ALL: Treatment Advances

New & Emerging Treatments: ALL 6.23.25 Transcript

Participants: 

Dr. Mark Litzow, Mayo Clinic

Lindsey Whyte, Leukemia Research Foundation

- Hello everyone. Thank you for joining us for the final installment of this year's New & Emerging Treatments series. The topic of this session is ALL and we're joined by Dr. Mark Litzow from the Mayo Clinic who will share some slides about the latest treatments and research for ALL and respond to questions from participants. My name is Lindsey Whyte and I'm the Director of Programs & Partnerships at the Leukemia Research Foundation.

- I'd like to take a moment to thank our supporters of this series, AstraZeneca, Autolus, Kite, Merck, and Pfizer. And for this session we were also supported by Vironexis.

- The Leukemia Research Foundation's mission is to cure leukemia through innovative research funding and to support patients and families. The Foundation has raised over $90 million in support of its mission since our founding in 1946, and we've funded research grants to over 750 investigators worldwide since that time. Our support programs for leukemia patients and their loved ones include information and resources, education programs like tonight's, financial assistance and a directory of other helpful organizations and resources on our website.

- For today's program, all participants will be muted, but we welcome your questions in the Q&A box at the bottom of your screen. Please note that you should check the box if you prefer for your question to be anonymous. If you don't want your name to be shown, please check that box. Otherwise, your question will not be anonymous. If you already submitted a question through the registration, please know that we have all the questions. We'll do our best to cover as many of those as possible, and some of them may be covered through the course of Dr. Litzow's presentation. After today's program, you will be sent a brief evaluation through email. Please take a moment to complete the evaluation so that we can improve our programs in the future. Also, this program will be recorded and a link to it will be sent to all registrants after the program.

- So we're grateful to have Dr. Mark Litzow with us today. He is a Professor of Medicine at the Division of Hematology at the Mayo Clinic. He was the Director of the BMT Program from 1992 to 2008 and the Director of the Acute Leukemia Group from 2002 to 2016. He was appointed Chair of the Leukemia Committee of the Eastern Cooperative Oncology Group in September, 2013 after having served as co-chair of the committee since 2001. He recently completed a three-year term as co-chair of the Acute Leukemia Working Committee of the CIBMTR. He was also a member of the Board of Directors of the Foundation for the Accreditation of Cellular Therapy for nine years, and he became board certified in Hospice and Palliative Medicine in 2012 and is a member of the Palliative Medicine Program. He's an author of nearly 700 manuscripts and multiple book chapters. So we're very, very grateful to have Dr. Litzow here today to talk to us about latest treatments, research and trials for ALL. Please take it away, Dr. Litzow. I need to make sure that you can share.

- Thank you very much. Let me bring up my slides here. I think they're evident- do they look good Lindsey?

- Perfect. Yes, thank you.

- Well, again, thank you Lindsey and I very much appreciate the opportunity to speak with you all today to talk about New & Emerging Treatments in ALL. I want to start by talking a little bit about what leukemia is, and so I'll define that and talk about how we think it develops. We'll review advances in treatment, especially with immune-based therapies, and then talk about some new targeted therapies, we call them, for ALL. And that's the abbreviation we use for acute lymphoblastic leukemia, ALL. So leukemia is a, we call it a clonal process. And a clone is a group of cells that arose from one abnormal cell. So that's where I say arising from one immature cell and it is a malignancy of, a cancer of, the bone marrow. And there's an excessive production of these immature cells in acute leukemia. And one can also get buildup of mature cells, mature leukocytes or white blood cells. And we call that the chronic leukemia and the accumulating the bone marrow, they can get out into the blood and sometimes they can invade other areas of the body. And so, excuse me, we broadly classify leukemias as either being myeloid predominantly from cells that are more commonly in the bone marrow or lymphoid like ALL that arises both in a bone marrow but sometimes also can be in the lymph nodes. So this is a breakdown of what I was just talking about in yellow. On the left are the myeloid cancers. And the previous session this meeting was on acute myeloid leukemia, but here we're discussing acute lymphoblastic leukemia in the blue on the right side of the slide. And it just shows some of the other types of lymphoid cancers that one can also encounter.

