CLL: Treatment Advances 2026

New & Emerging Treatments in CLL  2.24.26 Transcript

Participants:    Dr. Ryan Jacobs, Atrium Health Levine Cancer Institute

Lindsey Whyte, Leukemia Research Foundation

 

Hello. Thank you so much for joining us for the third of four sessions of Leukemia Research Foundation's 2026 New & Emerging Treatments series. The topic of this session is CLL, and we're joined by Dr. Ryan Jacobs, an Associate Professor at Wake Forest University School of Medicine, and CLL expert at the Levine Cancer Institute, Atrium Health System in Charlotte, North Carolina, who will share some slides about the latest treatments and research for CLL and respond to questions from participants. My name is Lindsey Whyte and I am the Director of Programs and Partnerships at the Leukemia Research Foundation. I would like to take a moment to thank the supporters of this session in the series, AbbVie, AstraZeneca, Johnson & Johnson, Merck and Autolus.

The Leukemia Research Foundation's mission is to cure leukemia by funding innovative research and to support patients and families. The foundation has raised over $95 million in support of our mission since our founding in 1946, and has funded research grants to over 750 investigators worldwide. Our support programs for leukemia patients and their loved ones include information and resources on our website, education programs, financial assistance, and a directory of other helpful organizations on our website as well.

 

For today's program, all participants will be muted, but we welcome your questions in the Q & A box at the bottom of the zoom screen. Please note, and this is very important, that you should check the box if you prefer for your question to be anonymous, because otherwise your name will show. If you already submitted a question through your registration. Dr. Jacobs has reviewed them all and will address as many as possible through his presentation or at the end, during the Q & A session. After today's program, you will be sent a link to a brief evaluation through email. We would appreciate it if you would please take a moment to complete that evaluation so that we can improve our future programs. Also, this webinar will be recorded and a link will be sent to all registrants after the program.

 

We're grateful to have Dr. Ryan Jacobs with us today. Dr. Jacobs graduated from Baylor College of Medicine in Houston, Texas in 2009. He then completed his internship and residency in internal medicine at Vanderbilt University in Nashville and returned to Houston to complete his training with the hematology oncology fellowship at MD Anderson Cancer Center. He joined Levine Cancer Institute in Charlotte, North Carolina in 2015. Dr. Jacobs has both a clinical and research focus in patients with lymphoma and chronic lymphocytic leukemia. In his role as a principal investigator, he oversees the clinical trials conducted at LCI that involve the treatment of patients with CLL As the CLL expert for LCI Atrium Health System, Dr. Jacobs is responsible for creating and overseeing the patient care pathways involving the treatment of CLL patients in the Atrium Health LCI network that spans North Carolina, South Carolina, and Georgia. In addition to clinical trials, Dr. Jacobs also has a research interest in real world outcomes of patients with CLL on novel therapies and has contributed to this field of research by utilizing the large LCI network and evaluating patients across LCI imprint treated in a variety of clinical settings.

 

Dr. Jacobs, thank you so much for joining us today. Please, let's get things started with an overview of the latest treatments and research and trials for CLL.

 

- Yeah, thanks everyone for tuning in. I understand it's quite a big audience, so very excited to give an update and thanks for the kind introduction. So I'm here in Charlotte, as mentioned, we have a brand new medical school. Charlotte was the biggest city in the nation without a medical school, so we have sort of, kind of consumed Wake Forest's medical branch there in Winston-Salem, and then now have opened a new medical school here in Charlotte. So that's what's pictured here. So that's a beautiful campus.

 

So for this talk, I wanted to focus the presentation around recent updates at the American Society of Hematology meeting that was just in December, and I think it has, as I'll show you, sort of a nice way of establishing where we are and where things are going. And I'm going to focus the majority of the discussion on treatment and treatment advances because what hasn't changed is the fact that for those 50 to 60% of patients that get diagnosed with CLL/ SLL that don't have symptoms, we're still not treating those patients. Even with our advances we are doing active surveillance. We used to call it watch and wait, but active surveillance sounds better. So we're, we're doing active surveillance for patients that don't have any clear problems that their CLL is causing. So that's objectively quantified as a hemoglobin of less than 10, a platelet count of less than a hundred, painful lymph nodes, recurrent drenching night sweats that are disrupting quality of life. Less common would be things like unexplained weight loss or fevers. And then there's sort of the fatigue element with an asterisk on it because a lot of times fatigue can be from other things, but if you don't have any of those things that we can attribute to CLL, we leave it alone because even with our newer treatments, there's still been no study that shows starting treatment early leads to a long-term benefit for patients. And there are a fraction of patients that won't ever have significant symptoms from their CLL and can live out their whole life without ever needing treatment. So that hasn't changed. No new data there. We're leaving those patients alone.

