This episode features Matthew S. Davids, MD, MMSc; Nelson Hamerschlak, MD, PhD; and Stephen Stilgenbauer, MD, discussing key conference highlights from the 2025 ASH Annual Meeting, with a focus on emerging BTK-targeted therapies in relapsed/refractory CLL. They share global perspectives on real-world use, sequencing strategies, safety considerations, and how new data may shape future clinical practice.
In this episode, Matthew S. Davids, MD, MMSc; Nelson Hamerschlak, MD, PhD; and Stephen Stilgenbauer, MD, discuss how recently presented data from ASH 2025 are shaping real-world treatment decisions for patients with relapsed/refractory chronic lymphocytic leukemia, including:
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Presenters:
Matthew S. Davids, MD, MMSc
Associate Professor of Medicine
Harvard Medical School
Leader, Lymphoma Program
Dana-Farber/Harvard Cancer Center
Director of Clinical Research, Division of Lymphoma
Dana-Farber Cancer Institute
Boston, Massachusetts
Nelson Hamerschlak, MD, PhD
Head of the Department of Hematology, BMT and Clinical Cell Therapy
Einstein Hospital Israelita
Sao Paulo, Brazil
Stephen Stilgenbauer, MD
Medical Director, Comprehensive Cancer Center Ulm (CCCU)
Head, Early Clinical Trials Unit (ECTU)
Head, Division of CLL Department of Internal Medicine III
Comprehensive Cancer Center Ulm (CCCU)
University of Medical Center Ulm
Ulm, Germany
Link to the full program:
https://bit.ly/4rsZlqF
This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Matthew Davids: In this section, we'll be setting the stage for the current use and limitations of both the covalent BTK inhibitors as well as non-covalent BTK inhibitors in chronic lymphocytic leukemia. We saw a lot of BTK inhibitor-related data at the 2025 ASH Annual Meeting, and before we get into the individual trials, we wanted to discuss the current role, as well as some of the limitations of using covalent and non-covalent BTK inhibitors in our countries and regions. As we know, this can look different based on where we are treating, and what's approved, and what gets reimbursed.
So, really, the first question is around how we're currently using covalent and non-covalent BTK inhibitors in our regions. And I can kind of start initially from the U.S. perspective here. I would say that covalent BTK inhibitors are far and away the most common treatment for patients with CLL these days, often being used in the frontline setting as a preferred modality, particularly in community practice. I would say we do have a fair amount of venetoclax-based time-limited therapy in our more academically-oriented practices, and increasingly we're going to have the opportunity to use covalent BTK inhibitors in combination with venetoclax as a time-limited frontline therapy.
But in the relapse setting, we do still see a lot of covalent BTK inhibitor use, and this can be in a few different contexts. So, certainly when patients start on covalent BTK inhibitors, they can experience various toxicities. We saw this particularly with ibrutinib, and then in the relapse setting, or second-line setting, we would see alternate use of a different covalent BTK inhibitor, like acalabrutinib or zanubrutinib. We're seeing this, I'd say, less commonly now, as patients tend to tolerate acalabrutinib and zanubrutinib much better, and are less likely to come off drug. So I'd say increasingly in the US, we're seeing more and more use of the non-covalent inhibitor, pirtobrutinib. It's had an accelerated approval for the last couple of years, and then just recently in the US, in December of 2025, received a broad label across all relapsed refractory CLL post-covalent BTK inhibitor.
And I think we'll get into this a little bit later, but I do think in the US already, we're starting to see pirtobrutinib being used as a second-line therapy after frontline covalent BTK inhibitor, quite commonly. Dr. Hamerschlak, Nelson, tell us how things are looking in Brazil with this question.
