Influence of BTKi-Related Adverse Event Patterns on Treatment Selection for Patients With CLLTN
Experts discuss that although first-generation BTK inhibitors such as ibrutinib were groundbreaking for CLL treatment, the field is now shifting toward second-generation options because of their better toxicity profiles. However, the choice between second-generation inhibitors should be personalized, considering individual patient profiles and adverse effects.
Asher A. Chanan-Khan, MD, MBBS: Is it fair to say that [although] ibrutinib was a first-generation BTK [Bruton tyrosine kinase] inhibitor that made a tremendous impact and completely changed the way we think about treating CLL [chronic lymphocytic leukemia], it seems to be going sideways because of the better toxicity profiles with the second generation? Is the role of ibrutinib becoming less in the frontline setting compared [with] the second generation just because of toxicity, not necessarily because of efficacy? And if BTK inhibitors [are] the way to go, if that’s the answer to the question that we pose for the patient first, then perhaps choosing one of the second-generation BTK inhibitors is more relevant than the first generation. Dr Parrondo,what do you think?
Ricardo Parrondo, MD: Yes, I agree with that statement. The field is using more second-generation BTK inhibitors [such as] acalabrutinib or zanubrutinib [because of] the toxicity profile and other factors. We have data from the phase-2 RESONATE study [NCT01578707], with the longest follow-up of any BTK inhibitor. I believe it’s an 8-year follow-up. We see that [approximately] 65% of patients are still in remission 8 years out, but we start to see the cumulative toxicities. Hypertension goes up over time, the risk of atrial fibrillation [A-fib] goes up over time, and we see high discontinuation rates of ibrutinib the longer [that] patients are on it. Some studies report discontinuation rates of 20% and some as high as 50%. With a longer follow-up of acalabrutinib and zanubrutinib, [I think] we will see less discontinuation of these second-generation BTK inhibitors. We’re also already seeing that zanubrutinib is superior to ibrutinib [in the relapsed/refractory setting], both in terms of toxicity and efficacy. So again, everything is pointing toward the second-generation BTK inhibitors in the first-line setting, and even in relapsed CLL.
Asher A. Chanan-Khan, MD, MBBS: A paper that was presented at ASCO [American Society of Clinical Oncology Annual Meeting] by Dr Wong in 2023 looked at this interesting analysis that showed that match-adjusted indirect comparison. I think this was looking at different clinical trials and comparing acalabrutinib and zanubrutinib in the relapsed CLL setting and comparing toxicity. I would give away the bottom line, but I’ll let Dr Parrondo and Dr Advani, if you have additional comments [regarding] comparable toxicity between the 2 for our audience. When picking the second-generation therapy as a primary way to go, should these 2 be contenders? What’s the difference, and what does this support show us?
Ricardo Parrondo, MD: These were very interesting abstracts. One of them [was] by Dr Huang from 2023, [where] they used this novel Bayesian statistical model to compare the incidence of different grades of adverse events [AEs] and relative risks of [AEs] with ibrutinib vs acalabrutinib vs zanubrutinib [across multiple clinical trials]. The study showed that, compared with ibrutinib, the average incidence of all-grade [AEs] was lower with acalabrutinib and with zanubrutinib. Additionally, the average incidence of grade 3 or greater [AEs] was lower with acalabrutinib and zanubrutinib compared [with] ibrutinib. Now, there were some differences between acalabrutinib and zanubrutinib; they both had similar average incidences of all-grade and grade 3 or greater [AEs]. But, for example, acalabrutinib was more likely to cause headaches and diarrhea compared [with] zanubrutinib. So, in patients with a headache disorder, for example, you may be more inclined to use zanubrutinib as opposed to acalabrutinib. And [regarding] the match-adjusted indirect comparison that was presented at ASCO 2023, [these] data [are] hypothesis generating because it’s not a direct comparison of acalabrutinib and zanubrutinib. It was an indirect cross-trial comparison of acalabrutinib vs zanubrutinib from the ALPINE study [NCT03734016] vs a study with acalabrutinib. It showed that the risk of having grade 3 or greater [AEs]—A-fib…hemorrhage, or having an AE leading to discontinuation—was similar with acalabrutinib vs zanubrutinib. The risk of having a serious [AE]—hypertension of any grade, any-grade hemorrhage, or an [AE] leading to a dose reduction—was lower with acalabrutinib vs zanubrutinib, so that is thought-provoking. But again, in the first-line setting or even the relapse setting, acalabrutinib vs zanubrutinib has not been compared head-to-head. So, [these] data [are] helpful, but you can’t make any definitive conclusions.