 

But a lot's changing in terms of patients that need treatment. And so I wanted to share what was going on at the ASH meeting, that's what we call the American Society hematology meeting. It's the biggest meeting for blood cancer treatment in the world, and it always happens in December every year. So I want to talk about, want to talk about that.

 

So a little bit of background, the diagnosis on CLL also hasn't changed. We are defining it as a monoclonal B cell population. So that's B cells that all look the same. You know, B cells are supposed to look different. They're a type of white blood cell as part of your immune system. And, the quantity that they identify to call it CLL, is greater than 5,000. And that's detected by peripheral blood flow cytometry. You can check it on a bone marrow. You don't need a bone marrow for CLL. So if your doctor tells you need a bone marrow, I would just be sure to ask, you know, why, what specific information are they trying to get? Because it's actually not required. I get a lot of patients that come to me with a quote unquote diagnosis of CLL, but then when I see them, their monoclonal B cell count is well under that 5,000. So that's not a cancer, we call that monoclonal B cell lymphocytosis. And it often never turns into a cancer. So I get to give those patients the good news that they actually don't have a cancer. About 85% of the time, that's how the disease presents. It's got an elevated white count, but then the other 15% it shows up just in the lymph nodes. We call that SLL small lymphocytic lymphoma. So that requires a lymph node biopsy. So, you know, these are just sort of the usual things that you can do. Scans are not required. Bone marrow biopsy is not required.

 

You know, you think about things like scans, if you're going to start treatment. You think about the prognostic workup, if you're going to start treatment isn't required if you're on active surveillance, but you can check it just to sort of get an idea of what to expect. Even on active surveillance, you know, the staging systems in a good way are all outdated. I try not to focus on them too much because we keep making advances faster than they can make staging systems. And I always get worried that I'll talk about, you know, some stage with a patient and they'll go look up their life expectancy and it'll be inaccurate. So what I'm going to use data from the ASH meeting to, go over, you know, as we shift into talking about treatment is this sort of evolving subject as we've moved away from chemotherapy to targeted therapies. There's this, you know, existing sort of paradigm of continuous therapy and that's almost always with a oral BTK inhibitor that you take indefinitely. And now we're coming up with more and more options for what we call fixed duration or time defined therapy. So that's going to be a theme of the discussion that I'm going to talk about, particularly for first line treatment.

 

So the big news that was out of ASH this year, and it was immediately published in the New England Journal was this trial. It was, the short title was the CLL17 trial, but the full title for the manuscript was fixed duration versus continuous treatment for chronic lymphocytic leukemia. And when we go to ASH, there's a lot of different smaller, you know, meeting rooms where they present on different diseases. And then there's one big meeting room where they present the plenary session and that's where they take the best presentations for the whole conference. And that includes malignant hematology and benign hematology. And there's only four to five total studies that were, that are checked and in my 10 years of focusing on CLL, there was never a CLL study chosen, but this was the, what they called abstract number one. So it was the very, it was the top presentation chosen to present. It was the very first presentation at the plenary session. So it was a big deal. And, and here's the background. So we all know about this drug called ibrutinib. You know, it's what changed everything in how we treat CLL. It's why we don't use chemotherapy anymore because ibrutinib, this oral drug was pretty well tolerated relative to chemo and it had this very long progression free survival. So this isn't like, this is just, if you take ibrutinib as a first drug, how long is it until the CLL even shows up again? And it's about nine years, which is incredible. And as you all probably are aware, we've come up with even better tolerated options than ibrutinib. So that's one of the backgrounds to this study. The other background was the first iteration of what we call time defined therapy, which for first line treatment using targeted agents.

 

So this is Venetoclax, which is a BCL2 inhibitor. It's still the only BCL2 inhibitor available. And it's combined with an immune therapy called obinutuzumab. So Venetoclax is oral like ibrutinib and, and then obinutuzumab iv, it's an antibody and immune therapy and it's given IV for six months. The total treatment time's about a year. And when you give that as a one year and stop, the median time, the average time until you see the CLL again is around 76 months. Okay? So that's another really excellent treatment. One year and stop, you don't see the disease for 76 months, Really, really good.