- So this is a little bit complicated slide, but I would just want to focus on the top there. The red arrow is pointing at what we call a stem cell and that's sometimes referred to as a mother cell. And then that as it matures can go to the right side and become a lymphoid stem cell and that's where it's committed to produce lymphocytes. And these can be either what we call B cells or T cells. T is, it stands for thymus, that's a gland in our chest. So it's a a T cell, so it's called a thymocyte, a B cell. The B comes from a word that actually arose from from an organ in chickens because that's where they were first identified. And so you can have a B-cell acute lymphoblastic leukemia or a T-cell acute lymphoblastic leukemia. Across the bottom you see the, the normal cells. So this is a normal production of cells, but when this all goes awry, then someone can unfortunately develop a leukemia. So acute lymphoblastic leukemia is an acute leukemia of immature lymphocyte precursors, either these B cells or the T cells. Here I'm reiterating this, the B stands for this organ in chickens called the bursa of fabricius. So that's the B and the T again is the thymocyte. It's more common in children and young adults, but it can be seen across the age span. And we see it also in in elderly individuals, but it is more common in children and young adults. It peaks in the two to 10-year-old age range. And in children the cure rate is very good, it's in the 90% range. Unfortunately we haven't quite achieved that in adults, but we are improving things, and the outcomes are getting better for adults in recent years. So leukemia can also get into other areas of the body and there's a less than 10%, but in the five to 8% range that it can get into the spinal fluid and the leukemia cells can circulate through the spinal fluid and up around it around the brain area. And that's something that we work hard to prevent and also can treat if that develops.

- Now you've probably heard, if you're familiar at all with acute leukemia, this concept of MRD or measurable residual disease. And this is where we can now have more sensitive techniques and we can find small amounts of leukemia cells in the bone marrow and the blood that we didn't used to be able to see. And what you're seeing on this slide is on the Y axis or the vertical column, you see these numbers 10 to the minus one 10 to the minus two, 10 to the minus three, et cetera. And you get down to 10 to the minus six. That that means that there's one in a million cells that that are being detected. And that's about the limit of what we can detect. Now, one could have one in 10 million or one in a hundred million, that's possible. And so 10 to the minus seven is one in one in 10 million. But obviously the lower down we get, you know, the dotted curve as you see it gets down there and it flattens out. And we hope that that's where someone will stay and we can say that they're cured. But sometimes people can get down to these low levels and it looks like we don't see the leukemia, it's not present on any of our testing. Then unfortunately the leukemia can come back and up toward the top, you see early relapse, that's where we've knocked the leukemia down to a lower level. But there's still leukemia in a sufficient amount in the body that it can start to grow again fairly quickly and cause what we call an early relapse. And then there can be a late relapse where the leukemia's at a lower level and the cells sort of lay dormant there, but eventually can start to grow again. So, you know, I kind of compare this to finding a needle in a haystack when the leukemia cells get down to a real low level and sometimes it can be difficult for us to detect them, but we have more and better techniques to be able to do that now. And so that's also led to us being able to intervene if we're picking up low levels of leukemia. And also to help tell us, you know, how well our treatment has gone.

- So you're going to hear a lot about immunotherapies, and this is really revolutionized the treatment of cancer in general. We're utilizing tools from the immune system to attack both leukemia and also other, you know, solid tumors like breast cancer, colon cancer. But in leukemia, we rely on what are called antibodies. And you can see the structure of the antibody. It's a bit complicated, but it's got, it's, what we call these chains that you're seeing these lines. So the longer blue line is the heavy chain and then the shorter is the light chain and there's two of each of these in each antibody. And these antibodies, they bind to the structures on either on the surface of the cell or on a bacteria or a virus. And we all have antibodies in our system and they help us fight infection. That's their original purpose I'll say. But some years ago, scientists were able to develop and produce antibodies that reacted against cells and the proteins or the substance on the surface of the cell that the antibody reacts against, we call an antigen. And that's what you see at the top there, those different colored structures. So the antibody binds to the antigen. So an antibody is this Y shaped protein that again can help us fight infection, but now we can use to attack abnormal cells. And these are the different antigens on the surface of of a B cell. So this is, remember a B cell, a B lymphocyte, and most acute lymphoblastic leukemia, about 80% are B-cell of the B-cell type and only about 20% are of the T-cell type.

