ALL: Treatment Advances 2026

New & Emerging Treatments: ALL 2.23.26 Transcript

Participants:    

Dr. Jae Park, Memorial Sloan Kettering Cancer Center

Lindsey Whyte, Leukemia Research Foundation

Hello. Thank you so much for joining us for the first installment of this year's New & Emerging Treatments series. The topic of this session is ALL and we're joined by Dr. Jae Park from Memorial Sloan Kettering Cancer Center in New York City, 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 am the Director of Programs & Partnerships at the Leukemia Research Foundation. I would like to take a moment to thank our supporters for this session. AstraZeneca, Cycle Pharma, Menarini Stemline, and Autolus. 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 $95 million towards our mission since our founding in 1946 and has funded research grants to over 750 investigators worldwide. Our support for programs for leukemia patients and their loved ones include information on our website, education programs like today's and financial assistance, and a directory of other helpful organizations and resources also 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 the zoom screen. Please note that if you want to have your question be anonymous, you need to click the button or the little, the little box that says anonymous. Otherwise, your name may show. If you already submitted a question through the registration, please know that we have your questions and we'll do our best to cover as many as possible. After today's program, you will be sent a link to a brief evaluation through email. Please take a moment to complete the evaluation survey so that we can improve future programs. Also, this program will be recorded and a link to the recording as well as the transcript and potentially the slides will be sent to you in a couple of weeks when we have everything loaded up to the archive on our website.

We're grateful today to have Dr. Jae Park with us. Dr. Park is the Chief Cellular Therapy Services Service and ALL Specialist at Memorial Sloan Kettering in New York. He received his medical degree from Johns Hopkins School of Medicine and completed an internal residency at Massachusetts General Hospital and a hematology oncology fellowship at Memorial Sloan Kettering Cancer Center. Dr. Park's research focuses to translate and establish novel targeted and immunotherapies for patients with hematologic malignancies. He is the principal investigator of several clinical trials in adult patients with ALL and CLL/NHL using CD19 CAR T cells, bispecific antibodies, oral targeted agents, and immunomodulators. He maintains an active clinical practice.

Dr. Park, thank you so much for joining us today and please let's get things started with an overview of the latest in emerging treatments for ALL.

- All right. Well thank you for having me here and then giving me the opportunity to to present here and talk to you guys as well. So I'm going to just share the slides. Bear with me. Okay, here we go.

So, as Lindsey mentioned, my name is Jae Park. I'm one of the Leukemia doctors at Sloan Kettering Cancer Center. I do focus primarily in ALL and then I'm also the chief of our cell therapy service where we administer some of the new cell therapy options including CD19 targeted CAR T-cells, which we'll talk about in today's presentation as well because it's very relevant for our patients with ALL. So here are some of the topics that I would like to cover in the next 20-30 minutes of my portion. I would like to go over some of the new uses of prior immunotherapy that have already been approved for last several years. Now what we are finding is that we can use those agents in earlier line of a treatment. For example, newly diagnosed ALL patients. I certainly will talk about CAR T-cells, which is kind of dear to my heart and which is research that I've been involved in for many years since the beginning of it being studied for ALL patients. I'll talk about what is CAR, who qualifies for those treatments, where are we today and where are we going with the therapy in the future in the next several years. I'll also end the talk a little bit with what are the novel therapies are being studied in ALL and what does the future look like for ALL patients, which is certainly brighter thanks to many research that's happening in this space. So I'll talk about first immunotherapy or antibody drug conjugate. It's abbreviated as ADC. It's a class of agents and there are these class of agents as already approved for many different cancer types. But this is one that's been used for our ALL patients. It's called inotuzumab, which is an antibody which is an immunotherapy that targets CD22, which is a, let me just get the pointer on here, which is CD22, which is a B-cell specific antigen or target that is expressed on your leukemic cells.