 

And then, what matters more actually for CLL is not when you see the disease again, it's how long is it until you actually need treatment? Because I've already told you don't need to treat if the CLL'S not causing any problems. So we actually don't know the average to quote patients, but at seven, sorry, six years of follow up, there still was 65% of the patients that didn't need any other treatment for their CLL. So that's really, really incredible.

 

And then finally, the other arm on this trial that was presented at ASH used this combination. And that is where I see a lot of the field going. It's can we give time-defined treatment that's all oral? Can we get away from IV treatment and still give time-defined therapy? And so it was done on this study with the combination of ibrutinib with Venetoclax for one year previously, you know, based on this study, there was a 42 month period, they followed these patients for 42 months and three quarters of them hadn't had their CLL come back. So this is the design of the study that was presented at ASH and I sort of tried to lay it out here because it's continuous ibrutinib. So that's why that bar is really big. You just stay on that for as long as it works. Or it's one year of Venetoclax with a ibrutinib, or it's one year with Venetoclax and obinutuzumab and it was about 300 patients in each arm and they followed them for three years. And the main gist was that all the arms are looking excellent and none of them look very different from each other. So about roughly 80% of people in each arm at three years have had no progression of their CLL and for a disease that it appears with, with how good our treatments are, no longer affects life expectancy.

 

So I just want to say that again, the data that we have indicates in this novel treatment era, if you get diagnosed with CLL and you are managed with these novel treatments, life expectancy does not appear to be impacted by a CLL diagnosis. So why this study is important is it shows, all right, we already have some really excellent options. Life expectancy does not appear to be affected. So does it make sense to give somebody an indefinite treatment or if we can do just as well, can we give time defined treatment?

 

So these are the first, this is the first study that's ever really compared these novel approaches to each other. So it, so it is a big deal. You know, some were, some might say, well this is using ibrutinib and we don't really use ibrutinib as much anymore. We use the newer drugs acalabrutinib and zanubrutinib and maybe even pirtobrutinib. But you know, I think ibrutinib is still historically a very effective treatment. And you can conceptually, I think use this trial to think, you know, with the other BTK inhibitors, it would be close to similar results. And, and so it's reassuring that we can do these time defined treatments, particularly the oral time defined treatment and achieve similar outcomes.

 

And some of you might be aware that just last Friday we finally got an FDA approval of the first oral time defined treatment in CLL and it's one year of acalabrutinib with venetoclax. So this study is, I think, important when thinking about that as an option. Ibrutinib and Venetoclax for some complicated reason was never approved by the FDA. It was approved in Europe, Canada, and other countries, but not the FDA. So we now have acalabrutinib and Venetoclax approved. So we do have this all oral time defined one year option available to us. It looks to be still very effective even in mutated versus unmutated. But you start to see a little bit of difference with the Venetoclax obinotuzumab group. If they're unmutated it still looks really good with the two with ibrutinib, venetoclax and ibrutinib.

 

The group that probably long-term is still going to do best with single agent BTK given indefinitely is the high risk chromosome 17P group. Luckily that's only about 10 to 15% of patients. But that's one of the reasons why it's very important that we check a prognostic workup before we start treatment. And that's on NCCN guidelines. Because things like whether a patient has a chromosome 17 aberration or not, or whether they're IGHV UNMUTATED versus mutated can affect your treatment decisions.

 

This is just some additional information on the trial that I put in here only to show there's a lot of discussion about MRD or response rates. But at the end of the day, what matters the most is PFS [progression-free survival]. And so you see how all these treatments had different response rates and complete remission rates and certainly MRD rates, but their PFS at the end of the day was the same. So just be careful when you start trying to think one treatment's better than the other based on MRD because that's not actually always applicable. And then in terms of tolerance, I think I just wanted to highlight, you know, if you do a continuous therapy, you're going to have a much more likely chance of having to stop due to a side effect as opposed to if you're only getting one year of treatment and stopping. We hope with the newer BTK inhibitors that the discontinuation rates would be lower. We know that ibrutinib is a bit harder to tolerate.

 

So I think I sort of highlighted why I felt like this study was important already, but these are sort of the take home points. I think, you know, optimistically you could look at this and say whatever you choose, you're going to do great with CLL. They're all doing, all the arms are doing great. But then I think if you, if you think about it from a patient-centric point of view, if I have these really great treatment options, you know, does it make sense to have somebody on indefinite treatment or if it works for the patient, can we do time to find treatment as a first therapy? And I think it's reassuring that we have this data.