Nelson Hamerschlak: Thank you, Matthew, for the question. And I have to point out that in Brazil, there is a clear disparity between the public and private systems. In the public system, unfortunately, treatment options remain limited to older chemo-based regimens. In the private setting, all covalent BTK inhibitors and pirtobrutinib are available. In practice, we use covalent BTK inhibitors as continuous therapy for high-risk patients, fixed-duration venetoclax-based regimens for lower-risk patients. And the noncovalent BTK inhibitors mainly for patients who are resistant or intolerant to covalent BTK inhibitors.
Matthew Davids: Would that include, potentially, in the private system, second-line use of pirtobrutinib before venetoclax?
Nelson Hamerschlak: Yes, it's possible, and mainly if the access of the patients are low, it's depending on the insurance company the patient have.
Matthew Davids: Okay, great. and Professor Stilgenbauer, Stefan, how are things looking in Germany and Europe more broadly with this question?
Stephan Stilgenbauer: Yeah, thank you, Matt. I think in Europe, overall, the situation is pretty much the same as it is in the United States. The EMA label is broad for covalent BTK inhibitors, ibrutinib, zanubrutinib, acalabrutinib that are licensed in the frontline setting and for any relapsed refractory patient with CLL. Pirtobrutinib is licensed and available by the EMA also, in the relapsed refractory setting after prior covalent BTK inhibitor treatment.
In Germany, we're in the fortunate situation that anything that is licensed is available and reimbursed; that may be different across other countries in Europe. So overall, with regard to use, there has been much development of venetoclax-based, time-limited treatments in Europe and in Germany in particular. I'd say there is a pretty good share of time-limited venetoclax-based treatment increasingly with covalent BTK inhibitors, such as ibrutinib or acalabrutinib, based on the recent combined label.
In the relapsed setting, on the other hand, covalent BTK inhibitors are a frequent treatment choice, due to their good tolerability, due to their long-term disease control. And after the licensing of pirtobrutinib as the first non-covalent BTK inhibitor, I think its use is picking up in the second-line setting, in particular in patients who had prior covalent BTK inhibitor treatment, who benefited from that treatment principle, and patients, as well as doctors, say, well, we have a second choice here available to treat CLL effectively. So I think this is… this is increasingly becoming important with regard to challenges and limitations. I think we still do have the class-associated adverse events—mostly mild bleeding, arthralgia, diarrhea issues, and then the arrhythmias with atrial fibrillation that can limit treatment with BTK inhibitors, but that is obviously also different.
Between the various BTK inhibitors that we have now available, and you know, coming to that point, I think updates of data with long follow-up are important, and coming back to your point that there was a lot of data presented at ASH, probably you can illustrate, Matt, what were your highlights with regard to BTK inhibitor treatment at ASH that you saw?
Matthew Davids: To me, the most impactful data that we saw at ASH related to BTK inhibitors was around the phase III trials with pirtobrutinib that read out and included relapsed refractory patients. In particular, the Bruin CLL 314 trial, which was the head-to-head study comparing ibrutinib directly to pirtobrutinib in this relapsed population. There was also a frontline cohort of that study, but we'll focus on the relapse patients here, where, you know, I think it was very interesting to me because, at least my clinical impression is that pirtobrutinib is a much better tolerated drug than ibrutinib with respect to various cardiovascular factors, as well as bleeding risks and sort of general things like arthralgias and so forth.
Interestingly, in the head-to-head study, although there were some advantages to pirtobrutinib over ibrutinib, the safety profiles looked more similar than I expected. Certainly, there was a much lower rate of atrial fibrillation with pirtobrutinib, which was good to see. There was a somewhat lower rate of hypertension as well, although not dramatic. Bleeding rates were equivalent, both in terms of all-grade and serious bleeding between ibrutinib and pirtobrutinib.
So this does kind of inform my practice, where often we do see older patients who have other medical comorbidities, for example, if they're already on systemic anticoagulation. Maybe previously I was thinking pirtobrutinib might have less bleeding risk, but now, perhaps if I have venetoclax as an option for that patient, I might prefer that in some scenarios. So, that type of safety data, I think, from the head-to-head study was very impactful. You know, we saw some other data sets, kind of updating longer-term follow-up from the older pirtobrutinib studies, which… which I think were incrementally useful.
