Chronic Lymphocytic Leukemia: Latest Treatments

Leukemia Research Foundation:

Hello and good evening. This is the new and emerging treatments for CLL hosted by the Leukemia Research Foundation. Together with our webinar partner patient Empowerment Networks. Thank you all for joining us for this first of four sessions of the Foundation's new and Emerging Treatments conference. My name is Lindsey Whyte and I am the Director of Programs & Partnerships at the Leukemia Research Foundation. I would like to take a moment to thank our supporters of this conference, AbbVie, Astellas, Daiichi Sankyo, Kite, Merck, Novartis and Pfizer. The Leukemia Research Foundation's mission is to cure leukemia by funding innovative research and to support patients and families. The Foundation has raised over $87 million in support of its mission and has funded research grants to over 600 new investigators worldwide. Our free support programs for leukemia patients and their loved ones include information and resources, education programs, peers support services, financial assistance, and a directory of other helpful organizations and resources.

 

Just a few housekeeping items for the program today. All participants will be muted throughout the program due to the large number of participants. If you already submitted a question at the registration, please know that we have your questions. We received a lot of questions, so we'll do our best to cover as many as possible. You can also type a question in the q&a box at the bottom of your screen as we go through the program. After today's program, you'll be sent a brief evaluation through email. Please do take a moment just to complete that evaluation so that we can improve our future programs. Also, this program will be recorded and sent to participants after the program and a recording will be available on our website. We are grateful to have Dr. Farrukh Awan joining us today. Dr. Awan is a professor in the Department of Internal Medicine at UT Southwestern Medical Center and a member of the Division of Hematology and Oncology at UTS W's Harold C. Simmons Comprehensive Cancer Center, where he serves as the clinical director of the section of hematologic malignancies, hematologic malignancies, transplantation and cellular therapies, and also lease the lymphoid malignancies program lots more to that.

 

He specializes in stem cell transplant, cellular therapies and evaluation of novel therapies for the treatment of patients with lymphoid malignancies and chronic lymphocytic leukemias. Dr. Awan completed a residency in internal medicine at the University of Pittsburgh Medical Center and received advanced training in hematology and oncology through a fellowship at the Ohio State University. He is a member of several professional organizations including the American Medical Association, American Society of Clinical Oncology, and the American Society of Hematology. He's also a recipient of the Young Investigator Award from the Lymphoma Research Foundation. Dr. Awan has delivered scores of presentations, administered multiple grants and clinical trials and published numerous academic articles and book chapters. Thank you so much, Dr. Awan for presenting tonight and I hand it over to you.

Farrukh Awan, MD:

Awesome. Thanks Lindsey and good evening everyone. So I hope you can see my screen okay and hear me okay. I obviously have two links here, so don't be confused by that. That's the second one is just a backup. If something happens to this, I'm happy to jump on the other one just in case it's a different network. So the goal was to talk about CLL. There's so much to talk about CLL, there's a lot of things happening in the field and I see a number of familiar names on the list so they know from our discussions what we talk about every day. So the goal is not to talk about every new development that's happening in the field. The goal is just to cover a basic overview of the disease and I'm happy to go into as much detail as possible. One suggestion would be that I'm happy to talk about specific cases, but a lot of times this is probably not the forum to share personal details about your disease and a lot of times making decisions about what's next. It's very, very tricky as a doctor because I don't necessarily have all the pieces to the puzzle and the situation and so on. So I'll try to stay away from those very specific questions, but I'm happy to talk about general questions related to any aspect of the disease as best as I can. We can talk about some new treatments. I have done these patient based seminars before and I realize that there are some patients who are very new to this conversation, to this area. There's a lot of anxiety.

 

I saw two new patients this evening a couple of hours ago, and both of them were newly diagnosed young folks, relatively young folks in their early sixties and obviously the biggest issue was anxiety and they don't know what's going on. So for them, the understanding the issues, what does it even mean? That's a completely different discussion from compared to somebody who's dealt with this for let's say 10, 15, 20 years. So to be fair, I'll start at that level where you're newly diagnosed, you are asking questions, you're trying to learn about the disease and then hopefully we can graduate to more complicated issues and treatment after the disease comes back and problems with the disease, living with the disease so to speak. And I'll try to wrap it all up in 20 minutes or so. So I want to give you as much time as possible. So my goal today is not to get too bogged down into specific details and show you too much graphs. There will be a few squiggly lines, so just bear with me throughout this.

