Matthew Davids:

Hi, everyone. I’m Matt Davids from Dana-Farber Cancer Institute and Harvard Medical School in Boston here in the US, and very happy to be joined today by two of my esteemed colleagues who I’ll introduce themselves, maybe starting with you, Jen. 

Jennifer Woyach:

Hi, I’m Jennifer Woyach from The Ohio State University. 

Matthew Davids:

And Toby. 

Toby Eyre:

Hi, everyone. I’m Toby Eyre from Oxford University’s Hospitals in Oxford in the UK. 

Matthew Davids:

Great. Well, today’s topic is BTK inhibitors in chronic lymphocytic leukemia, CLL. Certainly a lot to talk about on this topic. We have a lot of new data that have emerged and a lot of data that have accumulated over the last decade plus. So we have a lot to get to today. So why don’t we dive right in? And our first topic involves the idea of molecular profiling and treatment selection, in particular, as we think about sort of different biomarkers and how molecular profiling might influence BTK inhibitor selection, as well as the timing of this therapy relative to other therapies. So maybe for this topic, Jen, you could start with kind of giving us an overview, and then Toby, you can chime in. 

Jennifer Woyach:

Yeah, absolutely. So before I start treatment for somebody with CLL, we want to check some of the prognostic factors that are important, both in kind of understanding just the overall genetic risk of their disease, but also kind of how they will do with individual therapies. The molecular tests that I think are the most important prior to starting treatment, one is the IGHV mutational status. And then we have FISH testing where the 17p deletion is the most important for treatment selection. And then next generation sequencing, at least looking for TP53, but of course, there are other gene mutations that are relevant in this setting. And, you know, why I think this is important is we can kind of take a patient and put them into a very low-risk, so that’d be an IGHV mutated with no high risk TP53 or complex karyotype or other abnormalities, and then very high-risk, on the other hand, which would be 17p deletion or TP53 mutation, or if you have a full karyotyping, knowing that they have complex karyotype. Most of the patients still end up kind of in the middle where you have to have more of a discussion on the risks and benefits of different types of therapies, but at least when you know if somebody is a very high or very low risk, that can help drive treatment discussions. 

Matthew Davids:

Great. Thanks. And Toby, what would you add to that? 

Toby Eyre:

Yeah, very similar to Jen. Obviously, there’s a lot of information out there. There’s a lot of testing that you could do, but the sort of pragmatic point here is we need something to give our patients and to guide our therapeutic choices in clinic. And so there’s lots of small groups of small sub genetic groups but broadly speaking I do something very similar to Jen, I check IGH status and p53 deletion and mutation by FISH and mutational status and that I think gives you a broad three categories: high-risk, low-risk, and that sort of quite large intermediate risk group. But I think they really help us guide fixed duration therapy, continuous therapy, and just help guide the discussion in the first line setting, as well as, of course, information on things like time to first treatment with IGH and so forth, which obviously is very important for patients. So broadly speaking, I do a very similar thing to Jen. 

Matthew Davids:

Yeah, I would say very similar for us as well. You know, one additional point to kind of go into a little more detail on is karyotyping, since this is maybe not as widely done. It is important to know in CLL, if you’re going to be doing karyotyping, you want to use a stimulated karyotype, typically like CPG or something similar. And this can bring out some of these cytogenetic abnormalities we might not otherwise see. Historically, with chemoimmunotherapy, when we saw three or more different cytogenetic abnormalities that conferred a poorer prognosis, but it does seem that increasingly that we need to see five or more different abnormalities to confer a poor prognosis in the era of targeted therapies, particularly when we see TP53 as one of them that we know that’s more aggressive. But actually, even in the absence of TP53 aberration, if we see five or more cytogenetic abnormalities that can suggest, for example, a shorter time of progression-free survival, for example, with time-limited venetoclax-based treatment. Now, the other thing on this topic to get into as we kind of think in the relapsed setting, particularly in patients who’ve already been on continuous BTK inhibitors, is whether we should be testing these patients for BTK or other resistance mutations. So Jen, maybe what’s your approach in the clinic to doing that? 