- So some of the important antigens that we've been able to target with our immune therapies are CD 19, the other one is CD 22. And this is how we distinguish these proteins. We use these CD numbers that stands for cluster of differentiation. It's not so important, but it's a way for us to be able to communicate one person with another, one doctor with another about, you know, particular proteins that are on the cells. So the CD designation you'll see, and CD 19 and CD 22 are two of the important antigens on leukemia cells that, as I say, we are targeting. So we sometimes use this concept, the analogy of a lock and key. So you can see the antibodies here and they're coming in and they're binding to these substances that looks like a key attaching or binding going into the keyhole. And so it's just an easier way to think about this I think with this lock and key approach. So this slide is complicated, but it shows the different antibody constructs that we have developed over the years. And the upper left, we use this term naked antibodies. These are just antibodies by themselves. And one of the first ones that was developed to treat leukemia and also treat lymphoma was this one that I'm pointing to with the arrow called rituximab. And we still use that today. And then in the upper right you see one that I'm going to talk about more, this one's called blinatumomab. And you can see that these, all these words end in “mab”- M-A-B -and that stands for monoclonal antibody and then the way the word is constructed, otherwise it's partly to identify it and distinguish it from other antibodies, but also to help distinguish how it was constructed. So there's the naked antibodies, there's this blinatumomab that I'll talk about more. If you go down to the lower right, there are antibody drug conjugates. There's one called inotuzumab, that's the green one. And you can see again it's got the MAB at the end. So inotuzumab is an antibody against CD 22 that has a chemotherapy drug called calicheamicin attached to it. So the antibody is now delivering the chemotherapy drug right to the abnormal cell in the hopes that we lessen side effects. So we call that an antibody drug conjugate.

- And then on the lower left is I'll say the newest kid in the block. And this is the CAR T-cell therapy. And this is basically combining these two different immune approaches and we're putting an antibody into a normal T-cell or a T lymphocyte, and bringing the T-cell close to the leukemia cell to help kill it. So this is kind of the the fourth important antibody construct. So I want to talk a little bit more about blinatumomab. This is assumed quite a prominent role in the treatment of particularly of ALL. And this is taking an antibody that reacts against the leukemia cell CD 19 and it's linking it to another antibody that's against CD3. And CD3 is on T cells. So it's kind of doing what CAR T cells are doing but in a different way. And it's bringing a T cell close to the leukemia cell as you can see on the right there, that's a tumor cell and it activates a T cell to kill the leukemia cell. And so we call it a bispecific, it's "bi" means two. So it's reacting against two different cells and it's a bispecific T-cell engager molecule. This has actually been around for about 10 years and it was first approved for the treatment of patients where their leukemia had come back or where their leukemia wasn't responding well to chemotherapy. So that's this relapsed, that's when it comes back or refractory means that it's not responding while the treatment. And then later on it was used in patients where their leukemia was seemingly under control. But by these sensitive techniques that I talked about, the measurable residual disease, we could still see some leukemia there. And so blinatumomab was tested in that setting and found to be effective. And so these are the two indications that the FDA approved blinatumomab for up until recently.

- And then in a study that I had the good fortune to lead, where we used blinatumomab for patients that were MRD negative, you can see on the right side there. And this was a study that we published in the New England Journal of Medicine just under a year ago. So we know that even patients that are MRD negative can still have some leukemia cells hiding in their body. This is kind of that needle in the haystack that I was talking about. So, and we know that we, even if somebody gets to be MRD negative and we think they're going to do well, sometimes the leukemia can still come back. So we wanted to test blinatumomab for those patients and see if once a patient became MRD negative with with chemotherapy, could we then give blinatumomab and help keep their leukemia from coming back. And so this is how we designed this study. And I'm not gonna go through all of this. All of these rectangles that you can see are different amounts of chemotherapy in white. And then we gave four cycles of blinatumomab and that's what's in green on the left side. So half the patients got blinatumomab plus chemotherapy and the other half got chemotherapy. And what we found was that the patients that got the blinatumomab plus chemotherapy, their leukemia indeed did not come back as often and their survival was improved. And that's the black curve that you're seeing. So across the bottom of the, of this graph, you see the time in months, zero months, 12 months, 24, 36, and on the Y axis or the vertical line, that's the probability that they're staying alive. And the patients that got blinatumomab plus chemotherapy fortunately stayed alive more often than those that got chemotherapy. And at the time we didn't know if blinatumomab was going to work in this setting. So we asked patients to be randomized to one of these two treatments. And lo and behold, we did find that adding blinatumomab was helpful in this setting. And this led to the FDA to approve a third indication for blinatumomab just last summer just to almost exactly a year ago on June 14th last year. And so they approved it as consolidation for patients with this B-cell precursor or B-cell acute lymphoblastic leukemia. And so this is a third indication and another advance and another advantage of using blinatumomab.

