Oncologists Weigh BTK/BCL2 Inhibitor Combinations in CLL

As combination strategies continue to reshape the treatment landscape for chronic lymphocytic leukemia (CLL), clinicians are increasingly grappling with how best to translate emerging trial data into real-world practice. Recent results from studies such as arm D from the phase 3 SEQUOIA trial (NCT03336333) evaluating zanubrutinib (Brukinsa) plus venetoclax (Venclexta; zanu-ven),¹ and the phase 3 AMPLIFY trial (NCT03836261) which explored acalabrutinib (Calquence) plus venetoclax with and without obinutuzumab (Gazyva) (AVO; AV),² have sparked renewed interest in pairing Bruton tyrosine kinase inhibitors (BTKis) with BCL2 inhibitors (BCL2is) earlier in the disease course—particularly for patients with high-risk features.

In a virtual Case-Based Roundtable event, Andrew H. Lipsky, MD, assistant professor of medicine at the Columbia University Medical Center, moderated a discussion with oncologists in Pennsylvania examining how these data are influencing treatment decisions despite the absence of formal FDA approval for these combinations. The discussion also highlighted barriers such as toxicity concerns and insurance coverage, highlighting both the promise and the uncertainty surrounding these regimens as they move closer to routine clinical use.

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DISCUSSION QUESTIONS

Based on the latest data presented:

• If you used a BTKi + BCL2i therapy, which regimen would you prefer?
  • For these regimens, what patient type would you consider treating with?
  • Does your perspective change when considering a BTKi + BCL2i in combination with anti-CD20 therapy?
• What are the potential barriers to future consideration of a BTKi + BCL2i therapy?
• What are your final thoughts on combination therapy?

Andrew H. Lipsky, MD: I showed you these emerging regimens. Neither acalabrutinib/venetoclax nor zanubrutinib/venetoclax are FDA-approved combination regimens for CLL, but all of these agents are approved individually, and the NCCN [National Comprehensive Cancer Network] says you can now start doing these [combinations] as preferred regimens. So, this is relatively new.

I think we want to get your thoughts about these new data and this new NCCN recommendation. Most people have not done this yet in the community, and even in major academic centers, some people are not doing this. So, I want to know… has anybody ever given a BCL2i + BTKi combination? If you haven't, that's fine. Most people haven't. Who has done it? … What have you done? And why did you do it?

Joseph Vadakara, MD: It was a young patient, high-risk disease, and I offered it to him…. Many of my older patients, I tend to not use BTKi because many of them [are]… on anticoagulation. And this is a perfect individual with high-risk disease, 17p deleted. So, we used it and worked out well.

Lipsky: Which doublet or triplet?

Vadakara: I use the AMPLIFY triplet.

Lipsky: You use AVO for the 17p [patient]? And did you stop all the medicines at the end, or they’re still on it?

Vadakara: He’s still on it.

Lipsky: Do you know what you’re going to do? Are you going to stop everything?

Vadakara: [I’m] going to try to do an MRD [minimal residual disease]-based thing… [I will] discuss with him, but maybe I would continue something...

Chanh Huynh, MD: Same. [I use] AMPLIFY with high-risk patients. [I have] a younger person [who] just started. I think they just finished the old parts. It’s just AV right now.

Lipsky: So you went for the triplet?

Huynh: Yeah. I wasn’t as concerned about infection as we just went over, and he’s actually done very well.

Lipsky: Do you know if he’s IGHV-mutated or unmutated?

Huynh: I don’t remember, but he was 17p-positive.

Lipsky: Oh, he was 17p also? Interesting. … All right, so we have some high-risk people putting on [combinations]. Maybe more is better. Let’s ask some people who have not used these doublets where they see they might fit in… What are your impressions of these BCL2i + BTK combos? What would you need? Would you need full approval, or is the fact that it’s NCCN[-recommended] OK?

Dhwani Pandya, MD: I would say that if it's in the NCCN, it’s definitely a good starting point. It's encouraging to see that some of our colleagues have used it, but obviously I would be a little bit reluctant. But if it's a patient, as they've described— someone who's young, fits a disease profile—then you want to go in [with a] kitchen sink strategy to give them the best bet, so we can have a good response that would be the appropriate setting. But, as I think [someone] mentioned disease of the aging, so most of my patients are not going to fit this category where I would feel comfortable just because of the fear of toxicity.

Kevin Rakszawski, MD: I've considered using it in patients with high-risk disease, high tumor burden. I like the lead-in to prevent [tumor lysis syndrome]. I guess my 1 question that remains unanswered is, what do you do if they're [minimal residual disease; MRD]-positive at the end, probably keeping them on something. And then, are you gaining anything by doing a triplet long-term as opposed to sequencing BTK and then BCL2 later on? I understand the thought is that perhaps you get them MRD-negative sooner and then can transition to something either indefinite or potentially stop therapy. But would you gain anything or lose anything if you just waited to use say, venetoclax in the second line as opposed to the front line?

Lipsky: I think that's a good question. I don't think we know the answers to those questions, and we have some studies that are trying to answer them, and there's some maybe little bit of hint at [the 67^th American Society of Hematology Annual Meeting] about that. I'll stay tuned, but I'm not going to get into that right now. I agree with you that those are good considerations. [Does anyone else have] anything to weigh in?

Prerna Mewawalla, MD: I would like to try this, especially for a young patient, where you can consider limited therapy based on MRD negativity. I mean, it looks promising. I haven't done it yet, but definitely looks promising.

Lipsky: Got it. Who can come up with a barrier to doing this doublet? Does anybody think insurance or otherwise [is a barrier]?

Michael Seidman, MD: I think coverage. There are some pretty tough drug plans out there who need FDA approval as the rationale for approving or not approving a treatment.

Raghava Reddy Levaka Veera, MD: I agree, for the… patients with the certain deletion, definitely, I can consider the triplet. …The toxicity, that's the biggest thing that I get worried about.

Yacoub Faroun, MD: May I ask a question about SEQUOIA [arm] D? The doublet arm, [zanubrutinib and venetoclax] in TP53-negative and -positive. Progression-free survival [PFS] was not basically good for TP53-positive and -negative. They were equal.

Lipsky: The [PFS] arm for zanu-ven, we have 3 years of follow up for the TP53-aberrant and 2 years for the wild type. And you think those are not good? If you overlay those curves with CLL14 [NCT02242942], they do pretty well. What makes you say they're not good?

Faroun: The [PFS]… the TP53-positive did not fare good or better than TP53-negative.

Lipsky: You're referring to the idea that with the zanu-ven early on, the data for the mutated patients look a tiny better than the wild-type patients. … The explanation for that study is not clear. It's a small number of patients. [We] have to look at the success. It's not powered for a direct comparison between those 2 arms, but you are numerically correct. But both of those arms look pretty good. So, I would say… my interpretation of that is that it's noise.

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_{DISCLOSURES: Lipsky previously disclosed consulting fees from AstraZeneca, AbbVie, Synthekine, Eli Lilly, and BeiGene.}

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. Brown JR, Seymour JF, Jurczak W, et al. Fixed-duration acalabrutinib combinations in untreated chronic lymphocytic leukemia. N Eng J Med. 2025;392(8):748-762. doi:10.1056/nejmoa2409804