Chronic Lymphocytic Leukemia — An Interview with Prof Constantine Tam on Key Presentations from the 2025 ASH Annual Meeting

0:00Welcome to oncology today, keep presentations from the 2025 American Society of Hematology Annual Meeting, chronic lymphocytic leukemia. This is medical oncologist Dr. Neil Love. This program is a follow-up to a live activity we conducted at the 67th annual ash meeting, held last December in Orlando. I met with Professor Constantine Tam from a Nash University in Melbourne, Australia, who served as part of our faculty panel for that activity. I wanted to follow up with him regarding important data sets that emerged from ash and his perspective on the impact on the care of patients with CLL. Before getting into the discussion of data presented at ash, I first asked Dr. Tam to summarize his views on the current first line treatment paradigm for CLL. So at the moment, I think the default for CLL for a lot of countries is continuous BDI, which is a huge advancement upon chemotherapy, right? We all remember chemotherapy,

1:03and it really has changed the way we manage CLL to put patients on the tablet, they do well, they've got some side effects that manageable. I think where the world is moving towards is some way of fix duration therapy, just nobody likes continuous treatment, and there are two predominant ways to achieve a fix duration treatment. There is the combination of open enthusiasm map. I think we started to realize that when you combine open enthusiasm map that you have got the three major problems. The first one is that you require an infusion, and there is the risk of infusion reactions. Secondly, increasing the appreciation that it does increase the risk of infection death, especially in COVID era, and some will argue, okay, COVID is a once-off, but there will be an ex-COVID. There are respiratory viruses around, and we know patients on CD-20 who experience prolonged respiratory viral infections. And the third problem with a antibody containing regimen is that for patients with 17 pd lesion, they seem to do this well. Okay, so

2:06those are the things that we're trying to say, how can we achieve the same outcome of fix duration therapy without the antibody? And that's where the oral doublet's come in, right? So you get, you add a BDKI and a BCL-2, we know that they work pretty well, and the side effects are in general pretty tolerable, especially with the a color van and a zenovan combination. But the problem with those drugs is that the MRD clearance rate is not that great, right? So we've got MRD clearance rates of under 50 percent compared to 70 percent of open enthusiasm map containing regimens. Then the next step is, well, how do we make that better? How can we stick to the tablet format, two tablets, fix duration, and yet still get high MRD clearance? And it looks life in the emerging data that the key to do that is to upgrade the BCL-2, switch out the vinyl clacks for better drug, such as sominal clacks. At the same time, I think the other group of abstracts really looked at, you know, what happens if we bring in better BDKI's into the front line,

3:06like Perlabruthnet. And to be perfectly honest with you, I'm not convinced by the Perlabruthnet front line dollar. I think it is undoubtedly a better tolerable drug compared to I abruthnet. But I'm convinced that it actually is more effective than I abruthnet or zenovrutable k-e color in the front line. So I want to get into that in a second, but first just to kind of go back to where we are today. And assuming you have the option of BDK, Vanetta clacks, so now you've avoided the effusion, you've avoided issues with the Benetusumab. But you still have issues related to Vanetta clacks, although it doesn't really seem like it's that, you know, huge of a deal. I mean, that's what I wanted to ask you. So at least right now in terms of where we kind of have data and a lot of the approvals, when you think about a BDK-slash Vanetta clacks, whether it's a cowl of Vanetta clacks, or against at this point, maybe a brutanib and in the future, zenovrutanib, what kind of patient would you not want to give Vanetta clacks

4:08to or was it problematic to give Vanetta clacks to? Yep. So the biggest problem with Vanetta clacks is tumor loss syndrome, right? So there's still one that, and I think about tumor loss syndrome in terms of true major themes. The first theme is obviously it's dangerous, but the reality is that when you use the combinations of either open a to zenovrutanib, or BDK-i, plus Vanetta clacks, tumor loss actually doesn't really happen, because by the time the patients start their Vanetta clacks or their tumor clacks, they're so well debout that if you look across a clinical trial, the tumor loss is always reported in a very low percentage, but on the ground it really doesn't happen, especially with the monitoring practices that we're building. So the second aspect of tumor loss syndrome is we all have to go through the ramp up with the monitoring, which nobody likes, because you know, it's cumbersome, it takes up our time, it takes up the patient's time, it's complex, and it makes the regiment a lot harder to deliver than it should.