- So blinatumomab is a very good treatment, but it's not perfect. And there have been efforts underway to try to improve on the treatment. And this is what I'm showing you here is also an antibody on the right and this is a bit of a different structure. It also brings a T cell through CD3 close to a leukemia cell with CD 19 to kill it. And it's called AZD0486. So it's still not yet approved by the FDA, but it's being tested and it seems to work as well or better than blinatumomab. And it seems to have less side effects because it doesn't bind to the T-cell quite as strongly, but it still binds strongly enough to bring the antibody to the leukemia cell. And so this is tested in patients where their leukemia had come back and a little over half of them achieved a complete remission. And of those half, a little over half or 55% of that 55% or 12 patients out of 22, 92% or nearly all of them became MRD negative and 10 of 12 of them remained in remission. And two of them, unfortunately, leukemia started to grow again. And this study is continuing, but we just saw some early results from this new antibody treatment that we think will be as good or potentially better than blinatumomab.

- Now there's another approach that's being done with this company called Vironexis. And what they're doing is taking the CD 19 antibody and the CD 3 antibody and they're inserting them into a partial virus. That's the AAV. And then they're injecting this virus, which doesn't cause an infection, but injecting it into people. And then this virus can go into cells and start to produce this new protein that contains CD 19 and CD 3. So what's happening here is they're using this to allow the body to, in a way, make blinatumomab continuously. So it's sort of there all the time and working against the leukemia, which is different than we give it now. Now when we give blinatumomab, it's given by an infusion for four weeks at a time. So people wear a pump and it gets pumped into a catheter, but it's four weeks at a time and then we stop it and then we can restart it later on. But it's not given continuously. Whereas this treatment would give essentially the equivalent of blinatumomab continuously and we think and hope that this will be more effective. And this is a type of gene therapy and it's using, you know, it's giving it through this virus vector it's called there you can see on the lower left. But these, this type of virus vector has been shown to be safe and it's been used in many other indications and situations. So it looks like it's got the great potential to be an effective and also a safe treatment.

- And then there are CAR T cells and you may have heard a lot about them and remember, I said that this is where an antibody gets injected or gets put into a T cell and it's, and it's also where a virus is used. That's the thing you just saw come across the screen. That was a lentivirus it's called. And then that produces the antibody there that you see in red. The purple are not antibodies, those are what are called T cell receptors. So now the antibody is in the T cell and now it reacts against the leukemia cell there on the bottom and it kills it. And that's basically in a cartoon form how CAR T cells work. And over on the left cell, left side, you can see how they're structured. The upper part in red is the antibody and the lower part is where it's injected into the T cell. So the way these cells are collected is by what's called leukapheresis or blood is removed from a patient and it's put through a machine and the T cells are taken out the white blood cells, we call that leukapheresis. And then you see on the bottom left, number two, the T cells get activated and the virus gets injected into the T cells to make the antibody. And then these cells are expanded or grown. So a lot of them get produced. That's number three. There's not a number four, oh, there's number four here, I'm sorry, that's up on the upper left there. Patients then get, get a type of chemotherapy that's called lympho depleting chemotherapy. And that's to lower the number of T cells in their blood that would be their normal T cells. And that gives the CAR T cells more of an advantage to grow in the patient. And then those get infused into the patient and that's the green bag and the green line. And then they can attack the leukemia at that point. So the normal T cells get removed, they get the virus injected into them to produce the antibody, then they get expanded and then are given back to the patient. And this can take, you know, a couple weeks for this process to occur, although there are efforts to speed up that process as well. And those appear to be becoming more and more successful. So Dr. Carl June, who's in the back there, I've got an arrow pointing at him. He is the main person that really developed this CAR T-cell therapy and he's at the University of Pennsylvania and the young woman in the front, that's Emily Whitehead and she was one of the first patients that was treated with CAR T-cells when she was very young and her leukemia had become very resistant to all forms of treatment. The CAR T cells were very effective for her and she's now 10 years out from her treatment and there was recently a movie made about what she went through. So this is a combination of the doctors and nurses that took care of her and her family. It's a very exciting story.

