Transcription
Semi-governmental Gazi, some professor of medicine, bone marrow transplant, University of Louisville in Louisville, Kentucky, America, and a horde of telemark. While topic, yes, all right. Top, our topic today is chronic lymphocytic leukemia. We'll talk about its past, its present, and the future practices. Disclosure: Fish, a conflict of interests. We're gonna first talk about epidemiology, pathophysiology, diagnosis, and workup, treatment options, and hunger and clinical trials.
Epidemiology. So, chronic lymphocytic leukemia is the most prevalent type of adult leukemia. However, it's a leukemia of older patients. The median age is about 72 years old, with only 10% less than 50. Other level of training for the poor men are affected more than women, so you'll see a two to one ratio there. There's a possible environmental predisposition, Agent Orange, and they think that that we might have an implication for the development of this leukemia. There is also genetic predisposition, and these are presents with about 10% of patients have a first-degree or a vestige of a first-degree relative with CLL. This is from the Sears database.
Incidence and mortality. And you can see with the with the light green, this is the estimated new cases in 2018, last year, about all 54,000 new diagnoses. However, when you look at the dark green, that's the estimated deaths from in 2018. It's 0.3%. So, it's not a very deadly disease. It's a disease with excellent prognosis.
But what caused it is chronic lymphocytic leukemia? Simple answer is, we don't know. We know, however, that there is a clonal chromosomal abnormalities that are detected in approximately 50% of those. So, about 50% of our patients will have a genetic signature, something that if we feel strongly that is correlating to the development of chronic lymphocytic leukemia. The most common clonal abnormality in this disease is transmitted well. However, abnormalities affecting chromosome 13, 14, and 11, as well as chromosome 17, are prevalent, are present. Patients with abnormal karyotype have worse prognosis. So, the the more complex the cytogenetics, the worse the prognosis. However, I had cases with, you know, complex karyotype and CLL have been watching them because they did not require treatment, they're doing just fine.
This is just a look at the blood, at the bone marrow, and the development of and the normal amount of wheezes. As you know, the bone marrow, the bone marrow is where blood is being made. All these different blood types are made. There are lots of blood blood cells, platelets, amongst the white blood cells is the lymphocytes. The top of that, left force right here, and that's where, oh, that's in the lymphocytes, that's where the CLL developed from. To be more specific, it appears from mature B cells. Lymphocytes, as you see the one circled, that's a mature B cell.
Long to sites. Generally, generally, in terms of clinical manifestations of this disease, 40% of those patients are asymptomatic, and they're diagnosed on a routine CBC without any complaints to the primary provider. However, the most common complaints when they do complain is actually also something vague, just fatigue. They just be tired. Other symptoms as the disease progress would be enlarged lymph nodes, symptoms of X moves, but America, like a left upper quadrant fullness, early satiety, but they're not finishing the meals, things like that. B symptoms is not a common presentation in chronic lymphocytic leukemia, but it can happen. B symptoms, namely a fever, drenching night sweats, or unexplained weight loss, unexplained weight loss.
Now, as the chronic lymphocytic leukemia progress, it will infiltrate the bone marrow, and that's when you develop cytopenias. So, a patient becomes anemic, thrombocytopenic. You'll start getting symptoms of anemia with easy fatigability, dyspnea on exertion, and with from a slight rapini, easy bruising, as such. Always think of your differential diagnosis. It's not every case with elevated white blood count will be, even if it is a lymphocytic predominant, will be CLL. So, we have to look for infectious causes, bacteria, don't forget about TB, viral like mononucleosis. There is also other mimickers of CLL. They are not as common. Force CLO is the most common malignant cause, like B-cell prolymphocytic leukemia, or a T-cell phase of lymphoma, or a hairy cell leukemia, Waldenstrom macroglobulinemia, as well as large granular lymphocytic leukemia. All these guys can cause phases of significantly elevated levels to a predominant leukocytosis.
Workup. Remember, as a hematologists, we always like to look at the smears, and here's a smear. You see a significant increase of the white blood cells, that's the purple looking ones, white blood cells. Can you know, generally speaking, you have one white blood cell in every thousand red blood cells, but here you're seeing them way more common. And they're all small with a dense nucleus, not a very aggressive one. But you also see here on the on the right lower corner, these much cells, those are the cells that basically are the rupture during the preparation of their smear, and this is also one of the remarks or the findings on propulsion here for CLL.
The diagnosis of chronic lymphocytic leukemia comes to be confirmed with use of flow cytometry, and you can do that on a peripheral. What if you do peripheral blood flow cytometry, you're going to look at certain markers because you want to identify the seed that the B cell clone because in order to reach diagnosis, and we're going to come to talk about it first in a second, in order to reach that, you need to actually identify how much of the lymphocytosis is of a similar clone of B cells. And as you see here in the right upper corner of this slide, you see this is a flow cytometry graph. As you see the CD20 is on the the X axis, of the Y axis has the CD5, and typically CLL is positive on both ends. So, the red dots, these are all CD20 positive, CD5 positive B cells. The next assistant with the with a phenotype of chronic lymphocytic leukemia.