5:12So your question is which patients are not suitable for Vanetta clacks? The answer is actually very few. So patients who have got, let's say, a very poor renal function, where if they get tumor loss syndrome, you don't think that you can effectively treat them for the hypercalemia, in a very rare event that happens, yes, maybe I will avoid Vanetta clacks, but really with the more than combination regimens, they're very few who can't get it. I guess the only thing I would think about, I don't know how common it is where you are, maybe our situations where it's very difficult for the patient to get to clinic, because it does seem like it's going to be more clinic visits, but other than that, it's hard to see very much, but I don't know, do you have a lot of patients who come in remotely from a couple hours away? Correct. So I leave in a very big country, where we're very centralised and a lot of people live a long way away. So you bring me exactly to my second point, which patient is not suitable, it's not a biology, it's a logistics, it's where they live, and whether they can actually come into the clinic for the real-time

6:13tumor loss monitoring, because where they live, you can't get real-time labs, you can't trust someone to look after them, but that brings me to an next step, right? If someone to be overcome, because the reality is that we don't really see tumor losses, we have to go through the monitoring, and I think what would be really helpful would be some way to address the problem, you know, can we develop regimens of either more gentle rampups, which further decreases the research tumor losses risk to nothing, or are there better ways of monitoring this with new technologies? And I guess in my mind, I'm thinking about, let's say like an oral contraceptive pill pack, where you start from day one, and you go all the way to day 28, and you have a graduate buildup with a drug each day, to a point where maybe you've got such a graduate buildup that you just do not get tumor losses, and you do not require monitoring. Obviously that's for the future, but I think at the moment it's the logistics of delivering the drug, there is a barrier and not the biology of the patient. One of the kind of themes I want to run by you as we go through this

7:17conversation is, I don't know, but I'm going to use the term myths and misperceptions that you might see in community-based physicians, things that you would do differently, in terms of ineticlacks and monitoring for tumor lysis, we come a long way because of the fact we realize these people are going to get debunked. Anything you see people doing, people ramping up too fast, are they doing anything, is everybody kind of got the message about how you do this? I think at least in my area, most people have got used to the system of how it's done. I think a couple of important pointers is that the nail clacks actually has a fairly long half-life, so if you ramp it up without giving the full one week between the doses, then it means that you probably haven't reached a steady state before you step up to the next dose, and that's one advantage of some world of clacks is to get scored very short half-life, so you can ramp up faster. So I always, and as in extreme circumstances, I try not to dose escalate the nail clacks faster

8:21than the ones a week, which is what it's approved for. The second thing I appreciate is that the critical doses are probably the first two weeks, the 25 milligrams and 15 milligrams, which is usually where you will see tumor lysis, it will happen, and the critical time for tumor lysis is actually the six to eight hour post-dose time point. So that's probably when you're going to see the tumor lysis happen. What that basically means is that at least for those two doses, you want to dose the patient less than an early in the morning at about eight a.m., so that you can get a blood test by about two p.m. to three p.m. in the afternoon, in order for the laboratory results to come back by the time you check out from work. So those are probably the key points. It's interesting. Notice when you're talking about the study of perturbative root versus BR, there was actually one death in the BR arm from tumor lysis syndrome, which I guess reminds us that we can see it. Also, with the Benetusumab, how often do you see tumor lysis there and any caution you take, and particularly people with higher bulk?

9:24Yep, I actually do, excellent point. I actually do check Tumolosis blood for open the Tusumab for the day one and day two, and also check out blood tests on day three for patients with very high white cell count. Those are the same patients that you know about, because they're the ones with most likely to get reactions, and the ones that you pay of, you know, very close attention to. And you're right, you look to see our 14th study, which looked that, you know, Benetusumab versus Clarembusopus open the Tusumab, there was actually more Tumolosis on the Clarembus arm because of open the Tusumab. So ironically, the Tumolosis risk was lower than the Benetusumab. So, you mentioned sunrhodoclacks, and the fact that, quote, it's 10 times more potent, could you kind of draw that out a little bit in terms of, you know, your vision without slides on how you describe it when you're making rounds, walking down the hall about how these agents work, and what the implications of greater activity that you mentioned exists with sunrhodoclacks? Yep. So, sunrhodoclacks can be, it's basically just a really potent version of Benetusumab.

10:28It binds BCL too much more tightly. And one of the advantages, which we have to prove is that it might actually be active against the mutations that confer Benetoclacks resistance. So, in particular for Benetoclacks, you can get a mutation in the BCL to protein at the 101 position. And what it does is it makes BCL too less sensitive to Benetoclacks. It doesn't make it resistant, it makes it less sensitive. So, the whole idea is that you become with a bigger hammer by sunrhodoclacks, that you can actually inhibit those patients as well. And maybe when you go, you'll hit some of bigger hammer, they will not get those resistance at all. So, I think that's the main advantage of sunrhodoclacks. It's just a lot more potent than the bigger hammer. The other advantage is that it's got a shorter half-life, so it can ramp it up faster potentially, although at the moment it's still designed as a once-a-week ramp up. And lastly, despite being a bigger hammer, in terms of the side effects, in terms of the diarrhea, the reflux, and the nitripeanet that we see with Benetoclacks, it looks about the same or maybe even better. So,

