Treatment-naive chronic lymphocytic leukemia (CLL) requires careful consideration of efficacy, safety, and patient-specific factors when selecting initial therapy. The discussion was moderated by Dr. Andrew H. Lipsky, an assistant professor at Columbia University Medical Center and hematologist/oncologist at Columbia University Herbert Irving Comprehensive Cancer Center, alongside community oncologists in North and South Carolina at a virtual Case-Based Roundtable. The group debated the use of Bruton’s tyrosine kinase (BTK) inhibitors such as acalabrutinib (Calquence) and zanubrutinib (Brukinsa) vs venetoclax (Venclexta)-based regimens, weighing factors such as dosing flexibility, tolerability, and fixed-duration therapy preferences.
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DISCUSSION QUESTIONS
- Considering the data for acalabrutinib, zanubrutinib, and venetoclax, how do you interpret the efficacy and safety data and use it in your practice?
- What is the balance between efficacy and safety that leads you to choose between available treatment options?
Margaret Howard, MD, MSc: In terms of the acalabrutinib study [ELEVATE TN; NCT02475681] looking at acalabrutinib alone vs addition of obinutuzumab [Gazyva], I have to give that thought with regard to the specific patient population and their comorbidities and such. But I am definitely inclined based on the burden of disease to do 2 agents in that setting.
Andrew H. Lipsky, MD: Have you ever given obinutuzumab with acalabrutinib? Or is that just single-agent acalabrutinib?
Charles Kuzma, MD: Always as a single agent.
Lipsky: Do you have any opinions about obinutuzumab, or those data?
Kuzma: I'm intrigued by the data with the progression-free survival benefit,1 but a lot of times patients vote for that as compared with the BCL-2 because it doesn't contain intravenous therapy, and the convenience of it practicing here in a rural setting. The more recent trial did demonstrate an OS benefit with the addition of it, so I try to keep it simple.2
Rajesh Bajaj, MD: I generally give acalabrutinib alone.
Lipsky: We find that [makes sense]. I have given plenty of acalabrutinib in my day as well, and the number of times I've given it with obinutuzumab is only once. Sometimes people might say if you have someone with hemolytic anemia or autoimmune cytopenia and it's not well controlled, then you need an anti-CD20 or you need rapid debulking, maybe you might do that.
What do you think about the safety of BTK inhibitors in general?
Viral Rabara, MD: I think all of these BTK inhibitors are so good. I think a lot of the patients don't even need a full dose to get the effect in CLL. I rarely run into any major adverse events [AEs] with the BTK inhibitors, especially with lowering the dose initially.
Lipsky: Have you started a BTK inhibitor in the last 6 months at a lower dose than the initial label dose? Why did you do that, and who's the kind of patient you would do that for? I've also done that, but what made you think to do that?
Rabara: A lot of it also depends on if the patient is found to have CLL and is not very symptomatic, or if they're old and have lot of comorbidities. I practice in a rural part of the country, so a lot of the patients are also hesitant about taking all these drugs. Instead of scaring them away with the possibility of AEs at a higher dose, I'll start them lower, and if I need to, I'll slowly titrate it up. I haven't had to do titration up on the majority of the patients.
Lipsky: If you're doing zanubrutinib, are you starting at 2 pills or 1 pill?
Rabara: I'll start off at 1 pill.
Matthew S. McKinney, MD: We've had a couple of 90-year-old or older patients where that was just the plan. There are not high-level data. Zanubrutinib, especially if you can do 2 pills just once a day, is probably as good as acalabrutinib or ibrutinib [Imbruvica] in terms of BTK inhibition with the data we have. Whether that changes the AE profile, we don't know. But sometimes I'll start low and then try to increase or start low and keep it there if the disease is controlled.
Alexandra Stefanovic, MD: I think most of us at Duke Cancer Center prefer the BTK inhibitors in the first line, and that has to do with the fact that a lot of our patients come from far away. The logistics of using venetoclax are very difficult practically. The BTK inhibitor is easy to prescribe, and with zanubrutinib, we can titrate if there are AEs, such as diarrhea; one can easily go down to 1 or 2 capsules per day and either keep it at the lower dose or go back up when AEs subside. It's relatively more easily managed. With venetoclax, with the cytopenias, it is a little bit more difficult to titrate. Not everybody tolerates the full dose there, and that's a little bit more challenging.
Lipsky: Who's your ideal venetoclax/obinutuzumab patient, where you might move away from the BTK inhibitor, if you had to?
Stefanovic: I think the ideal venetoclax/obinutuzumab patient is somebody who lives close enough, but also from the risk profile has no TP53 mutation or deletion, and who wants the time-limited approach, who doesn't want to be taking medication on a daily basis for the rest of their lives. So that idea is sometimes predominant for patients. We do work with patient preference.
Lipsky: Dr Madadi, what about your practice with BTK inhibitors? Are you an acalabrutinib or zanubrutinib person, what's your preference there?
Anusha R. Madadi, MD: Mostly zanubrutinib, [because it is] better tolerated, and also you could do once daily for patients who find twice daily an issue. I've also done mostly venetoclax/obinutuzumab, because in younger patients, sometimes they just prefer the limited duration. They don't want to be on a pill forever, unless there are high-risk features.
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DISCLOSURES: Lipsky previously reported consultancy, membership on an entity's board of directors, or advisory committees with Abbvie, Loxo-Lilly, Synthekine, Beigene, and AstraZeneca.
References:
1. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2
2. Brown JR, Seymour JF, Jurczak W, et al. Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia. N Engl J Med. 2025;392(8):748-762. doi:10.1056/NEJMoa2409804