Exploring Toxicities Driving BTK Inhibitor Selection in R/R CLL

Bruton tyrosine kinase inhibitors (BTKis) are a cornerstone of chronic lymphocytic leukemia (CLL) therapy, with newer second-generation agents developed to maintain efficacy while improving tolerability compared with first-generation ibrutinib (Imbruvica).

During a virtual Case-Based Roundtable event, Andrew H. Lipsky, MD, assistant professor of medicine at Columbia University Medical Center, and participants discussed the safety profiles of various BTKis in the relapsed/refractory (R/R) setting, highlighting how cardiovascular and other adverse events (AEs) and real-world experience influence treatment selection.

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

DISCUSSION QUESTIONS

• Ibrutinib has been the standard treatment for CLL. Both acalabrutinib (Calquence) and zanubrutinib (Brukinsa) were studied compared to ibrutinib.
  • How would you describe the efficacy of acalabrutinib compared to ibrutinib?
  • How would you describe the efficacy of zanubrutinib compared to ibrutinib?
• Cardiac AEs, atrial fibrillation/atrial flutter, are considered a class effect.
  • Evaluating the AE profiles for all 3 drugs, what impact does cardiac AEs have on your choice of therapy?
• Other than cardiac events, how do other safety concerns affect your choice of a BTKi?

Casey Degen, MD: Can I ask a question about these [R/R] trials? Because I struggle with this too. I mean, I tend to write more acalabrutinib… and I think it was probably just studies were designed differently, that’s my feeling. But did they have different patient populations? Were the TP53 or 17p-deleted patients excluded or included from one of the trials?

Andrew H. Lipsky, MD: The short answer is no, they didn't have very different patient populations. They were both enriched for high-risk features, including 17p and what they thought 11q was at the time, was also in the acala study. They both had high rates of complex karyotype... The median prior lines of therapy was close enough. And so, the methodological differences, I would say, are small. There are some that if you look right across the numbers at all the things that I just mentioned, there may be small differences, but they were not huge.

One potential readout of that is that in terms of efficacy in the [R/R] setting, some people say that they don't believe the difference. To me, I tend to interpret… When you design a study, you [have] to believe the primary end point. I think that the kind of parsing of looking for small differences to explain what happened here, to me, if I was open-evidence, I say that we have efficacy data that show zanu was better than ibrutinib, we don't have it for acala, and that's in the [R/R] setting. And it's hard to explain that away. That's kind of my read of the situation. We are going to have more data now at ASH with…pirtobrutinib [Jaypirca] to ibrutinib. Some of that's going to be in the frontline setting for the first time. I used to say that we don't have frontline data, but we will have some frontline data.

I want to go back to you, [Dr Degen]... You said, “I'm worried about the hypertension and the bleeding risk” for that patient case that we did, and you said, “I would…consider giving them pirtobrutinib.” So tell me a little bit more about that. I'm curious. Is that because you have a fair amount of experience with pirtobrutinib? Have you been writing it in the FDA label-approved setting, or where'd you get that idea from? Is it firsthand? Is it from the data? Is it because NCCN covers that option for you? Would you do it if NCCN didn't cover it?

Degen: I actually don’t have any personal experience with pirtobrutinib, but I think about [it] a lot, because my sense is that it may be better tolerated in some ways. And I have seen some really bad outcomes with zanu and acala with [atrial fibrillation], and with ischemic chest pain and palpitations, even. That's such a distressing symptom for patients. So I would like to use it soon, and I'm eager to see that data.

Lipsky: I'm going to go in that direction a little bit, because I think that that is interesting. [Dr Degen] says she's seen some sort of nasty, bad outcomes on patients on BTKis, just in general, with acala and zanu. It's hard in some of these cases. We don't want to go into specific instances in too much detail, but put your hand up if you've seen a particularly bad [AE] that came on a second-generation BTKi, acala or zanu. Who has experienced a patient getting kind of…clobbered by one of those?

Kevin Rakszawski, MD: I have an elderly gentleman, very elderly. He's almost 90, who was on [zanubrutinib], and he came off of it for about 18 months due to [AEs], and then had disease progression. But he was off therapy for 18 months. When I restarted the medicine, he's tolerated and fine; he said, no issues. So, makes me wonder what his [AE] profile was when it when he decided to stop it initially, and if it was related or not, but he swore it was related and came off of it, but now he's back on it and fine. I've had similar experience with [acalabrutinib] as well, where I've had patients stop due to toxicities and then a decision whether or not to resume it at a lower dose, perhaps, or once a day instead of twice a day. So just trying to find a balance between disease control and toxicity.

Lipsky: Interesting. [Dr Faroun], what about your take on the [AE] profiles here? Is one worse than the other? Did you have a bad event on one? Did you try the other one?

Yacoub Faroun, MD: Yeah, [for] acala, I see headache. Headache is the most common one. In zanubrutinib, I have a lot of [patients with] fatigue. Again... 50% dose reduction when the patient continue[s] on.

Lipsky: Do you feel that there’s flexibility in terms of dosing adjustments with one rather than the other?

Faroun: I think [they’re the] same. They are 320 mg a day — 160 mg BID [for zanubrutinib] vs 100 [mg] BID for acalabrutinib. I think it does not make a difference in my opinion.

Lipsky: Any[one] going to weigh in here on cardiac events and safety profile of acala vs zanu vs pirto? If you’ve heard about it or used it, what do you think about this?

Prerna Mewawalla, MD: I generally tend to use zanubrutinib. I feel like it's better tolerated, especially in older people as well. So I use zanu more than acala.

Salman Fazal, MD: I used these as they came around. After ibrutinib, we had acalabrutinib, so I used it. Haven't had too much trouble with the headaches. And then, of course, I'm using, more recently, zanubrutinib. I haven't had trouble either. I haven't had much of a challenge in terms of these [AEs] that you mentioned, so I've been lucky, I guess, in my patients.

Lipsky: Interesting. [Dr Levaka Veera], where are you with this? …I showed you this efficacy data in the [R/R] setting, where zanu bested ibrutinib,¹ but acala didn't best ibrutinib.² Does that bother you? Or you just say, it's cross-trial comparison, can’t really trust [the comparison].

Raghava Reddy Levaka Veera, MD: Yeah, [the Kaplan-Meier curves touched] after 33 months² on that trial… That's actually a good question for fellowship, for fellow training and teaching, but… when you're treating the patients in the community…you are more comfortable with what you are [practicing]. So…I'm not super worried about that data.

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

REFERENCES

1. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Eng J Med. 2023;388(4):319-332. doi:10.1056/nejmoa2211582

2. 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