 

These are my disclosures. They will not impact in whatever I say today. So alright, so how is the disease diagnosis? The first and most important thing, fact number one, disease diagnosis is usually incidental patients get a blood test done or a lymph node biopsy. They have a CT scan for whatever reason. Most of the time it's that testing which was done for unrelated reason typically leads to the diagnosis. So generally that's the most common presenting problem. I had a blood test, exactly the same story that I shared with you. Two patients that I saw went to the PCP saw the blood test white count was slightly elevated. They did another test and that's how they found out. Most of the time patients have no symptoms whatsoever and they've been dealing with it for a while and then they finally get diagnosed when there's a problem with a lymph node or a blood test that was found and directed and then they do this confirmatory testing.

 

So it's usually an incidental diagnosis. Luckily, and most people are not symptomatic or they don't feel it when they first get diagnosed. There's another entity called monoclonal B-cell lymphocytosis. The problem is there's nothing wrong with being diagnosed early. The problem is a lot of people who are otherwise perfectly normal also have this thing called MBL. Now there are some MBL patients who is like a baby CLL, so they start off as a low level white count and then slowly change into CLL at 1% per year. But some of these patients will never progress. So the problem is that if we start testing everyone in this country, almost six to 10% of the people above 70 will have this MBL and a lot of these folks will die of old age and will never have to deal with CLL ever in their life. So if you test everyone and if you do these fancy testing, which is kind of what's happening nowadays, everyone gets tested, everyone gets their blood work, everyone gets the flow test done and they get diagnosed with MBL.

 

Again, nothing wrong with the diagnosis except for the fact that it leads to a lot of anxiety and problems with that patient. You may not have to deal with this problem for another 10 years, but the anxiety, the thinking about it, the big C word, the cancer word, that's the biggest challenge that I deal with is just telling the patients, yes, you have cancer and the second step is, well this is this type of cancer or this type of cancer. So sometimes not knowing can be a blessing in this scenario because like I said, there is an entity of MBL patients which is the early CLL, which will never get worse, ever, and that's a normal problem that a lot of people as they get into their seventies and eighties will have. And that's why you can hear both sides of the story. Some people are for diagnosis and flow testing and aggressive blood work.

 

Some people are against that. And so that's kind of where we are coming from. I think the point is that before we do the testing, it's probably reasonable to talk to patients about what it means. Sometimes they may change their mind, they may not want to get tested. So ultimately this is how CLL is diagnosed and a lot of times we don't necessarily treat them right away and that's what leads to a lot of anxiety too. How do we diagnose CLL? This the next step. We cannot diagnose somebody on a simple blood test the CBC that all of us get when we go to our primary care doctor. They will do that at least once a year or once every other year just like they do the cholesterol testing. A lot of the doctors do that routinely and basically that test shows that the white count is elevated.

 

Now in the past 20 years ago, we used to say, okay, fine, the white count is high, this is CLL, you don't need to do a lot of things. So we used to count the number of lymphocytes, which is a type of the white cell. We used to count that and if it was above 5,000 then we would call it CLL. The definitions have changed. You cannot just call it CLL based on the white count alone. You cannot call somebody CLL based on the CBC alone. You need to do the flow test. The flow test is the one that tells you a what population is there, is it abnormal or normal? Because sometimes when you have a virus infection, the white count goes up. Sometimes if you have a urinary tract infection, the white count goes up. So the flow test is the one that is again very commonly done.

 

This is the one that basically causes CLL basically makes a diagnosis of CLL because you need to have cells that look like each other. This is called the clonality thing. So the cells are basically identical copies of each other and they also have a certain phenotype which means that they have these antennas that are sticking out and if you find them, we call them CLL, and this is why we need to have the flow done which will count this cancer cell. And if that's above 5,000, that's when you will call it CLL if you find these cancer cells. But the number of cells that's less than 5,000, that's either SLL or MBL two cousins of CLL. CLL and SLL is the same thing. CLL is mostly in the blood. SLL is mostly in the lumps. That's it. That's the only difference. So that's why the blood test, the flow test tells you 5,000 or higher: CLL. 5,000 or lower: SLL, but you need to have lumps. If you don't have lumps. And if the numbers are less than 5,000, that's when you call it MBL. That's the one that we deal with a lot nowadays because a lot of these tests are done along with obviously the CLL and the SLL. So that question that I get asked all the time, can I just do a regular CBC and tell if I have CLL? The answer is no. You can guess, sure, but if you want to be perfect, you need to have the flow test, not just the CBC. Alright, second question that gets asked is all the time, do I need CT scans? Do I need all of these fancy testing, the fish, the IGHV, LDH? You don't have to do any of these. There are certain guidelines and recommendations, but basically before doing any of this, the most important question that we need to ask ourselves is, if I know this, how do I change what I do? How does it impact me as a patient or me as a physician?