11:32we're not paying really a price for the improved efficacy. Just out of curiosity, is sunrhodoclacks being looked at or has been looked at in other diseases, AML, myeloma, etc. Yep. It's been looked at, looked at across the full range. So, there's face ones going on for myeloma, AML, S.Y. It's from Manchester, I mean, phoma, and modules, I mean, phoma. So, maybe you could just copselize a little bit about what you went through in your presentation, in terms of the MRD results with sunrhodoclacks, and it'll look like MRD results for indirectly more impressive. Can you kind of summarize that? And also, where you see things heading in terms of MRD clinically, but also in terms of regulatory, you know, just this announcement from the FDA about MRD major end point in myeloma, do you see that coming in CLL? Any comments about, again, MRD was sunrhodoclacks, and where you see MRD heading in general in CLL?

12:35So, available with the other, it would suggest that you improve the BCL2 from Benetoclacks to sunrhodoclacks in either the BDK plus BCL2 combination, or basically the Benetoclacks open to two sunrhodoclacks combination, that you've got an improvement in MRD, and I think it's really marked in the overall combination, where for the Benetoclacks combinations, it doesn't matter who you partner with for the BDK, you're hitting the MRD ceiling at around 50%, and yet, when you're giving sunrhodoclacks, you've got MRD rates of about 90%. So, I think that's really where the real signal that sunrhodoclacks is coming from. Now, with the FDA-approved MRD as a primary endpoint, just like Marloma, we would love the FDA to do that, they have, and I can't speak for the FDA, but so far they have been less amenable to using MRD as an endpoint in CLL, and I think MRD as an endpoint in CLL is a little bit troublesome because there are MRD

13:40assessment in the blood, and there's MRD assessment in the bone marrow. Now, when you do not have a C-20 body on board, so you just use an oral combination, the blood in general is a reliable assessment of MRD compatible marrow, they look very similar, but when you include either retoximab, open the two-symab system in the mix, those drugs clear MRD faster in the blood compatible marrow. So, it means that when you're looking at the MRD dollar, for let's say, an open the two-symab containing regimen compared to a regimen that is only oral, the MRD in the peripheral blood is probably overstated for patients getting an open the two-symab, because open the two-symab preferentially clears MRD from the blood, and those patients still require bone marrow biopsies to get a true MRD state, and of course, nobody likes to implement it in CLL. Let's talk about the basic decisions in first-line therapy, and of course, the biggest one,

14:41I think, is whether it's going to be time-limited or not. Maybe you can just talk a little bit in terms of what the CLL-17 study looked at and found, and generally right now what we've learned, I mean, you've been going on this thought that time-limited therapy and single-agent continuous BTK were equivalent choices clinically for a while now. What evidence do we have? That's the case right now. Yep, so I'm going to say CLL-17 is to randomize proof of that, that's general feeling that maybe time-limited and continuous is similar, right? Now, there's a couple of caveats, so CLL-17 is three arms, one of which hybridical nail cracks is not really applicable to the US, so really it's a comparison between continuous eye-broughton and vinyl cracks plus open the two-symab, and then of course nobody uses our Brutum anymore, so that's the dials already updated. The second-generation drugs are probably going to be better tolerated and maybe more effective,

15:42depending on which one you look at, but ultimately it's a comparison between BTK eye and vinyl bin, and I think that at the dial-point, which is three years, that is probably the two early detail, the curves are identical at the three-year mark, but I don't really expect the difference to emerge until later, because we know that if you've got vinyl cracks open the two-symab, you don't really relapse until about the five-year mark, right? So you're probably going to see a separation of curve a bit later, and it would not surprise me with continuous follow-up that at least the headline result for continuous BTK eye would do better than vinyl cracks open the two-symab, because you've got one patient who's continuing drug and the other patient who stopped and is waiting to relapse. The one thing that we need to understand, though, is that there's a new incident in a dollar, because the indications for progressing on the two arms are different, and this is a way you need to think about the data a bit more deeply. If you're on a continuous

16:45BTK eye and you relapse, and you progress on the continuous BTK eye, that drug is formed forever. You know, if you develop resistance, or I have a bruise in it, or I have a bruise in it, or I have a bruise in it, you will be resistant to all the first and second-generation drugs. You have just lost a treatment for your patients, CLL. If you relapse after vinyl cracks open the two-symab, you can in general be retreated and get another response, so you haven't actually lost that treatment. So although the PFS one may be different, I think the bigger question in long term is, how long can you give a drug for before you have to lose a drug, before you lose either BTK eye or BCL to it, and have to move in the next one. So that's why I think a lot of a dollar for CLL 17 will come in. So, and I'm curious, too, in terms of the issue of re-challenged with vanediclacks, how long after, first of all, typically, how long is it after being treated with, say, a benedictus of vanediclacks up front that you would see, where do you see the relapse is occurring, and how do you determine whether to re-challenged or go into something else?