- Now CAR T cells do have side effects. One of the main side effects is called cytokine release syndrome and cytokines are proteins or hormones of the immune system. And so when a CAR T cell binds to a leukemia cell and kills it, leukemia cell releases a lot of these cytokines or proteins and these cytokines can activate the normal immune system and actually cause a person to become ill. It can cause high fevers, you can see it on the right side, the blood pressure can go down, people can get aching, cough, rapid heart rate. Sometimes they can affect their breathing. So in a way when we see cytokine release syndrome develop, it tells us that CAR T cells are working. But it's also telling us too that we have to monitor the patient carefully and watch out for this cytokine release syndrome and treat it when it develops. What I like to tell people is, you know when you get a viral infection like the flu, it's not so much that the virus itself is making you sick, but it's how our immune system is reacting against it to try to fight the virus. And the immune system can release a lot of these proteins and that's why people can feel poorly when they have the flu. And that's, you can see they can get some of these same symptoms, a fever, the achiness, a rash, things like that. So that's cytokine release syndrome. For reasons that aren't as clear, sometimes CAR T-cell therapy can affect our nervous system and it can cause I'll say brain dysfunction. So people can get headaches, they can get seizures, memory loss, got a whole list of personality changes, muscle weakness, difficulty speaking, they can become confused or delirious. If it becomes very severe they can even go into a coma. So, and this is called ICANS, immune effector cell-associated neurotoxicity syndrome. And we can also treat this and it's usually the situation where the patient can recover from it but it can be a serious side effect of the CAR T cell therapy and both the cytokine release syndrome and, and this CAR T cell therapy on this ICANS we can also see with blinatumomab because it works somewhat similar to CAR T cells. So there are now three CAR T cell products that are approved by the FDA and have been used. They have these very long names. This first one that was approved is tisagenlecleucel or Kymriah® is the trade name. And this is approved for children and young adults up to the age of 24. And there was a major trial called the ELIANA trial that initially utilized this tisagenlecleucel for treatment of ALL. And we just had this report a couple years ago of the long-term follow-up. So it's not a perfect treatment but it's giving some patients long-term benefit. In other situations that leukemia can come back again. So that means a CAR T cell is not perfect but it has been effective and helpful for many patients. And this is again for young adults and children.

- There's another one called brexucabtagene autoleucel. I've got the name across the bottom there. And where this was tested was called the ZUMA-3 trial. There have been different ZUMA trials using different CAR T products and the trade name for this is Tecartus® and you can see the results in the curves, the overall survival and then what we call relapse-free survival. That's where someone survives and their leukemia hasn't come back. And the purple curve is the patients that responded to it and how they do the black curve is everyone, the red curve is unfortunately the ones where it didn't work as well. But these results look encouraging. And this one, this we abbreviate, this one brexucel, this one is approved for all ages. It's not restricted to just children and young adults. And this was approved in October of 2021.

- Tisagenlecluecel, I'm going back to that. That was, this was approved by the FDA in August of 2017. So that was the first one, this was the second one. And then the third one is this Obecabtagene autoleucel or obecel we call. And this was just approved late last year in November. And this one is also one kind of like one of the antibodies that I talked about where this doesn't bind as tightly to the T cells and so it has less side effects, there's less of the cytokine release syndrome. Severe cytokine release syndrome developed in only about 2 1/2% of the patients and 7% of the patients had the ICANS. So you can see there that last bullet item that I have on the slide here. So this is a further advance and this is for again, all adults and it particularly on the, on the lower curve that I show you there, the D box, the top curve is patients that had less than 5% blast in their bone marrow. So they still had leukemia that was detected by sensitive techniques but at a low level and it worked the best in that setting, which we kind of expect to see. So we now have these three options for CAR T cells available. Now these treatments are very expensive. I've listed the three products here. These are one-time treatments so they're not, you know, given repeatedly, but you can see that the price tag is pretty steep for these products. The thought is though that if they work well and someone is cured that they're getting the long-term benefit.

- Now what about T-cell ALL? A Car T-cell therapy has been developed for T-cell ALL, but it's been slowed by concerns for fratricide. And fratricide is -comes from the word frater- brother and cidium- killing. So this is the act of killing one's own brother and you remember Cain and Abel from the Bible and this is the first fratricidal murder to be recorded or committed. And the idea here is that these CAR T cells, if they're directed against the T-cell of leukemia, they could also kill some of the patient's normal T cells. And if that happens then if you lose all your T cells, you're at risk for a very severe infection.

- Now we see some of that with the other CAR T cells that I have just told you about. The three that are there are directed against the B cells. And so the B cells can cause some of the normal antibody levels to go down and make a person somewhat more prone to infection. But we can get around that by actually giving some what we call immunoglobulin or antibodies to help prevent them from getting infection where we can't really give T cells. But scientists have figured this out and there's now a CAR T cell product that looks like it's working well and this was actually developed in China. You can see on the upper left there I listed for the authors of this study that was published about a year and a half ago. And these are all Chinese names. So these are doctors from China that developed this and they tested this in 60 patients that had T-cell ALL or a lymphoma form of T-cell ALL that we call T-cell LBL. And they got a single dose of these CAR T cells that are directed not against CD 19 but against what's called CD7 and that's on the T cells. And after a month, a month after this treatment, 94% of the patients their bone marrow was in a complete remission and they were MRD negative. Now many of these patients went out and had a bone marrow transplant because it was felt that their leukemia might still come back if they didn't. And it looked like that helped more of these patients to survive and keep the leukemia away. And you can also see cytokine release syndrome in this setting, although here it was not very severe, the severe form was only 12%. Again, they saw 5% of the patients that had the neurologic side effect or the ICANS. So CAR T-cell therapy is now available for T-cell ALL, although none of these have been approved yet and they're still being tested in clinical trials.