You get your diagnosis with the flow cytometry, but you don't finish a workup by just getting to the diagnosis of chronic lymphocytic leukemia because it's very important for us to prognosticate for this population as well as determine therapy based on other findings. So, we'll need to do a FISH to look for deletion 17, gain of chromosome 12, 30 deletion of 3q, 13q, or deletion of 11. We have to say deletion of 17p specifically is always pointed as the more aggressive disease. Deletion 11q is considered in also the VH gene status. So, the IG VH, and that's a molecular test. You need to get an oniony to get the status of that. Is it mutated or unmutated? And we will talk about why is that important in a second. ZAP-70 used to be a common test, a common prognostic marker. However, it's not a minute out sort of trial. The current time, beta-2 microglobulin. We don't need to do any CT scans unless symptoms necessitate. PET-CT scan can be helpful if if you're concerned of Richter's transformation, meaning the CLL is transforming into, um, into a more aggressive lymphoma, most commonly diffuse large B-cell. Last but not least, bone marrow biopsy and aspirate is not necessary in the ABS, in in in the diagnosis of chronic lymphocytic leukemia. So, you don't need a bone marrow biopsy to diagnose it or even gnosis aids or better determine therapy. However, if the patient has low blood counts and developing some cytopenias, and you want to investigate the infiltration of CLL into the bone marrow, that's fine. You can definitely go for it.
Here's the full set temperature pictures, a little bigger. All right. Now, the topic of chronic lymphocytic leukemia should also cover the other two terms that are closely related. So, chronic lymphocytic leukemia is the presence of lymphocytosis in the blood of a clone, monoclonal population of mature B cells. Lymphoma count is 5,000. All right. SLL, which is in our mind is considered a synonym to CLL, CLL/SLL. You'll find it everywhere written that way, CLL/SLL. That's when the the leukemia is is not actually in a leukemic phase. Most of the time, it's involving the lymph nodes in the spleen and the bone marrow rather than the plot. So, it's a monoclonal B-cell lymphoma that is not reaching 5,000 in the peripheral blood. However, it is associated with lymphadenopathy. So, when omega Lior sarcopenias. The last term is MDL, and that stands for monoclonal B-cell lymphoma choices. And this is when you don't need your cutoff for 5,000. So, monoclonal population of mature B lymphocytosis, B-cell lymphocytosis, less than 5,000 without adenopathy or any other organ involvement, and it is called its own thing, and it's mono from monoclonal B-cell lymphocytosis. This has the risk of developing chronic lymphocytic leukemia, CLL, as 1%.
Anyone staging. Rai staging is on the left. That's what has been done since the 1970s. Dr. Right Damien with this staging, and Binet came after women with a very, very soon after incorporation. All blood counts to all who also stage. So, very much ray is it's the stage zero as well if it's only lymphocytosis and there is no lymph node enlargement. Stage one is if it is lymphocytosis with enlarged lymph nodes. Stage two is if it's had splenomegaly or hepatomegaly in addition to an enlarged lymph nodes and lymphocytosis. Stage three is when the hemoglobin gets affected and become less than 11. Stage four is when the platelets expected and become less than 100,000.
This is the Lugano modification of Ann Arbor staging. So, basically, we're using the regular new Hodgkin's lymphoma staging. When it's one group of lymph node, adjacent lymph nodes, that stage one. Two or more nodal groups on the same side of the diaphragm, that stage two. Stage two bulky is when the size of electrons is more than 7.5 centimeters. Advanced stages is when it's safety is when it's above or below the diaphragm, and stage four when it is extranodal involvement, and it's not contained configure. So, it's not really just an encroachment of some solid organs by a surrounding moreish lymph nodes. It's a it's a separate involvement.
Prognostic marker. So, as I mentioned, after you get your flow cytometry, you have reached your diagnosis of chronic lymphocytic leukemia. You get FISH, and the FISH basically gives you 50% of the time a finding. The finding can be favorable, as you see here in the 13q deletion, or unfavorable, as at the top of the list is the 17p deletion, and there's also all the other findings in between the two. I mean, they say favorable and unfavorable because of the prognosis and the the need for therapy in those patients. And here are two graphs that compared to compared that treatment-free interval for the different mutations. And you can easily notice that the blue on the left graph, on the graph on the left, the that the blue line, which is the 17p deletion, they don't waste time to require treatments. So, almost 50% of those, of those patients will need treatment within two years. However, for example, if you look at the 13q deletion, those guys might live for five years and they still do not need treatments, and it might even live longer than that.
On the other hand, is another pair in regards to survival. And and this purpose is remarkable. As you can see that there is a significant overall sort of difference between these different mutations. 17p deletion, you're looking at course, you know, this is a disease where people where the patients live longer. So, I'm not talking about anything within a year or two that anybody would feel ill from diagnosis would be dead. But even in the when you compare them over a very long period of time, you will notice that, you know, 50% of those patients with a 17p deletion CLL are dead within about four years. However, with a 13q deletion, those people might be living 15 years without any compromise to their overall survival from the chronic lymphocytic leukemia, and most of the time they die from unrelated causes, some things that has nothing to do with CLL.