17:50Yep. So, depending on your prognosis subgroup, you typically should get 47 years. So, some region 47 years of progression free survival after van plus obeying. So, most, I think, most authorities around the world would say that if you have, you will relapse you think two years at the end of completing a vinyl clack space therapy, there's probably no point in re-challenging the patients at least partially resistant to vanediclacks, and that two-year cut point is not driven by dollar. It pays more of a so general consensus amongst experts. So, the general gap field that you will relapse within two years of vanediclacks is probably time to move on. There's pretty good dollar, though, to suggest both in real world and in fall of the clinical trial, therefore, patients who relapse beyond two years, that they do respond to another challenge of vanediclacks. What we don't know is how long that response is going to last for, because we need more follow-up. Chances are that we will not respond as long as second time, compared to the third time, to the first time, you know, with most of our treatment for any diseases,

18:50we'll roughly, you know, roughly lose about 50 percent of PFS this time, your challenge. But, you know, if you've got five years of first time and you get three years of second time, that's eight years total duration before you have to, you know, lose the vanediclacks and effectiveness. So, that's still pretty good. So, I think you made a pretty persuasive argument for time-limited therapy, whether that's going to be with vanediclacks and it's been a Tuesday map or with BTK. I wonder in how you would indirectly compare Zana Bruteno to Calabruteno, both in terms of safety, but particularly in terms of efficacy, and whether, again, putting aside Dell 17P for a second, you see any potential advantage, one or the other, you know, Zana, you reported a benefit with PFS, some curious whether you think that's something that is a consideration, do you have any preference? Sure. So, I think the first thing to say is that they're both really good options, okay? So, that's, we're choosing between, we're talking about very fine considerations and differences

19:54between two very good options. The second thing is to note is that there has been no head-to-head comparison between Eichala and Zana. So, everything else that we're talking about is going to be inferred from the data out there. Now, in that context, there's been two head-to-head studies between Zanu and Ibruteno and Eichala versus Ibruteno, both in real-life CLL and both head-to-head. For the Eichala combination comparison, it was equivalent to Ibruteno in terms of progression free survival. For the Zana Bruteno comparison, it was superior to Ibruteno in terms of progression free survival, especially in 17P, but across both groups without its superior. And on that basis, I can tell you that the data supports Zana Bruteno as being superior, then Ibruteno, and the data supports Eichala as being equivalent to Ibruteno, but I don't think I can confidently say that Zana is better than Eichala Bruteno because it has not been done.

20:57I can't compare head-to-head and you have to join your own influence. Then the next question is, why do we think Zana Bruteno may be better than Eichala Bruteno? And to that, I think you have to get really nerdy and think about the pharmacokinetics of BDKI. So Zana Bruteno has really high drug levels. So the drug levels are actually somewhere between 6 to 10 times higher than that of Ibruteno because it gets absorbed so well. And in fact, all of these drugs inhibit BDKI in both a reversible and irreversible manner. And what the BDKI mutation does is it converts the binding from irreversible to reversible. And Zana's drug levels are actually so high that it actually maintains both reversible and irreversible bind inhibition of BDKI across the 24-hour period. The same cannot be said of Ichala and Ibruteno. Both those drugs have got actually really low drug levels and really rely on the irreversible

21:59mechanism of inhibition of BDKI. So in simplistic terms, Zana just got much higher drug levels than the other two. And one can speculate maybe that's why it is superior to Ibruteno in the brand of my studies. Then the next question is, do you pay a price for the higher drug levels? Are there worse side effects for Zana compared to Ichala? And both those drugs are safe at the not Ibruteno in terms of age of fibrillation. And in fact, if you look at the card I get with my race, Zana bruteno and Ichala bruteno are both very similar. If not, maybe a little bit lower and a little bit better for Zana bruteno. But there is a difference in the hypertension signal in that for the Ichala comparison, there was less patients getting the hypertension on Ichala bruteno. Whereas for the Zana bruteno combination, it was identical to Ibruteno. So Ichala maybe advantage to in terms of reduce hypertension rights. Zana bruteno, a advantage in terms of pharmaceutical kinetics, high drug levels, and a superior outcome compared to

23:00Ibruteno. So getting down to clinic, assuming equal access to both, how do you decide between the two? Do you, is it matter where they have a history hypertension? They have history headache, anything that pushes you one way or the other is an equal option in your mind. I use Zana bruteno just because of femylarathy. And these are drug derivatives for a very long time since phase one. So that's why I tend to prescribe. But to someone who is very used to encounter with Ichala bruteno, I think that's still a very good option. As you pointed out, I feel subtleties. So someone who's got really bad headaches and migraines, Ichala bruteno may be less preferred. Having said that, those patients can be mentioned in Ichala bruteno, they had a tensile transient, equally hypertension with also good drugs against hypertension. It's more about paying attention to the blood pressure and controlling it. And I don't see someone with hypertension as being a deal breaker for either of the two drugs.