Jennifer Woyach:

So I think it’s important actually to do this testing on patients when they relapse on a continuous BTK inhibitor, or even if they have been on a continuous BTK inhibitor, come off for toxicity and then relapse at a later time. And the reason I think this is important is we have increasing access to therapies that we can sequence in the same class after the covalent BTK inhibitors. And the time of remission and whether they’re going to get into remission at all is somewhat dependent on the presence of these resistance abnormalities in the blood at baseline. The ones that are important, we know that with covalent BTK inhibitors, C481S BTK mutations can happen at the time of relapse or even prior to relapse in somebody who’s developing resistance. Less commonly, PLC gamma 2 mutations, that being a mutation that’s downstream of BTK, may influence how well they’re going to respond to other BTK kinase inhibitors like the non-covalent BTK inhibitors. And as well, I think we’re starting to gain more information about the second generation covalent BTK inhibitors, acalabrutinib and zanubrutinib, that are sometimes associated with mutations like T474 BTK mutations or L528W BTK mutations that can actually make pirtobrutinib either not work or more likely work for a shorter period of time than you might otherwise think. 

Matthew Davids:

And Toby, in the UK, is this something you guys are typically doing in clinical practice or more in research studies so far? 

Toby Eyre:

Yeah, it’s a good question. I personally still think most of this is investigational in terms of its routine validity in clinical practice. Maybe that’s just because of sort of restrictions on access. I think there’s certainly a story around kinase dead mutations and potential resistance to non-covalent BTK inhibitors that I think need exploring in slightly larger sort of series. I do agree that the data with pirtobrutinib PLC gamma 2 mutations, the response rates do look lower. Of course, they often coexist with BTK mutations, and so I think teasing that apart is quite difficult and that’s a pretty small subgroup. And actually we know that pirtobrutinib works in 80-85 percent of patients and so the question is is who won’t you give a trial of say pirtobrutinib to? But maybe in the future when we have BTK degraders and non-covalent BTK inhibitors and whether there’s a sort of, you know, whether we will choose our sort of mechanism of targeting BTK according to a mutation, I can sort of see its routine clinical value there, perhaps more. But I absolutely recognise its sort of value biologically and certainly in the future, I can see it being particularly useful. I also do find it useful if I’ve maybe got a slightly odd story around resistance or intolerance. Maybe they’ve been referred to me and nobody was quite sure whether when they were stopping a drug, they were actually resistant or intolerant. It can be a little bit useful there. But with the caveat that you mentioned that patients do, you do obviously notice a a sort of rise in the VAF of a mutation before relapse that’s been shown quite quite nicely in a number of studies, most recently in the FLAIR trial. So yeah, I think with those caveats it can be useful in that context so yeah but, a little bit varied. I do use it in targeted patients, but not routinely. 

Matthew Davids:

Yeah, I think we’re testing it pretty widely for our own patients, but I would say like in US community practice, not being used as much and kind of for some of the reasons that you highlight, Toby, I think right now it’s a little bit nuanced in terms of how it’s influencing treatment decisions. But I think you’re right that increasingly it is going to be more valuable as we have more ways to target BTK. Also, Jen and her group are doing some innovative work around whether it makes sense to intervene early on these mutations and try to reduce these bad clones that can emerge, and so I think there’s a lot still to learn here. And so it is, I think, valuable to test when you can, but not essential necessarily in community practice right now. 

Alright. So, you know, we sort of touched initially on some of these questions already, but I think maybe we can dive a little bit more detail now into our next topic, which is the sequencing of BTK inhibitors with other CLL therapies. So we have obviously a number of great options now. We have time-limited venetoclax-based therapies, we have continuous BTK inhibitors, and now we have combinations, time-limited BTK-BCL2. So Toby, maybe take us through how you’re thinking about this right now. 

