Transcription:
Diagnosing and Treating Chronic Lymphocytic Leukemia

Dr John Leonard (Host): Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care and research. I'm your host, Dr. John Leonard. And today on the podcast, we will be talking about blood cancers and, more specifically, chronic lymphocytic leukemia or CLL.

Our guest for this episode is Dr. John Allan. Dr. Allan is a medical oncologist and hematologist at Weill Cornell Medicine and NewYork-Presbyterian Hospital. Dr. Allan specializes in treating blood cancer patients with CLL and enhancing outcomes in quality of life for patients with this form of blood cancer. His research focus centers around improving CLL patient outcomes through novel diagnostic techniques and treatment options, including clinical trials and combination therapies.

Today, I'm really looking forward to speaking with him about the newest updates in research, treatment and care of CLL patients. So John, it's great to have you here today. Thanks for joining us. And I'm really looking forward to hearing your insights on CLL and where things are going in this field.

Dr John Allan: It's a pleasure to be here and I appreciate the invitation to share some thoughts.

Dr John Leonard (Host): So I'd like to start by getting a little bit of background on you. How did you find yourself heading toward the field of hematology and oncology in general and CLL in particular? What about these areas captured your attention and interest?

Dr John Allan: Every physician, researcher and doctor in the field has their own path on how they found themselves doing what they do. For me though, it's mostly about the exciting developments and genetic understanding of disease and the pathobiology of those processes, the new technologies that had been coming around as I was going into med school and graduating college, et cetera. And initially, I thought myself as a pharmaceutical executive pathway, honestly. As a teenager in high school and in my early college years, I'd be interning at pharmaceutical companies where I'm from, in St. Louis. But I was always a biochem major and was looking to marry all of these interests of mine into a single field. And, ultimately, it came back around to going to medical school, to where you can be in pharmaceutical drug development, as well as caring for patients and managing disease.

Why oncology? In medical school, it really just started to jump out at me very, very early regarding the genetics of hematologic diseases. And it really is pushing the boundaries more than any other field I found, looking at specific pathway mutations and looking at developing drugs to target these mutations. And really all of those things are the main reasons why I got interested in this field. And fortunately, I've been able to continue having these interests and passions incorporated into my career. And CLL essentially was all of these things. In CLL, we've had an explosion of drug development and understanding of the genetic underpinnings of this disease and really I've been just so fortunate to be a part of it and to continue to try to move the needle and push the field forward a little bit.

Dr John Leonard (Host): So let's get into the details of CLL or chronic lymphocytic leukemia. And maybe you can start with just a little bit of a summary of what is CLL. It's the most common of the leukemias. And people hear the term leukemia, they get scared, they think of intensive treatments and transplants and very challenging outcomes. But CLL, it differs from many of the other leukemias in a number of ways. So can you describe what's special and different about CLL amongst the different leukemias?

Dr John Allan: CLL stands for chronic lymphocytic leukemia. It also has a partner diagnosis called small lymphocytic lymphoma. So in reality, it's CLL/SLL. Regardless, these are both the same entities and diseases. CLL is the most common form. Eighty percent of patients present with a CLL state, meaning that the cancer cells are circulating in the blood. And, ultimately, this differs from other leukemias in that it's very indolent, it's slow-growing, it behaves itself for the vast majority of patients, and we don't really do anything about it at diagnosis. We monitor patients. In fact, that's the standard of care for almost all patients when they initially come and see me. My first inclination is never to be recommending treatment necessarily. It's about understanding this process.

It is the most common leukemia in the US. Its median age of diagnosis is around 70. There's about 20,000 cases diagnosed each year with close to 200,000 patients living with the disease in the US. So that just shows you that these patients are getting diagnosed, they're living long life expectancies and essentially normal life expectancies nowadays. There is a 2:1 male to female ratio and there are specific ethnic backgrounds that do seem to be predisposed to it. Most commonly, Ashkenazi Jewish, Caucasian, Eastern European ethnic background are where we see the highest rates of CLL. With that said, any patients from any ethnic background actually can get it. There are just some genetic predispositions that we don't quite fully understand that do lead to this predisposition to develop this disease later in life with the vast majority of cases being sporadic, though there are familial cases where we do see it inherited almost in a generational aspect with each generation developing a case as we follow these families along.