24:01So let's talk about the high risk patients, L-17P, and we saw some more data at ash focusing on what's the bottom line in terms of what we know, particularly in terms of continuous BGK versus time-limited therapy and choice of agents. Yep. So for the 17-key population, these patients are a lot better this day than can be therapy. But I would still worry a lot about these patients because they do develop resistance faster. They probably do not respond quite as well to the analysis compared to wild type patients. So I think it's really important to choose the best BGK inhibitor. So in this population, in this in my practice, if I am going to use a BGK, I I will use Xenu just because the largest, the best dial is behind Xenu and the drop levels of the highest behind Xenu. The next question is continuous versus short duration therapy. And the general doctrine is that these patients do better on continuous BGKR compared to the

25:03fixed duration regimen, which is true. And you can see that born out in C-L-17, where especially for vinaiglicics, open the tourism app, they do less well when they're 17-P deleted compared to patients who are wild type. But once again, I think there is a caveat. And this is where the discussion with the patient comes in. If I have a dial decision 17-P patient who is 40 years old, has a family, wants to travel a lot and is a stock. I really first run about fixed duration therapy. I don't want BGKR because I'm on any other drugs. I really want this. I'm not going to say no to the patient. I'm going to say, look, you understand that if I give you a vinyl bin that you're going to get a four-year progression free survival compared to seven years, it'll be shorter. But you might need to be retreated. But the thing is that you're not resistant. You can be re-challenged. So although the PFS is different, which is BGKR and vinyl bin, we do know that you can be re-challenged with vinyl bin. So for those patients who feel strongly about fixed duration

26:04therapy, I actually don't think, given that fixed duration therapy for 17-P is wrong, provided that they understand that they're going to get a shorter progression free survival of approximately four years compared to patients without those high risk features. And they may need to be retreated earlier. And there's actually an emerging data that probably the BGK containing doublets actually do study beta for this, the deletion 17-P compared to vinyl bin. So maybe a color van would do beta, maybe a zeno van would do beta, and certainly we saw for zeno-somero that the 17-P response rates are very high. So I'm going to move on in a second, finish out talking about relapse disease. But just a couple more questions as it relates to upfront therapy. First of all, can you just briefly summarize what you presented there in terms of the STARE study? Really interesting trial. A lot of times when I hear that you all in CLL talking, I think about prostate cancer because they had a trial a

27:04couple years ago looking at time-limited endocrine therapy that you now they're using all the time. But anyhow, what did the STARE study look at, demonstrate, and what do you think it means in terms of clinical practice, particularly in terms of patients who are having problems on BGK inhibitors? Yeah, so when we first started using BGK, the common perception is that it's continuous. It's down in the drug, it's stuck on it, there's no stopping it until they progress. And in fact, from the E.C.1912, which is the comparison between Ibrutum and FCR, there was an interesting piece of data in that patients who actually came off Ibrutum because of side effects. There were actually two years before those patients needed to be re-treated, and they called everyone's eyes and thought, oh wow, so if you actually have been treated with BGK eye for a while, not in the first 12 months, but if you've been treated with BGK eye for a while and you're in a pretty good response, that may be coming off the drug is not a disaster. No, maybe people do not relapse straight away. And I think that piece of information is what the

28:07STARE study really confirms, right? It says that, okay, we got treated at CLL for 18 months, you're in a pretty good response, and we stop it, what will happen? And what will happen is that you will relapse, but at a median of one year later, so if the patient gets a one-year time off drug, off side effects, and then if you restart the drug, you're all four survivors that are in code, so you haven't really lost anything except for that, you know, and you get the one year of drug holiday. So that really proves in a randomized fashion, what we saw before that, in someone who is in a pretty good response, that you can, a specialist side effects, that you can potentially stop the drug, and it takes them a little while before they progress, and you get the option if a drug holiday. I think an important consideration is the 18 month mark optimal, and it might still be that the 18 month mark is a little bit early, and maybe if they get to the two year, two and a half year mark before you give them a drug cessation, maybe they'll get an even longer time before they ultimately relapse, because they're more deeply treated.

