Update on Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma | LRF Webinars

Hello, welcome to the Lymphoma Research Foundation's update on Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma webinar. I'm Kendall, and I'll be the moderator for today's call.

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And now, I am pleased to introduce Jesse Brown. Jesse Brown is the Associate Director of Patient Education at the Lymphoma Research Foundation. Welcome, Jesse.

Thank you, and, uh, thank you to each of you for taking the time to join us on today's update on Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma webinar. We'd like to thank our sponsors of this webinar, Adaptive Biotechnologies and AstraZeneca. Access to expert disease information is so important, and we are thrilled to be able to bring you this educational program.

Before I turn the program over to Dr. Mock, I want to share information with you on the Lymphoma Research Foundation. The Lymphoma Research Foundation is the nation's largest nonprofit dedicated exclusively to lymphoma. Our mission is to eradicate this disease through investment in the most promising lymphoma research and to serve those impacted by lymphoma through quality education and support opportunities.

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We have a wonderful program planned for you today, and I'm honored to introduce you to Dr. Shuoma. Dr. Ma is a hematologist and medical oncologist at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, where she is also an associate professor of medicine. Her research focuses on chronic lymphocytic leukemia and novel treatment approaches. Thank you so much, Dr. Ma, for presenting today. I'll now turn the talk over to you.

All right, thank you, Jesse and Kendall, and good morning, everyone. Um, welcome to the program. So today, we're going to talk about CLL and SLL, uh, on current treatments. Here's the program outline. So first, we're going to go over some basic information about CLL, and then we're going to focus on the current treatment options, comparing the previous standard care of chemoimmunotherapy with the current new options of targeted therapies. And we'll talk about a number of randomized clinical trials comparing the old and the new standard. For now, and then the last part of the talk will be talking about some exciting new developments in the CLL treatment arena. So, as you know, that CLL treatment has been really evolving over the last several decades. So we're having a lot of new developments to share, a new exciting new direction to share with you today.

So, just to start about CLL, for those who are new to the CLL diagnosis, some basic information here. So, first of all, what is leukemia? Leukemia is the disease of the white blood cells. When there are clonal expansion of abnormal white blood cells in the blood and in the bone marrow, that shows us leukemia. So, we know that bone marrow is a place where all of our blood production occurs. There are three main types of blood cells: the white blood cells, red blood cells, and platelets. So, when there are leukemias, the leukemia can arise from any type of the different type of white blood cells. So, you can see their myeloid precursors and their lymphoid precursors. So, when making mature blood cells, you can see in the blood counts, the major white blood cell groups include neutrophils and lymphocytes, and there are some minor groups including monocytes, eosinophils, basophils.

So, CLL, the chronic and lymphocytic leukemia, is a disease of the B lymphocytes. So, this is a disease of a mature, what we call CD5 positive B lymphocytes, that's accumulating in the blood, in the bone marrow, but also involving the lymphatic system. So, what's making the lymphocytic leukemia different from other leukemias is that because the lymphocytes not only travel and grow in the blood and marrow system, but it also expands in the lymphatic system. So, we're going to see presentations of lymphatic involvement as well.

Another term for CLL is SLL, which is a small lymphocytic lymphoma. So, the reason why that's called is because, exactly as I said, CLL can have lymphatic involvement. So, people can have enlarged lymph nodes or enlarged liver and spleen. So, those are the features of the lymphoma. So, because it's a lymphocytic type of leukemia, it can have both leukemia and lymphoma type of features, and these two diseases are really the same process biologically. They are really the same. It's just some patients present in a different way when they're initially diagnosed. So, most patients with CLL initially were diagnosed because they have elevated white blood cells, which we can see the circulating leukemia cells in the blood. So, that's more of a leukemia feature. But they're also patients who present with normal blood counts, so with enlarged lymph nodes, and the diagnosis were made on lymph node biopsy. So, that's more like lymphoma, but it's really the same type of disease with different presentations. And most patients during the disease course will have both features.

CLL/SLL belongs to indolent non-Hodgkin's lymphoma. It accounts for about 20% of all B-cell lymphoma leukemias, but it's actually the most common form of leukemia in the Western society, accounts for about a third of all leukemias. There are over 20,000 new cases diagnosed per year and over 150,000 patients in the United States. CLL is a disease that's occurring mostly in older patients. The median age at diagnosis is about 70 years. They're more male patients than female patients, and it's more common diagnosis among Caucasian patients and much less common among African-Americans or Asian patients.

There's really no clear environmental or occupational risk factors that's causing CLL. There are a small number of CLL patients who have a strong family history, may have a genetic predisposition for developing CLL, but the vast majority of CLL patients, the cause of that is unclear. But we do know that aging is definitely a major component that's contributing to the CLL occurrence. If you look at the age-adjusted incidence of CLL, the incidence really goes up with different age groups. So, the higher the age, the more advanced the age, the higher the incidence of CLL. And if you look at the patient age distribution for all of our CLL patients, over 70% of patients are age 65 and above, and over 40% of patients are age 75 and above. So, it's more for older patients' disease, but we do have some younger patients, but it's much rarer.

So, the disease features of CLL. We talked about CLL being leukemia that involves the blood and the bone marrow. So, with time, most CLL patients will have an increase in their white blood cell count, primarily the lymphocyte count in the blood, and also increasing involvement in the bone marrow. If the bone marrow is occupied by increasing amounts of leukemia cells, at some point, it's going to affect its production function for other normal blood cells. So, people can develop low red cells, which leads to anemia. They can have a drop in the platelet counts or other good white blood cells such as neutrophils. So, that's what's going on in the blood and marrow.