So, there's other prognostic and for me, it's just that's how we look at it. So, TP53 is basically another marker for 17p deletion, which is the worst finding. So, you do TP53 as a molecular testing as well. However, you do the 17p deletion on your FISH studies, and they are both considered unfavorable. However, IGHV, or the immunoglobulin heavy chain variable region genes, mutation. This is more off. When it's mutated, it's better. So, patients do better when they are mutated with IGHV, which because the mutated IGHV basically is it gives the snow cells still the ability to spot despite the dysfunction, give them still the ability to make immunoglobulins, and they are they've been noticed to be when they are mutated, they were more sensitive to chemotherapy. Deletion 17 is resistant to chemotherapy, and tries has been made in improving those patients' outcomes with the use of targeted therapies that we're going to talk about in a little bit.
VH mutation, that's the heavy chain mutation. So, the B-cell naive lymphocytes, they have unmutated the virgin variable region, I'm sorry, variable regions. However, the hypermutated mutation of this area creates those memory B cells and make those antibodies with the higher affinities to their antigen. So, it's better to have that in those patients. CLL progression is dependent on mutation status on the B cells. So, unmutated VH means that it's an earlier and less mature B cell, progresses rapidly, and has a short survival, just make it simple. While the mutated ones is more mature, slow progression. Closer up here is to prove the difference between the variable region of the immunoglobulin between the two statuses, mutated and unmutated. And there is a significant difference. As you can see with the dark green, the unmutated heavy chain, always remember, we look at the 50%. 50% of them within a hundred months, which is less than 10 years, they are dying. However, they might be living double that amount, double that traditional sun before they for 50% from the unmutated IGHV develop, I'm sorry, succumb to their disease.
Here's a quick case. A six-year-old Caucasian male, patient hypertension, hyperlipidemia, type 2 diabetes, presented for a routine follow-up with his PCP. Patient had no complaints. Physical exams unremarkable. Public count was 15,000. Acute lymphocytic count was 10,000. Hemoglobin was 13. Platelets 250,000. What's the next step in management? Will you check a peripheral smear? Would you send this for flow cytometry? Would you refer to hematology? These are bone marrow biopsy. So, gotta say, the first step would be to get a peripheral smear. That that's the easiest to do. But sending to P, sending for flow cytometry, it's not a bad idea.
Six-year-old Caucasian male. This is the same patient. Comes in. This time, the peripheral smear you reviewed it showed no psychosis, the neoplasm, I'm sorry, the cytoplasm is thinning, it was dense and clumped. New nuclei, it's commonly called swappable lymphocytes. It's a lot of broken cells, which all smudge cells. The closet on she was done and should abnormal piece of bone that is CD5 positive, CD23 positive, CD20 dim. What's the next step in management? So, now knowing this, you have a large clone that has achieved the guys, they've reached the diagnosis of over 5,000 B lymphocytes, clonal monoclonal B lymphocytes. So, you've reached your diagnosis of chronic lymphocytic leukemia. Now, what you do next? Would you scan this patient? Would you perform a bone marrow biopsy or instruct chemotherapy? The correct answer is, we need to risk stratify this patient. So, we need FISH, cytogenetics, and molecular studies to know which mutations does this patient carry. But most likely, the patient does not need any treatment, and active surveillance is the right answer. However, we, in order to know for the future, how long is it going to take for this patient's very porous treatment, then we should do that.
Now, two weeks later, two years later, the same patient came after you've been going with active surveillance for all this time. He comes in with dyspnea, a breath or exertion. Labs shows white counts has gone up from 15 to 20. His ALC is now 15,000. His hemoglobin is 7.5. That's a drop for this patient. Platelet count 140,000, and T bili is 3.2, LDH is 800. What's the underlying process? So, this is just to touch base on one of the complications of CLL in this group, which is called autoimmune hemolytic anemia. Autoimmune hemolytic anemia. So, I don't even look at the amused will led to the drop in this patient's hemoglobin, leading to this bilirubin being totally honest 3.2 with elevation is in his LDH. You look at the purple smear in the right corner, and you see here, point to the psychosis, and also anisocytosis. You're also seeing some not created red blood cells, and if you pay a little more attention, you might find some reticulocytes. So, all these are signs that this patient is hemolyzed. Remember, the autoimmune hemolytic anemia, you diagnose with the look of the reticulocytes, have to globe indirect agglutination test or Coombs. Auto minimal area develops in this area in the setting of treatments or therapies. So, for daratumumab, which is one of the chemotherapy that we used to commonly use, not so much now, but we still use it in certain populations in CLL, the fluid area in itself can cause that. So, you have to actually pay attention to see which one is it's causing it. Is the CLL? Is the treatment for the CLL? ITP can be also development. It's an autoimmune cytopenia. So, however, in this case, you might want to look in the bone marrow pure red cell aplasia, which in this situation, you would always look or part would be 19. And upon your evaluation, the treatment for all those typically, this is a worm autoimmune hemolytic anemia, that's what it is, and steroids is the way to go. If steroids doesn't work, or the patient needs any further treatments, you can use IVIG or a toxin, and then you can look at all these second, third line, and fourth and fifth line of therapy, looking cyclosporine, up to splenectomy, or using those people my medics, but ill trauma Bangor on Boston.