Dr John Leonard (Host): Just to reiterate that point and that issue, because the family history or potential family association comes up, you don't do anything special or recommend anything special for children or siblings of a patient with CLL as far as their screening or monitoring, do you at this point?

Dr John Allan: Correct. So when you look at the data, by having a first-degree family member, you have about a sevenfold risk of developing CLL in your lifetime. With that said, the absolute risk of just the US population of developing CLL is about 0.5%. So it's sevenfold that. And in reality, when you have a first-degree relative, you're still looking at a 3.5%, 4% chance in their lifetime to develop CLL. So it overall still remains small. The vast majority of cases are sporadic. When we do see these familial cases, we do collaborate with some researchers in Boston with Jennifer Brown and some other colleagues at the Mayo clinic, trying to understand these genetic underpinnings, and so we do send samples off. With that said, these familial cases, while there may be identifiable inherited genetic loci, when you look at different families, they are inheriting a different genetic loci. And so there's no specific test to look for, because it's not like a BRCA gene where that is the gene that is being passed on for everybody that develops a familial breast cancer. This is very different in CLL where there's different predispositions occurring across families. And thus, there's no one specific perfect test.

When there is a family member or parents in their 60s and they have children now in their 30s, let's say, I just say to get with your physician and do your routine once-a-year checkup and get a CBC. And if you do see an abnormality, to have it worked up on, because many times what we see is that there are mild elevations of a lymphocyte count that the primary care doctors, because you look well, you're feeling well, kind of just say, "Oh, it's an infection" and all of a sudden it continues to persist over the years. So, the diagnosis can happen then or three or four years later, the treatment would be the same. Though when you have it in the family, it is worthwhile to explore these a little bit sooner, because obviously early diagnosis is always good and it's going to help educate you, prepare your life and identify something that may be a problem for you potentially into the future.

Dr John Leonard (Host): As we think about CLL, patients often ask, "Why did this happen?" or "What is happening in the cells?" CLL is not a disease where the cells typically are growing like crazy. They tend to hang around longer than normal. But what is the current state as to the pathophysiology of what's happening in these cells that makes them accumulate in the blood and the lymph nodes?

Dr John Allan: So the abnormalities, it's questionable if there is a stem cell, so to speak, that has a very, very early mutation in our bone marrow at very early maturation points of these lymphocytes. In general, we think that the mutations occur late and in more mature lymphocytes that are kind of already circulating in the body.

There are different loci that do get inherited that we believe may lead to disruptions in B-cell receptor signaling and B-cell maturation, et cetera. But those aren't very well elucidated. We understand areas of chromosomes, but specific genes that you knock out or knock in have never really come to full fruition in terms of true understanding of absolute development. We do understand there are driver mutations for sure that when these occur, they push the cell down the hill to where more mutations may start to occur, leading to this unbridled growth and inability to die off. We do understand that there are recurrent abnormalities. And these are all essentially leading to the development of CLL. These are occurring just in the CLL cells, they do not occur in all of the cells in the body, the normal skin cells and things like that. They're not developing these mutations. It is literally in the lymphocyte population only that becomes CLL.

And so we do have a good identification of these genetic mutations that occur in specific proteins and pathways that lead to CLL. At what time point do they occur and what sequence do they need to occur, that's a little less well developed and understood. But once we identify them, it does help us stratify our patients and start to predict the future for that patient depending on any certain smattering of different types of abnormalities that might be present at the CLL and then, assess that risk for the patient over the next two to 10 years of their life.

Dr John Leonard (Host): How are most patients with CLL diagnosed? How do they come to medical attention? And really, is there any sort of screening or warning signs people should think about as they think about the diagnosis in this scenario?