And as the disease is progressing in the lymphatic system, CLL patients can, with time, develop gradually enlarging lymph nodes. And we have lymph nodes throughout the body. Some of them can be easily palpable on exams, such as in the neck, in the armpit, and in the groin area. But there are also a lot of lymph nodes internally in the chest, in the abdomen, pelvis, which can only be visible on the CT scan. Some patients can also develop enlarged liver and spleen.

Sometimes, CLL, especially in patients with more advanced CLL, because of the cytokine release, they can have what we call B symptoms, which include significant fatigue, unexplained weight loss, loss of appetite, chronic fever that's unrelated to infection, or significant night sweats. But CLL can also cause some other complications. For example, it can cause some autoimmune destruction of the red blood cells, leading to autoimmune hemolytic anemia. It can have autoimmune destruction of the platelet count, leading to what we call autoimmune thrombocytopenia or ITP. Now, this doesn't happen to all patients, but a certain number of patients may develop this autoimmune condition during a disease course.

CLL patients are more prone to infection because of the immune, immunocompromised state. So, we do educate our patients to make sure they're up to date on all of their vaccinations to minimize the risk of infection, and also make sure they're doing cancer screening, age-appropriate cancer screening, because there are some increased risks of malignancies. Richter transformation is a very rare complication of CLL in which the low-grade becomes developed into a more aggressive or high-grade lymphoma, and the treatment will be very different from the conventional CLL treatment.

There are a number of prognostic factors that we have learned over the years. The most commonly used ones were number one, the FISH study, which is a study looking at certain chromosomes which are commonly occurring, the changes that those chromosomes are commonly occurring in CLL. So, for example, 13q abnormality, 11q, 17p, or 12 chromosome. So, those are the chromosome abnormalities again that can be found among the CLL cell. It does not happen in your normal tissue, but only in the leukemia cells. We know that some of those chromosome changes are indicating higher risk disease. So, you can see the arrow pointing to 17p deletion being the most unfavorable, followed by 11q deletion. The 13q deletion is actually the most favorable. If patients only have 13q deletion, that's typically indicating a more indolent clinical course.

The next important prognostic factor is the IGHV mutation study. So, we know that about half of the patients have unmutated IGHV, which pertains to a relatively less favorable clinical course compared to the other half of CLL patients who have the mutated IGHV. And in recent years, there are also some newer prognostic factors worth learning. One of the important ones is called TP53 mutation. This one has a very similar high risk compared to 17p deletion because they're really affecting the same important tumor suppressor gene called TP53. Another one is called complex karyotype. So, patients who have multiple cytogenetic abnormalities in their chromosomes tend to have a higher risk. But these are all relative speaking, because CLL in general is still a low-grade, indolent, meaning slowly growing type of lymphoma or leukemia. So, the high risk is relatively speaking to other CLL patients.

So, most of the CLL patients, when they were diagnosed, were actually diagnosed early at early stage, when their most common finding is just a high white blood cell count, but they're otherwise feeling fine, their bone marrow function is not being affected. So, most patients at diagnosis do not require treatment. They can be safely monitored with periodic tracking in their blood counts and physical exams to see how the disease progresses. But for most patients, at some point, they will require treatment.

So, these are the common indications for treatment listed here. Number one is if patients are having evidence of progressive bone marrow failure, which means that when their bone marrow production function is going down, people will start to develop either progressive anemia or progressive drop in their platelet counts or neutrophil count. So, those are indications that the bone marrow function is being affected by the growing amount of CLL cells. Another thing, an indication would be if patients are having gradually enlarging lymph nodes or enlarged spleen/liver, especially when those are becoming bulky or growing relatively fast. So, that would be another indication to treat.

Symptoms. I mentioned the B symptoms previously. So, these patients have significant B symptoms, such as low-grade fever, night sweats, fatigue, unintentional weight loss. So, that would be another indication to treat. But I do want to caution you that those symptoms often are not specific for CLL. There are many other conditions that can cause those symptoms. So, it's important to discuss with your CLL physician to see if those are necessarily due to CLL or due to something else, because people can have fatigue from many other potential causes. So, we don't want to treat a lot because, you know, fatigue can be actually caused by a number of other reasons, and typically those constitutional symptoms do not occur until a patient has much more advanced CLL, when they're actually having some other indication for treatment.

Sometimes we treat CLL because your white blood cell counts are rising very rapidly, but just because the patient has a high white cell count, that itself is not an indication for treatment. There's actually no absolute white blood cell count number that we use to judge when to start. A patient can have white blood cell count over 100 or to 300, that still does not necessarily indicate treatment.