 

All right, so now that was the big study. I've got a few more that are just not as big a deal but worth noting. I've talked about lots of BTK inhibitors. The newest one is called pirtobrutinib. And it's interesting because it's different from ibrutinib, acalabrutinib, zanubrutinib, it is a non-covalent BTK inhibitor - that just talks about chemically how it binds- and it binds to a different site than those other BTK inhibitors. So it has actually been shown to be effective when patients have already progressed on drugs like ibrutinib, acalabrutinib, or zanubrutinib. So historically if you progress on ibrutinib, you couldn't then go to zanubrutinib, it didn't work anymore. You know, somebody's resistant to one, they're going to be resistant to all three of those drugs. But pirtobrutinib, by and large looks to still be effective because it binds the Bruton's tyrosine kinase at a different site.

 

So there were a couple studies that were presented and actually just published. The first one was looking at first line treated patients with Bendamustine and rituximab. And the story with pirtobrutinib was how well tolerated it is. And you can see down there, you know, discontinuation rate of only 4%, only 1% atrial fibrillation rates, which is something we always look at with BTK inhibitors. But at the top you can see, you know, at two years 93% of the patients were still free of progression and, and it was much superior to chemotherapy. Why this is relevant is because, you know, the FDA approved pirtobrutinib to be used as early as second line at the end of the year last year. So that's another, all these new approvals in CLL just so much going on. But pirtobrutinib, is not done. They want to get in the first line setting. So this is why this is significant and we can talk about in the q & a session what that might mean if pirtobrutinib gets available in the first line setting. But right now, this is one of the studies that's going to try to accomplish that. No surprise that it beat chemo. But where I think there's a little more interesting information to talk about is it compared itself to ibrutinib. This trial included relapsed patients, which were interesting to discuss, but about 30% were previously untreated. So first line patients. And I actually think that is the information that is more interesting to discuss because if you look at this table I tried to highlight down in the treatment naive setting at 18 months, which is a very short follow up for CLL, you know, I've been showing you studies with follow ups as long as 10 years, this is only 18 months, but at 18 months pirtobrutinib had already beat out these ibrutinib patients. It also beat them out in the relapsed setting. But zanubrutinib also beat ibrutinib in the relapsed setting. So it's not necessarily a novel thing for the relapse patients. But this study in its first line comparison marks the first time ever that two BTK inhibitors have been compared in untreated patients head to head. And it surprised a lot of us that there's this big difference in PFS. Ibrutinib is a very good treatment as I showed you. So this novel mechanism of action pirtobrutinib 95% free of progression at 18 months versus 87%, which is very statistically significant difference relative to ibrutinib. So they're going to take these two trials and go for FDA approval for first line and we'll see what the FDA has to say about it. Again, very low rates of atrial fibrillation with pirtobrutinib 2.4%. That's about what you would expect in a CLL patient that wasn't on any treatment. So we wonder if pirtobrutinib increases AFib rates at all? Very low discontinuation rates due to toxicity pirtobrutinib, very well tolerated.

 

So that's the new drug, the newest drug on the scene pirtobrutinib. It got approved third line a few years ago, I believe it was 2023, 2022/2023. Oh there it says it there 2023. And now this FDA approval came in December, the second line approval and then we'll see about first line. So what we know about first line is that it's superior to chemo and it's superior to ibrutinib. And, but what we don't know, and this is what's giving a lot of specialists some pause is if you use pirtobrutinib first line, does that mean you won't ever be able to use drugs like acalabrutinib or zanubrutinib later? And that that's maybe a pretty big deal when you think about it. Because CLL is a marathon in how we manage it. So if we use one drug first and it takes away the ability to use other drugs that we really rely on, does it make sense to use it first? And I think that comes down to this discussion of sequencing and we have a lot to work out there.

 

Back to the time defined treatment discussion though what is great is if you do so all these BTK inhibitors as single agents, you take them till patients progress or they become resistant. The time defined treatments, you're just giving them a treatment for a block of time. And you know, the early studies have shown like with ibrutinib Venetoclax, and I've contributed to this data when these patients relapse, they're not resistant because they only got treatment for one year and then you stopped. So you can re-treat them. So we don't have to worry about resistance too much.

 

So finally this is the most kind of forward looking part. These are drugs that are not yet approved. So I've talked about how we're changing things, you know, just in the past few months here in CLL, what might come down the road back to the bruton's tyrosine kinase, we keep going after this one. This is, these are degraders, so instead of just inhibiting bruton's tyrosine kinase, can we just dissolve it? And it looks like these drugs are effective even in patients that have progressed on previous drugs like ibrutinib and pirtobrutinib, they're still effective. There's two companies developing them. They're sort of racing for approval. They've both been shown to be quite effective. I tried to put a table together, they're just early phase data at this point, but very treatment refractory patients for prior lines of therapy on average. But even so the overwhelming majority are responding and it's active against known BTK mutations. So that might give us a brand-new line of therapy over the next couple of years if these agents get approved and they seem to be quite well tolerated.

