Roswell Park specialists Francisco Hernandez-lizaliturri and Matthew Cortese are joined by Nicole Lamanna to discuss practice changes for treating various forms of lymphoma and leukemia in addition to the evolving role of bispecific antibodies in aggressive lymphomas.
So we're gonna introduce, um, our, um, next speaker. I have the privilege to introduce, um, Doctor Nicole Lamanna. She's the, uh, professor of medicine, uh, at, um, Columbia University, and she's the director of the CLL and leukemia program. So she's gonna talk about the front line therapy in CLL., welcome. Thank you, thank you. I have to thank Matt and Paco always for having me come back and do the CLL talk. Either I do an OK job or they're just being very kind, so it's really nice to see all my friends, uh, given that a lot of my, uh, former memorial colleagues are also at Roswell Park now, so I get to also see my family in return since I've known these people for 25-30 years. So it's always great. So this time I think we did a switch, right? Last year you did. I did relapse and you did frontline, so we're switching. Um, so I'm gonna update the data on the front line, uh, NCLL patients, and as here's my financial disclosures quite a bit. OK, uh, and more they grow every year, which I guess in, in CLL is a good thing, right? So there's lots of new drugs, you know, we haven't cured yet CLL, so I, I dare say that we're not done yet with our work, um, and we have sort of different sort of emerging. Players in CLL. So, so, yeah, new companies to work with and, and lots of new drugs that I need to deal with, uh, but what's nice is obviously we've really evolved and changed and, and I show this only historically because, because I'm older than most of you think, uh, so I started in 2001. Uh, giving chemo immunotherapy. So that tells you we've really moved away from chemo and CLL and hopefully, uh, by the time we give this talk next year, I hope that we won't see any more trials that have randomization with chemotherapy arms. There are a few that are still sort of rolling. Out there they might have started a long time ago and rolling out their data um that were presented, you know, with a chemotherapy based, you know, arm but hopefully we won't see many of those anymore um I actually don't participate in any of those studies sorry friends, colleagues, industry out there. I won't do those arms and those studies, uh, because I really don't think we should do that anymore, but we've come a long way between the, I, I can't say these therapies are new anymore, right? So the BTK inhibitors are not novel. So we have targeted therapies that have been around now over a decade, and then we have Venettalax. Um, I'm not gonna talk about PI3 kinase inhibitors, although they're still available and actually very active agents. So in relapse refractory patients, we should still think about them. Uh, and then of course we have now noncovalent BTK inhibitors and our first approval with CAR T. Uh, Matt will bring up a bunch of the new agents, so that's really exciting that we have lots of other newer agents, um, that some of you we've already talked about with other disease states like bio-specifics, and, uh, we'll talk about BTK degraders. OK, so the paradigm shift has changed quite a bit. Um, and I think our conversations with CLL patients are becoming longer and longer, um, in our clinics, uh, because we talk about chronic continuous therapy, which is, uh, you know, uh, still I think important and although we're gonna talk and focus on time-limited approaches, you know, that I still think, uh, chronic continuous therapies are applicable for patients. Um, you know, they don't give complete responses or MRD negativity, but they do have prolonged disease control, prolonged PFS, and if you have an older patient, although I'm not, I don't mean to be an ageist here, it doesn't mean that if you're older, you can't get a time-limited approach. I'm just saying if you're 80, 85, and wanna take a pill, that might be the only therapy you'll ever need for your CLL. I don't have a problem with that. Um, and I also wanna argue that we're gonna talk a little bit about high risk disease that I think that's the one group that we need to do better on, and I'll show you some data with chronic continuous and high-risk disease. Um, so it's clearly you have chronic continuous therapy and then you have time-limited approaches. Venne Clax and obintuzumab are obviously the longest data, and now we'll talk about the emerging data with oral, oral combinations and even triplet. Combinations with anti-CD20 monoclonal antibodies, so very different approach about getting people off of therapy, getting deep responses, getting complete responses, MRD negativity, and then they'd be monitored until their disease come back and that they actually need indications for treatment again. You don't need to necessarily give treatment for somebody whose disease comes back, but they still don't have cytopenias or bulky adenopathy. So we talk about all that we talk about patient preference being important for, for, for us to discuss, but we still look at their genomic profile. So we'll talk about high risk disease. Their comorbidities are important, although albeit I could say. It's maybe rare for me to think that I couldn't give a certain drug to a particular individual depending upon if they have cardiac or renal toxicities. You could probably get away with doing a lot of things if you're very careful, uh, but I think if I had a very brittle, frail cardiac patient who's on, you know, a DA, an anticoagulation, and anti-platelet agent, you know, you might say, OK, maybe I won't give a BTK and maybe I'll give a Ven-based combination. Um, but again, it's really hard for me to say I can't give a BTK to anybody. Um, and, you know, the same thing, uh, Venetta Clax, you know, if somebody has really poor kidney function, OK, so you have options. Uh, but I, I could say that majority of patients even with comorbidities can, can get either agent. Uh, financial toxicity, I think, comes a little bit more into play, of course, with the chronic regimens and then feasibility of administration is more with Ven OB than necessarily oral oral. So when you add in the intravenous component, and we'll talk about that with triplets too, of course, there's obviously a lot more, you know, uh, uh, laboratory monitoring and things that go into those, uh, combinations with the feasibility of administration and so you can your patient go back and forth and so on and so forth. So we do take that into consideration and to patient preference as well. Uh, uh, you know, obviously for, um, the all the agents are listed, and I just wanted to add that the oral oral with Acala Venettalax, which I'm gonna show you that data with, uh, Amplify was just approved, just hot off the press in February. So now we have our first oral oral combination of acaibrutinib and Venetta Clax just approved, OK, but you could see all the different covalent. Uh, and, and then and triplet combinations including MRD guided, although these are not approved, nor is a triplet approved, but these are the NCCN guidelines. I'm a, I'm a little surprised we have the, I'm not gonna lie, I'm not part of the NC NCCN committee. I am a little surprised that the triplet combination is on the list, um, and we'll talk about who that might be applicable for and maybe how to use that or think about that, uh, in the future, OK. So here's the amplified data. This is, uh, the calibrnib and venetalax plus or minus binatuzumab versus chemo immunotherapy. Um, and so there were no patients with 17P or P53. So keep that in mind. Uh, but you could see here the PFS was actually favoring the calibrinnib venetalax containing arms a little bit even higher for AVO versus AV. I think one thing to point in when you really start breaking down the data, uh, when we look again, remember, no 17P or P53, but when we talk about mutated and unmutated patients. With CLL, uh, the mutated patients do very well. The unmutated patients do less well with oral oral. So just, just, I think hopefully in the future we'll also start separating those individuals when we think about clinical trials and CLL, we should also think about mutated versus unmutated. So mutated patients do very well, um, but unmutated patients, I think we could do better, um, and so you could see that. For the unmutated patients, they did better with AVO than they did for AV and, and then you could see chemo, which I won't even talk about. Now, obviously with the, uh, combinations, the MRD undetectable MRD was higher with the triplets, so the antibodies really do give good additional, uh, uh, benefit when we talk about MRD. Obviously chemo immunotherapy, higher MRD compared to oral oral combinations. Now, what about toxicity? And this is where we do have to be careful when we talk about triplets. So there was the, um, the, the, you know, people think oral orals are easy. They are, but they do give toxicity. And so I always tell patients that just because you're on a pill doesn't mean you're not gonna have any toxicity. Uh, infectious complications are very similar, if not more so, which you can see with even oral oral and the triplet with chemo immunotherapy and right, and that was one of our biggest complaints with FCR and bendamustine, rituximab and PCR was infectious complications which really do plague our CLL patients and become chronic in nature, and you could see really no difference with that with even our targeted therapies and of course. The antibody adds to that as well, higher degree of neutropenia, of course, when you have the antibody arms, uh, and there was more deaths in the AVO. Now this was also conducted during the COVID era, so there was more COVID-related deaths with the AVO compared to the other two arms. And so there was an increase less, uh, increase, um, deaths in the AVO arm, uh, so we have to keep that in mind as well. Now what's easy about oral oral combinations as opposed to Ven OB, of course, is that you front load the BTK inhibitor for 2 to 3 cycles, which makes it very nice to debulk the patients so that then when you add the veneta clocks into the BTK, you know, combination, it makes it much easier and then you literally can do this as an outpatient. So that's what makes AV AV or or oral combinations a little bit more. More feasible, easier for older individuals than if you're worried about doing Ven OB and thinking about, oh, do I need to bring that patient in? They have high risk disease. They're gonna have a lot of tumor lysis, you know, I have to bring them in for monitoring into the hospital. So