So, we're going to focus mainly for today's talk on the CLL treatment evolution. It's quite amazing to see how the CLL treatment has really evolved over the last several decades. So, the first several decades, from the 1960s to the 1990s, is more as the entire oncology world is learning about chemotherapy. So, we're also testing different types of chemotherapies in CLL. Initially, we have the alkylating agents, which are somewhat effective, and then the purine analogs came out, which include the fludarabine, that many people are familiar with, that seemed to be an even more effective chemo compared to the previous one. And then in the 1990s, it's the combination of chemotherapies. And in the 2000s, it is when Rituxan first came along. The Rituxan, we're going to talk about, is one of the most important immunotherapy that first came about. Um, so we have learned that when you're adding immunotherapy to the chemotherapy backbone, you can really improve the overall response and, you know, the duration of the response. But since the 2014, really in the past five, six years, things have really developed at a much more accelerated rate. So, now we're looking into a new era of oral targeted therapy. So, we're kind of, we're finding really this daily or once a day or twice a day medication that's working great and it's very well tolerated. So, in a lot of cases, I'm going to show you some data to show that there may be even more effective than the conventional chemotherapy. So, we're really going into a new era, and we'll be talking about the three different classes of targeted therapies: BTK inhibitors, PI3 kinase inhibitors, and the BCL2 inhibitors.

So, first starting with the conventional chemoimmunotherapy. So, this is, you know, before the targeted therapy era, this is what this was the previous standard of care for CLL. So, among the chemotherapies, which were listed on the left, we talked about primarily the alkylating agents. The most commonly used ones were bendamustine, also cyclophosphamide, chlorambucil. And then the second class of chemo is the purine analog. The most commonly used one is fludarabine. On the right are the immunotherapies. So, the immunotherapies are monoclonal antibodies that's targeting about, targeting a certain specific antigen, typically an antigen that's expressed on the surface of the leukemia cell. So, when those antibodies are binding to that specific antigen, they're able to label those leukemia cells, and the immune system would then be able to come in to destroy the leukemia cells itself. So, that's how the immunotherapy works.

There are two types of antigen we can target. One is called anti-CD20 antibodies, so it's targeting a B-cell marker. And the most commonly used antibodies are the Rituxan or rituximab, which has been combined with a number of different treatments. And then in recent years, a newer form of anti-CD20 antibody called obinutuzumab or Gazyva has been incorporated more into the more modern regimen. There's another antibody called Campath or alemtuzumab. It has been a very effective immunotherapy, but it does have some potential side effects. But because the manufacturer has pulled the product from the market, so this is not really being used that much, but it had been playing a very important role prior to five years ago.

So, these are the chemoimmunotherapies, and as if you can see the effectiveness of the different chemotherapy. So, C stands for just cyclophosphamide, F stands for fludarabine. So, when we're combining these two chemotherapies, you can see that it's working better, both in terms of overall response rate and the complete response rate. But when you're combining the R, which is the Rituxan immunotherapy, so now we're talking about immunochemotherapy, the combination of immuno and chemotherapy are really improving the overall response rate and the complete response. So, the FCR, there has been a number of very important large Phase III randomized clinical trials demonstrating that, first of all, adding Rituxan, the immunotherapy, is better than the chemotherapy alone. So, FCR has become the new standard. And then there are a number of other immunochemotherapy combinations that have been tested. So, the most commonly used ones were FCR for younger patients, so younger fit patients who can tolerate FCR. And then the next most popular for fit patients is the bendamustine-Rituxan map combination. And then for more older patients or patients who have a lot of comorbidities, will be using something called a chlorambucil or the obinutuzumab, the newer immunotherapy combining with the oral chemotherapy. So, these three regimens have been really tested in clinical trials, establishing that they're very effective. And the effectiveness are really the most effective with FCR, and the BR is the second most effective, and then the chlorambucil-based regimen is less effective. But the reason why we're choosing the less effective regimen is because the FCR does have a lot of toxicity. In fact, most CLL patients, because of the age group, would not be a good candidate for FCR because of its toxicity. So, we often will be either using bendamustine or Rituxan map or the chlorambucil-based regimen prior to the targeted therapy coming along.

So, then really over the past decade, there has been a lot of very exciting new clinical trials establishing that oral targeted therapies are becoming the now the new standards for CLL treatment. So, there are two large classes of oral targeted therapies. One class falls into what's called B-cell receptor pathway inhibitors, but that includes two subgroups. So, it can be an inhibitor of the BTK enzyme or the inhibitor of PI3-kinase enzyme. And under each category, there are multiple products already being FDA approved or close to getting FDA approval. For example, along the BTK inhibitors, which is the most commonly used oral targeted therapy in the B-cell receptor inhibitor pathway, it includes ibrutinib, acalabrutinib. So, these two products have already received FDA approval for CLL treatment. Zanubrutinib is a newcomer. It has not yet gotten at the approval for CLL, but it is approved for some other lymphomas. And then the second category is the PI3 kinase inhibitor, which includes idelalisib or duvelisib. So, those are the two oral PI3 kinase inhibitors that's FDA approved for CLL.

The second big category of oral targeted therapy is called BCL2 inhibitor. So, the product now is called venetoclax, which is a very important oral targeted therapy that works in a different with a different mechanism. So, let's look at the first category, the B-cell receptor signaling pathway. You can block this pathway either by blocking the BTK enzyme or PI3-kinase enzyme. So, here's the pathway. You can see that, you know, this is looking at part of the leukemia cell on the surface, or a lot of proteins. One of the important proteins called BCR or B-cell receptor. So, this is the protein that's very important messenger that really helps to transmit the signal from the environment, the leukemia cells are living in the environment that leukemia cells are living in, we call it microenvironment. So, the microenvironment sends a survival signal, proliferation signal to feed into the leukemia cells, and those signals are transmitted through this BCR receptor and then through a number of enzymes to transmit a signal inside the cell. So, there are several important enzymes in this pathway that could be targeted using oral targeted therapy. For example, the SYK, Syk, or the BTK, or PI3K. So, all of those enzymes are important messengers along this pathway. By blocking one of those enzymes, you can block the signaling for the B-cell receptor pathway.

