From ASH 2025 to the Clinic: Global Perspectives on Evolving BTK Therapies in Relapsed/Refractory CLL

Hello and welcome to Disera of Clinical Education's Oncology Podcast.

I'm your host, Cat Lee.

Today I am joined by three international experts for a discussion focused on how recently

presented data from Ash 2025 are shaping world treatment decisions for patients with

relapsed or refractory chronic lymphocytic leukemia.

This episode is part of a larger educational program titled Global Perspectives on Emerging

Data and Relapsed or Refactory CLL.

For more information on our faculty, along with a link to the larger educational program,

please visit the show notes for this episode.

Now I'm pleased to welcome our fantastic panel.

Dr. Matthew S. Davids, Director of Clinical Research in the Division of Lymphoma at Dana

Farber Cancer Institute in Boston, Massachusetts.

Dr. Nelson Hammersleck, Head of the Department of Hematology, Bone Marrow Transplant and Clinical

Self Therapy at Einstein Hospital, Israelita, and San Paolo, Brazil.

And Dr. Stefan Stogenbauer, Head of the Division of CLL at the University Medical Center

in Oom, Germany.

Thank you all for being here and let's get started.

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 start initially from the US 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 front line setting as a preferred

modality, particularly in community practice.

I would say we do have a fair amount of the Natal clax-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 Natal clax as a time-limited front line 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.

Alternate use of a different covalent BTK inhibitor, like Acaliburinib or Xaniburinib.

But we're seeing this, I'd say less commonly now as patients tend to tolerate Acaliburinib

and Xaniburinib 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 perterbrinib.

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 relapse 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 perterbrinib being used as a second line therapy after frontline

covalent BTK inhibitor, quite commonly.

Dr. Hammerschlock Nelson, tell us how things are looking in Brazil with this question.

Thank you, Matthew, for the question.

And I have to point out that in Brazil, there is a peer disparity between the public and

private systems.

In the public system, unfortunately, treatment options remain limited to older chemo-basid

regimens.

In the private setting, all covalent BTK inhibitors and pifto-brutinib are available.

In practice, we use covalent BTK inhibitors as continuous therapy for high-risk patients.

With that included potentially in the private system, second line use of perterbrinib before

of an out-of-clock?

Yes, it's possible.

And mainly if the excess of the patients alone, it's depending on the insurance company

the patient has.

Great.

And Professor Stuggenbauer, Stefan, are things looking in Germany and Europe more broadly

with this question?

Yeah, thank you, Matt.

I think in Europe, overall, situation is pretty the same as it is in the United States.

The email label is broad for covalent BTK inhibitors, a-brutinib, pifto-brutinib, a-cala-brutinib,

that are licensed in the frontline setting and for any relapster refractory patient with

CLL.

Piotr-brutinib is licensed and available by the email also in the relapster 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, due to much development of Veneto-clock space, time-limited

treatments in Europe and in Germany in particular, I'd say there is a pretty good share of time-limited

Veneto-clock space treatment increasingly with covalent BTK inhibitors such as a-brutinib

or a-cala-brutinib based on the recent label combined.

In the relapster setting, on the other hand, covalent BTK inhibitors are frequent treatment

choice, due to their good tolerability, due to their long-term disease control.

And after the licensing of piotr-brutinib 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 patient

as well as doctor say, well, we have a second choice here available to treat CLL effectively.

So I think 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, astralgia, diarrhea issues, and then the arrhythmia

with atrial fibrillation that these can limit treatment with BTK inhibitors, but that

is obviously also different between the various BTK inhibitors that we have now available.

And 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 to us what were your highlights with regard to BTK inhibitor treatment

at Ash that you saw.

To me, the most impactful data that we saw at Ash related to BTK inhibitors was around

the phase three trials with piotr-brutinib that read out and included relapse refractory

patients, in particular the Bruins CLL 314 trial, which was the head-to-head study comparing

at Brutinib directly to piotr-brutinib in this relapse population.

There was also a frontline cohort of that study, but we'll focus on the relapse patients

here where I think it was very interesting to me because at least my clinical impression

is that piotr-brutinib is a much better tolerated drug than I Brutinib with respect to various

cardiovascular factors, as well as bleeding risks and general things like arthralges and

so forth.