(13:35):

And if you have a good answer to that question, by all means do all of them. Why don't I need to do a CT scan? That's perfectly fine to do a CT scan. What will that change? Why do I just want to get a scan for no reason? What about the bone marrow biopsy? We do bone marrow biopsies on a lot of our patients, but do we really need it? If you know the answer to that, if that test helps you answer a specific question that you want to ask, then sure by all means you can do that. But there are a few things that you have to do and that's primarily the karyotype FISH and IGHV. It's nice to have those. Some people argue, hey, you don't need to do that unless a patient needs treatment and that's perfectly fine.

 

But the reason why I as A CLL doctor recommend doing the fish, the karyotype, the genetic testing basically and the IGHV testing is it tells me how good or bad the CLL is and I'll get to that in a minute. But basically the reason why I do that is because I want to know so that I can guide the next steps of how I'm going to see you. Am I going to see you in three months? Am I going to see you in six months? So all of these things together allow me to see my patients at a certain time point and tells me how the cancer is expected to behave. That's why I do these tests upfront and not wait until later. But some patients and some doctors want to wait and that's fine. The point of all of this is we don't do testing just for the sake of doing testing.

 

You can do testing on everyone, but you have to really think about how will that change what I do? Alright, so let's talk about a few misconceptions. This happens all the time. CLL is a good leukemia. The answer is absolutely not. There is no such thing as a good leukemia. This is kind of what we do. I talked about the genetic testing. This is what we used to do. This is called a karyotype and as you can see, every human being that is born normal without any problems which we would consider normal, normally has 46 chromosomes. Now some people have different chromosomes and they have different presentations. But if you had what we would consider historically normal, you have 46 XX or 46 xy. That's the chromosome numbers that we have. 23 from the mom, 23 from the dad. And as you can see in this particular case, this is not 46, right?

 

This is a lot of extra chromosomes. So for example, chromosome two has three copies, three has three copies, 11 has five copies. This obviously means that the genetic message which makes us humans basically is all messed up. The copy numbers are messed up, the sizes are messed up. This is a bad situation to have. So even we can tell that this is not, and we are not experts in this thing called cytogenetics, but this is what a cytogenetic looks like and this is what we can do on our cancer patients, CLL patients, pretty much anything that we want, anything that cells, we can do this and we basically can look at the genetic makeup at a very crude level, microscopic, and we can look at these bands and we can say, okay, fine, there is a problem at this spot. This is the karyotype, this is the cytogenetics and the karyotyping and this is the fish test.

 

The second test we do is look at very specific problem sets. And so normal people will have these two dots like this for let's say you're looking at gene X, so this person will have one from the mom, one from the dad, and this is how the normal pattern should be. And then gene Y will be here and here. This is what it should look like. Now in a mutation or a fusion or where they're moving around, we can actually put these small probes in on the cells and this is the inside of the cell. Look at it under the microscope and you get this fusion or you get the fusion break apart depending on what you want. This is called the fish test. So the fish test is looking at very, very specific signals for certain genetic problems that we know about. Karyotype or chromosome analysis tells you the whole story.

 

Fish is very specific. These are the kind of tests we can do along with multiple other things and that puts people into different squiggly lines. The squiggly line, the green squiggly line means that those patients who don't do well and the yellow squiggly line means that patients do really well. So does that mean that all patients will behave the same way? The answer is absolutely not. Once you have that information, that's how you decide how the patient is likely to behave. And this is why it's important to get these genetic testing. CLL is not one cancer. Breast cancer is not one cancer colon cancer is not one cancer. There are so many different types of CLLs and breast cancers and every type is managed differently. There are nuances to how it's managed. For example, I'll give you small examples, 11 Q deletion patients. Those patients have big lumps.

 

17 P deletion patients- historically chemo never worked for them. They were the ones who had very aggressive disease. 13 Q, on the other hand, no problems whatsoever. This is why knowing what you're dealing with is important and this is why making general statement the CLL is good or bad is not the right thing to do. Luckily, most of our patients fall in the good risk one, the Dell 13 Q or breakage of the chromosome number 13. And that's why we get lucky that we make the statement, oh yeah, you're going to be fine. And we are right 50% of the time.