29:10So I think that's an interesting question for the practice. So I think what, you know, in my clinical practice, I definitely would not stop someone before 12 months, I would try and switch to the K.I. Between let's say 12 months to 24 months, if someone has got pretty unmanageable side effects, and the C.I. well seems to be in pretty good control, the lymph glands that go on the white cells alone, I will be comfortable facing the data to give them a drug holiday, but I think ideally, if you're going to take someone off probably more like 24 months, a longer before you take them off, and you might even get a longer time before you have to be retreated. It kind of looks like a pretty big difference there in terms of IGVH status. Clinically, would you take that into account? I would, and because we do know the occasion of IGVH mutated, are the ones who do relapse with stoic kinetics, so that the ones that I would maybe stop a bit earlier rather than later, that is dependent on your ability to do IGVH sequencing

30:11right. So I do that because I'm in a research center on my patients have IGVH results known, but that may not be available for patients in the community practice. Let's talk a little bit about Perter Burton who we saw two big phase three trials presented at the ash meeting. Could you kind of summarize what they reported, what you think it means? And also, whether you see any evidence at this point, again, you were talking about your thoughts in terms of Xana Bruton, maybe having more efficacy than a Cala and Y, whether you think you see hints of that with Perter Bruton of a greater efficacy. And if so, what the mechanism might be, let's just start out with the two trials. Yeah. So the two trials is a head-to-head study between Perter and Ibruton, including both frontline and relapse patients. And there's a second trial comparing Perter and Bender-Mustin retoxin in the frontline. So let's start with the second trial. So Perter versus BR, no surprise to anyone that the BDKI is better. And it does talk reasonably favorable in terms of Perter the results. What you expect for maybe even a little

31:15better than the historic point, what you expect for Ibruton or Xana or a Cala, in a same range or slightly better. So Perter is certainly an effective drug. The main advantage of Perter is that it's got very few side effects. So Perter has at least side effects or BDKI. And we all know that frontline patients are terrible at compliance. You know, I still remember from my CML days where if you treat some of the group of imaginative in the second line and beyond, they never stop the drug because they know what interferon was like. But we treat some of imaginative in the frontline for CML, their compliance is terrible. And the same thing is CML. So I mean Perter has a bit advantage. She's got so few side effects. So in the frontline, very few patients are going to stop Perter. Now the second comparison is Perter versus Ibruton. And I think that's the big question right. Is Perter better than Ibruton? And the signals are mixed. So the, you know, according to the investigates, assess responses. Perter may be better than Ibruton. But with the central reveal responses, it looks identical. And then if it dissect

32:21out between first line treatment and relapse your factory patients, it looks like the improvement potentially is only in the first line patients. So the way I'm interpreting this dialogue is I think it's all about compliance. We all know that Ibruton is side effects and Perter doesn't have any. And I'm thinking that probably patients on Perter Bruton are more likely to stay on drive than Ibruton. And that might be where some of the advantage tool of Perter comes from. Especially, as you can see, this advantage, especially in the frontline. We need more dialogue to tell. They said that at least on the global trial level, combining both relapse and refractory and frontline patients that the cessation rates are similar. I'll be really surprised in the frontline setting if Perter is not better than the compliance type Ibruton when this eventually released a dialogue. For my mechanism on the view, I don't see why Perter should be better than a covenant BDI. It's a reversible binding. It relies on a long half-life to achieve

33:25the same thing as a covenant BDI. And although it's somewhat immune to the system 481 mutation, it's susceptible to a whole range of other mutations, which we know we see in Perter when they relapse. So it's not likely degraded, which is immune to most of the mutations. It's actually one that is still susceptible to the mutations. So I don't see a reason for my mechanism on the view why Perter should be better. I also thought it was interesting that they saw a PFS advantage. I think it was versus Ibruton, I think. And the investigators would not central review what would be an example, not necessarily from this trial, but in general, when do you see investigators having different responses or efficacy outcomes than central? What's the reason? So that's a really good question. So the most marked example of that, to my knowledge, is actually the resonate study. So this is a study comparing Ibruton to over 2MAP, back almost a decade ago, where the central review showed actually pretty terrible outcomes

34:29for Ibruton in terms of PFS. But the investigators show really good outcomes. And the reason why was because of scans. So a lot of patients in that study on the Ibruton arm had a drug hole for side effect, and then had a CT scan done at the time of drug hold. And obviously the lymph glands got bigger, the central community said progression to investigate the ground, manage the side effect, restart the drug, and the patient did well, and the investigator never called it at the PFS. And I think a similar thing is happening here. I suspect that the central community is blended to what the patient is going through. I suspect that there might be some minor progressions on CT scan due to drug hold or other reasons that were called by the central community. But the investigator in the ground just basically adjusted the dose, managed the side effects, and kept it going, and never called it a progression. Really interesting. You mentioned the tolerability profile of Puerto Bruton. Correct me if I'm wrong, but it looked like A-Fib was