- Now there's another other drug, it's called Venetoclax and you might have heard that if you sat in on the AML session that happened just before this session. Venetoclax has been used quite a bit in acute myeloid leukemia, but it works in many different blood cancers and it looks like it's also going to be effective in ALL although we're not as far along in testing it. This is a study that was just published this year where we combined it with low intensity chemotherapy. We call this a phase 1b trial because we were testing the dose levels and of 11 patients that were reported here, none of them died from complications in the first 60 days. That's the third bullet here. And 10 out of the 11 patients went into complete remission and became MRD negative. And at two years 90% of the newly diagnosed patients are still doing well. The patients where their leukemia had come back, it wasn't working quite as well but 38% of them achieved a complete remission. So I think we're going to hear more and more about venetoclax and venetoclax works both for the B cell and the T-cell type of ALL.

- So we're excited to have another potential agent available to treat the T cell ALL. Now I'm showing you this slide because we now have many different subtypes of ALL that we've identified and they're based on these abnormal genes that we've been able to identify that we think play a role in the development of the leukemia. And so on the right side you see the old classification, what I call the revised fourth edition and there aren't too many listed there compared to the left side where you see more and that was the fifth edition. And so we're identifying more of these abnormal genes and that's going to allow us to develop more drugs that can react against these particular abnormal genes and help control the leukemia. So I want to talk about something called menin, MENIN. And this is a gene that is important in cell development and was originally identified in in patients that had tumors in their endocrine glands. So these were solid tumors and there was the MEN1 syndrome that was identified. But menin is also important in the development of leukemia and it interacts with other genes that regulate cell production. So if menin becomes abnormal then the cells can grow more and lead to the development of leukemia. So there's two different subtypes of leukemia, some that we see in AML or acute myeloid leukemia, that's the NPM1 that you see there. But the one on the left, the KMT2A that is seen in AML but it's also seen often in ALL and it relies on menin for its development. So we think if we can inhibit menin with what we call menin inhibitors, that we can prevent the leukemia from growing and progressing. And there are now quite a few of these menin inhibitors that are under development. You see seven of them listed here. So multiple companies are developing these menin inhibitors to treat leukemia and the FDA just approved, again this is in November last year, one of these menin inhibitors revumenib for KMT2A+ or where KMT2A is abnormal in this acute leukemia. And this can be seen both in AML again but also in ALL. So this is a new treatment for a subtype of ALL called KMT2A ALL. And we're gonna start combining this also with chemotherapy to see if it can help make the chemotherapy more effective and work better.

- So I want to turn and talk a little bit more about a subtype of the B cell type of ALL and this is Philadelphia chromosome positive ALL. And this is where two genes, you can see number nine with an arrow there. And number 22 at the bottom they exchanged some genetic material and this turns on a gene on chromosome 22 that stimulates the leukemia cells to develop. And so we call this Philadelphia chromosome positive (Ph+) ALL and it's because this gene abnormality was first discovered in Philadelphia. That's why we have the name. And this shows a little bit more detail how this develops. You can see in the picture there the normal chromosome number nine and the normal chromosome number 22 and then there's a break in each chromosome and they swap material. And over on the right side you see that change chromosome 22 with a BCR-ABL and that's the abnormal gene that forms as a result of this break in the two chromosomes. So in the BCR-ABL, it's an abnormal form of what we call a tyrosine kinase and that's a protein that's important in cell growth. And so when we get this abnormal tyrosine kinase, we want to inhibit that so it'll stop the leukemia from growing. And there are now six tyrosine kinase inhibitors that have been approved by the Food and Drug Administration. And I've listed them here with the most recent ones being this ponatinib and asciminib. And again, these words all end in “nib” N-I-B and that tells us that it's a tyrosine kinase inhibitor. Now there's one under investigation, there's actually several under investigation, but one of one that's in the most recent form of investigation is this olverembatinib. And it's in preliminary studies been found to be effective in patients where the other tyrosine kinase inhibitors have not worked. This one was actually developed in China but is now being tested here in the United States and may well get approved and be a 7th tyrosine kinase inhibitor. So this is kind of how this works. On the left side you see the BCR ABL binding to this other protein. Again, this is a cartoon where it's activating the cell so that it will grow. And on the right, one of the tyrosine kinase inhibitors called imatinib, it's binding in this pocket and it's preventing the BCR ABL from causing the cells to grow. So it's blocking it and so this is what, this is a targeted molecule and what I was referring to at the beginning, these targeted therapies that are playing a more prominent role in the treatment of leukemia and also in cancer. So this Philadelphia chromosome or Ph+ ALL. And this is more common in adults, it's rarely seen in children, but even up into older individuals it can get up as high as 50% of the cases. And it's really controlled by this BCR ABL, it controls the development of the leukemia and by inhibiting that we're slowing its growth.