it definitely makes oral oral combinations easier to use. And then the whole combination is 12 months with the, with the together and so it's about 15 months depending upon when you start adding the venetalaxin to the BTK. Now, there's been some data which I think will be helpful for the future, uh, looking at, well, what if we add obinituzumab later? I just showed you the AVO with increased infections and other complications. If we start thinking about where are we're gonna use our triplet combinations or how do we make these more feasible for our patients, what if you add obintuzumab in a little bit later? Um, so instead of adding it right off the bat, they get more. Infectious complications, more neutropenia. This was a study by my colleagues at MD Anderson looking at adding obinituzumab to AV after a year of combination therapy, and you could see here grade 3 neutropenia and infectious complications were less, and at least efficacy, now this is an early study time point, so I'll have to follow this over time. At least it didn't look like it, it did any impact significantly to efficacy. So this might be a way to. Figure out how we could use a triplet, uh, depending upon where we see that might work out best in our patient population, where we could see that, but maybe starting it a little later might make it easier and more feasible for patients to do a benatuzumab, not have to worry about all the TLS, um, or, you know, some, some of the, the infusion reactions if they're already adequately debulked by having oral oral combinations given earlier for a period of time. Now, this was a great study in some respects, uh, because it, it's nice to have the all the modern therapies we use for CLL with the exception of ibrutinib being the BTK inhibitor. Abrutinib was the first and is a great drug, uh, more used more so in our, with our European colleagues. So this is a European-based study. Um, and so maybe we don't, you know, use a lot of ibrutinib here in the US, uh, due to the fact that the second generations have best cardiac, uh, toxicities. However, I think this is a great study because it, it's continuous therapy versus Ven OB versus oral oral. So all modern therapies that we're currently using, they did include patients to deletion 17P or P53, uh, and you could see now this is early follow up. So to keep that in mind, we need much longer follow up with our CLL studies, um. A 3 year PFS, but on the on the whole, the PFS was pretty equal, uh, and so I think that's reassuring to patients to say, hey, you know, chronic continuous versus a time limited approach, you know, you can tell your patients that overall most patients do really, really well with either any of these combinations or continuous therapy. I think one difference here is the TP53 group. We're starting to see a little bit of emergent data still favoring chronic continuous. You can see that. Uh, in the red box and then of course, not expecting this is, we know this is that you're not gonna get UMRD with chronic continuous therapy given that there's very little, uh, uh, frequencies of complete responses but that we know compared to either our, our time limited either with Ven OB or with IV, uh, and the 3 year overall survivals on. The right, so very good therapy without any chemo, immunotherapy arms, um, and including patients with high risk disease, but they're starting perhaps, and we'll see what happens with longer follow up. We'll see if, you know, we get more data. They did not split this. We'll, we're obviously, I'm looking forward to seeing mutated versus unmutated data and, and of course what happens with the patients with TP 53. Now let's talk about MRD guidance. Um, this is a good study that I like to bring up because I think when we talk about our time limited approaches, you know, a lot of our time limited approaches got made up in terms of duration. You know, we took, we extrapolated from Ven Ritux with the Murano study, which was 2 years of therapy. We moved up, switched the antibody toobintuzumab. And said, hey, it's frontline. You get a better antibody. Maybe we could do half that time period, and that was a 12-month therapy. But do we know what the optimal, um, you know, time-limited approach is? Uh, and I would say I think we don't. Uh, and so I think studies like this are very helpful. So this is looking at ibrutinib and venetalax versus ibrutini monotherapy versus chemo immunotherapy. But the issue here is what they did is that they started valuing for MRD at 12 months. If you achieved a CR at that time point, they would then double the time point that you would continue on the I + V. So if it happened at 1 year, you were on a minimum of 2 years of therapy and so on. So you could be on a max, so now this, we're gonna get to the caveats of this. You could be on a max of therapy for 6 years, and actually the median time point that most people are on the doublet was 3 years, so. So now, of course, here's a time-limited approach. Does somebody want to be on for 6 years? I would argue probably not. They wanted a time-limited approach, but what it does say is that the longer you're on an oral oral combination, clearly even the better the data gets. So you could see how the PFS and the overall survival are, are, are much higher for a brutinib event versus even continuous ibrutinib. Certainly, we know chemo immunotherapy, but the question is, what is the optimal duration of therapy? And so, as I said, right now, the data is that patients on the study are minimally on for about 3 years. And you can see here, even with high-risk individuals, that data looks really, really encouraging. TP53, you know, still the 5 year PFS is 100%, which is better than any of the data we have. So. So far, so there's a little bit of caveats about, well, what's the right duration of treatment. I think this study sort of highlights that, um, and I'm not saying that we're gonna do 6 years of oral oral combination, but I think we need to think about that when we start breaking different patient subgroups out and who should we give maybe longer therapy versus shorter therapy. Now MRD guided approaches, this is a study we're looking forward to to data on, and so this will help with that. This is looking at a Calaven versus Van Obi, and patients are evaluated at 12 months. If they still have MRD, they'll continue whichever arm they're on for another 12 months. Everybody will stop at 2 years, um, regardless. Um, and so we're waiting anxiously for this data. And so I think this will help because maybe 12 months might be too short for some individuals. Maybe for mutated it's not because those guys do really well regardless, but maybe for unmutated or high risk individuals, maybe 12 months might just be too short. So hopefully some studies like this will help with that. Now what about if we switch the BCL-2 inhibitors? So this is data looking at certain rotolats, a different BCL-2 inhibitor, plus obintuzumab, um, and they can continue therapy, um, if they, if they still have disease, but they can come off therapy if they have UMRD at 15 cycles, um, and so this is some encouraging results, uh, with some rotoclax and obinituzumab with high levels of responses, but we'll see with longer follow up where this settles out and then, of course. As you guys all know, the, the celestial study is xibrutinib plus and rotoclax, uh, versus venetalaxobennatuzumab, and so, so these are studies that we're looking forward to more data, uh, with time-limited approaches. Now, the non-covalents are starting to make their way. So, pertabrtinib is the first non-covalent BTK inhibitor. It's approved in relapse refractory. Initially after, uh, both BTK and Ven failure, but now it's been moved up to even just after frontline failure. And so you could use. Even Purdo after let's say a covalent BTK or after Van OB if you want, um, and so now what about can we use time limited approaches if we combine Perdo with other agents and so there's some relapse studies that looked at PV plus PVR, um, and now even frontline studies looking at PV or PO and PVO in frontline. So you're gonna start seeing a lot of time limited approaches with Pertabrtnib. This was presented by my colleague Nit and Jean at MD Anderson. Looking at PVO in the frontline setting, um, and you could see here very high levels of response and undetectable MRD, um, very, very early follow up, so we're gonna see what happens, but you're gonna see a lot of head to head studies with Perdo and combinations of Perdo to see whether or not they're gonna beat out the covalent BTK inhibitors. I can say more about that, but maybe I'll save that to Matt because I don't know if you're gonna talk about some of that. So I just a little bit, so I don't wanna, I don't wanna step on any toes. OK, good. Um, so, now let's talk about, uh, so I said about duration and just to give you that sense, because I think this is, this will play into the future is clearly we know that, you know, if you continue, uh, some of the time-limited durations longer, you're gonna have a, a, a longer PFS and that's what I showed you with the flare data. But so some of our studies, we initially started at 12 cycles and then other groups had their own IITs and did it and so they extended out to 2 years and you could see the PFS starts to climb, and I think this is relevant when we talk about high-risk disease. So let's talk about continuous very briefly just to give you updates. Acaibrutinib, this is the Elevate the six-year follow-up of EOE with Acala plus, uh, obintuzumab versus Acala versus chemotherapy, uh, uh, of course, favoring acaibrutinib containing arms. I don't know in practice that a lot of people use obinattuzumab with the alabruib. I think most of us feel if you're gonna do a chronic continuous BTK inhibitor, Um, you're, you're, you're not really gonna give the obbinatuzumab, but there's no doubt there was a benefit in the PFS with the exception of the patients with 17P that there was no difference with adding Obina, but everybody else there was. So I do think that if you're thinking about that, you certainly could add that. It's just that most people's mindset if they're gonna continue a BT chronic. They didn't wanna have Obina, uh, you know, at an IV component added in, so you're just getting chronic continuous. Otherwise they'd get a time-limited approach, um, and, and so I think that's what most people do in practice. I don't know if they do that differently here at Roswell Park, but I think most of us would either be, if you're gonna choose one, you're gonna choose one or the other. And then this is updated data with Xanaruib versus chemo