35:29the same as BR. Does that mean like it does not have an increased risk of A-Fib in your mind? No, I think A-Fib is a BDK class side effect. So the impoto has a very low risk of A-Fib. If you look at the Sequoia study comparing Xenu and BR, the A-Fib rates are also very similar, between the two arms. With prolonged follow-up, maybe a touch higher numerically for Xenu compared to BR. But I think it just shows that with the modern BDK eyes, the second and third generation, is that we're getting such low A-Fib rates that it's very hard to get a show of difference compared to chemotherapy. What about bleeding with Puerto Bruton? So it probably is once again it's still a problem. So I would not, let's say, operate on a patient on Puerto Bruton with us stopping the drug. Because once again bleeding is a BDK class side effect. Worse for a Bruton compared to other drugs, but it's present across everything. And the reason we know that

36:29is because if we look at BDK deficient boys, so these are people born without BDK, right? Genetic, not how a BDK. Those patients actually have a plated defect. They actually have a defect in the collagen receptor response in the plated cont. So you will not have BDK. You will cause a bleeding deficit. The reason why I Bruton is worse than everything are now is because I Bruton not only knocks out BDK, it knocks out a whole bunch of other things, which makes to play the dysfunction even worse. So let's talk about the patient with double refractory. First of all, maybe you can kind of paint a picture of how often you see it and kind of what a typical double refractory situation looks like and particularly how you think it through, particularly in the younger versus older patient with comorbidities. Yep. So to start with, it's actually still a pretty uncommon scenario. So double refractory, we mean by someone who is progress on the COVID and BDK eye and someone who has resistant to vinyl clacks, either a progression on vinyl

37:33clacks or relax shortly after completing vinyl clacks. And it's actually still pretty uncommon, even in my population where patients who had really early access to these drugs in the 10-12 years ago from clinical trial. And the reason why it's uncommon is because these patients do so well. You know, you get seven years in the first drug and you get another five years in second drug before you get your double refractory state. And so the patients do come through but they're pretty uncommon. What did it look like? Well, they tend to be the patients who have got the 17P who's got the more complex carotypes, who may have come from a historic era where they got chemotherapy as their first line treatment. And these are patients who actually are pretty sick, right? So they, because you've lost the COVID and BDK eye and you've lost the BCL too. And probably standard treatment these days is perturbation. If these patients, although we know that hurdle is not a permanent solution, you know, we're looking at maybe a 12 month progression free survival before you have to move to something else, which would probably be the degraders.

38:34And these are patients that I was strongly considered lice yourself for because we know that once you get the double refractory stage that you've been looking at, Nick's line therapy is having fairly short progression free survival. And we do know that for you to proceed to CAR T cells, you want to be in the best response category possible. So you don't want the right to run up all the options and have no way to deep out your patients before CAR T cells. And I want to ask you about CAR T and lice this cell. It kind of reminds me at least in my own naive mind. It kind of reminds me of what I kind of have heard initially about CAR T with follicular lymphoma, where initially I kind of got like the feeling it wasn't very effective. And then it was he starts to be more data. I'm like, oh, that looks pretty good. And again, with lice this cell, I wasn't so sure, but the data that came out at ash was very interesting in that regard. Can you kind of talk a little bit about what your vision was in terms of efficacy before ash and then talk a little bit about the ash presentation? Also, can you comment on the issue of side kind of release syndrome in these

39:35patients? Sure. I might just go with the last one first. So suddenly I'm released. It's a problem for C.O.L patients, whether it's other histologies, whether you use CAR T cells or specific C.O.L patients probably have heavier tumor burden in terms of overall number of tumor and they do get more CRS for the bi-specifix, they probably need an extra step up. But CRS can be managed, right? You know, I can manage CRS in a clinic. Why can't manage is I can't manage resistant cancer? That's something I can't deal with. Let's head back to CAR T cells. Now people forget that in fact, the first disease to be cured by CAR T cells is actually C.O.L. You know, this is a new England paper from David Porter and company back in the early 2010s type range, where we had three patients have the advanced C.O.L. CAR T cells were cured forever of the disease. And then of course, CAR T cells move on to other diseases since then. And when I look at the last results of data, I actually think it's pretty terrible. I think the response rates are very poor

