Choosing CLL Therapy Around Molecular Risk, Comorbidities, and Patient Preference

Treatment selection for chronic lymphocytic leukemia (CLL) involves weighing the benefits and limitations of continuous Bruton tyrosine kinase inhibitor (BTKi) therapy against fixed-duration regimens, with molecular risk factors, tolerability, and treatment logistics all influencing clinical decision-making. In a virtual Case-Based Roundtable event, Jacob Soumerai, MD, associate professor at Massachusetts General Hospital Cancer Center and Harvard Medical School, moderated a discussion with oncologists in Michigan and Ohio on personalizing treatment strategies for CLL, including factors that guide treatment duration and selection between zanubrutinib (Brukinsa) and acalabrutinib (Calquence).

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DISCUSSION QUESTION

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

Aneel Chowdhary, MD: I think, especially with high-risk features like TP53 or 17p deletion, unless someone's very elderly, comorbid, or has a preference for fixed duration, absolutely I have done it. But for the vast majority, you can't take the brakes off of deletion 17p; they just need a much longer, profound level of pathway block. So, I think those are the main cases for high-risk patients.

Pallavi Jasti, MD: I echo the same thought process. In patients with those specific mutations, I tend to favor continuous treatment rather than fixed-duration treatment.

Jacob Soumerai, MD: Besides molecular features, does anyone have any other major decision points that would push you towards a continuous BTKi?

Brian Haines, MD: I’d say one of the things that I look at is the time that's going to take for the patients to commit to do the fixed duration. It is a little bit more labor-intensive upfront, especially with venetoclax [Venclexta]-obinutuzumab [Gazvya]. Some of these older patients don't have rides and it's hard for them to come in quite frequently, especially in Cleveland around wintertime when it's really snowy; they're not going to be driving 35 to 40 minutes in the snow to come in. Fixed duration is a little bit easier in that setting as well.

Adriana Alvarez, MD: It's interesting because initially, I sometimes pose the question to the patient because I think patient preference is very important. I have noticed that, to my surprise, sometimes younger patients have opted for continuous treatment. I was thinking that they would be more motivated for the fixed duration, but I think having to take time out of work for twice-a-week blood work or the potential adverse effects [AEs], sometimes they just prefer to take a pill.

Living in Cleveland, I agree that for older patients, sometimes we default to fixed duration, regardless of the molecular status, just because of the feasibility. But again, I echo my colleagues, and I think that the difference between one or the other, in terms of the potential AEs or cardiovascular risk, that we can go towards acalabrutinib vs zanubrutinib. Having said that, I have to say that with obinutuzumab and venetoclax, I haven't had many complications, even in older patients, so it's pretty tolerable. For me, I think the struggle is the scheduling situation and all that.

Soumerai: I think that's a very interesting point, and I was very surprised. One of the interesting [from CLL17 (NCT04608318)] things was that the sicker, more comorbid, less fit patients, I would have expected them to have a much harder time with fixed-duration therapies, with venetoclax-obinutuzumab in particular. But when these data came out, it was actually the patients on BTKi-based and continuous covalent BTKi on the ibrutinib [Imbruvica] continuously where we saw a larger difference in the 3-year progression-free survival between unfit and fit patients.¹ With venetoclax-obinutuzumab, there was really no difference, and it challenges us a little bit to think about what matters: is it number of agents? Is it duration of therapy? Is it class toxicity? And I think that your point about being surprised by patients is important. I'm surprised by patients constantly, and the question about patient preference and how to really personalize treatment to the individual is just so crucial here.

DISCUSSION QUESTION

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

Jason Stern, DO: I think this feeds into some of the previous question’s discussion. Most of my patients that I treat are well into their 70s and 80s. A lot of them have atrial fibrillation, and they're also on a lot of aspirin…and so it always becomes an issue. I've been treating this disease for decades, and between ibrutinib and once you go up to zanubrutinib, I notice the trend that there are less AEs, they tolerate the zanubrutinib better, and actually, I haven't had too many patients who've had a problem paying for it. From that perspective, I think I have less trouble with that with all these other problems I raised vs some of the other agents, including acalabrutinib.

Jasti: For me, in terms of toxicity, I feel like they're interchangeable. I have not noticed a major difference in the toxicity. One advantage with zanubrutinib is that you can do once-a-day dosing in patients who are worried about the pill burden if they're already on multiple medications. So that's one of the reasons I may pick one over the other.

Soumerai: Who uses more once-daily dosing with zanubrutinib over twice-daily dosing? We don't know what the right answer is, but it is interesting… We don't have randomized data comparing these agents; we've got randomized data comparing each to ibrutinib. There are 2 notable differences between them: I'd say that the zanubrutinib did not have less hypertension related to ibrutinib, whereas acalabrutinib did.^2,3 On the other hand, acalabrutinib clearly has the headaches, which are thankfully very caffeine-sensitive, but can be a problem for some patients. But other than that, in terms of cardiovascular risks and bleeding risks, which I think are the things that most of us worry about, both [agents] had a favorability in terms of the arrhythmia risk but did not seem to have a major difference in terms of bleeding risk, which is what we've seen across these agents.

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DISCLOSURES: Soumerai previously disclosed serving a consulting role for Bristol Myers Squibb, Roche/Genentech, LOXO@Lilly, Beigene, and AstraZeneca; and receipt of honoraria from AstraZeneca.

REFERENCES

1. Al-Sawaf O, Stumpf J, Zhang C, et al. Fixed-duration versus continuous targeted treatment for previously untreated chronic lymphocytic leukemia: Results from the randomized CLL17 trial. Blood. 2025;146(Supplement 1):1-1. doi:10.1182/blood-2025-1

2. Seymour JF, Byrd JC, Ghia P, et al. Detailed safety profile of acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia in the ELEVATE-RR trial. Blood. 2023;142(8):687-699. doi:10.1182/blood.2022018818

3. Brown JR, Eichhorst B, Lamanna N, et al. Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE. Blood. 2024;144(26):2706-2717. doi:10.1182/blood.2024024667