Oncologists Weigh Frontline BTK Inhibitor Strategies in CLL

With multiple Bruton tyrosine kinase (BTK) inhibitors and treatment-duration strategies available for patients with chronic lymphocytic leukemia (CLL), treatment selection increasingly depends on individual patient factors and the goals of therapy.

In a virtual Case-Based Roundtable event, Mazyar Shadman, MD, MPH, deputy chief medical officer for classical hematology, hematologic malignancies, transplant and immunotherapy at Fred Hutchinson Cancer Center, led a discussion with oncologists in San Diego, California on patients best suited for different treatment durations and agents shaping the evolving frontline CLL treatment landscape.

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DISCUSSION QUESTIONS

• In which patient types do continuous BTK inhibitor strategies feel most appropriate in your practice?
• After reviewing 6-year data from SEQUOIA (NCT03336333) and ELEVATE-TN (NCT02475681), 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?

David Hermel, MD: [Continuous is usually] how I use it in most patients… In my practice, the fixed-duration option is sometimes difficult to describe [to patients], and it's a confusing regimen for most patients. I think continuous BTK inhibitors work really well in many of the older patients specifically.

Mazyar Shadman, MD, MPH: My practice is a little bit different. The type of patients that come to us are sometimes more open… My understanding is that for patients who are taking a number of pills, it's not a big deal for them to add another pill as long as they don't have [adverse] effects. For me, that's for 20% of patients, but it sounds like in your practice, the number is higher. Is that true? And do you also hear that they don't mind taking an extra pill as long as they're not dealing with adverse effects?

Hermel: They don't usually mind it, but there are a couple of patients who don't want to be on a pill forever. But sometimes we can take breaks from it.

Shadman: But have you stopped BTK inhibitors after a few years?

Hermel: I have, actually, for some patients, and sometimes they do well off it… You can always restart it if you have to.

Shadman: Exactly. Any other comments about your practice, maybe with continuous BTK inhibitor compared with fixed duration? What percentage of your first-line patients would you say go on a continuous BTK inhibitor?

Mykola Onyshchenko, MD: It really depends on the patient’s age and performance status. I'm trying to use it more for elderly patients with comorbidities.

Shadman: But overall, would you say more than half of your first-line patients get BTK inhibitors or they get fixed duration?

Onyshchenko: More than 50% get it.

Shadman: Now, the question that has come up in the past few years, and you saw the first line studies, SEQUOIA with zanubrutinib and ELEVATE-TN with acalabrutinib: How do you select between the 2 drugs? We want to spend some time on that. Do you have a go-to BTK inhibitor that you use? Which one is it, and how did you make that decision?

Helen Moon, MD: A little bit on the question you previously asked [about patients receiving continuous vs fixed-duration BTK therapy]—I would say that my biggest group of [patients on] continuous BTK inhibitors are those I've inherited because they live a long time. Some of these are [patients previously on] ibrutinib [Imbruvica] that moved on to the second generation, and they would tell me things like, “They said I should never stop, right?” So, there is that crew, but the threshold to stop is very low. These [patients] tend to be older. Any cardiac [toxicities], atrial fibrillation, you name it... it doesn't take much to convince them to take a pause, so I would say they're inadvertent pauses. [With] my new patient, I talk a lot about continuous vs time-limited [treatment], and I think it's actually very popular to do time limited. Most people, when they first get it, the idea that “I'm never going to be off” is not attractive to them, and we talk a little bit about the cardiac [adverse] effects.

Having said that, I am aware of the data, and my conclusion from it, which may not be accurate, [is] it's a little thin to say one is clearly superior. In our system, which is Kaiser, there are pathways where they got a preferred contract with one, and I've seen no reason to fight specifically against it. I believe our current contract is acalabrutinib… I haven't flowed through [the pathway] to that because I've been using a lot of venetoclax [Venclexta]-based therapy, so I'm not 100% up on it.