- So what I'm showing here are results from the, on the left side, the MD Anderson Cancer Center where they have developed a lot of these treatments with using these tyrosine kinase inhibitors in combination with chemotherapy. And on the right side similar results from an Italian group, the Gimema group from Italy. And what you're looking at here is the survival of patients with Ph positive ALL over these multiple time periods. So on the left side, that red curve that goes way down showing that not many patients survived, that was from 1984 to 1989. And then you can see that over the subsequent years there's been improvement in the treatment. And one of the, another breakthrough has been combining blinatumomab, which I talked about earlier with these tyrosine kinase inhibitors. And you can see that that combination is leading to a very good survival. Now the follow up is short and there's not as many patients that have been treated, but this certainly looks encouraging and to test this and really see if blinatumomab plus this ponatinib, which is one of the tyrosine kinase inhibitors is effective. We are testing this in a study that my Eastern Cooperative Oncology Group is leading where we're comparing tyrosine kinase inhibitor and blinatumomab to this tyrosine kinase inhibitor and chemotherapy. And we're going to see if the blinatumomab is truly as good as it seems to be in combination with the tyrosine kinase inhibitors. So this is a clinical trial that's currently ongoing and we'll finish enrolling later this year.

- So with that I'll conclude. We talked about leukemia as a malignancy that produces an excessive production of either immature or mature leukocytes that build up in the bone marrow, the blood and other tissues. It's these two types, the B-cell and the T-cell. B-cell is about 80% of cases, T-cell is about 20%. And these immune therapies or immunotherapies have really led to dramatic improvement in treatment response and is showing improvement in survival. And so this has been an important development in the treatment. And then these targeted therapies, this is the last bullet item that's targeting the abnormal genes is also looking very good. And these can be combined with chemotherapy or with these immune therapies they just showed you -the TKI plus the blinatumomab. So we're excited about these results and certainly with the Ph positive ALL that just showed you the survival has gotten much, much better with these new treatments.

- So thank you. And we think the future is bright for further success in treating ALL. We're not perfect and we're not where we want to be yet, but we're certainly heading in the right direction. So I want to thank you for your attention and I'd be happy to take questions and I'll also try to answer some of the questions that Ms. Whyte sent me that some of you had submitted earlier.

- Great, well thank you so much. I feel like I just took a college class on ALL that was so informative and really well laid out and very clear. So I appreciate all of that explanation. And I'm going to go through, we haven't received any questions from the live audience. Just as a reminder, if you want to ask a question, you can put it in that Q &A box at the bottom of the zoom screen. But in the meantime, I wanted to ask you a question that was submitted through the registration. And the question is, and I'm going to preface it by saying we see a lot of ALL in a certain age group and that is adolescents and young adults. And I'm wondering if you could talk a little bit about how clinicians approach patients in that age group. Is there, are there clear guidelines on how to modify dosing for example, or other sort of standards of care for those patients based on, they're not pediatric per se, but they're also not, you know, full grown adults. Can you talk a little bit about that please?

- Yes, I can. That's a very good question. So traditionally we had had kind of two emphasis on treatment. So there was the treatments that were used in children that we call the pediatric regimens and then there were what we call the adult regimens. And they differed in, they used a lot of the same drugs but they differed in the amounts and the doses that were given. And so in pediatrics, they use a lot more of what I call non-myelosuppressive. And myelosuppressive means lowering of the blood counts. So the pediatricians use higher doses of drugs that don't tend to suppress the blood counts as much. And those are three in particular vincristine, corticosteroids or steroids, prednisone or dexamethasone or two steroids and then asparaginase. And so a few years ago it was found that if we took the pediatric regimens and gave them to adolescents and young adults, their survival was much better. And so these pediatric intensive, I'll call them regimens or treatments are now being used in adolescents and young adults and we've seen improved survival by doing that. So that's been a major breakthrough in treating adolescents and young adults. And now we're combining some of these immune therapies with these pediatric intensive regimens and we anticipate that the survival is going to get even better. And the clinical trial that I talked about that I led the E 1910 where we gave blinatumomab, we actually made that chemotherapy in that study more like a pediatric regimen. And so we know that blinatumomab can work with chemotherapy in that setting. And so I think by giving the pediatric regimens to the adolescents and young adults and now adding immunotherapy, we're going to improve the survival and control of leukemia much better for those individuals.