[Issue with slides not advancing was resolved]
- So this is a slide that I was on previously, which is the first drug that I wanted to talk about, which is the antibody drug conjugate. Inotuzumab is an antibody that is targeting against a B cell specific marker called CD22 and has a chemotherapy attached to it. So it is a form of immunotherapy that has a selective that allows selective delivery of a chemotherapy to any cell that expressed CD22. So as opposed to kind of the IV chemo that we all get, this is more selective again administration of the chemo. So this agent, this drug was already approved in 2017 for adult patients with relapse or refractory B ALL and for children in 2024. So it's been out there for many years and when used by itself it is given intravenously in a weekly, kinda once a week for two or three times per month. It can clear the leukemic cells from bone marrow about 70 to 80% of the time, which is quite remarkable without any chemotherapy just by itself can get rid of the leukemia that frequently. However, it has some side effects because of the chemotherapy that is attached to these drug inotuzumab called calichamicin. It can cause some liver disease called VOD- veno- occlusive disease. It has kind of clotting small blood clot that can form in the liver and is higher risk in patients with a prior existing liver disease or patients who had a prior bone marrow transplant and had a recurrent ALL and then receive this inotuzumab or patients who receive inotuzumab and then get to bone marrow transplant afterwards. The risk is a little bit higher for those. Now there are some ways that we can mitigate these side effects by lowering the dose or spacing out the dose as best as we can to make it more safer for our patients. Now I told you that this has been approved for many years.

So what are the new ways that we are using this drug? So it first was approved and mainly had been used for recurrent disease or after failing after recurrent disease for chemotherapy. Now it's being used for newly diagnosed older patients with ALL. Older patients with an ALL is particularly challenging because as may recall for some of you who have might have gone through or experienced this disease that ALL therapy is long. So you get induction chemo, which is the first part of a chemotherapy that is about anywhere between one to three months. And once you're in remission, meaning your first goal of achieving leukemia-free state in the bone marrow, you get more chemotherapy, what we call consolidation to make sure that we keep you in remission for long term. And the chemo block could be about six to eight months and then you do maintenance chemotherapy, which is an oral chemotherapy for additional two years. So this type of chemo for ALL for newly diagnosed patients could be quite long and it poses challenge for older patients or younger but frail patients because they may not be able to finish all of this chemotherapy blocks. So because of that reason, historically older patients with an ALL that were having a very low survival rate of 20 to 30% and older here usually, I mean by 60, 65 and older. Now what is happening currently because we, you know, yes that was with the chemotherapy, but because we now have effective treatment that is non-chemotherapy and easier to deliver, we can now use inotuzumab, this particular drug by itself or in combination with a reduced intensity chemotherapy for newly diagnosed ALL patients.

So these are just examples of the three studies that have already been done and published and has shown and demonstrated that it can be effective as a first therapy for newly diagnosed patients without any chemo for some or with a minimal chemotherapy combination. They get into remission for most of the patients. And then the survival curve on the right, which you may not be familiar with looking at them, but you basically, essentially want the curve to be flatter the better. That means that over the course of years, which is the x axis, the more patients are living. So you can see that some patients there are recurrent disease. So it is still a challenge for some of these patients because even after initial response to chemo, the leukemia can come back and maintaining the leukemia free state is still some challenges for older patients. But this curve without showing you the historical data, I can tell you just so much better than what we had before. So for those patients who are not able to get the multi agent chemotherapy block, which we are still administering to pediatric and younger adult patients, this is definitely a step up for those patients who are not able to follow those and still get a meaningful outcome for those patients. So the next several years what we are already seeing is using these agents in newly diagnosed older patients and it's already been happening.

The second immunotherapy that I will talk about is blinatumomab. This is also not a brand new drug, it's been out there for many years but it has a different mechanism of action than inotuzumab. So this one is also an antibody based treatment. It targets two different markers. One is called CD19, which is a marker that's expressed on leukemic cells and then CD3 which is a T-cell marker. So it's a small antibody, it's like a linker that brings the T-cells which is our immune effector cells infection fighting or cancer fighting cells to close to B-cells which is leukemic cells. So it actually essentially linked the T-cells to B-cells so that T-cells can now see the leukemic cells and start killing off the leukemia, leukemia blast or the cancer cells. So this class of agents is a very effective therapy. It's already approved in 2014 as a single agent in relapse refractory B ALL and for patients with a measurable residual disease or called MRD in 2018. So it's also been out there for many years.