So, what happens when you're blocking this pathway is that not only does it block the proliferation of the leukemia cells, but it also impacts the trafficking. So, those leukemia cells which were previously hiding in the bone marrow and the lymph nodes and the spleen are now being pushed out into the bloodstream. So, what we usually see is that when patients are starting treatment, you can see on the left, patients are having large lymph nodes or enlarged spleen. Once they start treatment, usually fairly quickly, within a matter of few weeks, they can notice a pretty rapid shrinking of their lymph nodes and rapid shrinking of their spleen. And that's because those leukemia cells are leaving those places and coming out to the blood, where they're no longer able to receive those feeding signals, and those cells will gradually die away as a result of that.

When patients are starting treatment, when you're looking at the peripheral blood white blood cells, looking on the left, the graph shows you before the treatment, patients' white blood cells are going up with time. Their hemoglobin, platelets may be going down with time because of the leukemia progression. The graph on the right is showing that once they start the B-cell receptor pathway inhibitor, you can see that their white blood cell counts can really go up. Actually, about 70% of patients who are starting on things like acalabrutinib will have an increase in their white blood cell count because those cells are trafficking out of those lymph nodes and spleen and coming out of the blood. So, you can see increasing their white blood cell counts at the beginning of the treatment, which may peak around a month or so during the treatment, and then after that, the white blood cell count will gradually go down. So, eventually, it's going to go below the pre-treatment level. And some for some patients, they may normalize. Other patients, it may not completely normalize, but they may at a relatively low level as the treatments are ongoing. You can see that the hemoglobin and the platelet counts often will improve with treatment because their bone marrow function is improving. So, this is a fairly unique feature of the B-cell receptor pathway inhibitors because conventionally, with chemotherapy, we expect to see the white cell count go down as soon as you start treatment. So, when we're seeing white cell count going up, we're worried, is this not responding? But it's actually, in this case, it's a sign of response. So, it's very common to see a transient increase in the white blood cells.

So, here again are the three, um, BTK inhibitors. We're going to focus on BTK inhibitors and not spend too much time on the PI3 kinase inhibitors, because I want to, since we have limited amount of time, I want to focus our talk on the frontline treatment for a patient who has CLL for receiving the treatment for the first time. So, in the frontline treatment, the BTK inhibitors have a much more important role, at least for now. The PI3 kinase inhibitors are more used in the relapse setting at this point.

So, the three BTK inhibitors: ibrutinib, or Imbruvica, is the brand name, is the first one that's initially approved in 2014. This is the one that has really the longest history of the clinical trial data. So, we have learned a lot about how BTK inhibitors work and the effectiveness, as well as the potential side effects. The next, acalabrutinib, or Calquence, and then zanubrutinib, or Brukinsa. These are what we call the second-generation BTK inhibitors. So, these are designed to be more specific for targeting the BTK enzyme and having less off-target effect in the hope that it may help to reduce some of the side effects. And then there are also newer BTK inhibitors that are currently being studied in clinical trials trying to overcome resistance. So, the first two, ibrutinib and acalabrutinib, are currently FDA approved treatments for CLL, both in the frontline and then in the relapse setting.

So, we're going to, I'm going to show you some clinical trial data for ibrutinib just as an example. The other BTK inhibitors are also looks like similar. So, ibrutinib, this is a study, one of the earlier studies looking at patients who are being treated with ibrutinib at 420 milligrams once a day. So, again, this is the oral medication. So, you take it home once a day, oral medication, and patients will continue the treatment for as long as it's working and as long as they're tolerating. So, this is a long-term continuous treatment. So, with this treatment, we can see that the response rate is very high, is in the close to 90% range. And the TN stands for treatment-naive. So, these are the patients who are receiving ibrutinib as a first-line treatment. And then the RR stands for relapse-refractory patients. These are the patients who had received prior treatment, other treatments, and now have been relapsed disease. So, for both groups, you can see that the response rates are close to 90% overall response rate. The green bar is showing the complete response. So, complete response is relatively low. Most patients have partial response, meaning that there's still some detectable disease, even though the disease burden is dramatically reduced, but there's still some small amount of residual disease. But despite this small amount of residual disease, patients actually do very well for a very long time.

So, this is what we call a Kaplan-Meier curve, where you can look at how patients do over time. If patients relapse, more patients relapse, the curve will start to drop. So, the more to the right, the better, meaning that the treatment remains effective for a longer time. So, for people who have relapsed CLL, you can see that the drug is very effective for most patients, with the median progression-free survival has not been reached yet at the 36-month mark. But for frontline treatment of CLL, you can see that very, very few patients actually relapse. And when they're receiving ibrutinib as a frontline treatment, so despite having still some residual disease, patients actually can do very well, having disease very well controlled for years. And now we actually have long-term follow-up data, five years, seven years out, still the majority of the patients on treatment are still doing great.

So, um, I wouldn't go into there are many clinical trials actually have been done on ibrutinib or acalabrutinib. So, we don't have enough time to go into the detailed clinical trial data, but just to give you kind of a general sense of how BTK inhibitors work. So, for ibrutinib, it's once a day, um, dosing, oral medication, you take it at home. For acalabrutinib, it's twice a day dosing. So, and then again, you continue this treatment. This is a continuous long-term treatment until progression or until intolerance. Ibrutinib or acalabrutinib can be used either by itself or combined with the anti-CD20 monoclonal antibodies such as obinutuzumab or rituximab. So, all of those indications are at approved indications, either alone or in combination.