And then similarly, we saw a 6-year follow-up from the Alpine study, which, as you know, compared zanubrutinib to ibrutinib directly, and looked similar to what we've seen from prior data sets from the Alpine study, where you do see improved tolerability with zanubrutinib with certain toxicities, particularly, again, atrial fibrillation, and also maintaining that sort of small but significant progression-free survival advantage. Although we know that there are some limitations to that comparison in the study. So, overall, I'd say there were some useful data sets from the ASH meeting with respect to the BTK inhibitors.
Stephan Stilgenbauer: Nelson, what is your take on the data that you saw at ASH? Were you similarly excited about pirtobrutinib and the updates that you saw?
Nelson Hamerschlak: I think that the study, which was a pooled analysis with pirtobrutinib in relapsed/refractory CLL, showed that pirtobrutinib was no inferior to ibrutinib, and numerically superior, in overall response versus ibrutinib, with an early trend toward improved PFS, and a more favorable safety profile, reinforcing the non-covalent BTK inhibitor as an effective and better-tolerated option. I think that, in the last ASH meeting, there was strong evidence that the non-covalent BTK could be used not only in relapsed/refractory patients, but also, as Matthew said, in first-line therapy in selected patients, based on the safety profile.
Stephan Stilgenbauer: Yes, I agree, and adding to that what Matt said, that he was a bit surprised to see not even better tolerability of pirtobrutinib as compared to ibrutinib. I think probably we have to remember that in that randomized comparison, median follow-up was less than 2 years, so we have limited exposure to both of these continuous treatments, and probably we all assume that with longer treatment duration, you know, and the incremental increase in adverse events, the better tolerability of pirtobrutinib as compared to ibrutinib will come out more clearly. And we have longer experience. We have this 6-year follow-up from the Alpine study with zanubrutinib versus ibrutinib where simply our comfort level is probably higher, starting with a covalent BTK inhibitor, and upon failure, switching to the more novel agent, to the non-covalent.
Or what would you think, Matt? How much more data, what more follow-up or data would you like to see before you could possibly prefer starting with a non-covalent BTK inhibitor over a covalent?
Matthew Davids: Yeah, I mean, first, I completely agree. My sequence right now is to start almost all the time with a covalent inhibitor, even if I have a non-covalent inhibitor available, because, you know, really a couple of main factors. One is, as you mentioned, the very short follow-up with these phase III pirtobrutinib studies, year and a half to two years, in most cases, is, particularly in the frontline setting, quite short. Maybe in the relapse setting, a little bit more representative, but so certainly longer follow-up of at least a couple more years, probably. But the other would be, and I think this is going to be more challenging to generate these data, is the sort of efficacy data of covalent inhibitors after a non-covalent inhibitor.
And this is not necessarily something that will be captured directly in these trials. It may require registry data or retrospective studies, but personally, to really feel comfortable with a sequence of a non-covalent followed by a covalent inhibitor, I would want to see data that proves to me that a covalent inhibitor can be active and, you know, effective in that setting, post-non-covalent. And right now, we only really have data the other way around, where we know pirtobrutinib can be effective post-covalent inhibitor.
You know, that being said, pirtobrutinib, especially in a double refractory population, post-covalent BTK inhibitor, and the BCL2 inhibitor, is not really that durably effective, with a median PFS of less than a year and a half. So, it may indeed be that it's better to start with a non-covalent inhibitor and then later go to a covalent inhibitor, but we really don't know that until we have data to understand that question.