Interestingly, in the head-to-head study, although there were some advantages to piotr-brutinib

over I Brutinib, the safety profiles looked more similar than I expected, certainly there

was a much lower rate of atrial fibrillation with piotr-brutinib, which was good to see.

There was a somewhat lower rate of hypertension as well, although not dramatic.

Leading rates were equivalent, both in terms of all grade and serious bleeding between

I Brutinib and Prutinib.

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 Prutinib might have less bleeding risk, but now, perhaps

if I have a netaclacks 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.

We saw some other data sets updating longer-term follow-up from the older Prutinib studies,

which I think were incrementally useful.

And then similarly, we saw six-year follow-up from the Alpine study, which, as you know,

compared Xanabrutinib to I Brutinib directly.

And look similar to what we've seen from prior data sets from the Alpine study, where

you do see improved tolerability with Xanabrutinib 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 BT Canada-bitters.

Nelson, what is your take on the data that you saw at ash?

Were you similarly excited about Prutinib and the updates that you saw?

I think that the study that it was a pulled analysis with Prutinib in refractory real

abs of the CLL, that showed that Prutinib, it was known inferior than I Brutinib and

numerically superior in overall response versus Prutinib with an early trans to world

improved BFS, and the more favorable safety profile enforces no convoluted BTK inhibitor

as an effectively and better tolerated option.

So I think that we have in the last ash meeting, a strong evidence that the no-covalent

BTK could be used, not only in refractory-lapse patients, but also, as Matthew said, in first-line

therapy, in selected patients, based on the safety profile.

Yes, I agree, I'm adding to that what Matt said that he was a bit surprised to see not

even a better tolerability of PETO as compared to Prutinib.

I think probably we have to remember that in that randomized comparison median follow-up

was less than two years, so we have limited exposure to both of these continuous treatments,

and probably we all assume that with longer treatment duration and the incremental increase

in adverse events, the better tolerability of PETO Brutinib as compared to I Brutinib will come

out more clearly, and we have longer experience. We have this six-year follow-up from the L-Pine

study with Sano Brutinib versus I Brutinib, where simply our comfort level is probably a 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? 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 non-covalent inhibitor available,

because really a couple of main factors. One is, as you mentioned, the very short follow-up with

these phase three PETO Brutinib studies. You're in a half to two years, in most cases is particularly

in the front line setting quite short, maybe in the relapse setting a little bit more representative,

so certainly longer follow-up, 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, 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

effective in that setting post-non-covalent, and right now we only really have data the other way

around where we know pertabrutinib can be effective post-covalent inhibitor. That being said,

pertabrutinib, especially in a double refractory population post-covalent BTK inhibitor and the BCL-2

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.

I agree completely with you both, and the question now is after the patient

has a progression on front-line covalent inhibitor, how do you choose between no covalent

BTK inhibitor or veneto-clux-based therapy or even a clinical trial? So I am going to talk about my

experience in Brazil that after progression on a front-line 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 inhibitor, particularly those with

high-risk features such as TP53, disruption or deletion of 17 p, giving the meaningful PFS,

doable disease control and favorable safety profiles. Veneto-clux-based arrangements are

preference in my country when I fix a duration strategy is desirable and two more reasons a risk

can be safely managed in the services. Clinical trials are prioritized for patients with a

double exposure disease, rapid progression, or when access to approved therapies is limited.

I would like to hear your comments about the sequential therapy that you use in your country.

I agree. I mean, it is great that we have a choice now after failure of therapy with a covalent

BTK inhibitor. We have Veneto-clux actually licensed quite a bit longer and now with Piotr Brutanip

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, a tolerability of the prior covalent BTK inhibitor treatment or, you know, if it had

to be stopped due or passed or those reduced due to adverse events, and obviously also some

disease characteristics probably a bulky disease in particular impaired with decreased renal function

is probably not favoring Veneto-clux-based therapy, while, as you said, when a patient prefers to

have time limited treatment, obviously, the Veneto-clux-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, there are mutations

that may cause resistance towards 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. 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 perturbative 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,

you know, 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, perturbative

inhibitor, 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

obinatusumab, which we have access to off-label in the U.S. in the relapse setting,

and that, again, allows for a time-limited therapy for the patients, and then the potential for

retreatment down the line, and thereby also leaving perturbative inhibitor 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.