Dr John Allan: The vast majority of patients, in fact over 60% of patients, present because they feel completely normal. They went to their primary care doctor for colonoscopy checkup or just a routine checkup. And it's been maybe a few years and when they look back at their CBC in 2018, it was normal. The CBC in 2021 now has a mildly elevated white blood cell count and lymphocyte count. The primary care doctor sees that, refers to the hematologist. We can do a very simple test, a blood test called flow cytometry and identify these cells in the blood. And well over 60% of patients are picked up in this asymptomatic state and basically identified because they had a routine CBC done for whatever reason and found this abnormality.

There is no real recommended screening outside of a complete blood count or CBC, which is just a routine test that your primary care doctor does on you all of the time. So there's no recommendations like a colonoscopy or mammograms, nothing like that has been recommended for CLL outside of just getting these CBCs and acting on any abnormalities that might be present, getting referred to a hematologist, so we can do these more definitive tests and give the actual diagnosis. But the vast majority of patients feel completely well and are always kind of surprised that there is something in fact going on in their blood.

Dr John Leonard (Host): One of the things that comes up in CLL, and you alluded to it earlier, is that many patients are watched without treatment at diagnosis. And for many patients, when they get a diagnosis of a cancer, the idea that they're going to not get treated and just get monitored and watch it seems kind of crazy to them, because it's not really what we think of in cancer. Why in CLL is the watch-and-wait or the careful monitoring strategy one that many patients can consider?

Dr John Allan: This is something I always go through with my patients when they come and see me.

And so, when we diagnose these patients back in the '80s and '90s, we had not great tools to identify high risk patients. And we only had chemotherapy that really didn't work for the high-risk patients. But we randomized patients to early treatments at diagnosis and randomized another group to just observation. Multiple studies over these early formative years in the CLL space continued to show that patients live the same amount of time, whether you start early at diagnosis or you start at the onset of the symptoms, the fevers, night sweats, the lymph nodes, the low blood counts, the big spleen, things like that. All the patients live the same. And really, the only ones that benefited were the ones that were sick and needed treatment. And so that set the stage for where we’re at right now.

This is potentially going to change though in the future and is an area of active research, because now we can identify high risk patients. I've had patients go 20 years without treatment. So the low risk patients, typically the median time to first treatment might be 10 plus years, so they're not going to need something at diagnosis. But we can now identify high risk patients that may need treatment within two to three years of their diagnosis. And now, we've got really good drugs that actually are well-tolerated, nontoxic and can target and overcome the high-risk features of these patients. And so we do believe that it is possible that, if you treat early in these high risk patients and preventing two to three years of additional mutations and abnormalities to occur, it's possible we contain the disease a little bit better, we prevent it from being more aggressive. And maybe on the back end of this five to 10 years from now, we might improve an overall survival in these high-risk patients.

So this is a question that's being asked. We still have probably five to six, seven years of follow-up before we really understand if early intervention in high-risk patient matters with these drugs. But these clinical trials are ongoing right now and are going to be an area of active investigation over the next five to seven years.

Dr John Leonard (Host): On the other hand, there's a group of patients that are diagnosed even earlier, this group of patients that don't meet some of the criteria for CLL yet are detected to have an abnormal percentage or number of lymphocytes in the blood. What about those patients and how do we approach them?

Dr John Allan: This is something I provide a lot of education for, because there are patients who get diagnosed with "CLL". And then, they come and see me and I'm like, "Well, you don't quite have CLL yet. You have this entity called MBL or monoclonal B-cell lymphocytosis." It's a precursor lesion to CLL. But it matters because it does change prognosis and expectations into the future. And ultimately, it's a little bit of nuance because there's still no treatment being recommended. But it does reset expectations. And so being diagnosed with this MBL state is a patient who basically has less than 5,000 circulating CLL cells in the peripheral blood per microliter. And so the diagnostic criteria for CLL is to have 5,000 or greater CLL cells per microliter of blood floating around. And so the patients who don't cross this 5,000-cell threshold actually and technically are diagnosed in an MBL state. Many times, it's 2,000, 3,000 cells. Sometimes, it's 500 cells. Why this matters is that it does impact prognosis and expectations. Patients diagnosed at an MBL precursor state have about a 1% to 2% chance per year to require therapy for their CLL. And so if you're diagnosed at age 65, 20 years from now, you have about a 25 to 30% chance of maybe needing treatment. You will potentially progress towards CLL and crossing this threshold and get the actual diagnosis in this period of time, but you won't be requiring therapy. That's the big change in thought.