- Great. There's a question that was submitted online. My son is CD 19 negative after Kymriah® on his third relapse. SCT has relapsed within the first hundred days. Is there any CAR T available that targets CD 22 Blinatumomab failed last year. He has had five courses of Inotuzumab. We are in Australia.

- Well there are CAR T products that target CD 22. So I don't know for sure if they're available in Australia, but they're available here in the United States. None of them are FDA approved yet, but there are clinical trials that are using CAR T cells to CD 22. So that would certainly be,

- Are those trials specifically for ALL patients? Yes. Yes. Okay. I know at the National Institutes of Health in Washington DC they have been using those quite extensively there.

- Okay. And then, oh, and she added chemotherapy protocol was ALL 06, which he relapsed during maintenance.

- Yeah, that's an Australian regimen, but it's like, I don't know the details of it exactly, but it should be a good, I'll say a good chemotherapy regimen. It doesn't work in every instance, but it's one that's typically used in ALL.

- Are there any long-term side effects of treatments you are seeing?

- Well, I mean, chemotherapy can have, you know, long-term side effects. Some of the drugs we use can affect heart function and that can be a later effect. Things like vincristine can sometimes cause nerve damage. CAR T cells, there've been very rare reports that the, some of the T cells that are affected become malignant themselves and these patients can develop a T-cell ALL, but that's very rare. So it's not something that I want to overemphasize, but that's potentially a more serious, you know, complication of CAR T-cell therapy. We're not aware of any, you know, long-term ill effects of blinatumomab. Inotuzumab, which you mentioned that's, and I talked about it briefly, it's CD 22 antibody linked to a chemotherapy drug. That sometimes can cause liver damage. It's rare and we have things we can do to try to help prevent that, but that occasionally can develop and cause significant liver damage.

- Okay, this is a good one to end on. I like this question so much because I kind of know the answer, but let's throw it out there. Has the prognosis for survival changed since I received treatment? It was 30% in 2014. I am currently 11 years in remission.

- Well that's great that you're 11 years in and the likelihood that your leukemia's going to come back now is very unlikely. And I would think and hope that you're cured. We can never say never, but I think that chances of it coming back is extremely unlikely. Now I don't know how old you are and the prognosis is different depending on a person's age, but, you know, overall I would say that the prognosis has definitely improved. You know, for the adolescents and young adults, as I talked about just a little bit ago, the survival there has gotten much better. I showed you the clinical trial with blinatumomab and that looks very encouraging. So, you know, the short answer is that the prognosis has definitely improved in recent years. So that's been very encouraging for us.

- Great. Okay. Well unfortunately we did run out of time, so I'm sorry to anyone who submitted a question that we didn't get to unfortunately, but I do think that we got lots of really great information tonight. I did want to point out that we have a lot of information on our website, if you'd like to read further. We have information about ALL, we have information about various tests, diagnostic testing, and then I also always recommend that folks take a look at the NCCN patient guidelines, which are available at nccn.org/patients/guidelines. It's down here at the bottom. And then I just wanted to thank our presenter. Dr. Litzow thank you so much for all your hard work in putting this together and I think it was super informative and any final things to add?

- Well, just that it's been an honor to, to participate and Lindsey, you know, you had mentioned that you have some, you know, the ability on your website to help patients find clinical trials.

- Oh yes, yes.

- And so I would, you know, hope people could take advantage of that as well if they're looking for a new clinical trial.

- Yes. So if there are people on the call or listening to the replay who are interested in finding out if there are any clinical trials available, we do have a feature on our website called the Clinical Trials Hub. There's information about clinical trials and the process of approvals, but also there's a tool where you can put some of your information or the patient's information in and it will generate a list of trials that you can discuss with your clinician. So it's a great resource for people who are feeling like they want to see if there's something out there that's kind of in development. And so thank you for reminding me of that. And also I will mention that we will be having, we have a great slate of webinars that we're kind of got in development coming in the fall and also next year. So we'll definitely have a clinical trial focused webinar in early 2026. So, you know, stay tuned. Lots of information coming on that, so. Great. Okay.

- Thank you so much Dr. Litzow and thanks to all our sponsors! Thanks to everyone for participating and please do click the link and fill out the survey for the feedback after you, well after this event finishes. So have a great night and thanks everyone for hanging in there. Good night.