The benefit of this treatment is that it's generally well tolerated, has a very high response rate, and even though most of the responses are partial response, but people do have very long duration of response, and patients who live quite a long time through the long-term follow-up data. The potential side effects, I would say, in general, most patients do tolerate the treatment very well. However, there are some potential side effects we do need to watch out for, and mainly that early on, there could be some mild gastrointestinal side effects such as nausea, heartburn, diarrhea, but those tend to get better resolved after a few weeks or a few months of treatment. There are some ongoing potential side effects we do need to monitor. One is the bleeding risk. It's a small bleeding risk, but it's definitely notable. So, we do educate patients to make sure they, you know, notify us if they're planning to have any surgery or biopsy, which in those cases, we need to hold the medication for a few days before and after the procedure. Hypertension, patients can have about a quarter of the patients may notice some increase in their blood pressure reading. So, some of the patients may require additional increased doses of their hypertensive medication or adding new medication to control their blood pressure. And then cardiac arrhythmia, in particular atrial fibrillation. This is something that we do recognize as something unique for the BTK inhibitors. So, we do need to screen patients for their baseline cardiac risk to see if they're appropriate for the treatment, and sometimes we may choose a second generation if we are concerned about a cardiac risk. Infection, low blood counts, those are the things that we do need to monitor throughout the treatment. And then some patients may have some mild muscle ache or joint ache. But for the most part, BTK inhibitors are fairly well tolerated. It's a long-term treatment.

The second important class of oral targeted therapy is the BCL2 inhibitor, which is venetoclax. So, what is BCL2? BCL2 is a protein that is important in protecting the cancer cells from cell death. I'll show you in this graph, a big rock sitting at the edge of a cliff. So, interestingly, we know that CLL cells are primed to go through apoptosis or programmed cell death, but at the last step, they're stopped by this increased amount of this protective protein called BCL2. So, there is an overexpression of this protective protein BCL2 in CLL cells, and we are blocking the BCL2 protein by using venetoclax. You're removing the last stop, so the big rock can actually go down the cell death pathway. So, and because of that, actually venetoclax is a very effective treatment for CLL. It can actually induce a very rapid death in those leukemia cells.

So, I showed you that with the previous oral inhibitor, the ibrutinib, for example, you see an increase in the white blood cells when you're starting treatment. With venetoclax, it's actually the opposite. Actually, you can see a very rapid drop in the white blood cells. So, this is just to show you, once a patient takes one dose of venetoclax, if you monitor their blood counts, you can see a very rapid drop in the white blood count, sometimes within several hours, within a few days, you can see a fairly significant drop. And this is an indication of how rapidly cell killing can happen. And so, it's a good thing for treating leukemia from a point of view, but it is something that can also be a potential risk. But the risk is called tumor lysis syndrome, because whenever you're killing off leukemia cells or cancer cells, the dead cells can release waste products into the bloodstream, and sometimes when the cell killing occurs too quickly, your body wouldn't have enough time to get rid of those waste products. So, there could be accumulation of those, and that can cause electrolyte shifts, and when we see that, it's called tumor lysis syndrome.

So, tumor lysis syndrome is something that can occur in any cancer treatment, but in particular, in a very effective cancer treatment that kills off leukemia cells rapidly, such as venetoclax. So, with venetoclax, we do need to monitor for tumor lysis very closely, especially when we're starting treatment. Sorry, going back. So, when if you're choosing venetoclax, you have to understand that this is the treatment that at the beginning of the treatment, you need a lot of very close monitoring, including potentially multiple blood draws within a 24-hour period of any new doses, and then the dose has to be gradually built up over a five-week period, because we don't want to give you a standard dose and causing too rapid of tumor killing. We want to give you a small dose and then over each week to gradually increase the dose to allow this tumor killing to happen more gradually. So, tumor lysis syndrome is one of the major, major risks, but it's definitely manageable, and with close monitoring by your treating doctors, this is something that we can definitely manage.

So, this is a very effective treatment. There have been a number of clinical trials using either venetoclax by itself or in combination with the immunotherapy such as rituximab or obinutuzumab. So, we do know that by combining with immunotherapy, it seemed to work better than just venetoclax alone. Just to show you one example of venetoclax plus rituximab in patients who had relapsed refractory CLL, you can see that the overall response rate is 86%, and most remarkably, the complete response rate is over 50%. So, most of the patients were able to actually achieve a complete remission.

Now, I want to introduce you to a new concept here. So, we know that usually when we're looking at how effective a drug treatment is, we use the term partial response or complete response or complete remission. So, complete partial response means that there's significant reduction in the disease burden, but there's still some detectable disease at the end of the treatment, or, you know, while you're on treatment. Complete response means that at the end of the treatment or during the treatment, there's no detectable disease by CT scans or exams, there's no detectable disease in the bone marrow under the microscope. So, when you're fitting those criteria, that's called complete response. But in recent years, now we're setting a higher bar, even for the response, a higher standard, which is called minimal residual disease. So, in this, we're using a special technique to detect a very tiny amount of residual disease that's not otherwise notable under the microscope. So, in this case, we can detect as little as, even if there's one leukemia cell among every 10,000 cells, we're able to detect that. So, it's a very high sensitivity detection. So, if a patient has no detectable disease with this very special test, then they're called MRD or undetectable MRD, or you can say MRD negative. So, that's a much higher standard of response. It means that there's, you know, even below the detection, if there's no disease at our best detection technology, then this is a much deeper response.