 

So that concludes the sort of the slides and again, I hope to have established a sort of a background in where things are and what's changed recently and then a little bit of a look a look to the future and now we can move into taking some questions.

 

- Great, thank you so much. That was very helpful and I just wanted to remind folks, I think somebody tried to raise a hand, that everyone will be remaining muted through this program, but if you do have a question you can click on this Q & A box at the bottom of the zoom screen and you can insert your question in there. And if you want your question to be anonymous, you need to click that little box. So we do have a couple of questions that have come in already. One was, the first one was what are the staging systems? I think you alluded to that briefly and if you could just talk quickly about that?

 

- Yeah, and you know, cancer patients always want to know their stage. I actually don't talk about it explicitly for reasons I mentioned earlier. If a patient asks me I tell them what stage they are and I tend to reference the RAI staging system, which really just has to do whether you have lymph nodes enlarged or your spleen or whether you're anemic or have low platelets. But I really caution them to not go and look up online anything about their stage. Because every time we approve a new treatment, all of the data associated with staging becomes obsolete because these staging data were created years and years ago before we had these treatments. So you're going to get unreliable information about what you should expect.

 

- Yeah, I think that, not to go off on a tangent here, but I think that a lot of patients are asked by, you know, friends and family, you know, in an effort to understand how serious their situation is. They're so conditioned to hearing with solid tumors you're stage one, stage two, stage three and in blood cancers it's just not done like that. And in CLL there is this, you mentioned RAI, which is R-A-I, it's a system that has been used but is not used consistently. So great. Correct. Okay, next question. You didn't include high blood, blood, white blood cell count in swollen or painful lymph glands. Do you want to address that real quick?

 

- I did, I did say painful lymphadenopathy. That's actually the second most common reason other than lab abnormalities why we treat, but I'm glad somebody brought up, I didn't mention high white count because it's not an indication for treatment. I have had patients whose white count has gone above 400 and remained without indications for treatment. So there's no white count absolute value that means you need treatment. I've had to start patients with low white counts. Actually sometimes CLL just stays in the bone marrow and you end up with a low white count. So yeah, white count in and of itself is not an indication for treatment. They used to say, oh, if it doubles in a certain period of time you should think about treating. But actually the international CLL criteria has tried to deemphasize that and no longer really explicitly uses that as an indication for treatment. Okay.

 

- Okay, great. So we, I'm just going to switch over to some of the questions that were submitted through registration. There are a couple of questions that are talking just generally about the concept of a cure. So maybe if you, I don't recall if you addressed this specifically? Yeah, but,

 

- And, and I think it's what do you conceptually think cure means? And with an aggressive leukemia or lymphoma a cure means total eradication and it never comes back. But with an indolent leukemia or lymphoma, I think the fact that the disease might still be present doesn't necessarily mean you're not cured. I think there is this concept that we refer to in the indolent lymphoma leukemia world called functional cure. And, and it means, yeah, maybe you don't totally eradicate the disease, but patients live a normal life expectancy and you've addressed the disease along the way as needed. And I mentioned there's some patients that actually never need treatment. So I consider a functional cure a type of cure. And I've mentioned already that the data suggests patients are living normal life expectancies with CLL. All that being said, we with these novel treatments only have about, you know, ibrutinib has the longest follow up with about 10 years and there's still some patients that have never progressed. You know, if we, if patients go 10 plus you know, 15 years, 20 years without another need, ever needing another treatment, maybe there are going to be some that are cured with these novel treatments and so that'll be really exciting to see as we get longer follow up. For a subset of patients that go through all these early oral targeted options, we do have CAR T available. We think for a fraction of patients that get CAR T therapy there's been, you know, all the way back to when CAR T was sort of first being invented, it got trialed on some CLL patients and there's some CLL patients that went, you know, over 20 years after CAR T and never had a recurrence. That's unfortunately just a subset of patients. That's not what you should necessarily expect. But, but maybe, yeah, after something like CAR T we are totally eradicating the disease.