immunotherapy favoring xibrutinib. So these are just longer follow-ups of older studies that recently got presented at AS. Um, and then here was a, a very big study that got presented was Pertabrutinib versus ibrutinib, uh, for, and this was presented at Ash. So both in a treatment naive as well as a relapse, uh, refractory cohort. Um, and you can see here that the treatment naive cohort, the PFS favored but not statistically significantly different, but favoring perterbrinib. But again, no difference between the covalent and non-covalent. Again, we need longer follow-up, uh, but Certainly, uh, encouraging data with Perto versus, uh, versus ibrutinib. Uh, the same we teach all our patients regardless of whether they're getting a covalent or a non-covalent BTK inhibitor. We talk about all the adverse events of special interest, the cardiac issues, the increased bleeding and bruising, hypertension, so on and so forth. And you could see certainly there's a much more markedly decreased incidence of atrial fibrillation and atrial flutter with perterbrinib versus ibrutinib again, and these are things that. We weren't surprised about. We saw them with the 2nd generations and certainly with the non-covalence, I think that they, you know, the side effect profiles, at least for the cardiac issues are much better. I think the bleeding issues, in my opinion, seem to be very similar between the covalence and the non-covalence. I still see a lot of bruising and easy bruisability between all these agents. I don't find much of a difference in my practice, uh, but definitely, I think the cardiac issues are certainly, uh, markedly decreased. So let's talk a little bit about high-risk disease cause this is a group I do think we can do better. You know, the good news is obviously, this was a group of patients that used to do extremely poorly with chemo immunotherapy. Um, and their median life expectancy was very, very short in a matter of years. They would initially respond really well for FCR but then they would relapse very quickly. Um, this is Venetta Claxtonobinattuzumab or the CLL-14 study. And you can see here that the five-year PFS without deletion 17P was about 65.8%. But if you had a deletion 17P it was 40.6%. So not as good as we would hope. Um, much better with the chronic continuous therapy with BTK inhibitors. So here's the ca Ibrutinib data. As I said, it really didn't matter if you added the obinnatuzumab. The, the incidence of PFS was similar, whether you had a 17p deletion. And so, the obina did not add much benefit, uh, with the caibrutinib. So, chronic continuous therapy for deletion 17P or P53 is good. Um, and this is the data with xibrutinib. Here is ARMC, which just had monotherapy with xibrutinib. And so you could see very good, uh, uh, outcomes for patients with deletion 17P. And ARMD was a little different. So it added xibrutinib plus venetalax, but it wasn't time-limited. So patients would then continue on with ibrutinib. Uh, uh, for, uh, for chronic therapy. So they did get the benefit of having the oral oral, but then they wound up staying and so there was a higher degree of responses in PFS if you added the additional agent and you could see, oh, very similar to patients even without deletion 17B. So we absolutely have improved the outcomes in our high-risk patient populations. There's no doubt about it. Um, I just think that there's, you know, those are still patients that ultimately still relapse if they're younger. And so we have to think about, are there ways, should we be giving longer therapy? Should we be giving chronic continuous therapy, or could we do something like this and do a triplet? So this is data from our Dana-Farber colleagues looking at a Caliburton have vinetolaxone benatuzumab in patients with high-risk disease. And you could see here that the, um, the 4-year PFS and overall survival. Was very high and encouraging in this patient population. So I do think that there are ways to tweak these regimens where we can increase the outcomes, albeit we have to consider the, you know, whether or not how fit and, and what our comorbidities of our patients are if we're gonna give a triplet or maybe we do this differently and add in the Obita later like I showed you in some of that earlier data. There's probably ways to finesse this data to see if we can improve the outcomes for patients with higher risk disease. So that saves us some time. So how do I treat treatment naive CLL? Um, I think the, certainly, the good news is lots of options in the frontline setting for CLL. It becomes more confusing when we talk about sequential and relapse refractory, which Matt is gonna talk about. Patient preference is still important. Um, and you still have to consider their comorbidities and genomic features. I tend to still use 7, if I didn't like implicitly say my bias, I still tend to offer chronic continuous therapy for my patients with 17P or P53. However, if I really have a patient who goes, Doc, I really want a time-limited therapy and they have 17P or P53, then I'm often saying, OK, but then we're really gonna factor in MRD guidance or I'm gonna continue the therapy longer. Or I might consider a triplet for that individual if I think that they can tolerate it. So I do, I think the data for chronic continuous is still better, but I think there are ways to improve our time-limited approach or for higher risks, and I don't think 12 months is enough. So that's what I do for my higher risk individuals. For younger patients, I tend to put more weight on time-limited if they're not a 17% or 53 just because we, when we think about patients, we have to think about not only their front. Approach, but the fact is if they're 50 and starting therapy for CLL, they need more therapies, right? They're undoubtedly gonna relapse and they're gonna need more therapies, and you have to think of your sequential approach to get them going and so hopefully get them to a more normal median lifespan rather than disease taking them. And so you really want to not develop resistance if you can, so you could reuse agents. So I really do put more weight on time-limited approaches for younger, although if my older wanted it, that's OK too. I'm just thinking about the next therapy and the next therapy. So it's very important to keep that in mind and then we'll see where some of these other agents as they move up, we'll see what happens as the sequencing. The sequencing and CLL is becoming much more complicated and with that, I will end. And introduce Matt. I feel like it was an updated us. Oh, yeah that. Hi buddy, um, Matt Cortez, you've seen plenty of me the last couple of days, so I'm sorry for that. Uh, just one final talk for me and then we'll get to do a little raffle after Paco's talk and we'll see you some hockey. It is 4 to 0, uh, so fortunately, uh, for the Sabres, so my, the urgency, uh, you know, of going to watch the game immediately, I would argue is a little bit less than it was, uh, an hour ago, not even an hour ago, yeah, about an hour ago, um, so thank you, Doctor Lamonto, fantastic talk. Uh, you're an aspirational speaker. I'm, I'm never really nervous about talking anymore except for talking after you, to be perfectly honest, so, um, see what I can do here though. So we're gonna talk a little bit about the evolving landscape of re refractory CLL and SLL, and I, I do sprinkle in a little bit of Richter transformation as well. We can't forget about that disease, uh, but thank you all for coming. Thank you for staying here till the bitter end. I appreciate everybody. Here are my disclosures. They do not influence my decision making, I would argue, but you'll be the judge of that. Um, Clo, I'm not gonna bore you to death. You know, it's, uh, the most common leukemia in the, in the Western world at least, um, you know, slow proliferation of these small mature obese lymphocytes, uh, more common in white dudes from Northwest Europe, but, uh, happens and it can affect anyone, uh, generally meeting the age of 70 years of age. So toxicity concerns when you have those kind of comorbidities that are common as we get older. Um, certainly are gonna matter. It's immunosuppressive in weird and fascinating ways. I'll show you a little bit of our multi-omic data here at Roswell. We're trying to get that published into blood in the near future, uh, but, um, you know, working on ways to cure this thing, right? So even with CAR T cell therapy and its approval in 2024, uh, with Lysoce, um, still only about a 20% cure rate, although that is now being challenged with some real world data. I'll show you as well with some optimal bridging therapies, uh, in some of our novel agents. Um, I am on the NCC guidelines. I'd love to. I can explain later, I guess, or I'll just explain now about the, uh, about AVO as a triplet. It's more, uh, of course, to unlock options, uh, is a shared decision with patients, really, um, you know, getting insurance companies off our backs. If you believe in the data, patients are motivated. They have their own aspirations, but I completely agree with Doctor Lamont as far as the triplet. Um, you know, proceed with caution. I'm a big fan of Delaobennatuzumab. Um, it's very early days, limited follow up with that trial from MD Anderson, but, uh, conceptually with our OMI data, uh, when you look at the mechanism of action, Vennetalax and, and, uh, anti-CD20 therapies and how the immune system really repairs itself, um, really with like say Calaveen in that example, uh, or, um, zanirutinibven, for example, or y rotoclax. Uh, you're seeing basically that, um, patients' immune systems are improving, right? And you're able to then maybe challenge them, have a little bit more wiggle room, immune function, um, to then knock out their B cells for a little bit longer. Um, but so I'm not gonna go into too much detail about kind of the conventional, so to speak, um, uh, sequencing of therapies in the sense of, uh, you know, the covalent BTK inhibitors, uh, historically, you know, you'd say let's, you start with a caibrutinib, brazanibrutinib in the front line. Oftentimes people would switch because there was no pertabrtinib available in the second line. Uh, that's now changed and it has full FDA approval as of this year. Um, so just recognize that pertibutinib, as far as a sequential approach, you always start with a covalent BTK inhibitor outside of a clinical trial. Uh, so again, uh, in second generation BTK inhibitor in my practice, I do not prescribe ibrutinib to anyone as a new patient, um, except for some notable relapse refractory exceptions I'll talk about, I will consider. Um, I will continue