Nelson Hamerschlak: I agree completely with you both. And the question now is, after the patient has a progression on frontline covalent BTK inhibitor, how do you choose between non-covalent BTK inhibitor, or venetoclax-based therapy, or even a clinical trial? So, I am going to talk about my experience in Brazil, that after progression on a frontline covalent BTK inhibitor, my decision is guided by disease biology, prior exposures, and treatment goals. Non-covalent BTK inhibitors are an attractive option for patients progressing on covalent BTK inhibitors, particularly those with high-risk features, such as TP53 disruption or deletion of 17p, given the meaningful PFS, durable disease control, and favorable safety profiles.
Venetoclax-based regimens are preferred in my country when a fixed-duration strategy is desirable, and tumor risk can be safely managed in the service. Clinical trials are prioritized for patients with double-exposed disease, rapid progression, or when access to approved therapies is limited, and I would like to hear your comments about the sequential therapy that you use in your country.
Stephan Stilgenbauer: I agree. I mean, it is great that we have a choice now after failure of therapy with a covalent BTK inhibitor. We have venetoclax, actually licensed quite a bit longer, and now, with pirtobrutinib, a non-covalent BTK inhibitor. So, indeed, as you do, I would kind of individualize my treatment choice based on patient characteristics, such as renal function, such as cardiac coexisting conditions, the tolerability of the prior covalent BTK inhibitor treatment, or, you know, if it had to be stopped, or paused, or dose-reduced due to adverse events. And, obviously, also some disease characteristics; probably bulky disease, in particular when paired with decreased renal function, is probably not favoring venetoclax-based therapy, while, as you said, when a patient prefers to have time-limited treatment, obviously, the venetoclax-based options are the treatment of choice. So, overall, I think it is good to have the choice between two agents in the future. Possibly, I think, mutational profiling of covalent BTK inhibitor-resistant disease may help, because we know that there are, beyond the C481S, the classical resistance mutations, mutations that may cause resistance toward non-covalent BTK inhibitors as well. To me, that data is still not fully valid enough to guide treatment choice, but this may emerge, at least in my opinion. But I'd like to hear, Matt, what you think about this.
Matthew Davids: Yeah, I fully agree with both of you. Often in the U.S, as I mentioned, the frontline therapy of choice is covalent BTK inhibitor given continuously, and what I've been finding as pirtobrutinib has been more widely available in the community is that, you know, there were certain reasons why people chose to go on a covalent BTK inhibitor initially, and often those same reasons are still present in the second-line setting. Whether it's related to their comorbidities, or the logistics of the venetoclax ramp-up, or the convenience of being on an all-oral therapy, it's very attractive for patients to then go directly from the frontline covalent BTK inhibitor to the non-covalent inhibitor, pirtobrutinib, and sort of thereby delay further the need for the inconvenience of the venetoclax therapy.
That being said, in my own practice, I have historically used venetoclax more commonly for covalent BTK inhibitor progressing patients. Often in combination with an antibody like obinutuzumab, which we have access to off-label in the U.S. in the relapse setting. And that, again, allows for time-limited therapy for the patients, and then the potential for re-treatment down the line, and thereby also leaving pirtobrutinib as an option for venetoclax refractory patients. I don't know that that's the best sequence, though, and we don't have any prospective data, really, to guide us on this question at this time.
Nelson Hamerschlak: I just would like to add, since Stefan talked about the resistance mutation testing, that this is not performed in my country. And as a result of that, many treatment decisions are still guided by clinical patterns of progression rather than by molecular testing. We have also a lot of barriers, as the delayed incorporation into the public system, restorative reimbursement, and prior authorization requirements in the private sector, high out-of-pocket costs and limited access outside major centers. In addition, inconsistent availability of molecular testing and limited clinical trial capacity, we can further delay access to no covalent BTK inhibitors when it is the most appropriate option in the country.
And I really don't know what is going to change in the next 2 to 5 years, but I would like to hear from you. And, what's the practice in your countries about the use of mutation testing and easy availability of the BTKI covalent and non-covalent inhibitors.