 

- So I'm glad that you mentioned that CAR T because there was a question about CAR T and maybe, I'm not sure if you did address the options currently for CAR T for

 

- Yeah, I didn't explicitly address CAR T yet. I knew we had some questions on it. There hasn't been a whole lot of new prospective data since its approval. It was approved a few years ago, I believe it was 2022 timeframe that the liso-cel CAR T product was approved for patients that had had at least three prior lines of therapy. They had to have at least seen a BTK and a BCL2 inhibitor. Then with clinical trials being available and everything and our treatments that we have available already, the uptake of CAR T, you know how often we're actually using it is actually quite low. And partly contributing to that is the initial data from CAR T in CLL was not very promising. The complete remission rates were pretty low only around 15 to 20% or so. And the MRD undetectable rates were a bit better than that but, so kind of all that rolled together, CAR T uptake has not been very strong but there are select, a few patients that may ultimately need it.

 

We are feeling a little bit better about CAR T these days. There's been some real world data which, you know, has, you can't rely on it as much as like a clinical trial because there's a lot of potential, you know, flaws that can come just from, you know, looking at real world data. But there was some real world data that they looked at ASH this year and it showed that now that we, you know, have pirtobrutinib which, when the CAR T trial was originally done to get the liso-cel product approved, pirtobrutinib wasn't around. But now that we have pirtobrutinib it seems like that pirtobrutinib third, you know, being used as a bridge to CAR T looks to be a pretty effective option and people that are getting bridged to CAR T with pirtobrutinib are having better outcomes than what we would've expected from the original clinical trial. So maybe with that encouraging information, you know, we might think about CAR T more. I would encourage anybody in the crowd that has, you know, already seen drugs like ibrutinib, acalabrutinib, zanubrutinib, has already seen venetoclax and is now on pirtobrutinib, I would encourage them to seek out a CAR T center to be evaluated because you know, I mentioned those degraders might be coming down the road in a year or two, but you know, right now after, after pirtobrutinib it really just is CAR T as sort of a novel option. So it's better to go to CAR T when your disease is under good control.

 

- Great. And then one person who did have the CAR T already asked what are options for her if and when that is no longer keeping it at bay.

 

- Yeah, so I of course, and I don't know that specific patient's background and what they have been treated with before, but you know, if that was a patient that didn't have the BTK inhibitors or Venetoclax or pirtobrutinib as an option and they went on, you know, CAR T after all those other agents and then they needed something, that would definitely be a situation where I would seek out a clinical trial because there's not, at this point, you know we've got four real solid lines of therapy I would say between, you know, the covalent BTK inhibitors, BCL2 inhibitor- that's Venetoclax- pirtobrutinib, non-covalent, and then CAR T. So we're working on trying to find, you know, for those very few patients that need something beyond four, we're working on it. So that that would be where a clinical trial would come in.

 

- Okay, great. Let's see, how do you decide at what point a patient who has been on acalabrutinib for two years and is now stable that they can go off of it and…

 

- Yeah, that's, there are a lot of physicians I've seen that are sort of doing this on their own and I would just be cautious about it in what I'm referring to is discontinuing BTK inhibitors because a patient's been responding well for a while. And how these drugs were approved was that you'd take them for as long as they work or unacceptable toxicity. There is some research interest in looking at maybe if a patient really wanted to stop, adding Venetoclax for a period of time and then stopping, but there actually was some data looking at acalabrutinib specifically at ASH and having sort of a point where you just stopped and the patients progressed pretty quickly. So it's not, you know, just stopping a BTK inhibitor because you've responded for a while isn't recommended at this point if you want to get your longest remission.

 

- And this is a question regarding the degraders. Are the BTK degraders, is the goal for them to replace the BTK inhibitors or use as an adjunct or something else?

 

- Yeah, and you can kind of see the pirtobrutinib story as sort of the model for how things work in this crowded treatment landscape. So what happens sort of sequentially is you get a drug approved in the patient population that needs something the most and that's the easiest population to do clinical trials in and find an approval pathway. So the degraders will get approved initially as single agents, again taken until progression or unacceptable toxicity and it's going to be third line plus. It'll be for patients that have seen BTK and BCL2 inhibitors, I don't know if the FDA will say they have to have seen pirtobrutinib as well, you know, we'll see Just like pirtobrutinib has, they'll try to work their way up. There are head-to-head trials of each BTK degrader versus pirtobrutnib. They think they can show superiority. So if they showed that, then in theory you could get degraders as early as second line and then, you know, they may try to move into the first line setting. I think in general, the way to get into first line setting is going to be through time defined combinations. I think that the days of indefinite, of trials looking at indefinite frontline treatment are going to be coming to a close. We've just got such good options, it's going to be too hard to do that kind of a trial. You know, putting something like ZANUBRUTINIB vs a degrader, that trial would take forever in the first line setting because like I was saying, it's quite reasonable to think Zanubrutinib could get 10 years of average progression-free survival as a first line treatment. So I think the way drugs will be working their way into the first line setting will be through time defined combinations and sort of the standard for time defined combinations has been venetoclax obinutuzumab. So that's what you're seeing as the control arm that new treatments are measuring themselves against, these time defined treatments in the more novel trials. And then now we've got Acalabrutinib Venetoclax approved Friday and so that that will be a standard to compare against the one year treatment with Acal and Venetoclax.