 

Similarly, IGHV is another test. Again, I don't want to overload the discussion with these testing, but these are some very common ones that we do. IGHV. Why do we do it? Because the fish, the ones that I showed you earlier, the karyotype and the fish, they change over time. IGHV never changes. Once you're mutated, you're always mutated. Once you're unmutated, you're always unmutated. It never changes. If you are unmutated, that means if don't have the mutation, you will do poorly in the sense that the disease will get worse over time and you will probably need treatment. On the mutated side, it's a very much slower process, so it might take much longer for you to have any problems with the disease. This is why we do these testing.

 

But since it's chronic, it has to be good, right? Chronic means good. And the answer is no. This is not diarrhea. This is not loose bowel movements, this is leukemia. Chronic has nothing to do with the aggressiveness of the disease or the prognosis. Some chronic can be bad, some chronic can be good. Chronic only means that the cancer developed in the mature blood cell. That is it. This is how we describe that. Acute, chronic. Acute means the baby cell blood cell got the cancer, babies are big in the blood world, babies are big. As they get more mature, they lose their baby fat. And that's why the mature blood cells are small. The baby blood cells are big because they have a lot of food in it, they have to feed, they have to grow, but as they grow they get smaller and leaner so they get smaller. And if they develop a cancer at the baby stage, those cancers are big, large, ugly one cells and they're called blasts usually.

 

And then if they develop a cancer at the CLL state, the cells are lean and they call chronic myeloid or lymphoid. That's a separate issue. But basically chronic and acute has nothing to do with how bad the cancer is. It's all about the stage of cell development where the cancer happens. So it's not just that one will do well, one will do badly. It just depends on all of the other factors that I talked about. So we basically recommend doing the fish in the cytogenetics. We also recommend IGHV status. And last but not the least, we need to test for both Dell 17 P by fish and TP 53 by genetic testing. This is a common misconception that people have. Oh, I had the 17 P deletion and oh, I had the TP 53 done. Nine out of 10 times, it's only done on the fish. And we know that if you have the fish and the genetic testing for TP 53, they're two different tests, not the same test. Even though the same test, the fish test would say Del17 P and TP 53. It is not the same test. I keep repeating it to everyone. So it's a different test. The PCR, the NGS testing is different for TP 53 mutation. The fish is different if you have one or both. Having both is worse than having either one of them alone. This is why we need to test this. This is very important.

 

Alright, so let's move on. So what about the stage? Do we even worry about the stage? So this is the Rai staging. Dr. Rai, some of you might be patients of Dr. Rai. He's still practicing, but he was in his twenties when he developed this 50 years ago. The Rai staging system came out in 1975 exactly almost 50 years ago. And basically all it had was if you had a high white count, if you had big lymph nodes or if you had an enlarged spleen. That's how we do it. Nothing wrong with the Rai staging. Dr. Binet was another one. Dr. Binet since passed. He was a French CLL doctor in 1979, he modified the Rai staging and came up with the European staging, which the Europeans used for a long time. Essentially the same thing. So the point is the Rai staging and Binet staging, there's nothing wrong with it, but those were the ones that was developed back then. But we can do much better than that.

 

So that's why we don't really worry about the staging. We use the staging as just one piece of the puzzle. We put you in a group of things and take the ones that's the most important one, which is the one that I talked about for 10 minutes now, del17P fish and TP 53, that gives you the most score, it puts you in a bracket and then if you're in the orange bracket, those are the patients I will see every three months. If you're in the light yellow, light blue bracket, I will see you once a year. This is how we decide based on age, stage, beta-2 microglobulin, IGHV and TP53. What is your score? That tells me how I expect you to do and that tells me how to prepare for the future. This is why we don't go by staging alone. We use all of them and make a much better educated guess.

 

Alright, last, there's a bunch of things like that. I can stop in a few minutes and then we can talk about drugs. So I have leukemia, I need treatment, which makes sense. You have cancer and you need to get treatment. The answer is no. We've known this for a long time that people have tried this in the seventies and eighties. So in the last 50 years that's all we've done is try to treat cancer early. Guess what happens if you have two people starting treatment at the same time, they live the same amount of time. If you're older and start treatment early, you die early because sometimes the treatment can be worse than the disease. So early treatment has never shown to prolong survival. Even with the new drugs. We have not shown that the cancer treatment will make you live longer even though the new treatments are so much easier than the old ones that we had. We don't treat the cancer early.