patients, however, who are tolerating ibrutinib well for years. Um, and we'll talk about dose reductions, dose interruptions. You can actually stop some of these drugs, frankly, with close monitoring, and people actually will do well with a good treatment break. Uh, rarely you'll see these kind of post-PTK, uh, you know, withdrawal syndromes that can kind of mimic Richter's, but. For most patients, you can, you can take a break actually for a little bit. Uh, makes many uncomfortable though. So, often they'll just keep trucking. Um, Lyso cell, um, now is with or without ibrutinib on our guidelines as well. So I'll talk about some of the data there. Uh, it's some fascinating immunomodulatory properties of BTK inhibitors I do want to focus on today. Um, obintuzumab is now preferred over rituximab. So despite the quality of evidence perhaps being less than the Murano trial with VNR in the second line plus setting, we've now on our guidelines adopted obinituzumab really for most lines of therapy. On most patients, despite it, it's having a higher incidence of infusional reactions, the efficacy, um, overall is superior to Rituxan in, in CLL, and that's kind of like follicular lymphoma, you can argue as well. But, um, in other diseases generally you don't really have a preference, but in CLL we do, um, so I really wanna focus on the patients where we've exhausted our covalent BTK inhibitors, we've exhausted our BCL-2 inhibitors, and really wanna focus on this really high risk population, so. Um, to get to that, I want to briefly define double exposed versus double refractory. Double exposed patients, our patients say that they got Venno, you know, let's say, uh, 6 years ago or something, right? And they have an indolent relapse of of CLL. You can talk about retreatment with venetolax-based regimens, including even Veno again, uh, when they have a relapse like that. But, um, we usually kind of arbitrarily define at least 1 year or so, um, until you're comfortable kind of re-challenging with those same drugs. It's kind of like adopted from the old school. Uh, oncology principles like in solid tumors, right? Uh, like bladder cancer, treat with a platinum. If you come back a year and a day later, you can reach on with the chemotherapy. You might be chemo sensitive kind of an approach, right? Uh, so it's, it's, we need more data, I would argue to define, uh, that, and we'll talk about some mutations here as well very briefly. Double refractory, these are patients who generally are gonna be growing actively through, uh, treatment, especially in the setting of a covalent BTK inhibitor. Uh, or early, uh, recurrence or actually growth or even transformation on, uh, BCL-2 based regimen. And so this is the population I'll be talking about, uh, today. So I'm gonna start with this, uh, 79 year old patient. He has no name. Let's call him, uh, I guess the Bruins right now, which is great, pretty beat up, um, uh, yeah, right. So he's treated with, uh, frontline, uh, Venno per CL 14, and then let's say he's, um, then is treated, you know, sequentially, uh, switching classes up, uh, to a calibrnib. And uh let's say he's done it for, you know, 5 years, kind of shorter than the median, or sorry, around the median, I guess you can say for the second line plus setting for a caliber nib. And unfortunately he has another recurrence, so he's retreated with venetalax. Um, he unfortunately developed some symptomatic anemia. His ALC kind of grows right through the treatment and flow confirms some active disease. So this is a patient who's a functional high risk, as, as you, if you saw our myeloma talks this morning, it was talked about quite a bit. Um, this is someone who's gonna need a little help, right? Um, PET scan is done looking for Richter transformation that's generally done for patients with refractory disease that may be clinically concerning or or have with a rapid tempo. Um, just to, I want to point out if you have a, uh, post-BTK, uh, progression that can behave clinically similarly to a Richter transformation, so that's one of those few cases where you might consider a PET scan if there's, um, you know, rapid growth. Um, so now he's considered double refractory. He just has CLL, so his SU max is low on his PET scan. Um, you know, you've done a couple of molecular studies. You're, you're really, you know, trying to dig in. So what's his prognosis, right? He's scared. What happens to me in the case of the Bruins, uh, horrible death. Let's say, I'm kidding, um, sport in sports terms. Um, but in our guy, we have some hope now, right? So, Prognostically, um, you know, he's got double refractory CLL. So historically these folks had abysmal outcomes. Uh, this is before the noncovalent BTK inhibitors, before, um, CAR T cell therapies which I'll be talking about, and then certainly some more novel agents, um, and then things like PI3 kinase inhibitors would work for a time for, for many, but again have toxicity concerns. These patients, um, so again we're talking, uh, 2.5, 2.2 years rather is the, the, um, median duration of overall survival for these patients. So people think of CLL. It's kind of a cherry picked, you know, easy disease to manage, which in many cases it is, and it's one of the reasons I love it, um, but it's also the other reason I love it is we, we integrate, uh, novel prognostication schemes, molecular testing, novel agents, and, uh, we have not yet cured CLL for most patients either. So this is another reason I also love the disease plus the complex immunology. I'll get to in a moment. Um, but many, many mutations are high risk mutations are enriched in these patients. No surprise there. That's why they're, um, prognostically significant, um, from the get-go. Things like complex karyotypes, um, can confer resistance, uh, relative resistance to, uh, venetoclax-based treatments, obviously TB 53 aberrations. Uh, Doctor Lamanna touched on as well. We, we generally prefer the indefinite covalent BTKIs, uh, if they're responding for those, um, and then you can actually have acquired resistance mutations for many of these as well. Um, I'm gonna keep going for that. Um, so there are some new and now very well established, uh, resistance mechanisms and mutations, um, for CLL that have been exposed to some of these targeted therapies. Uh, there's different buckets of mutations, different classes. So if you look within the BTK, uh, kinase C481S has been the poster child, the most common acquired resistance mutation, uh, was the, the basis for the development of things like pertabrtinib and nemtabrtinib and some of these other, uh, agents I'll talk about in a moment. Um, and then, but there's also mutations unfortunately that, um, you know, are not gonna respond or, or they're acquired rather with protobrtinib, for example. So we're talking about things like the gatekeeper mutation, you know, T474I, which blocks, uh, the binding site that kind of just is a gate that blocks the kinase, uh, kinase inhibitors or, or, uh, TKIs from getting in and, and doing their business. And then you're talking about, um, kinase dead mutations where there's still a BTK enzyme that's there, but it's kinase function has been, uh, abrogated. But it still serves as a scaffold to, to kind of collect and and deposit other proteins that can uh still use that pathway for signaling and growth and um I'll talk about those degraders in a moment that take the whole thing and throw it in the trash, uh, using um the proteosome. Uh, so what is my prognosis? Why did this happen to me? So we can talk a little bit now again. So historically, 50% chance of being alive in 2 years, pretty bad, right? Again, this is like before the last 2 years, 3 years, let's say. So very kind of just like the myeloma talk this morning, you know, you talk about historical, uh, it's all very, very new, uh, fortunately in CL, it's a rapid pace of development. Um, but in this case, let's say he has acquired, uh, one of the more common BCL-2 inhibitor, uh, mutations, um, uh, in G101V, and he's got a notch 2 mutation which up regulates another, uh, anti, uh, uh, anti-optotic protein called MCL1, for example, uh, and then he's got the, the most common BTK acquired resistance mutation, C4A1S. So what treatment options does he have now? Um, so you know how we treat, um, I'm gonna, this is kind of my busy summary slide, and, um, kind of, I'll just click through it for the sake of time so you can screenshot it if you like, um, we are gonna share our slides and our recordings in collaboration with Vie Medi just so you know for after the, the meeting, so they'll be available. Um, but the most important class that's now FDA approved completely are gonna be the non-covalent BTK inhibitors. Uh, pertabrtinib is the one that's, that's solely approved for the moment here. Uh, but there's a lot of action, you know, a lot of other targeted therapies nip it on their heels and their success. Uh, this was originally approved with the Bruin study. I'll show briefly as a third line plus option, but now it is fully approved for the second line after a covalent BTK inhibitors, uh, exposure. Um, uh, combinations like PVO are amazing, promising frontline treatment options, but they're not yet approved. So just know that you cannot, um, you should not, I should say, start with a noncovalent BTK inhibitor, uh, so a Perto or even if you could somehow get a Nemta commercially, which I don't think you can, um, you know, you should not be starting that for a treatment naive CLL patient without a clinical trial, um. And then, um, again in investigation also at Roswell we have a frontline nemtabrutinib compared to covalent BTK inhibitors, a calibrutinib or ibrutinib investigator's Choice. Um, all those folks are getting a calibrutinib, I will say, um, so again experimental, and then there's, uh, Rocbrtinib which is, is coming as well. I'll show you one quick slide on that. And then, um, the degraders we've got a malt 1 inhibitor trial also open at Roswell Park as well as the degrader, uh, with, uh, we've got B1s, but there's another promising Neurex compound in, in, in another, uh, that are coming. Um, one, unfortunately was just closed. I'm not gonna talk about that too much, uh, made by EV, but, um, there are 22 that are looking fantastic, and I think that's the reason why, to be honest. Um, so Lyso cell, I briefly mentioned, uh, and again, I'll summarize that as well, but, um, trying to immunomodulate and improve CAR T cell function outside of beyond monotherapy is gonna be the, the brave new world, new future here. And then allot transplant for those select few fit patients who are close to, close to or in a