So it changes expectations, prognosis, and how we think about a patient and ultimately how closely we follow them up. If you're in an MBL state, I frequently follow my patients on a yearly basis. I try to make their life easier. They have got other doctors, they're living their life, they're traveling, they're doing whatever. And they don't need to come and see me constantly just to see their blood count be completely the same as it was the year before. So, that's kind of how we think about it, this earlier state to be aware of. And obviously, it's a good thing in general, because it does mean the disease will behave itself probably for quite some time and you won't require treatment any time soon in the near future.

Dr John Leonard (Host): For a patient who has CLL who's been watched for a period of time, what are the scenarios or the changes in their condition that would say, "Okay, we've been watching you. But now, it's time to do some treatment or think about doing some treatment." What are the changes either to watch for or that you, as the treating doctor, would say, "Okay. Now, it's time to get going."

Dr John Allan: So, the iwCLL guidelines has put guidelines forward to help physicians know when to treat, because that's always the question. Some patients look very good, they feel very fine, but their white count might be 120,000, and have no other abnormalities. And so these patients may go a few years still without any abnormalities that are occurring that require treatment. And so that benefits them because you spare them toxicities of therapies and things along those lines. So the iwCLL guidelines has put forward about five indications, main indications. Those being B symptoms, fevers, night sweat, weight loss, fatigue. You got to be careful with fatigue. Everyone has fatigue. CLL definitely causes fatigue, but it is also very multifactorial. So when that is the only indication that somebody has, I typically say, "This is not enough." And in fact, the treatments that we have can cause fatigue.

The next indication will be progressive and/or symptomatic lymphadenopathy and splenomegaly. This can be a little bit subjective to the doctor and to you. But in general, we're not talking about a 1.5 centimeter lymph node that you only pick up on scans moving to 1.8 centimeters over the course of two or three years. That is not progressive. We really want to see things moving 3 to 5 centimeters or now getting to 6 or 7 centimeters big. That's where we're talking about needing to intervene.

Just like this is growing in the lymph nodes and spleen, it's doing in the bone marrow, so we see a hemoglobin drop and a platelet count drop or red blood cells. So a hemoglobin less than 11 or a platelet count less than a 100,000 are classic indications for therapy. Not that you have to do it at that point in time, but these are guidelines and technically indications for therapy.

And then, we see autoimmune conditions. So a lot of times, patients can develop an autoimmune hemolytic anemia or really bad ITP and it's being driven by the CLL and the T-cell synapse being dysregulated by the disease itself. So you really have to clear the CLL out. No amount of steroid is really going to fix this problem and you really need to attack the CLL.

And then, the fifth indication is CLL is not a disease that doubles. And in fact, less than 5% of CLL cells are doubling at any given time or cycling. But when you do see it double, that means there is a new mutation. There has been something that has occurred and it's changed its behavior in biology. And it's only a matter of time for all of these other things to be happening shortly following that. So a doubling time less than six months is an indication for therapy and something that we watch and is why we bring patients in every three to four months to make sure that we can track out the rising white blood cell count, because the natural history is for the white count to continue to rise over time. It may fluctuate. But in general, the trend over years will always be an upward slope. And so we want to monitor the changes of those slopes to be closely on top of it and to intervene and to prevent you from getting so sick and steer patients around as soon as they have these indications for therapy.

Dr John Leonard (Host): So before we get into therapy choices, maybe you could just give us a brief overview of some of the genetic or genomic or prognostic tools that we have available, particularly since some of these can potentially impact therapy and at various points in time should be checked from the patient's blood.