Toby Eyre:

Yeah, it’s a complicated topic or increasingly complicated. Well, I think the first thing to say is that naturally there’s a wide range of factors that go into decision making that are difficult to describe briefly, but often patient preference is very dominant, as well as, of course, the genetics that we’ve discussed. And in the first line setting, generally speaking, you’re either talking about continuous BTK inhibitors, often as monotherapy though not exclusively, or venetoclax-based fixed-duration therapy. Generally speaking, for those with lower risk disease I tend to push towards fixed-duration and in those with higher-risk continuous therapy with a BTK inhibitor. And then there’s a large number of patients in between where things like patient preference, comorbidities, other issues, you know, the desire to either avoid or engage with sort of venetoclax ramp up, et cetera, social support, all of those things, I think, play into those factors. And I think certainly in the intermediate risk group of patients, which is quite a lot of our patients, I think all options are on the table, and to my view, sort of, you know, reasonably speaking, equally valid. Certainly from CLL17 at least, continuous BTK inhibitors and fixed duration therapy, it looks sort of broadly equivalent, at least in terms of PFS1. So that’s where I’m sort of aimed for in the first line setting. I generally, I can use I plus V. I use I plus V in sort of younger unmutated patients and venetoclax-obinutuzumab, maybe in slightly older patients, as well as, of course, continuous BTK inhibitors. And then in relapse, I look at both exposure, tolerability to prior line of therapy, and also, of course, when you’re talking about fixed-duration therapy, the length of durability of remission. And I think that helps guide then either re-exposure to the same class or switching class in the knowledge that, you know, patients at least who are either younger with intermediate or high risk disease or older high-risk disease will eventually cycle through and become resistant to at least covalent BTK inhibitors and BCL2 inhibitors. But as we’ve already touched on, we have this sort of armamentarium of increasing numbers of therapeutic targets, non-covalent BTK inhibitors, particularly BTK degraders and, of course, T-cell engaging therapies as well on the horizon, or at least accessible in some geographies. So I guess what what I’m generally thinking about is not only PFS1 but also sequencing of sort of future therapies in the knowledge that both classes, particularly covalent BTK and BCL2-based therapy, will be the sort of cornerstone of first and subsequent lines of therapy moving forward in most patients. So that’s that’s sort of how I view things for now, but of course practice always evolves and I’m sure we’ll see the evolution of BTK degraders further up the pathway, non-covalent BTK inhibitors further up the pathway. So yeah, that’s how i see things, at least for now. 

Matthew Davids:

That’s great. Thanks, Toby. That’s a fantastic overview. Jen, anything to add to that or different opinion? 

Jennifer Woyach:

No, I mean, I very much agree with what Toby had said. I think you didn’t mention acalabrutinib and venetoclax, and I can’t remember if that’s because you don’t have it. 

Toby Eyre:

Well, we don’t have it. It’s on the verge of being approved in the UK, but not at the moment. But yes, that will also complicate things further. But another great option for patients. 

Jennifer Woyach:

Right. So I think, you know, that’s the only other option I thought it might be worthwhile to touch upon, because it does allow for the fixed-duration regimens to be given a little bit easier. And especially with the recent changes to the package insert for venetoclax, where the ramp up isn’t quite as onerous as it was before. I think more and more people are interested in a fixed-duration regimen if they don’t have to come weekly for nine weeks in a row. I think the, you know, the one caveat when looking at I plus V data and A plus V data, and we don’t really use a lot of I plus V in the United States, that A plus V data looks very good for the low-risk patients. And I think it looks like the remissions might be a little bit less durable for those intermediate-risk patients, not saying that they shouldn’t be given that regimen or offered that regimen, but I tend to sometimes lean a little bit more towards VO in those intermediate risk patients just because we have longer follow-up with those data. And then we also do have an option according to the NCCN guidelines to use AVO either just as a one-year fixed duration or with the work from Matt’s group in higher-risk patients, potentially using it as an MRD-guided strategy where you might continue the acalabrutinib longer term. From the data that have been generated in multicenter studies, it looks like that can be challenging, especially with the COVID pandemic, but we don’t know whether that’s going to translate to other flu season and things like that, whether there’s a higher risk of death or infection with that strategy. So I tend to consider that for patients who are maybe intermediate risk, who are young, fit, and you think might tolerate that regimen. 

