well, [Dr Sendilnathan], do you like acalabrutinib for a certain profile or zanubrutinib for a different patient profile?

Sendilnathan: If I feel like somebody is not going to be compliant on their regimen, like the twice-a-day dosing, then I definitely choose zanubrutinib.

DISCUSSION QUESTION

• As data around newer options like pirtobrutinib (Jaypirca) emerge, how does the 6-year data for acalabrutinib and zanubrutinib influence your frontline BTKi choice?

Karamlou: I think that pirtobrutinib data, for me, don’t really change the bar, because obviously I'm not surprised that the data were positive relative to ibrutinib [Imbruvica] or compared [with venetoclax and rituximab (Rituxan)]. I think pirtobrutinib for me is more in that second-, third-line setting, because I know you have data that [suggest] it works after noncovalent BTKi, so I’d rather have that available for that setting.

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DISCLOSURES: Coombs previously disclosed receiving consulting fees from AbbVie, AstraZeneca, BeiGene, Octapharma, Lilly, MEI Pharma, TG Therapeutics, Janssen, Genentech, Allogene, Mingsight; research funding from AbbVie, CarnaBio, and Lilly; payments for lectures from AbbVie, Genentech, AstraZeneca, and BeiGene; payment for developing educational materials from Achilles Therapeutics Aptitute Health, BioAscend, Cardinal Health, Clinical Care Options, Curio, DAVA Oncology Mashup, MJH Life Sciences National Association of Continuing Education OncLive, Oncoboard, Physicians Education Resource Peerview, PRIME Education, LLC Prova Education, and Targeted Oncology; holding stock in Pfizer and Bluebird Bio; and receiving fees for serving on data monitoring boards from Octapharma and AbbVie.

REFERENCES

1. Tam C, Munir T, Robak T, et al. Sustained efficacy of zanubrutinib (zanu) vs bendamustine + rituximab (BR) in treatment (tx)-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (TN SLL/CLL) and continued favorable survival in non-randomized patients (pts) with del(17p): 6-year follow-up in the phase 3 SEQUOIA study. Blood. 2025;146(Supplement 1):2129-2129. doi: 10.1182/blood-2025-2129

2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib-obinutuzumab improves survival vs chemoimmunotherapy in treatment-naive CLL in the 6-year follow-up of ELEVATE-TN. Blood. 2025;146(11):1276-1285. doi: 10.1182/blood.2024024476