complete remission. Uh, multiple relapse, right, including, um, I would argue through clinical trial or, or no clinical trial available. Um, this is one algorithm I, I found helpful. This is, uh, published by, um, Mizar Shedman and, uh, Matt David, some trusted colleagues in the CLL world. Uh, this is, um, publicly available, so I'm just gonna keep trucking, but long story short, um, actually, before I go truck too too quickly on that, um. I Wanna say that really you should be starting pertabrtinib and for me if you're prescribing pertabrtinib, um, in the traditional sense, you should really be referring or talking to at least someone um who does cell therapy, um, and has some clinical trials as well. um, so just that's my shameless plug really, but for I think patients benefit. Uh, you want to treat the best response with protabrtinib, but the, the duration of response as a single agent is not all that long. So you, you really wanna make sure at least you have your, your ducks, um, in a row for your patients. I always talk about having 3 lines of therapy in mind, right, for all your patients. I'm always trying to walk in that room, uh, ready to go, you know, with 3 lines of therapy in mind. If I don't have them and there's no clinical trials I'm thinking about that are, they're potentially eligible for, I'm, I'm, you know, gonna keep, I'm gonna be honest with patients, but unfortunately that doesn't happen very often. Um, so with pertabrtinib, uh, again, this is the Bruin study, um, um, we participated at Roswell Park on this trial as well, uh, incredibly effective, you know, overall 73%, uh, response rate, um, you know, or 82% if you talk about the expected lymphocytosis, which, uh, we all should be aware of is a known, um, side effect or, or, uh, phenomenon, uh, chemokine receptor signaling related, uh, thing that happens after you start a BTK inhibitor, um, but basically extremely well tolerated. Uh, one of my colleagues at Cleveland Clinic, my old mentor Brian Hill, said it's like giving water, uh, basically with pertubutinib, I think it's a little bit more toxic than that, but, um, that has a very favorable side effect profile overall. Um, and one thing I really wanted to talk about, um, in the last 6 minutes here, um, and I'll be brief and try to be brief, um, is that Pertarini also has some new data showing it can improve T cell function. This is from Alexei Danilov's group in City of Hope, really intriguing, fascinating work. We're, we're doing a very similar work here at Rosswell Park with, uh, with Venettala. I'll show you in a moment, um, but really kind of showing that, uh, T cell cytotoxicity, uh, parameters and, um, their stemness, their TH1-like polarization, has actually improved with, uh, with protabrtinib. So, and that might reflect some of the real world data as well, uh, which I'll show you just in a little bit. Um, and then, uh, some again well established publications looking at the resistance mechanisms to pertabrtinib and and noncovalent BTK inhibitors. Um, largely again these are these gatekeeper mutations or these tiny stead mutations, uh, but about a third of patients will have no mutations within BTK, and there are actually other growth pathways that are kind of popping up and they're bypassing, um, the BTK pathway. So a lot of these are kind of NF Kappa B, uh, driven pathways, um, that are up regulated and then you're gonna lose your B cell receptor signaling, uh, efficacy. Um, one of the, the most promising, uh, new agents, again, this is open at Roswell Park. So if you've got any patients who are sick and in need of, um, uh, clinical trial with a, a really good BTK degrader, we've got one. this is B1's product, uh, on the cadence 101 study. The overall response rate, I should have put it in my slides, was around 85%, which is incredible, uh, right? And these are really heavily pre-treated patients. These are double refractory, uh, pretty much by definition. Um, and many of them also were actually triple refractory, and the overall response rates is still around 75%. Um, in the early days of the trial it was like 40%. It was kind of sketched, and now it's fortunately gone up dramatically. Uh, duration of response again, like any single agent kinase blockade, uh, generally it's gonna be measured in a couple of years or less. So just gotta be, again, it's a great bridging option. Hopefully we'll have some favorable immunology as well as, uh, you know, strategy pre-cell therapy, uh, but this looks awesome. Um, another one that looks awesome as well is, uh, Neurex, uh, this Neurex compound, uh, Bexobrigg. Um, this is the, uh, degrader. This is a poster that was presented in Ash, um, again, very, very promising, almost the same exact overall response rates. Um, I think the overall response rate in the whole cohort was actually over 95%, uh, so it was unbelievable. A lot of these patients again were, were, uh, at least triple exposed, if not, uh, outright refractory. And safety signals look similar to other BTK based uh regimens. So it truly is a BTK-based, um, side effect profile as far as the bleeding and atrial fibrillation rates, although they're relatively favorable, uh, I would say at least compared to ibrutinib, um, so I, I would anticipate these are gonna be approved hopefully in the near future. And accessible, uh, around the world for use and I say world, not just United States. That's my plug for all of our, our wonderful sponsors and former partners. Please talk to your, uh, your leadership teams and, and, uh, let's try to democratize and liberalize access around the world. Uh, we've, I'm sick of seeing patients like say in Bermuda getting BR, you know, for, for CLL. So, um, some companies are better than others. So I would, I would say let's all, let's all do better together. It's my, my little plug, um, Rockbritib is also this is very, very early, a couple of posters at Ash, uh, with some updates, um. Gen Wex group, um, and John Bird, uh, himself, the godfather of, uh, BTK inhibitors, um, was the last author on this particular, uh, paper. Overall response rates look really good. It's also gonna, uh, overcoming some of these gatekeeper mutations, uh, that are problematic. So there's some new updates on that as well. Looks favorable there, um, even though it's still again a, a kinase inhibitor. Um, this one can actually kind of flip back and forth between, uh, actually in two different sites of the BTK enzyme. Uh, can be a covalent and a noncovalent kind of in one, kind of a cooled hybrid molecule. And then again back to cell therapy. My nickname is a fellow in, in, uh, from Doctor Pullman at Cleveland Clinic was Doctor Cartiz because I'm so fascinated with these technologies, um, but again, it took over 10 years of development with cell therapy to get our first approval right in, in March of 2024. I remember our Ash review, um, a couple of years ago it was like I think the March 17th, it was like three days before our, our talk, and I had to kind of, uh, throw it in there real quick at the last minute. So it's been, we've had some experience now and now we have some real world uh data to talk about. But again, the overall response rate, at least on the clinical trial, uh, was around 40% and the CR rate was only about 20% with obviously CART side effects that you've already heard about quite a bit throughout this meeting. Um, ibrutinib was looked at in one of the cohorts for that trial, uh, Transcend CLL 004, and actually doubled the overall response rate and doubled the complete remission rate, improved the progression-free survival, improved the time the next treatment. Um, so there's this signal of, of course, improved overall survival, especially when you're talking about someone who's double refractory again, like 2 year median progression free survival historically, um, so Bill Weirda had a, a little follow up poster that this is an ASCO last year, uh, basically doing a, uh, propensity based, uh, matching showing that, um, ibrutinib actually does kind of improve outcomes, um, even when you're trying to, you know, compare and contrast and kind of use a MAAC type model to, to adjust for comorbidities and, uh, and patient characteristics. So it's now in our guidelines, um, on the basis of that. Um, of course, ibrutinib is ibrutinib. I, I will mention this is also replicated or emulated in the mantle cell lymphoma space. So it does seem to be a true BTK, um, you know, it has a pathophysiologic basis for improving T cell function. Um, but again, it's ibrutinib, right? So it can still cause, uh, hypertension, skin fingernail cracking, uh, ventricular arrhythmias, which are sometimes lethal, you know, CNS bleeds. I've only seen a couple of BTK inhibitors, and they've both been with ibrutinib, unfortunately, and both were fortunately in fellowship. Um, but again, we're, we're trying to keep our patients alive and, um, right, keep them on therapy and, and improve their outcomes. Um, this has been some real world data. This was presented at tandem this last year in Salt Lake City, um, showing that the complete remissionary actually in the real world setting is more like 60%, which is unbelievable. Um, we'll see how durable this is with longer follow-up with more patients. Um, we are gonna contribute to this with our consortium, the ABC Consortium, and we, we are participate in some others as well around the country. Um, so this is gonna be a really intriguing, uh, look. This was multi-center as well, but only 41 patients. So again, CLL, uh, CART treated patients are relatively uncommon still, but in the near future as our novel therapies become less novel every year, um, we're gonna unfortunately be seeing more of these double triple refractory patients. Um, we're gonna need our new approvals to be fully approved, and then we're gonna need to get better with, uh, with cell therapy. This is again I would highlight, um, and then as I met was, uh, with Doctor Edmonds in Kentucky. Uh, immunotherapy and immunology is the key to cure, right? So without that you cannot cure patients, and you're seeing that with high risk mutations like TP53, uh, when you look at again, uh, novel agents that don't use chemotherapy, um, you're reliably helping our patients. So it's gonna, we're gonna keep forging ahead with that approach. One of our efforts, uh, this is Doctor Hernandez's, um, lab, but fortunately he let me join his group, so I don't have to pay for the pipettes or anything like that, um, uh, with this is our effort with Venettalax. Um, pre and post treatment, just I spent, spent $90,000 on 13, uh, patients using my startup funds, um, and we fortunately it led to an