It's currently given as a continuous infusion. What that means is that it's given intravenously so you do need an indwelling line like a PICC line or a central line and you need to wear a pump that infuses this medication. So over 24 hours for 28 days. So it's not the easiest one to carry around because you do need to carry this small pump portable pump with you. But it's quite effective. It is effective in clearing leukemic cells from bone marrow about 50 to 60% of the time for patients with a morphologic disease, meaning more than 5% blast leukemic cells in the bone marrow. It's even more effective when you use these agents when you have a very little leukemic cells. So you got chemotherapy for example, it's almost gone but not to 0% because zero to 5% of those, zero to 5% leukemia cells in the bone marrow when you get blinatumomab it's much more effective in getting rid of those, the residual cells. So sometimes we call this MRD eraser, meaning you kind of mop off any remaining cells from the chemotherapy. The leukemic cells quite effectively.

It also has its own side effects that are different than inotuzumab that I mentioned before because this is an immune activating drug. So it activates the T-cells and as the T-cells get activated you can get what's called cytokine release syndrome or CRS and that is very similar process as if you're getting fever, infection. So fever, low blood pressure, high heart rate, difficulty breathing, so having a bad flu-like syndromes can happen, which is the same result in that in when you're getting infection the T-cells are fighting those bacteria or viruses. Here our immune cells are fighting the cancer cells. So kind of end result is quite similar. So it this is expected phenomenon for this type of immune therapy. The other side effects which is unique also is a neurological side effects. So patients can get confusion, disorientation, word finding difficulties. Luckily these side effects are transient and reversible and quite manageable with appropriate therapy.

So I'll talk about what's called measurable residual disease even though it's not a treatment but it's a new entity that we all talk about a lot and I want you to be aware of it. Any patient with an ALL. So this is kind the, you know, the picture of an iceberg. So at the top is kinda what we are seeing in our routine blood testing or bone marrow and we call it, we call our responses complete response if we see less than 5% blasts or leukemic cells in a bone marrow. But as you can imagine the 5%, you know we want it to be 0.0%. It's completely none. So there are testings that we can do and these kind of different lines as indicates the kind of the advancement of a technology to detect as little of the leukemic cells as possible. So MRD measurable residual disease or previously called minimal residual disease is defined as having less than 0.01% leukemic cells. There's a one in a hundred thousand leukemic cells that we can pick up. Now the newest thing currently is that there is even more sensitive testing called clonoSEQ or by next generation sequencing we're now able to pick up one leukemic cell out of normal 1 million cells. So we can actually get to sensitivity of picking of leukemic cells that 0.0001%. So that's quite remarkable. And why is that important to know how much disease you have? Because having the low level disease at 0.0001% after initial chemotherapy or prior bone marrow transplant lead to higher risk of relapse, which is kind of intuitive. The more disease you have before the next line of a therapy, the more likely the disease will recur. And this survival curve on the left is showing you without going too many details, having no MRD or no detectable disease, which is in the top, there's a clear separation about how well they do or how poorly the other patients do who have a residual disease. So this really points at the fact that you know that we want a response, we want a therapy that can get into MRD negative response and if you have an MRD positive disease or detectable disease, you want to get a therapy to convert that MRD positive to MRD negative. And there's one drug that's currently approved in this setting it's called blinatumomab, which we already we talked about and I told you that it's more effective in low burden setting. So it's effective in clearing MRD and about 80% of the time.

So what happens typical sequence is that you make a chemotherapy, they do a bone marrow biopsy, they may detect this low level MRD, you get blinatumomab either one or two cycles, go, hopefully, go into the MRD negative state and most of these patients still do proceed to bone marrow transplant. So it's not, you know, it still mainly as a bridge to bone marrow transplant but quite effective in getting rid of MRD and then their outcome will be better after bone marrow transplant because they got the transplant with no detectable disease. So the point here that I'm trying to make is MRD must be checked if possible because it is prognostic and we have an effective therapy against it.