Asher A. Chanan-Khan, MD, MBBS: [That was a] good summarization of things. To highlight your point, even though we always want to default to a head-to-head comparison—and I would like Dr Advani’s point of view from a toxicity perspective as well—in this setting…I don’t think there will ever be [a head-to-head comparison of] acalabrutinib vs zanubrutinib. I think we have enough efficacy data that we are very comfortable. There [are also] enough toxicity data, [as well as] these cross [-trial] comparisons…[which] allows us to start looking at patient profiles and pick the right ones because we are not worried about efficacy outcomes…. Dr Advani, from a toxicity perspective…do you think the oncologists who are picking either zanubrutinib [or] acalabrutinib should be leaning toward one as a default within the 2 second-generation BTK inhibitors, or is one becoming redundant? I can see my practice evolving away from ibrutinib. But in the second generation, do you think the toxicity data you have reviewed would allow us to make that distinction, or should it be a case-based analysis?
Pooja Advani, MD, MBBS: I definitely think it’s case based. As you and Dr Parrondo appropriately summarized, there is no head-to-head comparison, and that never would be a case-matched analysis. It’s always hypothesis generating. But when I think about it from my lab perspective and mechanistic perspective, and we think about what causes arrhythmias in patients [who] are receiving BTK inhibitors, it’s postulated to be the inhibition of HER2, HER4 in TAK [-285], and the P13K-AKT signaling pathways [downstream]. The sodium currents are [also] prolonging cardiac action potential. When we look at second-generation inhibitors acalabrutinib and zanubrutinib, they’re mostly inhibiting HER4, [and] maybe slightly TAK, [which] can be one of the reasons why the safety profile for cardiac events is much better than the first generation, which is inhibiting a lot more kinases Mechanistically, it makes sense. But there is no mechanistic difference between acalabrutinib and zanubrutinib from a cardiac arrhythmia perspective, [which] translates really well into the clinical numbers. A number with zanubrutinib of A-fib/[atrial] flutter of 3.7% is quite comparable to acalabrutinib of being [approximately] 4% when we think about all-grade A-fib and flutter. It’s important that we’re personalizing therapy now in [patients with] CLL and matching the right patient to the right treatment. But as far as the second- generation BTK inhibitors go, I would say they’re fairly comparable as far as the [AE] profile. The other comment I also wanted to make is that A-fib, hypertension, and these other cardiovascular [AEs] can not only happen during therapy but can also happen subsequently later on. It can be a lifelong event for the patient, adding to the toxicity of taking more medications. And I think the challenge, especially if the patient continues to be on a BTK inhibitor, is that we have to think about drug-drug interaction. So, there is a challenge in the choice of therapy for these patients, for the management of hypertension and A-fib, because we have to be careful to avoid the CYP3A4 inhibitors.
Asher A. Chanan-Khan, MD, MBBS: Fantastic. [That was an] excellent point of view…. Just a small caveat for [those] who are in the clinic. When I was in clinical trials with ibrutinib, I saw a lot of bruising and so forth. If somebody develops…a small bleed on top of A-fib and you end up having to [use an] anticoagulant, the risk of bleeding increases. I [learned the hard way] because one of my patients had a colonic bleed when I was on a clinical trial, [which] was distressing because the disease was responding so very well.
Transcript AI generated and edited for clarity.