 

So then if you don't treat the cancer early, fine, when do you treat? So you treat the person, you always treat the patient. You don't treat necessarily only the numbers. How do you feel? Are you losing weight without trying to lose weight? Are you significantly fatigued and beat up? You feel like you can't do anything out of proportion to getting old? Obviously if there's a thyroid issue, sometimes there's a testosterone issue, endocrine issue, whatever. If you don't have any other reason to explain the fatigue and if you're getting worse and worse and worse, it could be from the disease and we have treated patients for fatigue. Fatigue is a legitimate problem in patients with CLL. If you had low grade fevers, if you're drenching night sweats, not necessarily hot flashes, but these are night sweats that you cannot ignore. You'll have to change your clothes, change your sheets, that kind of drenching wet, you're like lying in a pool of water. If that keeps on happening more days, more nights than not, then those are some of the reasons why when we talk about treatment. Obviously we also look at the numbers, but they all go hand in hand.

 

What do we treat? Hemoglobin of 11 or 10, low blood count, low platelet count of less than a hundred. So basically we are looking at the normal numbers. If the normal red cells and normal clotting cells start to drop and if they get below certain levels, that's when we treat. If your spleen is huge and you feel like there's a big stone or football in your belly, that's a good enough reason for me to treat. If the lymph nodes are getting huge or if they're getting painful and for example, you cannot breathe or you're having coughing or something, even if it's a small spot that's a good enough reason to treat somebody. So you have to put it all together and then take the decision about when to treat.

 

We do not treat low IGG level. We do not treat a monoclonal protein. Some of you have this question, do I treat for that? The answer is no. We never ever treat for a white count. White count is the single most useless test for CLL to make a treatment decision. We never treat them on a white count. Some people say a hundred white count, 50 white count, 300 white count, absolutely not. White count is only good for anxiety. It only causes anxiety because it keeps going up. We look at the normal numbers along with the white count. White count is good for trend. We do not pull the trigger just because the white count is high. Why? Because people also used to think treatment was chemotherapy. We have moved on. We do not use chemotherapy. Chemotherapy should not be used end of discussion, period, in this country, unless there is a very, very, very good reason to treat somebody with CLL with chemotherapy in this country in 2024, I can say for the last five, seven years at least, maybe 10 years, chemotherapy should not be used unless there's a very legitimate reason.

 

Now obviously if you're in other parts of the world where they do not have access to different treatments that you can argue about that and there's multiple arguments. I'm not going to get into those arguments about chemotherapy. People ask me all the time, but basically they say, oh, chemotherapy does very well for a small group of patients, but it also hurts a lot of people in the process. So we do not use chemotherapy. We do not use chemotherapy. We look at the different switches in the cancer cell. These are multiple switches. Any one of those switches can turn the cancer on. You just have to turn it off. And basically that's how we deal with the cancer. Turn the switch off that makes the cancer live. This is exactly one of the reasons why we use the white count. When we started treating patients with the new drugs, the first one was ibrutinib. The white count actually went up. Imagine how scared we were the first few times we treated patients with CLL, with ibrutinib. The white count kept going up. Ibrutinib for those of you who don't know, is a pill that changed the way we treated CLL in 2009, 2010, 15 years ago. So it's not been too long.

 

So ibrutinib, when we started using it, when we gave it to patients, the white count went up and we were like, whoa, what's happening here? We don't want the cancer to get worse. But the point was that as the cancer was supposedly getting worse, the lymph nodes were shrinking, the spleen was shrinking, people are feeling better and turns out that this is how the drug works. It pushes out the cancer cells from its hiding places into the circulation and the cells are being killed by the body. That's what happens with these new pills.

 

Ibrutinib was just the first one and the rest, as they say, is history and remember the squiggly line at the top. The blue one means that those patients do it really well and some of these patients are still doing really well and we have come a long way since ibrutinib and then ibrutinib was compared to chemotherapy. Again, without going into details, I will just show you this. Now, this curve shows you that ibrutinib was the first one right there. The red dot shows you how specific it is to the target that I've wanted to hit the switch that I wanted to turn off. It does a really good job. All the others are also important and these are the new drugs. Some of them are much cleaner and it only hits the target that we want and others are not as clean but better than ibrutinib.

 

So this is why as the cancer gets smarter, we are getting smarter too. So this is just, again, this is already old because there's multiple other drugs out there, but this just shows you that the benefits are by hitting the target that you want, turning off the switch that you want and then working on the next generation one, which may be even better than ibrutinib. But the problem is because you're hitting all of these other switches, it leads to a lot of problems. Problems like bleeding, problems like heart issues, rhythm issues, high blood pressure. It's not super bad. People can be managed. The point is that you have to realize that all of these new drugs that are coming out, they do a really good job. But you also have to deal with some problems that some of these things can have. And if you know and can predict and can manage it effectively, your patients are, all of us will do much better because we can continue treatment for a long time.