So, 61% of patients treated with venetoclax plus rituximab were able to achieve this very deep response with the undetectable MRD, so which is very remarkable. It's almost unseen in all of the prior CLL treatment history. So, for patients who had undetectable MRD, they tend to predict a very long remission. So, you can see that here's the duration of response, the green curve of a patient who had undetectable MRD with a complete response, and you can see at the 16 months, which is a five-year mark, very few patients, so close to 90% are still remaining in remission. So, very few patients relapse. So, this is a very important message here is that we do know that the deeper the response, the longer the response tends to last for this treatment. And because this treatment is able to achieve such a deep response, we can actually stop treatment. So, this is not a continuous treatment. This is a treatment you can treat for a certain period, and then once you achieve a deep response, you can actually stop treatment, and patients can still remain in remission for a number of years before chance of relapse.

So, just to summarize what we learned about venetoclax or BCL2 inhibitor, it's once daily dosing. It does require a five-week dose ramp-up and very close tumor lysis monitoring. Would typically combine that with anti-CD20 monoclonal antibody such as rituximab or obinutuzumab. It is a limited duration treatment, and currently, the FDA approval for venetoclax plus Gazyva or obinutuzumab itself for 12-month treatment for frontline CLL treatment, and then for relapse-refractory setting, it's approved venetoclax plus rituximab for a total of 24 months treatment. So, this is different from the BTK inhibitor, which is a continuous therapy. So, the advantage of this treatment is that it can give you deep response, and patients can potentially have durable response off treatment. And the other thing we learned from clinical trials that when if patients do relapse several years down the line, they could be retreated with a venetoclax-based therapy and still can potentially have another response. The main side effect is tumor lysis syndrome early on during the treatment. So, it does require very close monitoring. Can cause some mild gastrointestinal side effects, infection with low blood counts, so all of those needs to be monitored.

So, the next question is, how do we actually compare the targeted therapy with conventional chemoimmunotherapy? Because that's really when the targeted therapy first came along, and that's really the biggest question is, you know, we know that previously we used chemoimmunotherapy as a standard, but now with the newer treatment, how does it compare to the previous standard? So, over the past number of years, there has been actually an amazing number of randomized large Phase III clinical trials enrolling hundreds of patients to each trial trying to address this question. We don't have time to actually go into all of this study, but I just put in this table here to show you a few of the important studies. For example, the top one, the ECOG 1912 study, compared for younger patients, younger fit patients, FCR versus ibrutinib plus rituximab. So, the patients are randomized to one of the two arms, and then they're being observed to see how they do over the long term. And then the next study is for older patients, comparing bendamustine-rituximab as the chemoimmunotherapy versus ibrutinib with or without rituximab. And then there are a number of studies comparing chlorambucil plus obinutuzumab combination in older patients with comorbidities. So, you can see there are three clinical trials using comparing this regimen to different types of targeted therapy: ibrutinib plus or obinutuzumab, venetoclax plus obinutuzumab, or acalabrutinib with or without obinutuzumab. For the sake of time, I wouldn't go into the details, but just to show you a quick one, the FCR versus ibrutinib-rituximab treatment, you can see that the red line is the ibrutinib-based regimen, the dotted line is through the conventional chemoimmunotherapy. So, both in terms of the progression-free survival and the overall survival, the targeted therapy actually are doing better. So, even compared to the most effective immunochemotherapy, the targeted therapy really are superior. There's one exception is that for people who have IGHV mutated CLL, they seem to do relatively similarly. The difference is not that big. So, if we're nowadays considering immunochemotherapy, probably the IGHV mutated patients is the only group who will still consider it. But chemo is no better compared to targeted therapy.

For the interest of time, I wouldn't go into the details of the study for venetoclax, but this is a study with venetoclax combined with rituximab, again, very high response rate over 90%, and very high complete response rate with over 50% of patients achieving an MRD undetectable state, and it's much superior compared to the conventional treatment of bendamustine. Okay. So, um, it's in the details of the studies. Just to show you that based on all of the trials that we mentioned, basically the bottom line is that targeted therapies seem to outperform conventional chemoimmunotherapy in virtually all of the studies for all CLL patients combined. The only exception is that for IGHV mutated patients, they seem to be relatively similar, but definitely chemoimmunotherapy seem to be inferior in most of the other situations. So, that's why there has been really a shift in the standard of care over the last several years in terms of the choosing more of targeted therapies for CLL treatment in the frontline.

So, in 2020, 2021, we're having a number of choices. Conventional chemoimmunotherapy is playing less of a role now, especially in the COVID era, where we're concerned about the risk of infection. So, it's mainly the discussion primarily focusing on whether to choose the BTK inhibitors or the BCL2 inhibitors plus the monoclonal antibody. Again, the BTK inhibitor is the continuous treatment, and the BCL2 inhibitors are limited duration treatment. So, it's really a personalized decision as to what's the best treatment for you is the discussion between the patient and the treating physicians.