Shadman: So you have a pathway, but you don't see a reason why you need to disagree with it because you see both drugs being comparable. That's very helpful. Does anyone have a preferred second-generation BTK inhibitor, and how did you come up with that conclusion?

Ben Goldenson, MD: I think they're very similar. About the question of continuous vs fixed duration, I have been using more venetoclax with acalabrutinib recently, so it's pushed me to use that BTK inhibitor in the first line. But to answer the first question, I'm using the continuous BTK inhibitor more for the patients who have some of those risk factors like 17p deletion or p53 mutation, so there, I'd say it’s much more evenly split between zanubrutinib and acalabrutinib.

Shadman: If you have a new patient in your practice, do you also have pathways?

Goldenson: No, we don't have pathways, so it does sometimes depend on the payer. One insurance will have preferences sometimes for one or the other. That can push me to pick one. But if I really had to pick, I talk to patients about some of the small differences, like once-daily vs twice-daily dosing, risk of headaches vs more hypertension. We have to really nitpick and choose one.

Hao Zhang, MD: I think my impression clinically is both are interchangeable, very similar. I have more experience with acalabrutinib, and [in my practice], more patients are on continuous BTK [therapy].

DISCUSSION QUESTION

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

Shadman: Just a little bit of a background: as you know, pirtobrutinib is a noncovalent BTK inhibitor. It's not approved in the first line, although recently at ASH [2025], for example… there was a frontline study [BRUIN CLL-313; NCT05023980] that compared pirtobrutinib vs bendamustine-rituximab [Rituxan], which was positive.¹ There was a pirtobrutinib vs ibrutinib study [NCT05254743], which was mainly relapsed but included one-third of patients in the first line.²

So, there are some frontline data with pirtobrutinib, and the question is, we have longer follow-up with acalabrutinib and zanubrutinib, and some limited data with pirtobrutinib. Would anyone go with pirtobrutinib before using one of the covalent BTK inhibitors? Let's say access is not a problem, and you have a patient tomorrow, and patient is a candidate for continuous therapy. Would you go with pirtobrutinib over acalabrutinib or zanubrutinib?

Xinting Fu, MD: My major problem with pirtobrutinib is that you're probably never going to get a direct head-to-head comparison and prove which one is better. But my biggest problem with pirtobrutinib is, what do you do after that? We do have data showing that the pirtobrutinib works after acalabrutinib and zanubrutinib, but we don't have data in reverse, so it could develop resistance to acalabrutinib or zanubrutinib. We just do not know, so that's my biggest problem.

Shadman: That’s the main concern, and at least for the continuous therapy, right? Because if you keep someone on pirtobrutinib for 5, 6 years and they develop a resistance mutation, then that resistance mutation most likely will exclude them from a covalent BTK inhibitor, and basically, you're losing 2 classes.

And you are right; I don't see that they would compare these drugs head-to-head. Honestly, I don't know if it's necessary… these are all great drugs. We really don't need to pick a winner. But in terms of sequencing, I agree with you. And if fixed-duration pirtobrutinib becomes a thing, that may be a different story. But we'll see.

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DISCLOSURES: Shadman previously disclosed serving a consulting or advisory role with AbbVie, Genentech, AstraZeneca, Pharmacyclics, BeiGene, Bristol Myers Squibb/Celgene, MorphoSys, Kite Pharmaceuticals, Fate Therapeutics, Lilly, Regeneron, Genmab, Merck, and Nurix.

REFERENCES

1. Jurczak W, Kwiatek M, Czyz J, et al. Pirtobrutinib vs bendamustine plus rituximab (BR) in patients with CLL/SLL: First results from a randomized phase III study Examining a non-covalent BTK inhibitor in untreated patients. Blood. 2025;146(Supplement 2):LBA-3-LBA-3. doi:10.1182/blood-2025-lba-3

2. Woyach J, Qiu L, Grosicki S, et al. Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory CLL/SLL: Results from the first randomized phase III study comparing a non-covalent and covalent BTK inhibitor. Blood. 2025;146(Supplement 1):683-683. doi:10.1182/blood-2025-683