All right, okay. So, that patient you said did not need to be treated? No, this patient needs to be treated for autoimmune hemolytic anemia. And if you respond, you might still continue to monitor their CLL and not have to treat it itself. Okay.
So, when do we treat chronic lymphocytic leukemia? There is no advantage in treating chronic lymphocytic leukemia until symptoms develop, regardless of its genomic features, unless we have a clinical trial that is putting patients for asymptomatic without any kind of cytopenias, without any kind of symptoms to the treatment group. There is no evidence that supports that we should always watch them until they develop. All right.
So, now the IWCLL in 2008, they came up with these criteria for treating those patients. Primary or relapsed large, symptomatic lymph nodes, more than 10 centimeters. That's largely for symptomatic. Doesn't have to be more than 10. If it's causing symptoms, it's it's big enough to be treated. Enlarging symptomatic spleens. So, typically, that's the spleen that is more than six centimeters below the costal margin. So, cytopenias due to CLL, like a hemoglobin less than 11, or platelets less than 100,000, or the patient develops B symptoms. If you could not control the autoimmune hemolytic anemia or ITP, so you treated them and you couldn't control them, then you look into that, look into treating the CLL itself, and maybe that will decrease the progression to will decrease the development of these autoimmune and other means. Progressive lymphocytosis, like cytosis with an increase of more than 50% over two months period, or lymphocyte doubling time of less than six months. And that's a controversial point. Typically, you see a patient comes to you, and if there is a 50% increase, let's say you saw a white count was 30,000, they came in two months later, and the white count is 45,000, you know that this patient is likely going to require treatment very soon. This is not always adopted by a pathologist. Some of it is as being studied, and also time, it's up to the discretion of the treating oncologist.
All right. So, that's these are the when do we start treatment? These are these are the treatment options, which is a big list of options. The blue on the left is your old therapies. That is the past that still occupies a very small population of the present. Daratumumab, but the most important pentostatin, it's like a fossil, my parameter. They development of targeted antibodies with the turn of the millennium had a massive magnitude in the treatment of CLL. The appearance of a toxin over - mmm, open it - Samia, how long a Tuesday map, all these are targeted therapies. The first three are all directed against CD20. Then we've got even other targets like intracellular targets like a brutinib, idelalisib, BTK 199, which is venetoclax, along with others. And this is the present, and the future is what lays on all the way to the right, lower former cellular therapy, CAR T cells, and immune therapy.
CD20 antibodies are a major component of our treatments in CLL. As you see, both Rituxan and obinutuzumab have a similar binding sites on the CD20. Here on the graph on the right side, so the right well alpha-2 have binds to CD20 at a different site. What happens as it binds? It develops complement-mediated lysis of those cells, also stimulates the effector cells, as well as a direct effect into very binding. You just induce antiproliferative signals, apoptosis, and cell growth inhibition.
All right. So, now, what is the standard? What is the standard in treating those patients with CLL? The standard ops in treating treating CLL depends on the age, as well as the thickness in general, and there are genetic mutations. So, not every young and fit CLL patient will receive FCR. But if they do not have this deletion 17, maybe for therapy in cyclophosphamide and Rituxan is the way to go. Well, bendamustine, rituximab, we know it's not as good as FCR in this population, but it's also an option. He can use fludarabine, Rituxan, and cyclophosphamide. It's not as good, but it's used. And to stand including therapies, as well as obinutuzumab, chlorambucil. B cells. Another option.
And here is the study of FCR versus BR. This was done in patients who untreated active CLL without deletion 17 and in good shape. In good shape, either got FCR, fludarabine 25 milligrams per meter squared IV days one through three, cyclophosphamide 250 milligrams per meter squared days one to three, rituximab 5, 75 milligrams per meter squared IV on day one, day, and this is cycle one, and then you're going for reflux and 500 IV on day one of cycles two through six. And they compared that to the bendamustine, which basically similar dose of rituximab and just got rid of the fludarabine, cyclophosphamide, used that the musty. Here's outcome. This is the CLL 10 trial. FCR median progression-free survival was not reached, while it was reached at bendamustine rituximab at 44.9, almost 45 months. That's statistically significant in the favor of FCR. Overall survival at two years were quite similar. There's no difference. Response rates were pretty much identical, but higher CRs observed with FCR compared to BR. And when I say CR, complete remission means the disappearance of the clone, as well as the resolution of adenopathy, or whatever is the indications that led to the treatment. So, in this population, you see if you combine complete remission as well as complete remission or complete response with incomplete hematologic recovery, you will see that 47.4% of the FCR population achieved it, while 38% achieved it in the BR arm with a p-value of 0.3, 0.03, which is statistically significant. However, if you look at the bottom of the table, whole objective response rate was identical.