Dr John Allan: Absolutely. So there are three big classes of molecular tests or genetic tests that we do, understanding these abnormalities within the CLL cell. And the first is fluorescent in situ hybridization or FISH. This is a test most patients get. And this is very predictive and prognostic in terms of how patients may respond over the next five to ten years with treatments, et cetera. Eighty percent of patients have one of five abnormalities that are present on this CLL FISH panel. And each abnormality that is present has a little bit of a different prognosis.

In general, the vast majority of patients have good prognosis abnormalities with deletion 13q being the most common, trisomy 12 being the next most common, also a good risk. And then, we have our high-risk abnormalities that fortunately only about 20% of patients at diagnosis harbor. These being deletion 11q and a deletion of 17p, which is still the group of patients, the deletion 17p patients that we absolutely still worry about and are still thinking about if we need to be treating them differently and how best to manage those patients going forward. So we send those tests. We get it back. It's peripheral blood. You don't need a bone marrow biopsy.

The next big test that we do is we send the IGHV mutational test. This is an antibody gene. CLL cell requires this gene to survive, and we can tell by sequencing, the mutated form paradoxically is good risk. The CLL cell and its normal maturation purposely mutates this gene in order to finely tune the antibody against whatever antigen that CLL cell might be against. And so the mutated form of this gene is actually a good risk, showing that the cell is following the rules and behaving itself and kind of maturing normally. The unmutated form is actually the higher risk, more activated, aggressive CLL. And ultimately, we don't know at diagnosis which one you'll be, because it's 50/50 mutated or unmutated.

And then, the last big group of testing that we do in our center here is the next generation sequencing where we sequence about 200 or more genes or so that are known to be a part of lymphomagenesis. And out of these 200 genes though, in fact, only about five are independently validated at identifying a patient's time to first treatment or how they may respond to a specific treatment, et cetera. So we look for these five, but we get a lot of other information that in the future we'll probably use, because as you look in the literature every six months to one year, there's a new mutation that's being called that may have some important prognostic impact, et cetera. And as our therapies change, it's important to collect this information going forward. So we send all these tests and then we identify your risk, low, intermediate, or high. And then we set a following pattern for you going into the future. And then, we set some expectations on when we might think that you might need some treatment.

Dr John Leonard (Host): For many years, chemotherapy was the backbone of treatment for CLL. But now, things have changed so much in the last few years to the point that chemotherapy is rarely used for patients with CLL. So maybe you could tell us a little bit about how for the most common scenarios for patients who reach a point of needing therapy, what are the options and choices, recognizing that there are a number of them, the most common scenarios that patients might consider as far as starting treatment and choosing options?

Dr John Allan: Since early 2016, we've had targeted agents, like ibrutinib, available, non-chemotherapy approaches in the frontline setting for our patients. And so, particularly in the US, we have been getting away from chemotherapy as the frontline choice. And it wasn't until about 2018, 2019, when the first clinical trials against the standard chemotherapy arms of ibrutinib-based therapies against FCR and BR started to report out showing improved outcomes and better safety profiles for the BTK inhibitors and targeted agents over these standard chemotherapy options.

And so it was really then that it was solidified that targeted agents are the absolute standard of care in the US. And to support that, the NCCN guidelines have now stated that the targeted agent approaches, the BTK inhibitors of which we have three and venetoclax-based therapies are the preferred options for frontline therapy for patients. There can be arguments in the field still that low-risk patients might be able to get away with chemotherapy. But we have just so much data that supports these targeted agents as being the standard of care. And in the US, that has been widely adopted. And frankly, in the world, it's moving towards that, to where chemotherapy for CLL is pretty much not the standard. And I do implore patients, if they are being recommended for chemo, to ask their doctor why and/or potentially even seek consultation, because there may be other options for you that might not be chemotherapy-based and might be actually even more ideal for you.

And so really, these are the best options. They're well tolerated. There's several classes of drugs. The vast majority of patients are going to need just two classes of drugs, in my opinion, going into the future. And we've really hit homeruns in CLL and these drugs have revolutionized lymphoma care across all histologies, not just CLL, but in other aggressive lymphomas, and even in diseases like AML, we're using these new drugs.

