Evolving Approaches to BTK Inhibitor Therapy in CLL

Chronic lymphocytic leukemia (CLL) management has expanded with the availability of multiple Bruton tyrosine kinase (BTK) inhibitors and fixed-duration treatment strategies, prompting ongoing discussions about treatment selection and the role of minimal residual disease (MRD) assessment in clinical practice. In a virtual Case-Based Roundtable event, Catherine Coombs, MD, hematologist and oncologist at UCI Health, led a discussion with oncologists in Ohio about treatment selection, the role of MRD testing, and strategies for managing patients receiving BTK inhibitor therapy.

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This is part 2 of a 2-part series. Read part 1.

DISCUSSION QUESTIONS

• How do cytogenetic and molecular features (eg, del(17p), del(11q), TP53, IGHV, complex karyotype) influence your treatment decisions in the relapsed/refractory setting?
• At this stage of disease, are you incorporating MRD assessment into clinical decision-making and if so, how are you using it in practice?

Catherine Coombs, MD: We talked a lot about how the cytogenetic and molecular features influence frontline. How do you think about it in the second line or beyond? Is it something that you're rechecking with respect to everything except the IGHV, which doesn't change? Do you prefer certain regimens over others in high-risk vs non-high risk [cases]? Can anyone comment on your own practice?

Timothy Moore, MD: I would say that if the tempo of the disease has changed substantially—ie, the [lactate dehydrogenase (LDH)] is going up, white blood cell count is going up, the hemoglobin or platelets are going down, performance status is going down—I'm going to recheck all of those relevant features. But in the absence of that, no, not necessarily.

Coombs: Now, the next hot topic…I'd love to now ask you all, how do you incorporate MRD into practice, if at all?

Ike Onwere, MD: Not at all.

Coombs: Is it because it's hard to send or because it doesn't change what you do, or both?

Samir Abraksia, MD: It’s not standard of care.

Onwere: It's both for me, actually.

Kasra Karamlou, MD: I think MRD right now is really complex, because if you want to truly use it, are we supposed to use it based on what the FLAIR [EudraCT: 2013-001944-76] data did, as far as treating beyond a certain point?¹ I'm really confused by the data, to be honest with you, and I'm not sure how to incorporate it into my practice, because I don't really change anything based on it, and I don't know what to do with that information.

Coombs: I don't think you're alone, Dr Karamlou; I would agree it's pretty confusing. I don't think that there's any need to send MRD outside of maybe a research setting. I send it for prognostic, but again, I consider that optional, because it doesn't actually change what I do, except for maybe I monitor patients a little closely. But we may end up with a study in the next year or two that incorporates an MRD-guided prolongation of therapy, the MAJIC study [NCT05057494]. If you had a study that looked pretty good that did extend therapy based on MRD, would that be enough to change anyone's mind? And there actually are these 2 regimens in the NCCN that I've not even used—zanubrutinib [Brukinsa]-venetoclax [Venclexta] and acalabrutinib [Calquence]-venetoclax-obinutuzumab [Gazyva]—that are MRD-guided, but they're just single-arm studies.

Arun Sendilnathan, MD: I would definitely be tempted to use it. If I'm doing a fixed regimen, at the end of the fixed regimen, if a patient asks, “Hey, am I safe to do away [with therapy]?” I can definitely do an MRD. And I did use MRD in some of my patients that had cardiac toxicities that were hospitalized, and then they were on prolonged breaks from the BTK inhibitors. It was very helpful for me to reassure them…because they still wanted evidence—“Can you really tell me whether this is gone? Is [the disease] there?” So, I did it, and I said, “Everything was stable, so we don't have to really worry about it.” So, short answer, I did use MRD already, and I would be interested to use it especially in fixed regimens. If I have to decide, do I have to continue something beyond the 2 years?

Coombs: Dr Sendilnathan, that's actually another situation where I've used it—not in a BTK inhibitor patient, although they occasionally can get negative with long use. But I've had other patients on venetoclax with pretty significant gastrointestinal toxicities like diarrhea, and it helped reassure me that [the patient is] 9 months into therapy, and they’re MRD negative. Now, I don't know for a fact that they do better or worse if they completed the year, but it was more reassuring for both of us.