How about in older or unfit patients without the deletion 17p? Always remember, clinical trials is a great option. It's a great place, great place to start. However, if they do not have deletion 17, you can consider chemo immunotherapy with use of bendamustine, rituximab, because we know that the FCR is is by toxic to other or unfit populations. In somebody in good shape to tolerate it, however, in in older and unfit, then the obinutuzumab maybe has a repressor room or of the detrusor mare, a toxin, as I'm sorry, obinutuzumab. Using a Ferengi cell has room. And here comes a brutinib, which has been approved in this population as well. And here is the trial comparing obinutuzumab to rituximab, chlorambucil. B cells. So, it was randomized. It's the CLL 11 trial, randomized obinutuzumab to chlorambucil as well as rituximab. And here are the responses. Clearance alone was poor. However, when we use chlorambucil with a toxin, you had an overall response rate of 65% with CR of 7%. But if you use obinutuzumab instead of rituximab, which in both are CD20 antibodies, just to be clear, the response rate improves to 78% overall response and 21% complete responders. We have to state that clearly in here to pay attention to that. That in terms of toxicity, over the two zmapp is more toxic than rituximab, has more infusion reactions, that's clear. One, it also is associated with more infections. It's like bikinis. You. This is the curve comparing the two together, looking at the probability of progression-free survival. Now, obinutuzumab versus rituximab. The obinutuzumab, you see the median probability of progression-free survival was, um, about a little over 10 months apart between the two.
Now, this is the CD20 antibodies in cooperation with chemotherapy. Now, this is a busy diagram, but it actually illustrates to you how much we have added, how many therapies have been added to our toolkit in treating CLL, from cell surface markers to intracellular cytoplasmic markers, and all of them are either under a current clinical investigation or already approved. Ibrutinib, and I'm just going back to this, Ibrutinib. You can see it's here in the middle. It's inside the cell. It's a Bruton tyrosine kinase inhibitor. So, it sits under the BCR receptor on top of the surface, and with its with the inhibition of this, you develop three ways of cell death. And here, it inhibits the proliferation of survival. It also inhibits the adhesions from those lymphocytes are are less able to break through the, you know, bloodstream and get to the lymphocytes again. So, it blocks them from going back to the lymphocytes, and also, that's another way of modulating its chemotaxis and traffic ants, and they don't travel appropriately. And that's why you want to kill them. You don't want them to to go and proliferate in their various parts of the body.
Resonate trial. So, this was the first trial studying ibrutinib in relapsed refractory CLL population, and this was studied with ibrutinib against ofatumumab. The primary endpoint was progression-free survival. Progression-free survival here, when you look at her car kappa lockers like this, it's very easy, but you can see that there is a significant difference between the two arms. You can, and this is one of my mentors, and during my training, we tell me, you know, there's something called the rule of thumb. And the rule of thumb is, when you were able to look at the diagram and put your thumb between the two curves and it fits, that means this is significant. You don't need a statistician to tell you that, and it's obvious these two curves are separated very well that you can actually, without anything, notice that the difference is significant. You can see this is as good as a hazard ratio can be. Hazard ratio of 0.23, telling you that there is 78% of those patients had a significant benefit of using ibrutinib over ofatumumab.
So, in when using ibrutinib, you have to be familiar with what will go once you start the drug because it's a great drug, it works very well. However, it has some points that you need to pay attention to. So, you don't think that this is progressing, and you don't interrupt treatments. So, the pattern of response between the lymphocyte, the the lymphocytic count or the CBC, and the leukocytosis in general, as well as the lymph node size. So, on the left hand side, you see a graph where the lymphocytes after the initiation of ibrutinib, they go up. So, this patient were, for instance, started at a baseline AL, this group of patients started at a baseline of around 50,000 lymphocytes, it went to as high as over 350,000 before in him, within two months, before it declined back within six months. So, the first six months of treatment using ibrutinib, which is an oral pill that they can take on daily basis, and you should tell them that, remember, don't worry about the white blood cell count. The white blood cell count is going to at least double over the coming couple of months, but within six months, it will come down, and everything should be fine.