 

So there's two concepts to it. One of them is called the drug effect. The other one is called the class effect. For example, there are some side effects that all the drugs will have. For example, bleeding in the BTK class, the first type of drugs that came out for this disease, bleeding was a very common problem. It is still a problem with even the newer ones. Heart problems are still an issue. Blood pressure is still an issue. Some better, some worse. But you have to realize that that's a problem that's universal to this class of drugs for whatever reason. But the point is that this is something that we need to manage. So we avoid aspirin, we avoid blood thinners, we make sure the blood pressure is okay and the patients do really well. Similarly, if you go drug by drug, arthritis, fatigue, ibrutinib causes those. Headaches, acalabrutinib, and so on.

 

There are some unique things that one particular drug causes and the other doesn't. And there are some that all of them cause for example the headaches we talk about with acalabrutinib, it can easily be managed by caffeine. Just drink a couple of coffees a day. When you take around the time that you would take the pills, it's a vascular headache.

 

Fatigue. Fatigue is the problem with ibrutinib. That's harder to manage. So these are small little tricks that you can do to make sure that you anticipate the common problems and manage perfectly fine. And patients can do really well for a long period of time. And this is kind of why it happens. So I showed this earlier, it's hitting the target but it's hitting a bunch of these other targets and if it hits the target in the skin, it causes the rash, it hits the target in the platelets, it causes the bleeding, heart same way.

 

So this is why we are getting smarter, we're getting better, but we still have a long way to go. So this is why I said common sense. Make sure you're not taking any medicines like fish oil, which will make the bleeding worse like aspirin, like Plavix, like other blood thinners. If you have to go for a minor procedure, stop the drug for three days. If you had to go for a big surgery, stop it for seven days to allow the body to come back to normal so you don't have a bleeding problem. Common sense things can make a huge difference. We then also talked about the guidelines that we developed. We started with an international guideline and now we're developing the European and the Australian and New Zealand guidelines, which is just to tell the doctors how to manage patients if they have a heart issue and maybe they have unique challenges in those parts of the world, which we may or may not have.

 

Similarly, we have to control the blood pressure. We have to make sure the heart doctors are involved. We have to make sure that there are no two pills for example. There's some blood pressure medicines that can interact with army strongly and we have to be careful with those. So common sense, small little endeavors can make the side effects risk very low.

 

People talk about tolerability and resistance. If I fail one, can I go to the other one? Absolutely. These are nuanced decisions. You can start with one, you can go to the other, you can go to the second one, you can go to the third one. We right now have four or five generation of drugs. First, one, second, third, fourth, fifth. Everyone has their own nuances. Everyone works better this way or that way. This is why you need to talk to a CLL doctor who knows this. Pertobrutinib, nemtabrutinib are two of the famous ones, but there's so many of them and they look pretty good. They seem to be working very nicely and we are very excited with both pirto and nemta.

 

But no, I want to stop treatment after 12 months. I want to stop treatment after a certain amount of time. Perfectly reasonable. We have the option for Venetoclax in that setting. It is an option where you stop treatment after 12 months and we are now trying to come up with various combination in which you take pill plus pill 12 months, 24 months and then stop. We're still figuring this out. This is why clinical trials are so important. Venetoclax keeps you take it for 12 months, let's say, or 24 months depending on the situation. And then you stop and then patients will do fine for a while without any problems and then the cancer will eventually come back and then you treat it again at that point.

 

Similarly with the BTK inhibitors, we start the pill, we put the cancer in remission and we keep a lid it so see on/off strategy, is that going to give me the best results in the long run or is it on strategy all the time? Which one will give us the best outcome? Only time will tell. But these are the discussions that you need to have. Maybe you are the one who doesn't want to take a pill for the rest of their lives and that's perfectly fine. Not a lot of people want to do that. So let's talk about how we can stop treatment, how we can modify treatment. This is why clinical trials are so important because these are the questions we're trying to answer.

