Oncologists Discuss Ibrutinib Switching and Fixed-Duration Therapy in CLL

Emerging Bruton tyrosine kinase (BTK) inhibitors and fixed-duration combination regimens are expanding treatment considerations for chronic lymphocytic leukemia (CLL), prompting discussion around long-term treatment tolerability, the potential benefits of switching from ibrutinib (Imbruvica), and the role of time-limited therapy.

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 the evolving CLL treatment landscape, including the safety of newer BTK inhibitors, considerations for patients receiving long-term ibrutinib, and emerging fixed-duration combinations.

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

DISCUSSION QUESTION

As data around newer options like pirtobrutinib (Jaypirca) emerge, how do the 6-year data for acalabrutinib (Calquence) and zanubrutinib (Brukinsa) influence your frontline BTK inhibitor choice?

Adarsh Vennepureddy, MD: I feel like pirtobrutinib is better tolerated than acalabrutinib or zanubrutinib, based on my experience.

Jacon Soumerai, MD: It's quite interesting. I think that the safety data for pirtobrutinib have been quite compelling through the early-phase development, with low rates of severe toxicities. We don't show the data here today, so maybe I'll just highlight that we did see recent randomized data of comparing pirtobrutinib and ibrutinib in CLL; it was a mixed treatment-naive and relapsed/refractory population. I was a little bit surprised that the only difference in favor of pure ibrutinib was atrial fibrillation risk.¹ All other adverse events of special interest appeared similar; in fact, some, including neutropenia, were numerically higher with pirtobrutinib, calling into question whether this is dramatically better than the other agents. Although I think I agree; I think that with atrial fibrillation risk, this is probably the safest agent, but again, we don't have the randomized data against the second-generation inhibitors.

Tarek Chidiac, MD: I have patients on ibrutinib still; toxicity is toxicity until you find the appropriate dose. Plus, these small percentages—5% atrial fibrillation vs 10%—what about the 90% who are now on a generic drug that are doing very well? None of these toxicities are irreversible… all these toxicities are manageable. So, the fact that one drug causes less atrial fibrillation, in my mind, is not a reason to choose it over the other one. I don't know how you feel about that.

Soumerai: It's a good point… It's not that long ago that ibrutinib was really raised as the be-all, end-all safest drug in CLL. There are some toxicities that I think are still important; hypertension risk grows over time and is does not always get better when we stop, so that one can be an issue.^2,3 The ventricular arrhythmia risk is very rare but appears to be higher with ibrutinib vs the second-generation inhibitor, which obviously can be irreversible.⁴ So I think that there are some toxicities that still worry me, but to your point, there are clearly toxicities that are going to get better with a better dose. If you've got a patient with bad myalgias, that's going to get better with reducing dose, as we all know.

Baidehi Maiti, MD: Along those lines, I wanted to say that I, for the lack of a better word, chickened out when I had patients on ibrutinib forever, around 7 to 8 years. With cardiac comorbidities increasing as patients get beyond a certain age, I talked with them about lower cardiac toxicity with the new generation BTKs. [My patient’s disease] was very well controlled, but she decided to switch after discussion, and thankfully insurance covered it. For the same reason, I was worried that the cardiac comorbidities might become more relevant as she's advancing in age. So, I don't know what the right answer is; I just didn't want her to develop something...and be committed to long-term anticoagulation for that matter. Again, I would love to get everybody's thoughts, but I think there are pros and cons to both approaches.

Soumerai: I still have one patient who's on ibrutinib. I have switched everybody else over, but that one patient was on it for 14 years, and it had zero toxicities. It was very difficult for me to justify a change, and I was worried that they would end up with a toxicity on something else. But in a patient on long-term remission tolerating therapy for a decade, I appreciate that it's also very reasonable to continue therapy. It depends on the patient, I think.

Maiti: Exactly. I presented the new data to her. We know that this has less cardiac comorbidities, and ultimately, she made the informed decision. If she wanted to stay on ibrutinib at least, I felt like I've done my due diligence.

DISCUSSION QUESTION

Among fixed-duration combination approaches, which strategies are you most interested in learning more about, or are already incorporating into practice?

Neeraj Mahajan, MD: I have a question. To me, fixed dose of acalabrutinib and venetoclax [Venclexta] looks like a winner in all respects; you are mitigating the risk of [tumor lysis syndrome], you are making the BTK time-limited, you are done in 14 months, and on a long-term basis, that cost may be less than 5 years of BTK. So, what's wrong with that? [Excluding] if somebody's TP53 or 17p unmutated, but for everybody else, I think that could be the new standard of care… and get rid of the obinutuzumab [Gazyva]. Obinutuzumab makes it more complicated, but if you get rid of that, then you start one pill and then 2 months later you start another one, and they have the same number of office visits as you [would when you] are starting somebody on a single agent.

Soumerai: It's a great point. I think for the acalabrutinib plus venetoclax, first of all, there's definitely not anything wrong with that. Anytime I give a talk about CLL and treatment selection, I usually lead with a slide where I show that overall survival for patients over 65 is normal, as long as you're using one of the appropriate first-line options. So, any preference or strong preference for one regimen for the others is usually just that; it's a preference. I think that for acalabrutinib plus venetoclax, the one group I worry about is del17p, TP53. These patients were excluded from the trial,⁵ and there were some other exclusionary criteria that were important, including older, more comorbid patients, I should say. But it was really the del17p that I think is important. I think that some of us felt that maybe we need some additional follow-up time to make sure that we see similar outcomes to what we've seen with venetoclax-obinutuzumab, but this is clearly a very appropriate option for patients.

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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. Woyach JA, Qiu L, Grosicki S, et al. Pirtobrutinib Versus Ibrutinib in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. J Clin Oncol. 2026;44(6):476-485. doi:10.1200/jco-25-02477

2. Coutre SE, Byrd JC, Hillmen P, et al. Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood Adv. 2019;3(12):1799-1807. doi:10.1182/bloodadvances.2018028761

3. Gordon MJ, Jones JE, George B, et al. Long‐term outcomes in patients with chronic lymphocytic leukemia treated with ibrutinib: Focus on hypertension and cardiovascular toxicity. Cancer. 2023;129(14):2192-2200. doi:10.1002/cncr.34787

4. Lenihan D, Bloom M, Copeland-Halperin R, et al. Considerations for the practical management of cardiovascular risk with Bruton's tyrosine kinase inhibitors for patients with chronic lymphocytic leukemia. Oncologist. 2025;30(9):oyaf237. doi:10.1093/oncolo/oyaf237

5. 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