Well, how do you pay attention then to the disease? Then you need to look at the lymph nodes. If this patient had lymphadenopathy, and this is here, the curve shown you in the same population, how the lymph node size, the change from baseline in this diameter has declined significantly, as despite the rise in the white blood cells. And we believe this is because the the ibrutinib blocks the cell, the white blood cells from going back into the lymph node. So, it's a one-way track. The lymphocytes are just going out of the lymph node, and based on that, the white count goes up. But soon they die, and you achieve your goal of a reduction of all these findings that is associated with chronic lymphocytic leukemia. And this is a patient that on the left is before starting ibrutinib. If this was a refractory CLL with 11q deletion, at the left is a patient before starting ibrutinib. Him and she did not have any kind of plastic surgery to get rid of a double chin or anything like that. She actually just took a pill a day, and here you go, boo, completely. The neck has come, is very different. You can even tell how the necklaces is fitting around her neck. Um, this is trying to tell you that ofatumumab is not at all as good as ibrutinib in all groups, no matter what you're looking at, which stage. Ibrutinib is way better. However, you have to pay attention to the side effects of ibrutinib. So, ibrutinib can cause cytopenias. So, you need to keep an eye for the CBC. It can cause GI symptoms like diarrhea. It also, which is not mentioned here, but it's very important because this is a finding that came after this drug was actually used in humans because it wasn't known to do it in animal trials, its atrial fibrillation. So, atrial fibrillation has been linked to ibrutinib. If so, I have to pay attention to that.
Now, this is pretty much ibrutinib. Now, the next in line, the next very, very interesting target is BCL-2 inhibitor, venetoclax. And venetoclax is a unique small molecule that goes and binds to BCL-2, BCL-XL. It's proliferation, and it makes the cell allows the cancer cell to evade apoptosis by sequestering pro-apoptotic proteins. But when you inhibit the BCL-2 with use of venetoclax, those pro-apoptotic proteins gather around the mitochondria within the cytoplasm and need to activation of the caspases and cancer cell death. You. And venetoclax monotherapy in the use of in relapsed refractory CLL/SLL. So, this is an initial study with show in a high affinity for BCL-2 evaluated patients who both had deletion 17 or fludarabine refractory, and the response rate was significant. Project a world response rate was over 80% on both arms with 12% responded complete remissions in deletion 17 versus 22% remission in, um, we're being refractory CLL. And this is the data from the Murano clinical trial. Say it's stating that, and that's, you know, small percentage of the patients also needed to discontinue the drug.
Idelalisib. Idelalisib is another target in the toolkit in treating chronic lymphocytic leukemia. This is a phase three trial using idelalisib with rituximab for previously treated patients with CML. They stratified them between the different risk groups, either deletion 17p/TP53 mutation or IG HV mutation status to either idelalisib plus rituximab versus rituximab alone plus placebo. The clinical endpoints were primary endpoints was progression-free survival, and events were assumed as disease progression or death. And here is the difference. Idelalisib plus rituximab is significantly more efficacious compared to rituximab plus placebo with a hazard ratio of 0.15. That's again, as good as it gets. Again, idelalisib can cause the same issue in terms of the absolute lymphocyte count and tumor burden. But on this curve, you see the both curves, the blue line is the absolute lymphocyte count. It goes up the first couple of months, and then within within six months, it goes down. However, the lymphocyte, the lymph nodes are actively shrinking throughout from this get from the store. Here's a patient. She's started on the left before treating with idelalisib with significant adenopathy. She got idelalisib, and there she is again. Comparing idelalisib plus rituximab to rituximab placebo. Of course, idelalisib plus rituximab one on all levels, regardless of the risk, 17p deletion or not, it works. However, idelalisib is a white toxic, and that's why it sits in the third line of targeted therapies in our book. So, common side effects are fever, fatigue, nausea, transaminitis, the liver enzymes below, severe infections can happen, cytopenias can happen, as well as GI symptoms and diarrhea.
Now, ibrutinib. So, ibrutinib, after being approved for relapsed refractory CLL, they now said, we're going to go for the kill. We're going to put the first-line therapy to get approved in CLL all comers. So, this is the RESONATE-2 trial. RESONATE-2 trial included treatment-naive CLL/SLL with active disease. But they said, okay, we're going to look at the older, 65 or older, for patients 65 to 69, comorbidities that may preclude them from FCR, deletion 17p were excluded. So, they did not even so, they know they are very effective in 17p, so they didn't want to keep those guys in comparison because we know that ibrutinib will win it. And patients on warfarin, because how it routed can increase the risk of bleeding. So, they have excluded those and they compared chlorambucil, which is a criticized widely as an option because nobody uses for em, as a single agent in treating CLL. Well, compared to ibrutinib on the standard dosing. That was a phase three open label, multi-center international study with a primary endpoint is progression-free survival. And here is another application for the rule of thumb. Now, you can easily fit your thumb between those two curves and know very well that you're not going to touch either curve, and this tells you that this is statistically significant. And again, their response rates is an official rubbish really high, even on a on a longer follow-up.