 

- Okay. We have a couple of questions here about Sonrotoclax.

 

- Yeah. - When do you think Sonrotoclax will be available, approved as an individual treatment and as a combination with zanubrutinib? And then second, based on early clinical trials, sonrotoclax appears more potent and potentially safer than Venetoclax. What are your thoughts on this?

 

- Yeah, I think safety kind of to be determined. So I personally have done a lot of trials with sonrotoclax, I'm excited about it. I think it's going to be unclear initially how effective it is in patients that have progressed or have had significant treatment on Venetoclax already. So this isn't necessarily something that's going to be developed to give after Venetoclax. It's trying to directly compete with Venetoclax. So how much sonrotoclax will ultimately help somebody that's already been treated with Venetoclax is unclear. The timing of when it could become available. So the phase three trials with sonrotoclax in the relapsed setting directly going head-to-head with Venetoclax are still ongoing. So interestingly enough it could get approved first as a combination with Zanubrutinib in the first line setting because the head-to-head comparison in the relapsed setting with Venetoclax and anti CD20 I have that trial, you know, ongoing right now at my institution. But the frontline trial that compared one year of Zanubrutinib and sonrotoclax to one year of Venetoclax and Obinutuzumab, that's called the Celestial trial. And that finished enrollment well over a year ago. It was a super popular trial that enrolled very quickly. I have a lot of excitement for that combination. I think, you know, it will be a little while before we get a head-to-head comparison between that and acalabrutinib and Venetoclax, but I think when just the response rate data get presented, I think it's going to look really good and the numbers will probably, you know, sort of side by side look better than what we see with the Acal and Venetoclax. So I could see sonrotoclax coming available in the next couple of years.

 

- Okay. One person asked if there's any updates in bispecifics -bispecific antibodies, right?

 

- Yeah, I've got a sort of a sad update. I was very excited about epcoritimab and its use in CLL and it has phase one data that was looking even better than CAR T. Epcoritimab has had numerous approvals across many different lymphomas and I was informed at ASH that they've, you know, the company made a business decision and even though there was promising data, they just feel like the oral treatments with the degraders coming and everything and what we have, they're just so good that there's not going to be many people that need BISPECIFICS in CLL. So at least as of you know, just a couple months ago what they were telling me was that they're not pursuing additional clinical trials with epcoritimab in CLL. Okay.

 

So that doesn't mean that all bispecifics are gone. There's this other bispecific that I'm in clinical trials with that hits a different target. It's called Surovatamig and it hits CD19, which is the same target that CAR T hits. You know, the epcoritimab hits CD20 which, for those of you that aren't totally familiar with what I'm talking about, bispecifics, they hit a target on the cancer and then they also bind a T-cell and they bring the T-cell into close proximity. So they've been wildly successful in different lymphomas at having efficacy in patients that have progressed on monoclonal antibodies. And so epcoritimab, which is one of these CD20 bispecifics was looking, you know, at how they would do in CLL patients and it looked pretty good, but that one's not getting developed. We'll see about this CD19 bispecific that has some ongoing clinical trials. I think again, initially it would be for multiply relapsed patients, but there is some interest again in using it earlier as a time defined intervention to get really deep remissions.

 

- Okay. We probably only have time for one or two more questions. This one's an interesting one. This is an individual who has had eight treatments, BTK, btk one, btk two, btk degrader, CAR T cell. Now they're looking at pirto and obinutuzumab.

 

- Hmm, okay.

 

- Different combination.