Quickly, I want to touch on some of the very exciting future directions. There are next-generation targeted therapies, including novel BTK inhibitors, which are trying to overcome potential resistance to the first or second-generation BTK inhibitors. Their novel PI3 kinase inhibitors, their novel BCL2 inhibitors as well. So, next-generation is in the pipeline. And then there's also a discussion about what about if we combine the two classes of targeted therapy? So, combining BTK inhibitors with BCL2 inhibitors plus anti-CD20 antibody, or combining a PI3 kinase inhibitor with this combination. So, so because there has been data showing that when you combine the two classes of targeted therapies, there does seem to be an increased chance of getting into a very deep response and potentially a higher rate of undetectable MRD.

And then lastly, there's exciting CAR T, which is a novel cellular immunotherapy. Briefly touch on CAR T, but CAR T is using your body's own immune cells called T cells. So, we're harvesting your own T cells because these are really the most robust immune cells that can potentially be educated to become cancer-fighting cells. So, we collect patients' T cells, we do some express a new protein on the surface of T cells, so now they will be able to recognize the CLL cells and able to mount a very robust immune attack on the CLL cells. There have been a number of studies ongoing. This is not yet FDA approved, so this is still experimental, but the early data looks very exciting, even for CLL patients who have failed all of the standard treatments. We can still see a very high response rate, and some of the responses are very durable. So, when people were able to achieve a deep response after CAR T, after 24 months, there has been no relapse. So, this is a potentially very exciting salvage therapy in the future.

We do have a number of exciting clinical trials ongoing for patients who are living in the Chicago area at Northwestern. We have the frontline treatment comparing combined targeted therapy with the ibrutinib-based therapy, so the large NCI sponsored studies. And then there are also a number of clinical trials for relapse-refractory CLL using the second-generation BTK inhibitor, PI3 kinase inhibitor, or second-generation BCL2 inhibitor. We also do have a CAR T clinical trial for relapse or refractory. So, really, the future is very bright for CLL patients with a lot of exciting treatments in the pipeline. But even the current standard of care, the targeted therapies are looking very, um, effective and well tolerated.

All right, thank you. And now we're open for questions.

Great, thank you so much, Dr. Ma. Just before we move forward, I just wanted to double-check, are you okay if we go about five to ten minutes over just to get to a few more questions? That's fine. Yeah, okay, great. Um, so we already have our first question in, and the question is, can you talk about COVID and CLL? Specifically, what have you seen for patients both on watch and wait and undergoing treatment, and should CLL patients get the vaccine when it becomes available? Yes, this is the elephant in the room, right? Yeah, yeah. So, so COVID, obviously, right now, it's really occupying everyone's mind. It's really affecting our life in many ways. But in particular for CLL patients, it's quite concerning because CLL patients are considered at high risk, high risk for COVID-related complications. So, I do educate my patients to be extremely careful about trying to do all of the standard precautions, social distancing, wearing masks, washing hands and hygiene to help to prevent COVID infection. If everybody in the society does the same, they really help to reduce the spreading of the COVID. In terms of all we know about how patients do if they do get infected with COVID, there's really not a lot of information available yet. There was a small study early on.

Very early on in the first two, three months, where a number of centers are pulling their data together, including our center as well, to look at, you know, how the CLL patients hang out when they did get infected, it did show a quite grim picture with a fairly high rate of severe complications, and including mortality as well.

Um, however, we have to keep in mind that, um, at that time, the only patients who had confirmed COVID were those who had severe enough symptoms to have to be admitted to the hospital. Because back then, we didn't have enough testing kits to test asymptomatic or mild symptom patients. If the patients needed to be admitted, they were not tested. So this is not a very accurate, I wouldn't say that would be representative of how CLL patients would do necessarily.

And now, over the past number of months, we have definitely seen more numbers of CLL patients. I would say from my personal experience, the vast, vast majority of my patients were able to pull through okay. Some of them did have a few weeks of not feeling well, some of them did require some hospital stay, but the vast majority of them were able to pull it through. But still, you know, consider yourself high risk and do all of the precautions you can.

Um, in terms of vaccines, um, so the vaccine, um, I'm sure you have many of you have read the exciting news recently about the new CLL, a new COVID vaccine that has, two of the large vaccine studies have reported very exciting data showing 94% or 95% effectiveness for the COVID vaccine. So it does seem to be fairly effective, much, much better than what we're expecting to see. And those vaccines were able to, sound like they were able to produce it in a matter of, um, several months to be able to supply the country. So I would imagine as the vaccines are being, uh, of course, we have to wait for the approval. Once they're approved, it will be distributed. Um, we don't know how they're going to allocate the vaccine first, and I would imagine the higher risk patient probably will have a higher priority of getting the vaccine. I don't think there's any, I've seen study specifically in immunocompromised patients yet, at least there's no data out yet because now it's all kind of rushing to do on the large general population. But once we do have the vaccine, we will need to look at what type of vaccine, whether it's live virus or non-live virus, whether it's appropriate for our CLL patients, because we generally do not recommend any live virus vaccine. So we'll have to wait to see which one comes through.

Thank you so much, Dr. Maffer, for speaking on that. I know it's a topic, like you said, on everyone's mind. And our next question is, over two years ago, I was treated with BR for SLL and have been asymptomatic since then. Is it advisable to get an MRD test to see if cancer is returning?

No, we do not use MRD to monitor the disease because we know CLL is the disease that we cannot yet cure. So if you search hard enough, you probably will find some MRD, especially if you have already been a few years after the treatment. So MRD is still relatively a research concept. It's more to guide us in like, for example, treatment for example, to see whether it's, you know, a good time to stop treatment. But I would not use MRD to monitor disease. The routine blood counts and the exams will be sufficient.