oral abstract, my first ever in, uh, 2024, and, uh, we basically showed that, uh, be at day zero and then at day 30, um, we're there's, you're showing massive improvements of the immune system. We wanted to see if we can improve CAR T cell killing Xvivo as well. Uh, I also get to meet Charles Barkley, uh, in the Buffalo airport, which is like the coolest part of my whole life short of having children. I, I animate it 3 times just to be a jerk I guess, but, um, so this is gonna be in our upcoming publication in, in, in Blood. We're working on, um, basically correlating with single cell sequencing. I'll tease you a bit in the, in the next slide, but we're still working on this very, very heavy bioinformatic lifts, uh, going through again, um, epigenomics, uh, transcriptomics, metabolomics, um, you know, phenomics as far as CAR T cells, uh, cytotoxicity ex vivo. Um, we're doing maps now with our bulk initiatives, especially to look at certain subclusters of the immune system. We have this intriguing, intriguing signal of neocles actually improving the myeloid repertoire. Uh, so you're looking at things like macrophages and neutrophils actually being favorably reprogrammed in this, in this context. And at least we're hoping to show that, um, CLL is, is this multifaceted, nasty immunosuppressive disease. It doesn't just touch on T cells, it touches on multiple layers of the immune system. And, um, Venetoclax, since it's such an effective drug, uh, you're, you're at least washing away the CLL and you're seeing kind of what's what like what changes basically, right? We think we do think there's a drug effect. Uh, Taylor Mandeville had an an oral abstract at the same meeting. She's gonna be defending her PhD, I think, uh, next month, uh, hopefully, yeah, after a very, very, uh, you know, years of labor in, in our lab, and, um, she's gonna be dis discussing actually Venneta Claxton the large cell context, kind of X vivo data there, really cool. This is one of our, our figures for single cell sequencing. If you look on the left, you'll see a baseline, uh, patients had really this paucity of T cells, and now you're seeing this, uh, buffalo chicken wing, uh, figure popping out, which I thought was awesome. Uh, many, many more T cells, um, with overall, I would argue, a, a favorable immuno phenotype, although it's not a clear cut picture, uh, so far. So, um, ways to again, immunomodulate the immune system, hopefully explains some of our clinical trial data as well as far as our efficacy. Sorry for that animation, it's gratuitous. And um, finally I'm gonna wrap up here um I know we're almost I'm over time now I apologize um our last poster was um looking at um can we predict CRT cytotoxicity uh with multi-Mix. This is my, uh, rock star PhD student Jacob Wright here at Roswell Park with me, uh, got his abstract Achievement Award, and we're basically showing that IL-18, for one, so Carl June's work, and I, I believe, uh, Doctor Brenn's may have created the first IL-18 Carl. I'll let them talk about that. Um, but basically showing the IL-18 abundance does correlate with cytotoxicity in our X vivo modeling. Uh, again, kind of multi-center, uh, multi-omic, um, uh, multivariate analysis looking really good, honestly, um, for IL-18 as a potential target for, for cell therapy is, is an armored car, uh, which I won't even talk about today. Briefly, um, eutumabbispecific antibody therapies are also being investigated. Unfortunately, EPCO, um, did not, uh, meet its prime pre-specified primary endpoint. Um, so they're not really pursuing it in CLL, um, at least actively, but I would argue that, uh, doublets and triplets using ecridumab, again, are doubling down on our, our, um, immune efforts, you know, with our immunomodulatory drugs to make them better, just like with CAR T cell therapies, there's gonna be some synergy, I think, uh, with some of our, our new agents to improve the immune system and make these drugs better. And then, of course, next generation molecules. I don't want to completely ignore the PA3 kinase inhibitors. They are still on our guidelines despite their toxicity. Proceed with caution, but as a bridge to clinical trials, um, they can certainly help in a pinch, and they, they can be used, um, and they have their place. So in the triple, triple refractory trial ineligible CART can't get there quite yet kind of a scenario. Um, I would argue, you know, collect CAR T cells and then, uh, talk about, uh, debulking with a PI3 kinase inhibitor, for example, would be an option. Um, so again, in summary, um, we have multiple new options, um, looking for some data with maltwater inhibitors. I didn't even talk about PVO or PVR or PV, um, you know, there's many, many new combinations, triplets all the time. Overall response rate for that was, I believe, close to 100%. Um, many of them were, are CRs and they're durable with, um, great undetectable res, um, uh, undetectable MRD rates. So we're gonna have more options basically going forward. We're excited to see more updates in that regard. Um, so lots and lots more come. There's going to be data for some roto clocks and certainly in the relapse refractory setting as well, there's already a little bit. And also in mantle cell lymphoma, you saw earlier yesterday. So another small molecule that you're looking forward to, um. Helping patients. With that, I will conclude. I'm not gonna talk about Richter's for the sake of time. I apologize. I do have one summary slide, uh, but let's say our gentleman, um, is treated with pertabrtinib, has a great response for two years, so then he kind of just putzes around, didn't really refer right away for self therapy, starts to progress. He's got a kind of dead mutation, um, and then he, uh, basically goes on a clinical trial with one of these degraders. He responds as expected, undergoes leukapheresis, has some cytopenias along the way, but he's one of those lucky. Uh, lucky folks, you know, those 60% folks now, uh, to get a CR and, and hopefully durable for him. Uh, Richter's, I'm gonna say in two lines. I, my shameless plug is I have an NCCN sponsored, um, whole online tumor board with many of these same slides presented virtually and that are recorded, uh, with my colleague Doctor Balakrishna. Historically, chemotherapy has been, uh, the, the old friend for, for Richter transformation. It doesn't work very well. Um, I just wanted to show you that there are many new targets including checkpoint inhibitors plus CLL-based therapies. And um our NCCN guidelines have changed now uh to reflect that. So just know that the, the guidelines have changed if nothing else, and I'm happy to talk to folks offline. Um, one brief update for PVO though was Nit and Jane's cohort, uh, for Richard transformation showed an overall response rate of 80%. Um, and then this is my, uh, shameless plug for my clinical trial with nemtibrtinib again that noncovalent BTK inhibitor with a checkpoint inhibitor that is active and open here at Roswell Park, and, uh, I am looking for a couple more sites to participate if there's anyone out there who would, who needs a Richter study. And with that I'm done. So thank you for your attention. Thank you. Thanks everyone, and thanks for staying here so late. Um, I know we're almost past time, so I was gonna speak briefly about the emerging role of bio-specific antibodies. I know this is for, um, it's part of our program as part of our CME regulations. Um, I will, they basically 2 minutes of it and then really I would spend time, um, looking into questions because I think we want the opportunity to talk to Doctor Romana and Doctor Cortiz about CLL, so. We need these are my disclosures when it comes to the evolution of bite, and we spoke extensively yesterday. I think bite therapies in aggressive lymphomas, they have a setting, well, uh, um, we certainly, uh, studied them in the relapse refractory setting after car therapy. This is what happened when a patient with Larson lymphoma progressed after car therapy. The survival is very, very, uh, dismal, especially those patients that progress within 3 or 6 months post therapy. This was data presented at Ash. We know that those patients, unfortunately, uh, the survival is bad whether they got one product or the other ones. It's really hosting the progress of the therapy. It's what really tells you what's gonna happen with them. So, bites have been a story in this kind of patients. In general, most of the clinical trials that led to the approval of bites in the third line setting. In kind of enrolling like 20 to 30% of patients with bites. This is retrospective data looking at what is the efficacy of next line therapy after CA, whether to use a drug conjugate by specific antibody, polar, Rituxan, chemotherapy, etc. and in general, I think the best options other than polatuzumab or a drug conjugate is about specific antibodies. Um, and again, um, this is kind of spread the data, but in general. Uh, we know that bites, uh, seems to be better than other options, uh, especially chemotherapy drugs. Um, the data for glofetoszumab, glofeumab, again, we talked about doing yesterday in the meeting, um, so I want just to quickly go through it. We know that it's very active. Around 39% of the patients achieve a complete remission. Uh, around half of the patients respond to treatment, and you respond, tend to stay in remission for a year or so, you know. And again, um. There is data that has been presented at us looking at patients who they progressed after car therapy that they were treated with uh with by specific antibodies. And again, kind of what we see is the objective response is pretty much similar to what we have seen in the deadline setting, 60% response rate, 30% complete response rate, and again, patients, they tend to respond, they tend to stay in remission a little bit longer compared to those ones who they don't, 10 months or like 2 months, so. And again, um, there have been some attempts to compare the efficacy of CA versus other kind of treatments. There was a retrospective analysis looking at patients treated with clofetumab versus, um, kind of archived databases from prior registration studies. And again, what we have learned is that bites, they have an objective response of 75%. I would say half of them, they are actually complete remissions. If you stay in remission, you're gonna get more than 1 year. If you don't, you certainly tend to die from the disease. And again, bites they tend to perform better than the next line of uh chemotherapy drugs. So, um, again, this is something that is similar with EPCO. So I just don't want in lieu of time, I'm just gonna go through