So, we've really seen just a tectonic shift over the past five to six years since I've been practicing, which I started in 2015 and was fortunate to come into a time era where we didn't use chemo for our patients anymore. It's been just amazing to see these long-term outcomes and how well patients are doing and how well they're tolerating these new drugs.

Dr John Leonard (Host): As people go forward with their therapies, how does one think about choosing between different options? I know that the duration of therapy or a time-limited approach is one of the factors. How should patients think through their options as they speak with their doctors and what are the general themes of strategy when or if the disease comes back?

Dr John Allan: This is where it's still kind of tough to have true evidence-based data to really guide the best therapy for each patient based on their biologic underpinnings of their disease. Because right now, we don't have head-to-head data of targeted agents against each other. These studies are ongoing and we are looking forward to the future of them. But a big conversation about what is best for the patient, what are their preferences, what is their lifestyle like. There's obviously a little bit about the biology of the CLL that might dictate in the treatment approach. But it's important to remember right now what we have available are BTK inhibitors. And these drugs are used as monotherapy, generally, sometimes with an anti-CD20 like obinutuzumab or rituximab. And these drugs are great. They're the first ones that change the world and have eight plus years of follow-up data and are leading the way in terms of expectations for long-term outcomes.

The downside is that they do have toxicities and you do need to continually take these drugs, we believe, to really suppress the disease long-term. And if you can stay on them and take them, it's possible there may be many patients, 10% to 15%, 20% that might be 10 years plus out still taking these drugs. So, the longest patients I have going on them are now about six or seven years. And I don't see any reason that they're going to fail these drugs potentially in any time in the near future.

The other approach that we have is a fixed duration approach using venetoclax and an anti-CD20 antibody, obinituzumab. This is very attractive for a lot of reasons. One, venetoclax is probably the better tolerated agent or class of drugs compared to BTK inhibitors. And two, it's a fixed duration. So patients can get off of therapy after one year of treatment. The downside is that the drug can require a lot of intensive monitoring. Sometimes patients who are not living near the center that you're being cared at can have difficulty getting in for all of this intensive monitoring. And you do have to have an infusion with it to really have the good long-term outcomes and so that requires additional treatment and needing to be in the infusion center, where other approaches are just pills.

So, the outcomes are outstanding. Historically, they are equivalent essentially. They have not been head-to-head studied yet. They are ongoing currently. So we'll know the answers. But there are very different approaches and you can see just me trying to explain this how complicated it can be for a patient to understand all of their options and how complicated this conversation is. So I typically start this conversation months in advance. Once I see the disease starting to progress, I start to lay the groundwork for trying to understand what the patient's wishes and which approach they seem most attracted to and do I agree with this based on the biology, et cetera, and really let the patient make their decision and help them along in this decision-making. We can work together at tailoring the best treatment for you at this point in time until we have evidence that suggests that we need to go one direction or another based on a certain set of features and factors on that disease staying and comorbidities of the patient.

Dr John Leonard (Host): One area of your research has been in Richter syndrome. And I wonder if you could just take a minute and tell our audience a little bit about that scenario and how we approach it.

Dr John Allan: Richter's is a scary thing when patients get diagnosed with CLL. They start reading about it, because it's an event that occurs. The CLL transforms into an aggressive lymphoma that frequently does not respond very well to treatments and can be life-threatening, unfortunately. And so patients hear about it and they worry about it. Now, fortunately, only about 10% of all CLL patients will transform in their lifetime. As we get away from using chemotherapy, we think we might be able to actually impact upon that transformation rate. And the 10% of patients that do transform, we can pretty much predict, if you will, in your lifetime or not, based on all of these genetic features. And so I can give a lot of patients reassurance based on their genetic features at their diagnosis, that it's unlikely that they will ever transform in their lifetime because it is enriched in these patients with very high risk features of their disease. And we find them, we identify them, and we manage them differently.