Great. And our next question is, after disease progression on venetoclax, what treatment options are available?

Uh, so all of the treatment options we discuss are available. So, you know, if you're, we're treated with venetoclax and the disease relapses, if it's after several years, you could consider to be retreated with the same regimen, or you could switch to a BTK inhibitor type of treatment. So they're chemotherapy, we haven't really, nowadays we're really not using that much anymore, but that remains a potential option. And then of course, consider the clinical trials.

Thank you. Um, our next question is, do you know if there's a way to freeze your T cells if you are on watch and wait? They would want to do it before they get any treatment as possible.

That's an interesting concept. I don't think there's a way to do that yet outside of if there's any research program, uh, clinical trials to specifically look at that. Um, it's not a standard yet, but we haven't really so far had much problem collecting T cells for the CAR T, if that's what you're thinking about for a patient who had been previously treated.

Great. Thanks so much. Our next question is, what symptoms or side effects should I look out for after completing treatment that would indicate relapse?

It would be the same as how you're monitoring the CLL from the very beginning. So your doctor will be watching blood counts, do the exam to look for lymph nodes and spleen, liver changes, and then you'll be watching for those, uh, B symptoms we mentioned, like unexplained fever, night sweats, significant fatigue, or weight loss.

Alright, thank you so much. And we have a couple questions that came in, uh, in terms of, uh, people just wanting to clarify again that SLL/CLL and someone asked, can you explain how SLL differs from CLL in terms of selection of treatment?

In terms of treatment, there's no difference actually, because they're biologically really the same disease. Um, some patients, you know, were diagnosed with SLL because their blood counts were normal. Their diagnosis were made based on lymph node biopsy, but it's really the same, same disease. So the treatment is exactly the same.

Great, thank you. Another question, I'm just exercising any benefits to maintaining baseline CLL?

What I tell my patients is that it's very important to maintain a good general health. Um, so from all aspects, from your immune system aspect and from your ability to potentially tolerate any treatment. So it's important to actually maintain a good general physical health, including exercise regularly.

Thank you. Our next question is, can you explain if TLS is more of a concern with SLL and what is done to prevent?

So TLS is not specific for any disease or any particular treatment. So any cancer treatment has a potential risk of TLS or tumor lysis syndrome. But usually you don't notice it if the treatment works in a more gradual fashion. But it's more notable when you have a treatment that works very quickly, such as venetoclax.

Our next question is, are there any guidelines to treat patients with CAR T option at this time in the COVID era for CAR T? Yeah, any specific, um, precautions or guidelines because of COVID?

Oh, I think, okay, yeah. Uh, yeah, obviously. And, you know, CAR T treatment does involve, um, some, you know, immunomodulating treatment. So it might, at least for the short term, increase our risk of the immunocompromised state. So, but a lot of times people who are needing a CAR T are when their disease is progressing, they have to get treatment. So you have to talk with your doctor to see what wayne, which is weighing the risk and benefit of any treatment, not just CAR T in the COVID era, to try to balance out the benefit of the treatment and there is a on the immune system.

And I think we have time for a couple more questions. Um, this question is, what would be considered an effective low dose of ibrutinib?

Well, the standard dose of ibrutinib is the one that has been studied in all of the clinical trials. The low dose, there is no tested low dose. Sometimes your doctor may reduce the dose because you're taking some other medication that's interacting, or sometimes because of side effects. If it's, you know, because of side effects, we don't really know how well the low dose works. There's no clinical trial data to give you exactly how well it works. So we would not recommend a low-dose ibrutinib treatment unless if it's necessary because of three things I mentioned, because there's not enough data to know how well it works.

Thank you. And our last question for the day is, we got a few more questions on MRD and I know you clarified that a little bit, but we had one more that asks, can you clarify when MRD status is used with treatment and what a negative status means for immunocompromised?

Data. MRD has nothing to do with immune systems. It's more a measurement of CLL, like how much residual CLL we can detect. So we don't have to use MRD for any, uh, treatment for CLL. For example, there's no point of doing MRD when you're on a BTK inhibitor with ibrutinib or calibrating it, because there's always going to be some MRD, but it does not matter. It does not really matter in terms of how long the treatment can remain effective for that class of treatment. It does matter when you're being treated with venetoclax or with immunochemotherapy, because at some point you're stopping treatment. So if you're able to get into a deep response, then likely that a period of treatment remaining in remission will be longer if you have a decreased bone before the stopping treatment.

Um, thanks so much for clarifying that. And just with a thank you, Dr. Ma, for joining us today, um, on this really comprehensive talk. Uh, you know, we had a lot of patients on the call today, and I know they all appreciated your time. So LRF and all of patients online really appreciate it, and we thank you for joining us today.

You're very welcome, and it's a pleasure. And I also appreciate the LRF's work to support our patients.

Okay, thanks so much. And thank everyone, um, on the call too, for joining us today, and we hope you found the information both informative and also hopeful. We'd also like to thank our sponsors again for making this program possible, Adaptive Biotechnologies and AstraZeneca. Please remember, if you have any additional questions or you'd like to be connected with someone who's been impacted by lymphoma, you can reach the LRF helpline at 800-500-9976. Also, at the conclusion of this program, you will receive an email prompting you to complete a program evaluation. I ask you please take a few moments to complete this, as they are very important for helping us to ensure we deliver the most useful and meaningful programming to you. And with that, I'd like to thank you all again for joining us and have a wonderful day.