 

And then finally, can we cure this cancer? Well, we don't know if we can cure this cancer yet, but we can put it in a long remission. And this is the early results from the CAR T, which is just another approach for treatment in which we can put people in a long remission. Now it doesn't work in everyone and we're trying to again optimize it and make it better. But the point is that there's so much happening in the field which is so promising, and patients have tons and tons of options. I haven't even touched like half of them. So that's why you need to keep talking to the doctor. Your team chemotherapy has no role. There's a really, really good outcomes for the vast majority of our patients. Patients are expected to live a normal lifespan if there are issues related to insurance, drug compliance because of interactions with other drugs. All of these issues need to be resolved after a discussion with the patients. We can work with different organizations, funding organizations to allow us to control the extent of the disease and allow us to get the drugs for at a abated number or get help with back and forth blood work scans. So many things can be done to ensure that our patients are able to get the best possible treatment and hopefully live a normal life.

 

So this is why we also need to talk to other doctors, tell them, “Hey, my patient's coming in, you need to stop the blood thinners if you're going to do a procedure, if you have a dental extraction, stop it for three days so they don't bleed.” Small little things can make a huge difference and our patients are expected to do well. They will continue to do well and we are very positive about what's happening right now in the field and what's in store for us. So I'm happy to take any questions that you have and you can feel free to email me with any questions you have. But Lindsey, I see one question that's come up, but please let me know if you have any specific questions. I can take this one if that's okay.

Leukemia Research Foundation (38:00):

Yeah, sure. That sounds good. I can read it. Is Pemgarda available yet for use and is it recommended for CLL patients?

Dr. Awan:

Yeah,

Leukemia Research Foundation:

I cannot find an infusion site in my area.

Dr. Awan:

Yeah, Pemgarda is the new antibody against covid. It technically has been authorized for, it has an emergency use authorization. I think that's the correct word, EUA. So that's something that we are trying to get to. The problem is the manufacturers haven't given us a way to bill for it. I was asking our people, Hey, how much is this going to cost? Apparently nobody knows. Nobody knows how to order it, nobody knows how to get it. If you guys know about it, let us know because we would also like to have that as an option for some of our patients. Now I would be cautious though it does cause a little bit of reaction sometimes you have to be careful that your doctor is familiar with this medicine and they're ready to handle any side effects that you can have from this medicine. Apparently it's going to be 6,000 bucks, but that's what they told me. I'm still trying to get it at my site. It's challenging. I don't also know a lot about how effective it's going to be, so more to be seen. But yeah, pemgarda is up in the air right now. Nobody knows much about how to get it in their hands.

Leukemia Research Foundation:

Okay, I'll just remind everyone that if you have a specific question, feel free to put it in the q&a, enter the q&a and then in the meantime, I'm just going to go to one that was submitted during the registration process. Please comment on the degree to which BTK inhibitors suppress the immune system potentially contributing to secondary cancers.

Dr. Awan:

So that's always a difficult one to answer. Secondary cancers. Now theoretically, if you reverse the cancer or if you put the cancer in remission, your ability to have your immune system should recover. And that does happen with CLL at some point in time. But the problem also is that CLL is cancer. CLL is a cancer, which, how should I explain this to make it simple? So CLL is a cancer in which, okay, Lindsey, let's just repeat the question one more time so that I can get my chain of thought again.

Leukemia Research Foundation:

Yes, please comment on the degree to which BTK inhibitors suppress the immune system potentially contributing to secondary cancers.

Dr. Awan:

So rewind my bad. So the CLL cell is basically a lymphocyte. This lymphocytes are designed to do a certain job in the body in which it basically is supposed to make antibodies and be part of the immune system. So at baseline, your immune system's messed up and that's how it developed the CLL. And so then what you do is if you target with different drugs, which basically are shutting down the lymphocyte, you are by default also shutting down the immune system of the body. As a result, your immunity will never be as good as a normal person's immunity, but that is partly the problem of the treatment, but it's also partly the problem of the cancer because the cancer is supposed to be the one that is supposed to protect you and now it's all messed up. So this is why we see that our patients don't have a good immune system. Our patients don't respond to vaccines as well as other patients. Our patients also get secondary cancers.

 

Initially when you start to BT inhibitors or other treatments, you do decrease the amount of cancer and that results in some improvement in immune immunity. But over time you will hit a plateau and then you will not be any better than a certain plateau, even if you're in remission, if you keep taking these pills because you're still suppressing the normal lymphocytes along with the cancer lymphocytes. So our patient's risk is definitely higher for secondary cancers and also immune related issues, but not as bad as other cancers. Not as bad as patients with chemotherapy. But unfortunately it's an ongoing thing. The other problem also is, I guess it's a good thing is that our patients live for a long time, which that allows you to do is develop cancers like you would normally as we all get older. So that doesn't help our patients too because they get skin cancers most commonly and other cancers because of the fact that they are getting older and their immune system is naturally declining and not as robust. So CLL is a problem of the immune system and that's what happens.

