Oncologists Weigh Pros and Cons of Dual Oral Therapy in CLL

Oral therapy has transformed the treatment landscape for chronic lymphocytic leukemia (CLL), offering patients convenient and effective options. Oncologists in North and South Carolina at a virtual Case-Based Roundtable discussed their thoughts with Andrew H. Lipsky, MD, an assistant professor at Columbia University Medical Center and hematologist/oncologist at Columbia University Herbert Irving Comprehensive Cancer Center. They considered the potential benefits and barriers of combining BTK (Bruton tyrosine kinase) and BCL2 inhibitors, including FDA approval status, insurance coverage, and optimal patient selection.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

DISCUSSION QUESTIONS

• If you used a BTK inhibitor plus BCL2 inhibitor therapy, which regimen would you prefer in CLL?
• For these regimens, what patient type would you consider treating with?
• What are the potential barriers to future consideration of a BTK inhibitor plus BCL2 inhibitor therapy?

Andrew H. Lipsky, MD: I'm giving you the option of treating a patient with CLL with 2 pills, as opposed to what we've been doing previously. Would you do that? Who would be the kind of patient that you would do that for?

Michael M. Goodman, MD: Not right now, until it's FDA approved.

Lipsky: Got it, so NCCN can do whatever they want—until the FDA puts the stamp, you're waiting.

Rebecca Roques-Davis, MD: I practice in a pretty rural community in western North Carolina. I think for people who have deletion 17p, who I would give a BTK to anyway, depending on how fit they are and what their preferences are, 2 oral drugs sound reasonable. The toxicity data and the safety data look good, so definitely something to consider.

Lipsky: Interesting. So you probably notice that zanubrutinib [Brukinsa]/venetoclax [Venclexta] with a dedicated deletion 17p arm looked pretty good and it's time-limited therapy, so maybe an option of time-limited therapy for those patients might be better.¹ I like that response.

Rajesh Bajaj, MD: I think it's a very good option, provided that all the final data stand. I think my favorite would be zanubrutinib with venetoclax.

Saritha Ravella, MD: I think I'll wait for more data. Sometimes we also run into the issue of authorization. If it's not FDA approved, it gets declined.

Lipsky: What are other potential barriers? Dr Goodman already told me it's not FDA approved. Somebody else want to chime in with a barrier of why they wouldn't do this? We also heard from Dr Ravella that maybe it won't be paid for. Any other considerations for why you wouldn't do this?

Matthew S. McKinney, MD: We don't know the best way to sequence these things. I was having a conversation other day about [how] if you get 6 years from a BTK inhibitor and you get subsequent-line therapy 5 to 6 years from a venetoclax combination, you're going to need a lot of data to know if sequencing those things together is any better than sequential therapy. The optimist would say pirtobrutinib [Jaypirca] comes in there, chimeric antigen receptor T-cell therapy comes in there, and the BTK degraders will probably be here in a few years for BTK failure. But if you can control [disease] with a single agent, we don't know the impact downstream of what it does to your future therapies. That's my only concern.

Lipsky: So [using] sequential monotherapy vs throwing everything at once. What does the resistance profile look like? What's the total time the patient's going to be alive after getting through all these things, depending upon the sequence? No one knows the answer to that. The studies that are earliest to read out are going to be with ibrutinib. We'll see.

McKinney: The last patient I put on obinutuzumab [Gazyva]/venetoclax, I was trying to get on the zanubrutinib/venetoclax study. The study closed to accrual when the patient was coming back to consent. It was a 75-year-old, very healthy woman who lives right around the corner from our center. She goes out and runs 6 miles twice a week with her friends. So I was thinking you can tolerate venetoclax and obinutuzumab very well, and then probably live out almost all of your expected lifespan in remission, not on therapy for CLL.

Shebli Atrash, MD: I started the combination of acalabrutinib [Calquence] and venetoclax 2 months ago for a patient, but he was a little bit different. He had CLL and Waldenström [macroglobulinemia], both are confirmed, and I thought 2 drugs work for both of them.

Lipsky: There are some combination data for intravenous therapy and stuff like that in Waldenström [macroglobulinemia].²

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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. Shadman M, Munir T, Ma S, et al. Zanubrutinib and venetoclax for patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma with and without del(17p)/TP53 mutation: SEQUOIA arm D results. J Clin Oncol. 2025;43(21):2409-2417. doi:10.1200/JCO-25-00758

2. Solia E, Kastritis E. Optimal use of BTK inhibitors in Waldenström's macroglobulinemia: combination or single drug approach?. Ther Adv Hematol. 2024;15:20406207241308771. Published 2024 Dec 23. doi:10.1177/20406207241308771