it a little bit quickly. Um, and again, when it was presented at Ash was looking at the 3 year follow-up of EPCO post car therapy and the long-term follow-up, and again, we can see that patients, they tend to respond better to uh bite are patients who they were in remission after car for more than 6 months or 3 months. Patients that progress within 3 months after car therapy, chances are they're not going to benefit from a bite and. Those patients, they should refer primarily to hospice. And again, um. What has led, I think these studies have shown that post by car therapy by this uh the kind of the, the, the, the go to go treatment, and again, that has led to combining with chemotherapy. Jeremy Abrahams talked about the Starglow trial yesterday. Again, it was easy to beat Jamu, but again, certainly by plus chemotherapy seemed to be better than chemo monotherapy. And again, that's led to the approval of the combination that we are now we're using in the 2nd or 3rd line for transparent eligible. And again, um, this was kind of something that was presented at Ash. It was the 3 year follow-up date of the Star glow that showed to be a consistent positive stories. And again, similar, there's a phase two story looking at EPCO plus Jambox was updated at the AS meeting and then I'm kind of suggesting that this combination seems to be quite effective in patients with a large refractory, the LBCL, and again, um. Certainly this kind of combination treatments in the um in the 2nd line or 3rd line has led to really looking at other combinations that are less toxic somocetuzumab and um uh poletuzumab in the 2nd line or 3rd line for transplant eligibles was compared to Jamox and again, not surprisingly when we look at it there's complete response rate, the bi-specific and polatuzumab was better than Jamox and Rituxan. And again, that leads to an improving overall survival and progressive survival. So right now, certainly bites are moving from 3rd line, 2nd line with chemotherapy. And now, two things, and before we move forward to the Q&A is looking at fixed duration of EPCO in the frontline setting in patients with the LBCL and comorbid conditions. These are patients that they were frail, had at least more than one comorbid conditions, either vascular disease, um, cognitive problems, renal failure, etc. And again, when we look at this particular patient with the median age was actually through elderly patients, 82 years of age, with 60% of them having a performance status of 2, you know. And again, when we look at the best response, it was 70%, 58% of the patients achieving a complete remission only with a monotherapy in the first line setting. What's very important is short term follow-up, but that one year of follow-up, a significant number of patients are still free of progression. And again, that certainly has led to the ongoing clinical trials. This is the phase two trial that led to the phase 3, looking at combining MCO with RCHOP in the LBCL. This is the data that at least has shown an overall response rate of 98%, a complete response of 85% of patients with IPA score 3 to 5. Those are patients with very high tumor burden. And again this has led to actually the development of phase 3 randomized studies which we're hoping to see the readouts hopefully in the fall, uh, um, international meetings or maybe as soon as I have and again with this I will finish this quick presentation. And really I would like to move forward to the Q&A on CLL, you know, so we can really, really kind of pick Dolaman and Doctor Coti's brains about what to do with CLL. Thank you very much for your attention, so. So I have a, we've got a quick question for Nicole, you know, so what, you know, when we look at, uh, at CLL, you know, so what do we like, what do we do when a patient basically fail like the triple refractory is there's any role about recycling another drug based on gene mutation. or do you go quickly and naviate the grader? No, it's a really, really good question. Can you all hear me? Oh, good. OK, sorry. So, I mean, obviously testing for resistant mutations isn't standard of care. However, we obviously do do that because there's some data that Matt obviously presented, alluded to. That depending upon some of the resistant mutations, the question is how could you go back to older therapies? That's one question based on that. If they got some time limited approach, could you potentially go back to that? Or are you looking at either bridging, you know, going to. Um, uh, a clinical trials such as a BTK degrader or we didn't talk a lot about the bio-specifics, which I think, you know, there, there's obviously a lot of bi-specific combinations for CLL as well that are going on also again only on clinical trial. So we will look at resistant mutations and see because sometimes people lose some of their prior resistant mutate. It's always important to sort of test with subsequent lines of therapy. Um, so sometimes people do pick up and lose certain mutations and the question is, can you go back and then recycle drugs? That's one. And then part of it is depending upon, uh, their last therapy or if they were on a time-limited approach, could you go, you know, again, it, it also does depend on what they might have gotten in their prior lines of therapy. The whole issue about can you go back to then antibody combinations really does depend on, um, their duration of therapy on a prior combination. Um, so sometimes you can go back to that. There's obviously definitive studies such as the revenge trial, trying to look at that, um, in a prospective rather than retrospective data, which is what we currently have. But it is true that if somebody is really triple refractory, so meaning they're refractory to covalent, non-covalent, and veneta clocks based combinations, that they have very limited options, um, and so I would argue that those are patients that absolutely should be going on clinical trials and it depending upon their age and comorbidities, yes, we're teeing them up. They should be, I agree with Matt, if somebody is on a non-covalent after they've truly failed covalent and and ven based combinations that they really should be thinking. About bridging to CAR T if they can do that and so we, we do have them sort of get evaluated when they're starting any kind of third line therapy that's standard of care and not clinical trial, uh, otherwise they're gonna look for clinical trial. Now the EPCOre development in CLL, we don't know that that's going forward, uh, but there are other trials with by specifics. You certainly can get it off label because it is approved for the other lymphomas and so I would also consider that as well, but again, that's completely off label, sorry. Um, uh, but, you know, depending upon can you bridge then to CAR T because all the responses are going to be less than, probably less than 2 years depending. And so, at least, you know, when you think about even bridging, like when we think third line with Perto, the response is going to be less than 2 years. You really do have to think about CART or other alternative strategies. Um, we have some patients who are stage 0, maybe 1. Who I don't know if the guidelines of treatment have changed even with the adverse cytogenetics or mutation like 17%, but they're clinically doing very well. What is the initiation of treatment, the guidelines? It's a, it's a great question. There's an active SWAG study I will, I will plug for them. Um, it's open at Rochester, uh, locally for us, so high risk disease features, you know, with, without any, uh, IWCLL, uh, treatment, you know, uh, classification criteria for, for treatment rather, um, so generally for the asymptomatic we follow I IWCLL. You leave them alone, right? You can still watch and wait outside of a clinical trial. Long story short, the high risk features though you can use to. Tailor surveillance, I would argue, right? So if you're ultra high risk and maybe threatening some, you know, one of those treatments, you have some symptoms I call it the damp, you know, the pre-night sweats, you get some lymph nodes that are, are getting up there in bulk, but not, not really painful, not threatening organ function. Um, you know, you can, you can still watch and wait, but I tend to follow them a little bit more closely, you know, more than that once a year for the, the low risk patients, you know, you, you want to, uh, surveillance accordingly. Yeah, we don't have the data treating early is better. There was a German CLL study that looked at this in the context of ibrutinib, and there was no difference for early high risk patients than placebo, so we don't. But the Alliance trial included time limited therapy, so a lanatuzumab, so we'll see what the results of that study are in high risk patients. But up until then, I would not do that. What, what do you think will happen when you have, like, if you are doing triple therapy now up front, are you gonna have a different panogenetic mutations that can lead to a harder patient to treat, you know. Um, I, I think that, you know, so similarly to, just to extend that, so when we talked about some of even the non-covalence moving up to frontline, and I agree with Matt, we should not be doing outside of that, outside of a clinical trial, because we, you know, we know sort of the resistant mutations that can develop from the current paradigm. And again, obviously historical because of covalence and Ven based and then the way they got developed. So, you know, we don't know what type of resistant mutations if we move Perdo to frontline. Uh, what, what will be the paradigm? Will they develop different resistant mutations? Now, time-limited therapies, whether, whatever the combination is, whether that's doublets or triplets, do have potential advantage of theoretically they're time limited. So, again, the, the development of resistant mutations should be far less because you're getting people off of therapy. So we haven't seen a lot of development of resistant mutations with time-limited approaches, but it is a, you know, it's obviously something we need to consider. And I. I would argue that even though the data looks good for triplet, I still don't think everybody needs a triplet, you know, I think our mutated folks do really, really well. So I don't know that they need to be exposed and have triplet therapy, given how well they're salvaged and how well they do even with doublets. But I do think that triplets might be advantageous for high risk individuals or, um, you know, um, other high risk genomic features where that might be important unless we're gonna extend therapy a