Leukemia Research Foundation:

Great, thank you. I'm going to pull a couple of questions from the Q&A. The first one is how do genes unmute?

Dr. Awan:

Yeah, so I read that and I was trying to think of a question, a way to answer that. So it's not that unmutated or mutation is happening in certain genes, it's more complicated than that. So there are certain CLLs developed in patients who have gone through the mutation. The mutation is more of a maturation. So during the maturation process of the cell, I guess the silly analogy I used to use was, think of it as a marriage. You can be a corrupt person before marriage or you can be a corrupt person after marriage. So once you're married, you're settled down and generally you can still be a little bad, but hopefully generally not as bad. But if you're a teenager and if you're aggressive, basically if you develop a cancer there or you're super aggressive. So that's kind of the silly analogy that I used to think of when I was thinking about this concept of the IGHV mutation status.

 

So basically, the maturation process happens and the cells acquire mutation, which is a sign of maturation. So maturation. Then when the cells mature and then they develop a cancer, these cancers are called mutated CLLs. If they develop a cancer, a CLL, before they went through the maturation, before they got the mutation, those cancers are a little bit more aggressive within the same cell type. So that's the IGHV mutation. It's a little difficult to understand, but basically it's the stage of maturation of the cell. So if you develop a cancer after the germinal center maturation, you call them mutated CLLs. If you develop the cancer before the germinal center mutation, you call them unmutated. Okay. I hope that makes sense.

Leukemia Research Foundation:

Okay. If a patient is on fixed duration treatment and, after a period of a drug holiday, the disease comes back. Do you repeat the previous treatment?

Dr. Awan:

Yeah, that's an area of debate and there's a lot of debate about this. There's a lot of debate about BT K inhibitors. So if you stop a BTK inhibitor, let's talk about BTK inhibitors first because they're older. If you stop a BTK inhibitor after being on it for a few years, you typically get an average of two, two and a half years of remission before the cancer comes back. So anyone who's thinking of stopping ibrutinib, for example, we expect them to be in remission for a good long time. And there are trials that are trying to address that issue. Like somebody mentioned about ibrutinib, we've been doing it for a long time. A lot of patients get off of drug for various reasons and they do just fine. So we expect them to be in remission for a while, and then once the cancer gets worse, you can treat them back again and they do fine.

 

Now the question is, what about venetoclax, which is a unique situation? Can in that situation, you go in knowing that you're going to stop after 12 months or let's say 24 months. There's no consensus on how long it should be lasting before you repeat it. So generally the consensus is that if the treatment lasts for two to three years, then it makes sense to repeat it at that point. But if the remission doesn't last even at six months and if the cancer comes right back, chances of the treatment working again is not as good as the first time around. More work needs to be done. We have some evidence that the second treatment is not as effective as the first one, but it's still pretty decent. As we get more information, then we can tease that out further. How often, how much, how fast can you repeat?

Leukemia Research Foundation:

Okay, we have one last quick question. I'm going to take this one that is touching on the latest drug approved by the FDA for CLL. I know there was something in the immunotherapy category that was approved recently for CLL. And then the second part of that question is, is there more coming that are close to approval?

Dr. Awan:

Oh, every day there are more drugs coming out. I mean, calquence, acalabrutinib, zanubrutinib, all of these drugs have been around for a long time and they do well and patients are doing well. The most recent one was pirtpbrutinib and then we have an nemtabrutinib that is getting close to approval. We have a new BCL2 inhibitor sonrotoclax that's getting close to approval. We have a CAR T-cell that just got approved recently. So there's so many new things that are happening right now. Sky is the limit at this point.

Leukemia Research Foundation:

Well, that's good news. I think that's a nice point to end on. I really appreciate everything that you shared tonight. Hopefully other folks felt it was useful. I'm going to put back up our sponsors once more and say thank you very much to Dr. Awan for your participation and sharing everything you did tonight. And remind everyone that there will be a link coming in an email to complete a survey post-program survey. So please do fill that out. And Dr. Awan also shared his email address if you have questions specifically. And there will be a link to a recording of this program after the fact on our website. So please do visit our website, leukemiarf.org. Thank you so much, Dr. Awan, and thank you everyone for your participation. Hope to see you again on another program soon. Thank you.