 

- Well the pirto combinations that I'm aware of have been, there's been a completed pirto Venetoclax combination for relapsed patients with a triplet, you know, it's with anti CD20. That trial's done, there's frontline data with pirto Venetoclax obinutuzumab from MD Anderson. Just adding obinutuzumab to pirtobrutinib, I haven't necessarily seen data on that specific combination. I don't know if this is done, it's not how it's approved, but I don't know if this patient's talking about a clinical trial. If they are talking about clinical trial, then they're in the right, you know, place having seen so many prior therapies, you know, clinical trial enrollment would

 

- She said that her white blood cell count is 5.3 lots of swollen lymph nodes, but had CAR T-cell treatment in December, which changed the white blood cell count and her bone marrow is now normal, but CT scans show that the lymph nodes are growing.

 

- Hmm. Okay.

 

- Lots of information.

 

- Yeah, yeah, I would just always, one thing that hasn't come up in this presentation is the low percentage risk of a CLL changing to a more aggressive lymphoma. We call that Richter's transformation. Anytime that there's lymph nodes and somebody that historically had disease that would progress with elevated white count. If I encounter a situation where just the lymph nodes are progressing but not the white count, I always want to make sure to do a lymph node biopsy just to make sure that there hasn't been that transformation yet. It sounds like a tough case.

 

- So in a situation like that, if an individual is not at an academic medical center, would you recommend that they

 

- A hundred percent Yeah. Yeah. And it's not that we pretend to be smarter at academic medical centers, it's just that I've talked about just two different FDA approvals in the last two months in CLL and CLL is only going to be a tiny fraction of a general oncologist's practice. They see way more breast cancer, colon cancer, benign hematology. So CLL's not a rare disease, but it's just, you can't expect an onco, a general oncologist to keep up with everything to the degree that a specialist can. So when you, when you're getting beyond, I would say even when you're getting to third line, if you have access to a specialist and you haven't seen one already, it really would be in your best interest to get there. There is data to show not surprisingly that CLL patients that at least have some interaction with a specialist live longer. It's published data. So it makes sense.

 

- Okay. Okay. Were there any other questions that you felt you'd like to address? I think there's some, there's a couple of individuals who followed up specifically on questions that we had and I can try and follow up with you directly, but other than that, yeah,

 

- I think just in terms of the sea change and I tried to identify this with spending a lot of time talking about that CLL 17 trial because, you know, I think you could look at that trial that showed all of the kind of three approaches had similar outcomes and say, you know, well everything works good, I'm just going to keep doing what I'm doing. And in general, what has been the most common prescribed treatment for CLL patients has been single agent BTK inhibitor given indefinitely. And those are really excellent treatments and they're still going to be a really excellent treatment for a lot of patients under certain situations. But I think I'm just hoping in general with this data and more time defined options, I talked about acalabrutinib Venetoclax now available, you know, before too long, the zanubrutinib sonrotoclax is going to become available. I'm just hoping patients are at least getting discussed the option of time defined therapy because it looks to be just as good potentially and, with longer follow up, I think it's going to be really interesting. There were a lot of questions that came through about you know, BTK resistance and, and resistant mutations for different things. But, and what we've found with time defined therapy is it doesn't lead to resistance with the short exposure period. So I think it'll be really great if more and more patients are having these time-defined options ultimately discussed with them. And, and I think it's going to benefit a lot of patients because we're in a great place and I think it's a good point to conclude on, you know, we already know we've got for the overwhelming majority of patients, we're with enough good treatments that their life expectancy is not going to be affected by a CLL diagnosis. So now can we figure out the safest way, the safest and most effective way to give these treatments and take into consideration things like even like financial toxicity too.

 

- Okay, great. Well unfortunately, as I said at the beginning, we can't get to everything, but I think we covered a lot of ground during this session and I want to remind everyone that we do have another session coming in the fall. It's called Leukemia Q & A and it's really a great opportunity to kind of share your specific situation and, you know, get the take of usually two experts that are speaking from the chronic leukemia perspective. So we'll be sending some more information about those sessions out soon. We also have our spring series coming where we focus on clinical trials and also immunotherapy. So we'll have individuals representing the chronic immunotherapy treatment options as well as the acute immunotherapy treatment options, and then a separate session specifically on clinical trials. So these are all things that are coming in the near future. So please keep an eye out on your emails and social media, et cetera.

 

So wanted to just lastly, just acknowledge again, our supporters of this program. Thank you so much to the companies that provide support for our patient and caregiver webinars. And point out that the NCCN guidelines are always a great place to go for information. We also have some information on our website. And finally, just thank Dr. Jacobs for your time and thoughtful consideration of the questions and any final closing thoughts?

 

- No, it's just great to get, you know, it's not often you can get this many patients together and I love doing events like these. So thanks for all the good questions. Thanks everybody for tuning in.

 

- Wonderful, thank you so much everyone. Have a great day.