Stephan Stilgenbauer: I agree that we need more data, and fortunately so, in Germany, we have access to mutation testing. However, I think evidence is still not completely, you know, rock solid.
We know that there are some mutations in BTK that may cause cross-resistance between covalent and non-covalent BTK inhibitors. Much of that, what we know. However, it's based on patients who had first covalent BTK inhibitors, and then non-covalent, and then possibly progress, so we don't know much about, you know, patients who had received only a non-covalent BTK inhibitor, and possibly then progressed what their mutational profile may be, and I think this is where we indeed need more data from clinical trials over the next years, to define this sequence of treatment potentially based on molecular markers, even better.
So I think, you know, the way forward will be to follow up on those trials, possibly also look at new combinations. I mean, pirtobrutinib, for instance, is also tested now in clinical trials in combination with venetoclax to, you know, come to time-limited treatment options, and obviously to study more, in particular, this difficult-to-treat patient population, you know, that is double or even triple exposed to covalent BTKI, non-covalent BTKI, and venetoclax. And I think, also coming back to ASH as a topic.
And to you, Matt, I think at ASH we also saw exciting data, I would say, about a novel class of BTK targeting agents, namely the degraders. What was your take on that?
Matthew Davids: Yeah, this is a very exciting development, I'd say, in the field. The degraders are targeting BTK like the inhibitors, but they work in a fundamentally different way. They're not kinase inhibitors, but rather degraders that basically target the protein for destruction in the proteasome. And because of that, they will have a very different pattern of target engagement, even in the setting of mutations.
You know, at the ASH meeting, we saw more mature data from two of these drugs, NX5948 and BGB16673, both of which are BTK degraders, which we've seen data sets on before at earlier meetings, but the numbers of patients continue to grow. The response rates remain pretty consistently high in the 80% range or so, generally in very difficult-to-treat patients, similar to the ones that you were just describing. Many of whom have had, now covalent BTK, non-covalent BTK, and a BCL2 inhibitor, and are still responding to BTK degraders.
And one of the exciting aspects to me, particularly of the BGB16673 data that we saw at ASH, is that we saw 18 months of PFS data, and so that's kind of the longest-term follow-up we've seen in these patients, and the PFS curves still look good in that range. Three-quarters of patients are still progression-free, so median not yet reached at 18 months. So, you know, response is one thing, of course, but we need durability as well, and I think I think it's early days still, but the durability results look promising for these drugs. So, I think going back to the question of the different resistance mutations that can arise, this is really encouraging and gives me confidence that maybe even regardless of which sequence of covalent and non-covalent, if I have a BTK degrader as a backup, I can further extend the progression-free survival for patients, and so it's really exciting to see these data.
Nelson Hamerschlak: In my country, we have some clinical trials with BTK degraders. And, I agree that the sequencing could involve towards covalent BTK inhibitors, noncovalent BTK degraders in the end, particularly for patients with mutations. And for those that were not ideal candidates for venetoclax-based therapy, while venetoclax in trials became the key alternatives based on patients' goals and sex in our country.
Stephan Stilgenbauer: I totally agree with you and your excitement about the 2 degraders, and there are more in development, but the two where we saw, really good data sets at ASH. I was impressed about several things. I mean, firstly, you know, the median age of the patient population studied was 70, which is unusual, and in particular unusual in phase I trials. The median number of prior lines was 4, so the patients not only had, you know, covalent BTK inhibitor or venetoclax, they also had chemotherapy or other regimens.
The characteristics were also impressive with 80% about of patients having unmutated IGHV, close to 70% having a 17p deletion or TP53 mutation. And, you know, also biologically, therefore, a high-risk population.