little bit longer for the doublets. I, I'm just gonna revisit this issue of early therapy because in plasma cell disorders now we have the concept of MGUS and high risk smoldering and a full blown myeloma and now there's emerging data about how to predict risk within smoldering with things like Gbabeck genes and the immunoeffectiveness uh score and MC and RAS mutations over time. By the time full blown CLL starts therapy, there were already so many monkey wrenches thrown into the immune system that immune-based strategies are falling on their face compared to other diseases because of the things that Matt's studying that co-opt the immune system. So should we be developing paradigms to predict these patients earlier to make immune therapies better suited to these diseases that will by the time they need therapy, fall to immune uh therapies because they have so many problems associated with them. It's, it's a great question. I mean, I, I think we're a little bit more cavalier in, in the, in the watch and wait, uh, camp for CLL for a couple reasons. Number one is we don't have reliable evidence that by treatment you're making them better as far as their immune function. I think that's changing slowly. How do you quantify that, sort of, you know, just with history, right, with frequent infections with or without acquired hypoglobulinemia is again just one marker of the immune system, um. I think we're gonna get better at at predicting uh the the immune paresis of CLL patients. That's a that's a hot area that we're working on right now with other people from around the world. Uh, one such effort, uh, that I wanted to highlight was Carson Nieman's work from Denmark, uh, using AI to predict infection risk with CLL using, uh, kind of a limited Omics approach with, um, you know, a lot of, uh, clinical pathologic variables as well. Um, fascinating work, right? So it's getting to that level of sophistication where you, you can predict the future and then maybe steer the ship in one direction or another, right? Um, there's also fascinating work, um, it was by Ferran Nadu, uh, in Spain, um, playing with, uh, Mission Bios tapestry platform looking at single cell sequencing with like a limited, um, um, uh, proteomic panel. Uh, very, very expensive technology but basically showing that you can find a pre-transformed Richter's clone 19 years in advance. Uh, it was an archive, you know, going back in old lymph node biopsies, um, with using single cell technology, so that's eventually gonna become also mainstream, you know, predicting the future with this scary, uh, precision, um. For the moment though, I, I still think we're best served leaving folks alone because the vast majority of folks, even sometimes with high risk features again because it's this, this interactome of all these other mutations that, that are not always cooperative and not always as deleterious as, as one might think, um, I think we're, we're better suited for the moment, um, leaving folks alone because the vast majority of folks are gonna do well. You can capture them with with response rates approaching 100%, um. And curing CLL, I think, should for the moment again because of how toxic CAR T cell therapies currently are, um, including by specifics even, right, there's still, there's not a free lunch, um, once our technology gets better in that regard, I think we'll, we'll have a better shot at it, but for now it's, it's, I think best left for patients who are, uh, triple refractory, frankly at this point. I, I think we've been a little bit of a victim of our own success. I mean, so immune, you know, where is CAART gonna fit in CLL? I think, you know, there's no doubt you need a really good response. You know, he, he briefly showed Matro that data where patients who get CART really need to be in good disease control to get a complete response to therapy. Although, hopefully by adding things like A BTK inhibitor or other combinations into, you know, the, the CAR T will help improve those responses as noted from the transcend when they added the brutinib to CAR T improve the CRs because if you don't get a CR, it's not durable. So you really, so that's a problem. So the and the problem is because these were multiple relapse refractory patients, of course, they, they didn't do so well. So moving CAR T, of course, would be important, but the problem is we've had all these great therapies that have emerged. And the majority of patients don't need all these therapies and so you're really talking about a smaller subset of patients who are younger who are gonna be getting these sequential approaches and so I think and now with by specifics too, I think it's problematic because now patients are getting by specifics before they get caught. Um, and so I, I think that we just don't know quite yet where the, where CA and the immune therapies are gonna settle out in CLL and now we have BTK degraders. So I think they're, you know, I think that we, we need a lot of work. I agree with you. I think it would be more advantageous when the immune system. Isn't as deleterious. I mean, that's one of the biggest problems in CLL compared to some other diseases is the microenvironment so complicated. But I, I'm, I, I question where we're gonna, where we're going to go and how who, who's gonna be, you know, who's gonna get CART in the future depending upon the development of some of these other agents. So stay tuned. Thanks. Thank you. 11 quick question, if you have a patient that had a BTA on a noncovalent BTK that it was proven that was drug related. Uh, would you challenge the patient with, uh, covalent BTK or with a BTK degrader? No, I would try not to. I'd be very nervous. I'm not gonna lie. I'm gonna be nervous. We'll be talking about dose reductions with, uh, uh, you know, an EICD that's functional and a cardiologist. We have a patient like that, yeah, so look for ischemia always, right? I know, again, we have a patient like that, clear coronaries, and it was clearly dependent right now locally doesn't have any BCL2 and not one mutations for now, but yeah, that's, you know, that's concerning, so. Thank you, thank you. Any other questions? I just, just wanted to emphasize as well on the guidelines we did put up about the mutations of prognostic significance. Um, I, I agree completely with Doctor Romana. As much, as much as I love the molecular world and testing, I try not to overt, but. Um, the clinical picture is, is still paramount, right? So if you have a patient who's, who has, um, you know, let's say some cavalier doc, uh, ordered an NGS because they found a couple of lymphocytes floating around. They had a viral infection, right? And let's say they're non-CLL, right? Got a little trigger happy, found like a, you know, a C4A1S mutation that's like, say, a, a very, a little frequency of 5%. Patients doing incredibly well. Again, for me, you're gonna continue treatment, you know, based on the clinical parameters as you would before. But I also don't want to completely ignore the data there, the, the data you've now obtained either if it's a known mutation that that's. Likely gonna be a subclonal resistant mutation that's gonna probably increase over time and so it may just again uh influence your surveillance schedule for those kinds of patients like I I follow that patient in particular a little bit more closely uh than someone without something like that. So I have a quick question. Last one, how often do you do, well, who, how often, and what kind of MRD testing do you do in your CLL patients? Well, those on chronic continuous BTK, I'm not doing any, um, unless they're, you know, are discussing about whether or not they want to come off therapy, uh, but otherwise I'm not doing anything. And then the ones who are obviously on a time-limited approach, you know, we do flow, but we also do NGS testing. So we're doing both, um, you know, more to see, there's about a 10% discordance between blood and bone marrow with flow. Obviously, it's much less so with NGS, but remember you have to send a baseline as well, so you gotta remember to do that. Uh, but the NGS testing is much better. So I am testing patients, um, you know, if they're on a time limited approach because most patients wanna know what, you know, what the quality of their responses and more or less also they're asking how long will this last and how, you know, what is the anticipated time that I might be off therapy. So we are testing for, for that in time limited approaches. Thanks. I, I completely agree. I just wanna say briefly, um. There's some data, emerging data. So as far as intolerance to venetoplaques, it's a common question. You see those cytopenias right in the very beginning, the GI side effects. There's the TLS. Fortunately with the BTK lead-ins and or with just debulking with standard anT-CD20 therapy, uh, which I prefer for young fit patients, no, uh, comorbidities without excessive bulky disease. If you have an lymphocyte count of 500,000, I'm, I'm not gonna be giving obintuzumab front, uh, front line unless I absolutely had to. Um, right, um, and because you're gonna kill patients like that with an infusion reaction, especially very elderly patients, but. Um, I just gonna say there's some data from, um, presented by Doctor Thompson and Ash, um, in 2024, uh, again phase two of about 150 patients showing that if you get, uh, NGS data MRD negative at 6 months and 9 months and, uh, basically do equivalently well, uh, basically, but again limited follow-up single center study. I think uh Lindsay Rucker, I think, wrote the study and then, uh, Megan pre uh presented it, but, um, so it's intriguing. Um, but we're not using that quite yet, and, and I, I use it basically if people are having side effects, intolerance to treatment, despite dose interruption. Uh, some great data, um, published by Doctor Al Sawaf, uh, who also did CLL 17, plenary session, uh, CLL 14. The guy's unbelievable. Um, that basically showed that, um, a 70% dose intensity of venetalax is probably good enough, um, right, to get, you know, comparable outcomes, um, but if you do less than 70% cumulative over the, again, a year or two years of duration of therapy depending on the context, um, you're not gonna do as well, so you really do wanna try to keep people on treatment, but the MRD approach eventually might help us refine and hopefully even limit and de-escalate, uh, treatment for, for some patients, but. For now, I use it as a surrogate for intolerance and try to push them a little bit harder, maybe to get them already negative, but not too much harder. Thank you.
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