Neeraj Mahajan, MD: Is there any other company doing MRD other than clonoSEQ? It's not a very user-friendly test.

Coombs: No, there’s not. I send mine out. When I was at the University of North Carolina where I was for 6 years, I just sent it to Mayo Clinic, but it's just 10^-4 flow. And now at UCI, our lab sends it out to the University of Washington. So there are some university-based flow tests; it might be a little cheaper than clonoSEQ, but clonoSEQ is FDA approved, which I don't know if that does or doesn't help with coverage. There are some other places that do flow –based [testing].

Sendilnathan: I’ve never had any issues.

Coombs: No issues? That's good.

As far as MRD, I think it's really complicated, because MAJIC’s not going to tell us that it's better to prolong; it just [tells us that] everybody prolonged if they were positive.² So, another study that I think might be more compelling for me to use MRD to guide duration is the German CLL Study Group doing venetoclax-obinutuzumab vs pirtobrutinib [Jaypirca]-venetoclax as a fixed duration, and then there's a third arm, MRD-guided pirtobrutinib-venetoclax. So that I think will be a cool study—is it better to do the MRD guided vs not? I would think they'll probably have longer PFS, but I think you probably have to follow them longer to know [whether] it’s the right thing to do, or does it maybe not matter. Anyway, that one's going to be a long time away.

DISCUSSION QUESTION

• Based on comparative data with ibrutinib (Imbruvica), how do you view the overall efficacy of acalabrutinib and zanubrutinib in contemporary practice?

Coombs: Does anyone think the efficacy of zanubrutinib vs acalabrutinib is any different? I see some people shaking their heads.

Abraksia: No.

Onwere: Zanubrutinib is actually cheaper though.

Coombs: That's right, I've heard that. Now, is it cheaper for the patient though? I guess [there’s] the bigger societal cost, and then there's the cost to the patient.

Onwere: Societal cost is cheaper; [for the] patient, [it’s not].

Coombs: Have you or has anyone encountered insurance plans that prefer one or the other? And then, what's your practice? Do you dig your feet in—I want to give zanubrutinib—or do you just say acalabrutinib is fine? Or are they suggesting ibrutinib?

D’Anna Mullins, MD: I've never had that problem, but I have wanted to give a patient zanubrutinib, and [the insurance company] didn't want to cover it, and I was able to get it approved.

Coombs: Did they suggest acalabrutinib?

Mullins: I believe it was acalabrutinib. They did not bring up ibrutinib, but I was somewhat surprised, because that was the first time that it ever happened.

Brian Haines, MD: I had a case within probably the past 2 or 3 years in which I started acalabrutinib or tried to, and the insurance actually preferred ibrutinib. I had to write them back an appeal letter with the ELEVATE-RR trial [NCT02477696] and basically said, “Look, acalabrutinib’s safer.”³ They approved the acalabrutinib eventually, but it's annoying to have to do all that.

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DISCLOSURES: Coombs previously disclosed receiving consulting fees from AbbVie, AstraZeneca, BeiGene, Octapharma, Lilly, MEI Pharma, TG Therapeutics, Janssen, Genentech, Allogene, Mingsight; research funding from AbbVie, CarnaBio, and Lilly; payments for lectures from AbbVie, Genentech, AstraZeneca, and BeiGene; payment for developing educational materials from Achilles Therapeutics Aptitute Health, BioAscend, Cardinal Health, Clinical Care Options, Curio, DAVA Oncology Mashup, MJH Life Sciences National Association of Continuing Education OncLive, Oncoboard, Physicians Education Resource Peerview, PRIME Education, LLC Prova Education, and Targeted Oncology; holding stock in Pfizer and Bluebird Bio; and receiving fees for serving on data monitoring boards from Octapharma and AbbVie.

REFERENCES

1. Munir T, Cairns DA, Bloor A, et al. Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease. N Engl J Med. 2024;390(4):326-337. doi:10.1056/NEJMoa2310063

2. Ryan CE, Davids MS, Hermann R, et al. MAJIC: a phase III trial of acalabrutinib + venetoclax versus venetoclax + obinutuzumab in previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Future Oncol. 2022;18(33):3689-3699. doi:10.2217/fon-2022-0456

3. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210