Matthew Davids:

Yeah, I think that’s a really, really important point. And, you know, we initially saw that data from AMPLIFY with the higher COVID infection rate in AVO versus AV. Thought maybe this is a one-off, but now the CLL17 study has also shown with randomized data that VO had a significantly higher rate of grade three or higher infections compared to IV or ibrutinib monotherapy. So, you know, I do think that you buy some additional risk of infection with the obinutuzumab. That being said, in the AMPLIFY study, especially if you look at that censored analysis for COVID infections, there does seem to be a significant PFS benefit to the addition of the obin. And so I think as you’re saying, Jen, to me, it’s really all about patient selection there, and if you have a younger fit patient who’s really looking to maximize their initial PFS, I think it is worth considering the triplet. Now, it’s true that we don’t have any randomized data right now of that AVO triplet versus a venetoclax-obinituzumab doublet. Hopefully, we’ll get that eventually from the CLL16 study, which is looking at that in a randomized fashion in Germany. But yeah, I think for now, it’s a little bit challenging. I guess one of the other factors that I sometimes think about is the internal lymph node bulk that has emerged as one factor that can predict a shorter progression-free survival with venetoclax-obinutuzumab, particularly lymph nodes greater than 5 centimeters and especially greater than 10 centimeters. Those are patients where I tend to think they might benefit from the BTK inhibitor component of the therapy, and I may be thinking about AVO, for example, in a patient like that, if they have bulky internal nodes, unmutated IGHV, and they’re young and fit enough to tolerate the obinutuzumab. 

Toby Eyre:

I tend to use I plus V, as you mentioned, in those with bulky disease. It’s particularly good at sort of debulking those patients before venetoclax, a very valuable option there. I mean, in terms of when A plus V becomes available in the UK, I mean, like Jen mentioned, I can see its role in those who might want to use all oral fixed-duration therapy, but you’re nervous about some of the toxicities with I plus V. So those patients sort of over 70, maybe with some comorbidities etc and I agree i think we’re we’re learning all the time, aren’t we, about toxicities and we’ve learned about obinutuzumab. And I think it has altered my practice a little bit, you know patients with recurrent respiratory infections, maybe bronchiectasis, poor vaccination responses, I’m a little bit more nervous about using obin perhaps maybe than I historically was. So I think we’ve certainly learned a lot over recent times about that therapy. 

Jennifer Woyach:

Yeah, one thing I found interesting from those data, which I’m going to be excited to see in longer follow-up, is though, yes, the infectious toxicity seems like it’s worse with obinutuzumab, those people who were frail actually did better with VO than with IV. So I think we’re going to get a lot of more data from that study to help us with like those nuances for individual patients. 

Matthew Davids:

I agree. And I also think CLL17, the sort of the overall story and message may evolve over time as we have longer follow-up. You know, right now, as Toby mentioned, we have similar PFS for all three regimens at a three-year time frame. But as we get to five years and beyond, we may see that continuous BTKi is leading to a longer initial PFS. But of course, that’s not necessarily the goal for many of our patients, especially our younger patients, where we’re trying to get to a good PFS2 and beyond and prolong overall survival. So I think that will be a study that will continue to provide very valuable data for the field over time. 

Toby Eyre:

Yeah, and hopefully, because that’s an academic study, and we’ve certainly seen it from the previous German CLL studies, there’ll be data on subsequent lines of therapy, and they’ll be able to look at the PFS2 perhaps in a more robust way than we’ve seen in some of the industry-sponsored studies historically. So yeah, it would be an important one to follow. 

Matthew Davids:

Now, one topic that we haven’t dived deep into yet, which I think would be helpful to at least touch on in a little more detail, is how we treat our patients with TP53 aberration. And so maybe, Jen, you could start with that. What’s your typical approach and what are some variations on that? 