And efficacy, as Matt said, was at least very promising, if not impressive. But also, tolerability, to me, in that heavily pre-treated patient population looked very good with, hematotoxicity, neutropenia being actually the only frequent grade 3 or higher adverse events. Obviously, there were some infections, as we are used to in such high-risk patients, but most of, or actually all of the other AEs were of low grade and manageable, and led very rarely to dose reductions, dose interruptions, or even stop of that yet still experimental treatment, so I found, The data are truly impressive and, really a hope, potentially, once available, and now in clinical trials for those patients who are triple exposed, or possibly even triple refractory, where we are desperately in need of new developments of agents. So, to me, that is looking very inspiring, and I'm also looking forward to potential combinations.
Matt, where do you think this development of the degraders will take us.
Matthew Davids: Well, I think, based on the very promising data, naturally, the next thing to do would be to explore the degraders in earlier lines of therapy. And I think the first target that they'll be going after, of course, is pirtobrutinib as the more common second-line therapy, and already there's head-to-head studies that I know are being planned comparing pirtobrutinib to BTK degrader therapy in that post-covalent BTK inhibitor population. You know, it's possible eventually they could look even into the frontline setting, particularly in combinations. Going into this kind of second-line population, I think, is going to be very interesting, and we'll see, kind of, more data sets evolving over time. So, with the rapidly evolving BTK targeted therapies, what is the most important things clinicians in your region should reconsider in relapsed refractory CLL treatment?
Nelson Hamerschlak: I think that clinicians should reconsider the idea that progression on equivalent BTK inhibitors represents the end of BTK targeted therapy. With the emergence of non-covalent BTK inhibitors and BTK degraders. The BTK pathway can now be leveraged across multiple lines, making truthful sequencing rather than abandoning the mechanism. The key paradigm shift, that's my opinion.
Stephan Stilgenbauer: I agree. I mean, we have more choices now. We can for tolerability issues, and in particular, when a patient became resistant to covalent BTK inhibitor continuous therapy, we still… we have a choice now. We can use pirtobrutinib as a non-covalent inhibitor, that showed really very good tolerability data and proven efficacy in the post-covalent BTKI setting.
Matthew Davids: Yeah, I fully agree. In my region, in the US, where we see a lot of covalent BTK inhibitor use, and I feel like there may be some confusion or under-appreciation of the role that pirtobrutinib may play, because this is now the fourth BTK inhibitor, and if you're not following CLL as closely, why do we need a fourth BTK inhibitor? But I think it's very important that we underscore that pirtobrutinib is fundamentally different from the three covalent inhibitors, and I think we'll have an increasing role based on the data we saw at ASH in the second-line setting, and possibly eventually in the frontline setting.
What is one key area where we still need more data before changing practice?
Stephan Stilgenbauer: As we discussed earlier, I think, sure, we have this license available for pirtobrutinib in the relapse setting, likely in the not-too-distant future, also in the frontline setting, and then really the question that we discussed before becomes pertinent, what to start with, and what will lead to the best long-term outcome data. We have more evidence for starting with the covalent inhibitor, but with, you know, time and evolving data, this may change. And based on the very good tolerability profile of pirtobrutinib, I think there's a chance, a good chance, that it stands to be moved into the frontline setting.
Nelson Hamerschlak: This is really a challenging question, and in my opinion, as we have in all new fields in hematology and oncology, I think that we need more prospective data defining the optimal sequencing of covalent BTK inhibitors, non-covalent BTK inhibitors. Venetoclax-based regimens and BTK degraders, ideally guided by resistance, mutations, and long-term outcomes before fully reshaping routine clinical practice. So, I think that we have to take care in this field, as in all new fields we have in our specialty.
Matthew Davids: And I would just add, again, in the US, where covalent BTK inhibitors are by far the most common frontline therapy, that a key data need is what is the optimal second-line therapy for these patients progressing after frontline covalent BTKI, and I think pirtobrutinib, venetoclax, and perhaps even the BTK degraders are all viable options in the future. So a prospective study comparing those three modalities would be great. I'm not sure if we'll see that in one big study, but hopefully we'll have enough prospective studies to kind of piece that together, so we know what's best for that scenario.