I just would like to add, since Stefan talked about the resistance mutation testing that this

is not performing 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 delaying the incorporation into the public system, recently to give you an

embarrassment and prior autorization requirements in the private sector, high out-of-pocket

costs and limited access outside major centers in addition. In consistent availability of molecular

and limited clinical drive capacity, we can further delay access to no-convalent BTC inhibitor when

it is the most appropriate option in the country, and I really don't know what's going to change

in the next two to five years, but I would like to hear from you what's the practice in your

countries about the use of mutation testing and the easier availability of the BTC I overlayed

and no-overlating inhibitors. 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 BTC that may cause cross-resistance between

covalent and non-covalent BTC inhibitors. Much of that, what we know, however, is based on patients

who had first covalent BTC inhibitors and then non-covalent and then possibly progressed. So

we don't know much about patients who had received only a non-covalent BTC inhibitor

and possibly then progressed what the mutation of 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,

peer-to-approvisioning, for instance, is also tested now in clinical trials in combination with

phenytoclux 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 BTC i non-covalent BTC i and phenytoclux. 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 BTC targeting agents, namely the degraders. What was your take on that?

Yeah, this is a very exciting development, I would say, in the field. The degraders are targeting

BTC 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 and the proteusum. Because

of that, they will have a very different pattern of target engagement even in the setting of mutations.

And, 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 response is one thing, of course, but we need durability as well. And I

think the 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.

In my country, we have some clinical trials with BTK degraders. And I agree that sequencing could

involve towards covalent BTK inhibitors, no covalent BTK degraders in the end, particularly for

patients with mutations. And for those that were not ideal candidates for venetoclux-basid therapy,

while venetoclux and trials became the key alternative-basidone patients' goals and as

sex in our country. I totally agree with you and your excitement about the 2D

graders, and they 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 1 trials.

The median number of prior lines was 4, so the patients not only had covalent BTK inhibitor

or venetoclux, they also had chemotherapy or other regimens. The characteristics were also

impressive, with 80% about of patients having unmuted IGHV close to 70%, having a 70%

p-dileation or TP-p-difimutation, and 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 appreciated 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 a stop of that yet still experimental treatment. So I found the data

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 also looking

forward to potential combinations. Matt, where do you think this development of the degraders will

take us? 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 pertabrutinib as the more common second line therapy, and already there's

head-to-head studies that I know are being planned, comparing pertabrutinib to BTK to greater therapy

in that post-covalent BTK inhibitor population. You know, it's possible eventually they could look

even into the front line 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 relapse refractory CLL treatment?

I think that clinicians should consider the idea that progression on a covalent

BTK inhibitor represents the end of BTK targeted therapy, with the emergence of no 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.

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 haven't a choice now. We can use Pietro Brocinipe as non-covalent

inhibitor that showed really very good tolerability data and proven efficacy in the post-covalent BTK

eye setting. Then the US where we see a lot of covalent BTK never use, and I feel like there may be

some confusion or under appreciation of the role that pertabrutinib may play, because this is now

the fourth BTK inhibitor, and if you're not following CLL closely, why do we need a fourth BTK

inhibitor? But I think it's very important that we underscore that pertabrutinib 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 front line setting.

What is one key area where we still need more data before changing practice?

As we discussed earlier, I think sure we have this license available for Pietro Brocinipe in

the relapse setting, likely in the not too distant future, also in the front line 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 time and evolving data, this may change, and based on the very good

tolerability profile of Pietro Brocinipe, I think there's a good chance that it stands to be moved

into the front line setting. Okay, 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 inhibitors, no covalent inhibitors,

venetoclox-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 these fields as in all new fields we have in our specialty.

And I would just add again in the US where covalent BTK inhibitors are by far the most common

front line therapy that a key data need is what is the optimal second line therapy for these patients

progressing after front line, covalent BTKI, and I think pertabrudnib, venetoclox, 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.

Thank you Dr. Stogenbauer, David, and Hammersleik. And many thanks to our listeners for joining us

today. As a reminder to view the full program, please click the link in the show notes,

and be sure to check back with us frequently for more episodes on important oncology topics.