Jennifer Woyach:

Yeah. So for most patients with TP53 abnormalities, I try to steer them to a continuous BTK inhibitor, as I think we have the longest follow-up data in that setting. And also, especially from the initial ibrutinib data, but probably the same with the second- generation inhibitors. It looks like if given in the frontline setting, you do eliminate some of the high risk nature of that mutation by using the continuous BTK inhibitor in the frontline setting, as opposed to the relapsed setting where people with 17p deletion or TP53 mutation clearly have shorter PFS. So I think kind of in the interest of giving our most effective therapy first for those patients, that’s what I would usually choose. However, I think, you know, the emerging data, you know, especially with all these options we have for sequencing, if a patient wants a fixed-duration regimen in the frontline setting and they have a TP53 abnormality, I don’t think that it’s an absolute contraindication to that certainly. And there’s a couple of fixed-duration regimens that seem to be a little bit more promising or at least have more data associated with them. One is mentioned would be AVO given potentially in a MRD-guided fashion, with the knowledge that many patients are going to continue the acalabrutinib. The other one that has been studied in the SEQUOIA trial was venetoclax-zanubrutinib, again, given in an MRD-guided fashion, and again, with the knowledge that most patients will be continuing the acalabrutinib if you follow that regimen exactly. Though I think, you know, as well, again, if somebody really wants a fixed-duration regimen, you could do either one of those and just plan on stopping it at a defined period of time rather than doing it in the MRD-guided way, knowing that remission durations are likely to be shorter, but that’s probably the only way you’re going to get some time off treatment for those patients. 

Matthew Davids:

Yeah, and I would add that in our AVO trial, which we did conduct across a number of different centers, including some smaller centers, the vast majority of patients did actually stop therapy by two years. So only I think 10 out of the 72 patients continued beyond two years, and a couple of those patients had just chosen to do that, even though they were already undetectable for MRD because it was an optional MRD test. So I do think if that’s sort of been my practice, if I have a patient who’s very strongly feeling like they want a time-limited therapy, I think either AVO MRD-guided, or Ven-Obin I think is a reasonable choice, especially in a patient who might be older, where you might be worried about the triplet toxicity, or maybe they have significant cardiovascular comorbidities, and that’s why you’re trying to avoid continuous BTKi. You know, we do see about a median of four-year PFS with Ven-Obin, even in these high-risk patients. So I think it’s a reasonable option. But that being said, for the majority of these patients, I totally agree with you. I would use continuous BTKi. Toby, what do you think on this topic? 

Toby Eyre:

Yeah, I very much agree with the comments that have been made. Yeah, I mean, we have had sort of some experience with MRD-driven I plus V mostly outside of p53 mutated disease but there’s a sub cohort within the FLAIR study that will report looking at that. I tend to agree that 12, 15 months probably is not enough therapy for these people, and as a general principle, I sort of don’t want to be treating relapsed refractory TP53-mutated disease any more than I need to. So I sort of tend as a general principle to focus on PFS1 a little bit more in these patients and give continuous BTK inhibitors. Generally speaking, zanubrutinib, primarily extrapolating some of the data from the relapsed/refractory setting to the first line setting, and it probably has the most robust data in the first line setting in terms of at least patient number treated with p53 deletion so yeah that’s my sort of general treatment choice. Sadly I don’t have access to AVO and MRD-driven AVO, but I think, certainly in a younger patient, that was a very attractive proposition to use that triplet. 

Matthew Davids:

Alright. So let’s move on to our next topic, which involves the community physicians. So we sort of have our own way that we’re practicing in our larger academic centers, but often our community colleagues may not have access to sort of some of the same testing modalities or their patient population may be a bit different with different comorbidities. So Jen, maybe you can kind of take us through some of the challenges and practical considerations in the community practice setting, resistance, access to sequencing of therapies? 