If a transformation occurs, we have to use aggressive chemotherapy. We typically use chemotherapy that we use for other diffuse large B-cell lymphoma therapies. In particular, we have a clinical trial here enrolling now, where we're using a new drug called polatuzumab and combining it with the standard chemotherapy backbone that we use for Richter's transformation called R-EPOCH. And so this is a clinical trial that we have open and enrolling, and we're opening several sites around the city in New York and potentially one site out of state to enroll patients with Richter's transformation newly diagnosed. So that's an option for patients out there, and is kind of our approach that we're using right now. But if you don't have a clinical trial, we're typically just using standard chemo immunotherapy approaches.

Dr John Leonard (Host): So before we wrap up, I just wanted to ask you, what you're most excited about for the future, what's on the horizon? I want to ask you first about CAR T-cells, and then just any other things on the horizon that you think patients should keep an eye out for in the coming years.

Dr John Allan: There's a few exciting things that we're doing here that I'm involved with. One is learning how to combine all of these drugs that I briefly spoke about into frontline therapy. We know that when we use them together, there can be synergies and, in fact, get really, really deep responses in high-risk disease patients. And so, I have designed another clinical trial that we will be hopefully opening maybe by November, by the third or fourth quarter of this year, enrolling newly diagnosed CLL patients utilizing BTK inhibitor called zanubrutinib in combination with venetoclax, so an all-oral treatment approach. And then, in those patients who do not have the deepest remission, that we find CLL floating around in the blood, we actually extend the treatment for about six months and we add on the anti-CD20 obinutuzumab to in a way rationally maximize and optimize a therapy for all patients. And we hope that the vast majority of patients will be MRD negative, meaning we cannot find CLL in their blood. So, stay tuned for that. And obviously, that is something exciting that I'm very proud of and, hopefully, we have up running soon.

The other treatment advances, we're looking at understanding resistance with other small molecule inhibitors. These are pills. We have several on the horizon that can overcome resistance to the drugs I was already previously talking about, the classic BTK inhibitors and venetoclax. And so these drugs are on the forefront and might get approvals in the next year, year and a half or so, the first generations of them.

And then, we have another exciting clinical trial that we're opening here soon, probably in early September, utilizing what are called PROTAC degraders. So that will be an exciting way to address resistance in BTK resistant patients, and CLL patients that are progressing through these drugs that I've been speaking about.

And then, the immunotherapies, as you spoke briefly about, CAR-T cell has activity in CLL. It hasn't gained as much fanfare as we've seen in other histologies, but it's getting there. The studies are ongoing. It's just that we have so many good small molecule inhibitors that, do we need the toxicity and the chemotherapy treatments and all these things that you require for CAR T-cells? And right now, I think that's one hindrance to development of that space is the toxicities, and the fact that we've just got great, great therapies for CLL already, that many patients don't even need the CAR T-cell for their disease.

But outside of CAR T-cell, we do have bispecific antibodies that are being developed in CLL as well, that are showing some nice activity. These are basically like CAR T-cells in a bottle in a sense. It's like giving rituximab. It's just an antibody. You can dose patients relatively quickly and get them to max doses over a couple weeks. And while they may have toxicity similar to CAR T-cells, it is much more tolerable, much more manageable and much more lower grade. And so, in CLL, maybe this is the way we go and not just CLL, but all lymphomas.

These are exciting classes of drugs, exciting immunotherapies that are available in CLL right now only in clinical trials and not currently FDA approved for commercial use right now. But they're there. We have these studies open and we do look for patients and a way to push these advancements forward.

Dr John Leonard (Host): Well, thank you very much, Dr. Allan. This has been a great discussion and really, you've given us an overview of a detailed and complex topic. So thanks for joining us.

Dr John Allan: Absolutely. It's a pleasure. Nice to speak with you. And hope to be back in the future.

Dr John Leonard (Host): I'd like to invite our audience to download subscribe, rate, and review CancerCast on Apple Podcast, Google Podcasts, Spotify or online at weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments, and topics you'd like to see us cover more in depth in the future.

That's it for CancerCast, conversations about new developments in medicine, cancer care and research. I'm Dr. John Leonard. Thanks for tuning in.