40:37and I think that, you know, the responses are infrequent. But it did not surprise me. In fact, you know, patients who get onto CAR T cells in the transplant type era were really the last long patients. These patients, if anything, you should be surprised that CAR T cells work for these patients. They've been through chemotherapy, they're through therapy, and they've had every time that children are possible, they do not have a single T cell to their name. And yet we're getting this really disease dysfunctional T cells and trying to make CAR T cells out from these patients. And we're trying to treat them when they've got really poorly controlled disease. And we're surprised that the patients don't respond. You know, we put poor quality CAR T cells into a patient with a lot of disease on board. You're going to get poor outcomes. So we have always thought that these patients probably need to be treated in an earlier line when they not so have the exposed. And hopefully we now have a cohort of patients who've never simply done everything. And so the T cells numbers are better. And they should be treated with

41:40good disease control. We see in the real world data that you have balcony inflows that you've got nothing to do as well because you've got poor disease control. That's not new. So I think the real world data is reassuring that now that it's in the real world, we've got patients who are relatively fitter, we've got investigators who are understanding more how to use CAR T cells that we need to use in healthier patients before they run out of all the other options. We treat them at a time when the disease is under good control with at least one biological drug. We continue the drug during the CAR T cell process so that they don't get these so paradoxical rebound when we stop the drug before the CAR T cells, then we get better outcomes. And these are the results that I think should have always been, should have always happened with CLL. It's just that the clinical trial, unfortunately, we're standing at home where those patients, you know, we're not enrolled. So it also looked like they did better if they got a burden. Yep. So the probably two theories of that. So the first theory is that I've

42:44brewed it all. In fact, any BDKI probably improves the T cell quality at a time of life recess. So you're getting better quality T cells to make CAR T cells. And the second thing is it probably affects that these patients actually had disease control coming into CAR. We were able to control the disease with the I brewed out BDKI before we car them and we're not doing CAR in the context of someone who's got rampant and control disease. So one final question. If you and your colleagues, let's say two or three years or now, want to sit down to do another review article on upfront treatment of CLL just like this year when you did it and then he had all this great stuff come out at ash, but just curious what your prediction is in terms of where you think we'll be two or three years. Also, you mentioned BDKI degraders. You think in two or three years, they'll be online and where they're going to fit in, but would you like to sort of paint a picture of your vision for CLL two or three years from now? Or maybe five, I don't know. I actually think that there's going to be two types of patients. There were patients who got

43:46started on a continuous BDKI pathway who will end up on a continuous BDKI pathway. So they go from a COVID into a non-COVID into a degrader and then migrate to other things. And then I think they'll be a fresh new cohort of patients who got down the maturation therapy who will get either vanalbin or van BDKI who then will get five years and then be retrieved with BDKI plus van. So it's the same combination on different combination again and we'll get another you know, five years or three years after that. And you know, even if you think about the MRD clearance rate of someone like Xanders Omro, right? You know, we've got 90% MRD clearance rate. How pathetically these patients can be in remission for seven or eight years with the first treatment and then another four years after that. And that's 12 years of total duration with two lots of fixed oral therapy in 80 year old. By the time they relapse for the third time and require treatment, then they meet 90s. So maybe these are, you know, we're moving to the age where

44:46double therapy to be repeated will be the only treatment that these patients were ever seen in their life and they're never going to go down the path of having pertabrutinib or degrade this. Also, just kind of curious whether you think pertabrutinib is going to move into time-limited therapy your previous institution MD Anderson is all excited about pertabrutinib, Vaneta-Claxton, Abeditusumab. Do you think that pertabrutinib is going to end up being the PTKI in time-limited therapy? I think pertabrutinib is a great choice for time-limited therapy because of its side effect profile. I suspect that PVO would not take off in popularity because of open-intusumab, but PV might, my expectation given haven't seen the other drug so is that I think PV is once again going to hit a warrant of the MRD clearance. I don't think it would be that high without open-intusumab. No dialogue, but this is my general feeling. And I suspect that probably, you know, some of that pertabrutinib or zander-sombrote, or a color-sombrote will be the way forward.

45:50Interesting. Do you see PTKI degraders ended up in first line? I do not actually, at least not as a time-limited duration therapy because the main advantage of PTKI degraders is reduce resistance and mutations, but at the moment we don't simulate resistance mutations. We time-limited duration therapy. Maybe they will change your time, but a current follow-up you get fixed duration therapy and you will have you do not have resistant mutations. So the advantage of PTKI degraders already gone from that in terms of that setting. All right, Khan. Thank you so much. I learned a lot as I always do every time I talk to you. I really appreciate it. Wonderful. Thank you very much for the interest. Subsequent to the recording of this program, the FDA approved a color-brutinib with phonetic lacks for chronic lymphatic leukemia on the basis of data from the Phase III Amplified Trial. This concludes our program. Conflict of interest statements for the faculty can be found in

46:52the program notes. Use of agents and treatments that are not approved may be discussed, so check out the package inserts for more. Special thanks to Professor Tam, and thank you for listening. This is Dr. Nealope for our college today.