Jennifer Woyach:

I think, you know, one of the big challenges is that CLL therapy and testing strategies are evolving really quickly. And, you know, especially for a relatively uncommon disease, I think it’s hard for somebody in community practice who might be seeing kind of the gamut of solid tumors and hematologic malignancies to know all of the data or to be familiar with things that have been recently updated. You know, I think, you know, as mentioned before, I think it’s really important prior to the first line of therapy to know the risk stratification, and usually that’s something that can be done. There are a number of commercial laboratories that will test IGHV status, will test FISH and TP53 by NGS. And so I think those are important and, you know, making sure that we kind of get those FISH cytogenetics and NGS prior to each line of therapy. And then I guess the other thing I would just kind of be thinking about is that, because we have all these options, we need to be thinking about sequencing from the first line of treatment. So, you know, I think it’s easiest to prescribe a BTK inhibitor continuous in the frontline setting, and it’s probably easiest for the patients too in many cases. But kind of thinking about the risk stratification and the patient preferences, I think is really important because what you do in the frontline setting certainly dictates what’s going to be available for relapsed disease as well. And also, you know, thinking about whether there are access to clinical trials around, there’s a number of ongoing national studies that many community practices have access to as well, and so thinking about the utility of clinical trials as like a treatment modality for your patients, I think is really important. And then, you know, I guess in the subsequent settings too, you know, thinking about doing those mutation panels for TP53, BTK PLC gamma two, to kind of help understand like what might be a good next line of therapy. And then as we get more and more data for CAR T-cells, I think that’s becoming more in the community practitioner’s wheelhouse with the access to it in lymphoma and thinking about that for appropriate patients too. 

Matthew Davids:

That’s great, Jen. Toby, in the UK, a little bit different scenario, maybe more patients treated in the larger centers, but you have district hospitals, like how are things going in there? 

Toby Eyre:

Yeah, absolutely. So setup’s a bit different. So CLL patients are all looked after by hematologists, either in a large tertiary referral unit or in a district hospital, but they’re not looked after sort of oncologists who look after all the solid tumours. So they’re sort of… the hematologists will look after all lymphoma and other heme malignancies. What tends to happen in the UK is access is the same wherever you are, and the district hospitals are supported by a sort of central hub, a central tertiary centre that have a weekly sort of what we call MDT meeting, probably like a tumor board meeting for you guys, where I will chair for sort of three hours or so lymphoma and CLL cases and we do this every week for like the three million people in our region and that happens all over the UK. So although decision-making is made by individual district hospitals, there is sort of specialist interaction on sort of most cases across the UK, which is great. That said, the challenges are encouraging people to do sort of full genomic work up, so IGHV status, getting that message out, getting the message out that fixed-duration therapy for younger patients certainly with lower-risk disease is a really good option. Continuous BTK inhibitors have been by far and away the most popular therapy in recent years, I think two or three years ago 60 percent of first line treatment was acalabrutinib monotherapy in the UK, so you know there’s certainly going to be sort of some work to do to move away from that, because it’s clearly convenient and popular for all the reasons we’ve outlined. And yeah absolutely we we do have some of the district hospitals involved in clinical trials, but most of them are based in the sort of larger tertiary centers. 

Matthew Davids:

Alright, great. So our last topic, Toby, I’m going to have you take us through this a little bit more. We’ve touched on a lot of these issues as we’ve gone along here, but maybe help pull this together for us around the idea of strategies to individualize therapy for patients and sort of balancing that efficacy and tolerability depending on patient age, comorbidities and genomics, other factors. How do you think about that in practice? 

Toby Eyre:

Yeah, so I mean, I think in most patients when they’re coming up to first line therapy, particularly it’s quite a daunting thing – there’s a lot of information out there, there’s a lot that people can read about. And I think our job is to sort of break down the options for individuals. And certainly the buzz phrase in the UK is ‘shared decision-making’. So, you know, we might present the fixed-duration/continuous options, different therapeutic classes, maybe clinical trials, and try and just identify what the priorities are for that individual in front of us, maybe for their family as well, and select something that is going to sort of meet their needs, really. I mean, it’s a sort of very holistic thing, but in essence, that’s what we do most of the time, right? And it’s no different in CLL. And I think we have to remember that, you know, the vast, I tell my patients this regularly, the vast majority of our patients, we’re fortunate now that most people have an age and gender matched life expectancy compared to sort of the normal population. I tell people this and I tell people that we’re going to sort of take them on a journey. Their diaries will be full of a few extra appointments and tablet taking and blood count monitoring, but actually, you know, we want to keep their life as normal as possible. And I think you select the therapies that will achieve that for individuals. Of course, there are specific comorbidities that will drive decision-making one way or another. And I think we know about the therapeutic classes that we want to avoid, continuous BTK inhibitors in and we want to avoid BCL2-based therapy. But in essence, in most people, it’s shared decision-making based on comorbidities and practical sort of aspects that maybe trump some of the fancy medical things that we we think about all the time. I think that’s that’s the way I view it most of the time. I think my my role often in our clinics is just trying to simplify the decision-making for patients, particularly now in an era where, I mean we’ve just been speaking about sort of complex array of different medical sort of decisions and different therapeutics, our job is to say actually you know we think this might be best for you because of x y and z and have a read of this. And I often give patients information about two or three regimes if they’re undecided and ask them to come back the following week with a list of questions for me, and that tends to sort of work fairly well. I’m sure you have similar experiences. But it’s complex for people to navigate when they’re not medical and, you know, everything is sort of rapidly evolving and new and yeah, I think our role is just to help people navigate through that decision-making process.

Matthew Davids:

Those are great perspectives. Jen anything to add to that? 

Jennifer Woyach:

No, I think that was a tremendous answer and yeah I feel the same way. I think that my job is to try to make the regimen simple enough that anybody can understand them and understand like really what the differences are between them. I usually start by the continuous versus fixed-duration, just kind of in general, and then see if we can narrow it down to one versus the other. And then, you know, if we settle on fixed-duration, then kind of talk about all the potential options there. But yeah, very much agree. 

Matthew Davids:

Yeah, I certainly agree as well. I would just say like a couple of things to add would be just around, you know, I think especially what Toby was saying about the likelihood that patients will live the same as someone their age matched control. I find that to be more compelling as the patients get older. And I still worry more about my younger patients since these great targeted therapies we have just haven’t been around that long, and hopefully they will be working for 20 or 30 years, but we don’t know that yet from data. So I think that the other factor, of course, is the genetics. And so if I have a patient with very low genetic risk CLL, I’m also sort of a little bit more open to sort of whatever the patient wants. They’re probably going to do well with any of these therapies. But just to mention, sort of as the age ratchets down a little bit and as the genetic risk ratchets up, that’s where I start to be a little bit more prescriptive in terms of kind of guiding patients toward the therapies I think are going to be most beneficial for them long-term. Obviously, ultimately it is the patient’s decision and it’s shared decision-making, but I do think we have a lot of influence in terms of how we present these options to our patients and what they end up ultimately choosing. And so those are just a couple of themes that I think about – my young high genetic risk patients, I worry more about, I try to really give them very clear guidance on what I think is best, my older patients, especially those with lower genetic risk disease, it’s really kind of up to them what, what fits best with their lifestyle and their preferences. 

Toby Eyre:

Yeah, I’d absolutely agree. And that’s very, very similar to my practice as well. 

Matthew Davids:

Yeah. Great. Well, I think that sort of wraps our wraps our discussion here. I think it’s been a great roundtable discussion here on the role of BTK inhibitors in CLL. I’d like to thank Jen and Toby for all of your great comments. And thank you, the audience, for listening. Take care.

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Toby Eyre:

Consultancy and honoraria: Beigene, AstraZeneca, Roche, Gilead, Kite (Gilead), Takeda, Johnson and Johnson, Loxo Oncology, Incyte, Autolus, Nurix, Galapagos.

Jennifer Woyach:

Consulting/Advisory: Pharmacyclics, Janssen, AstraZeneca, Abbvie, Beigene, Loxo, Newave, Genetech, Merck

Research Funding: Abbvie, Loxo, Verastem, Karyopharm, Morphosys, Schrodinger, Mingsight