All right. So, this is the current practices in the past. So, chemotherapies with with C20 antibodies as was our past. Or present is more in the small molecules and the use of ibrutinib, venetoclax, and idelalisib. Well, what's next? So, in the works, hopefully soon will be approved, next-generation ibrutinib, if it's called acalabrutinib. It's more specific in inhibiting BTK, which is the first on this table. And this is something called the, this is something that they use to differentiate the ability of those inhibitors to affect different targets. And if you look at the ibrutinib, acalabrutinib, it actually is able to inhibit white a bit of all these off-target markers that you generally might not want at all in the treatments of the CLL, specifically. However, if you look at the acalabrutinib, the dose that will get you to inhibit BTK, which is your goal, is much much lower than the dose that can inhibit any tech, EGFR, ITK, JAK3. They, you need a much higher dose in order to inhibit those. While ibrutinib, the dose that is therapeutic to affect the BTK is also able to affect a whole bunch of others, if not very close. And this is the response in terms of lymphadenopathy in the with the use of CT scans, the use of acalabrutinib in the CLL, and you see here the gray is stable disease, which is only one patient, partial responders, or ton of them, and then a partial remission was in addition to the resolution with no system sources.
How about mixing it all together? Ibrutinib, venetoclax, and obinutuzumab. How does it work? You could deal with choose a web started early, get the ibrutinib, and you've started the next cycle, and then you get this venetoclax thirdly added on the third line. So, my, so based on this, this is a trial to combine targeted therapies that we know that they work independently, that maybe if we mix them together, we'll be able to achieve a better response. All right. And this is on a preliminary results. Look at it, complete remission. So, this was a small number of patients. You see, we're only talking about like 12 patients total, achieved a complete remission in two out of those 12, partial response in ten, partial remission in ten, and progressive disease, none. Now, when you look at the colors, these are when you're comparing peripheral blood minimal residual disease assessment to bone marrow, and and our goal is to maybe achieving more and more know the, you know, our goal is to eradicate this clone from the bone marrow if we can. And you see here, the very, very light tan color, that's the peripheral blood, bone marrow negative of clones. And and that's significant. That's significant with the use of just targeted therapy, non-chemotherapy. I like it. And then there is the CAPTIVATE trial, which basically makes the ibrutinib, venetoclax, an impressive early results in CLL, phase 1-2 clinical trial population, relapsed within three years of FCR, we are having 17p deletion, and it's failed at least one line of therapy, or to be recruited after eight weeks of ibrutinib monotherapy. You add venetoclax, started 10 milligrams a day with weekly escalations, 25 to 20, 50, 100, 200, and to finally dose of 400. There was no TLS tumor lysis syndrome in the first three patients starting at 10 milligrams a day venetoclax. So, all subsequent patients began when I relaxed at 20 milligrams per day. Primary endpoint, poverty eradication, devices less than 1 CLL cell in 10 to the power of 4, assessed by an 8-color flow, multicolor flow cytometry in the marrow after 12 months of the road, another clax. And the key secondary endpoints were MRD eradication from the marrow after 6 and 24 months of improvement networks, as well as safety. Force because that phase 1-2 results, 25 patients reached their eight months follow-up, six months of their ibrutinib, venetoclax together. Marilyn CT scan assessments, all 25 patients have responded, 100% overall response rates, very unapologetic, apologetic response. However, 60% of those achieved complete remission, inquiry remission with a complete count recovery. All the remaining PRs due to small volume was not inside of larger lymph nodes at baseline. So, sometimes you cannot completely get rid of your lymph nodes.
Conclusions. Combination of ibrutinib, venetoclax is well tolerated in relapsed refractory CLL. Only two out of four patients experienced biochemical TLS, which to date, all 25 patients reaching initial response rate assessment after six months of ibrutinib, venetoclax had responded, 60% in CR, 28% achieved in MRD- remission in the marrow. These early results are just a potent synergy between ibrutinib, rituximab, I'm sorry, ibrutinib and venetoclax. And here comes the Brits. So, FLARE trials currently recruiting. One gets ibrutinib, if group two gets ibrutinib, bendamustine, group three gets ibrutinib, but venetoclax, and group four gets FCR, the old standard. There is currently recruiting. So, we don't want too much about it now.
There is the IFCR. You know, is in America and everywhere, iPhone, iPad, iPod. Now, we have IFCR as frontline therapy for younger CLL patients. So, this is mixing the old standard FCR with the new standard, ibrutinib, in one line. And FCR belongs disease-free survival for many SLL patients with mutated IG HV. Our patients with unmutated IG HV typically have less durable responses. CR with bone marrow minimal residual disease negative, so they could not detect it at all. Historically, FCR can get you 20% of those patients, given the excellent efficacy and tolerability of the frontline ibrutinib across CLL risk subtypes. Investigator-initiated multi-center phase 2 study of ibrutinib plus FCR as a frontline treatment for young, fit CLL patients was initiated. Primary endpoint was the rate of CR with negative bone marrow or any residual disease at two months after FCR. Secondary endpoints are included response rates, PFS, and safety tolerability. They used 420 milligrams daily monotherapy is giving 70 days, then you start the combination FCR first, up to six cycles. Responders continued on ibrutinib maintenance for at least two years. Recent study amendment allowed accrual of 50 additional patients who discontinued ibrutinib MMR if bone marrow already negative after two years of maintenance and can restart ibrutinib if they recur. And similar fractures, a growth factor of course were needed. Populations were younger patients who meet the initial indication for treatment. Ecom services is one or less was a good organ function criteria are evaluated already assessed by poor color flow cytometry and by also by adaptive flow new sequencing results. Data cutoff July 2017. Almost 50 patients have been accrued within 35 patients of the energy original cohorts at fortification and the new expansion or safety net exceed data or not yet available. All those 50 patients need an agent enrollment for 55 years. And these are the characteristics for them. The baseline blood counts, as you know, the white count was high, so median was 87,000. Hemoglobin, platelet counts, and all these baseline characteristics. MXC overall response rate 100%. But what's what's more impressive is the 63% complete remissions. And then you look at the rate of complete remission with bone marrow negative MRD, that's the primary input. 37% 37% were MRD negative, which is an increase with a best rate that increased with host FCR, ibrutinib maintenance to 57%. So, an even higher best rate of bone marrow negativity by flow, irrespective of the IWCLL response was 83%, including 7% of patients in PR with a medium follow-up of 20 months. All patients are alive, and 86% remain on treatments. Simple measure negative patients elected to discontinue ibrutinib. Two patients who discontinued ibrutinib due to toxicity. I want patients with deletion 17p to achieve them MRD negative post PR and elected to pursue allogeneic stem cell transplant.
Conclusions. FCR reduced deep responses and relatively high-risk group of previously untreated young CLL patients for 57% achieving CR and 83% achieving bone marrow minimally these negativity significantly higher than 20% rate seen historically with FCR alone. Low rates of neurological issues, toxicities may be due to mandatory cofactor and some complexes. Updated results are they brought in discontinuation cords will be presented in the future.
Now, last but not least, and just all finished. This is CAR T-cell therapy. So, to those who are not familiar with CAR T-cell therapy, CAR T-cell therapy stands for chimeric antigen receptor T-cells. These are T cells that we collect from the patient. We take them to the lab, you get a vector that is carrying a marker, it gets into that, it gets basically transduced in and in expressed once its incorporated in the T-cell DNA on the surface as a detector/killer to those T-cells, to those B lymphocytes. You give them some lymphodepletion to the patient, and then you give him those T-cells back. And now you're and trained/educated those cells to do the job. You monitor the patient's scans, mayoral, peripheral blood. Remember, this, this is a line that got quite a bit of toxicity that we have to pay attention for, such as cytokine release syndrome. Have to pay attention for neurotoxicity. And these are the different generations. There's now a fourth generation as well. So, you're basically carrying a marker on top that is detecting those with a costimulatory domain that is very important. We believe now on which domain you are using in the race for 4-1BB or CD28. And we're working on getting those more and more advanced with each step of development. And this was published by Carl June, who is the first to actually study this type of therapy in humans in the New England Journal of Medicine. Chimeric antigen receptor modified T-cells in chronic leukemia. And you can see here, before therapy, all these lymph nodes, enlarged lymph nodes, how they have shrunk with the therapy. You can see the lymph from both sides on the actual as well as the coronal where the nose has shrunk significantly and almost disappeared. There's a few anti-CD19 CAR therapy for CLL already been studied and reported between University of Pennsylvania, the NCI, Memorial Sloan Kettering, and more and more centers come in. The challenges we have CRS feasibility, it's very expensive. One dose of these of these cells is worth an average about four to five hundred thousand dollars per dose. You need physicians trained to deal with this. There is relapse in the form of CD19 negative. So, you're basically selecting CD19 negative cells because you're eradicating better because you're already can the CD19 positive. But also, there's some relapses that are sitting 19 positive, and you cannot reuse the same car. Defining the best car, because there is different viruses, there's different vectors, there's different costimulatory domains, and all these things are still in the works.
In summary, CLL is the most common leukemia, often asymptomatic, and not treatment needed. No treatment needed on diagnosis or to tolerate on the treatment depends on the prognostic markers. Elderly, frail patients treated with targeted therapy like ibrutinib and venetoclax, while that young patients are treated with chemoimmunotherapy like FCR or ibrutinib, as long as they don't have those worst prognostic markers for which you generally head toward the targeted therapies right away. And then clinical trials, a combination of targeted therapies and CAR T-cell therapy alone. Let me just tell you, this is what I use as my diagram. This is the diagram that I use to actually follow to treat my CLL patients. So, you get a patient, untreated desk CLL outpatient. If they have TP53 or 17p deletion, if it is mutated, ibrutinib right away. If they are TP53 intact, then I look at the IG HV mutation. If it is mutated, that is the better risk. If they are younger than fit, I would give them FCR or chemotherapy. If they are old and frail, given ibrutinib versus obinutuzumab. Remember, chlorambucil, you can pick while if they are unmutated IG HV, and those are the people who are known as good responders to FCR or chemotherapy. So, the younger than the fit, I'll give ibrutinib personally. And if they are older and frail, continue to give ibrutinib also. So, with this, that's the end of it. And you can reach me at the email dr.jesse@louisville.edu if you have any questions. And that's it. You. You.