So where else is blinatumomab used? I think the biggest advancement that we have seen the last several years for this subset of an ALL called Philadelphia chromosome positive or Ph+ B-cell ALL. So as you may remember the B ALL is a large tree which is one set is Ph negative, patients without the mutation, and then the other one is Ph positive patients with this Philadelphia chromosome mutation. What it is is a translocation of chromosome 9 and 22. The result in fusion of this transcript called BCR and Abl together. This is the same mutation actually that's also picked up in another type of blood cancer called CML chronic myeloid leukemia. But this can also happen in ALL and this mutation must be checked for any patients with newly diagnosed B ALL because the treatment is so different between Ph negative and Ph positive. And Ph positive used to be one of the worst leukemia, the B ALL leukemias that you can actually have because before the effective targeted therapy, most of these patients did not make it long term and as the survival curve is kind of showing historical data, but now we actually are using dasatinib or ponatinib, these are oral medications that target specifically against this BCR-Abl this chromosome abnormality. You get that plus steroid which is another oral medication just by two pills. You know almost always we can get our patients into a remission, not MRD negative as we talked about, not to 0.0001% but we can actually get pretty darn close to that.

After those kind the treatments now we combine the blinatumomab with one of the tyrosine kinase inhibitor with Dasatinib or Ponatinib with no chemotherapy at all and we can actually cure majority of our patients, like 80 to 90% of the patients could be cured with this chemotherapy free regimen with the Blinatumomb and the TKI and that's quite remarkable and most of these patients don't even need to get to bone marrow transplant afterwards. So this is kind of the one thing that has changed a lot for both older and younger patients to spare chemotherapy and bone marrow transplant, which is effective new therapy. So chemo is still being used for some subset of the Ph positive B ALL, the Philadelphia chromosome positive patients. But it's good to know, certainly for older patients, and the Ph positive is actually more common the older that you get. So if you're over the age of 60, you have about 50% chance to have a Ph positive and if you do have it, your treatment is actually a lot easier because you don't have to use any chemotherapy at all. So this is kinda the one new change that's been happening by repurposing or reusing the old drug like blinatumomab in the newly diagnosed setting and can actually reproduce remarkable outcome.

The last thing I'll talk about blinatumomab before I go to CAR T-cell is that this is the second kind of probably the new information that we have recently learned in the last year or so in this ECOG 1910 study. I told you the Blinatumomab was even used for even MRD low level disease. This is actually probably surprising to all of leukemia treaters like including myself that this actually clinical trial tested the hypothesis. What if we use blinatumomab for those patients who are MRD negative meaning seemingly no detectable disease, the below the curve, the below the iceberg at the lowest time. So all intents and purposes, we would presume those patients had no disease left. So and we didn't think there was gonna be, oh maybe it'll be a little bit better but you know, since there's a very little disease to begin with adding two months or two or three cycles Blinatumomab, how much better can we get? But this survival curve on the left that is showing the Blinatumomab on top and chemotherapy on the bottom, you can actually see the survival dramatically increased just by adding blinatumomab for those patients who are already in MRD negative CR meaning no detectable disease. So based on that, this also led to newest indication of these drugs for patients with MRD negative. So bottom line is that all patients in B-ALL are kind of entitled to get some degree of blinatumomab. Whether you have no disease at all based on this data that I just showed you or if you have a MRD low level disease, you should get it because it's also indicated therapy and for some of the newly diagnosed patients that is kind of indicated in treatment. So it is very effective, it has its own side effects, maybe cumbersome because continuous infusion in a pump but I think it's quite effective medication that we have in our armamentarium for treatment of B-ALL.

So I'll get to CAR T-cells as the third immunotherapy option for our ALL patients. So this is actually, you know different than what we just have looked at. It is probably the most potent powerful form of immunotherapy we currently do have for our patients. So CAR T-cell, some of you guys may have heard about. CAR stands for chimeric antigen receptor which is genetically engineered T-cells expressed in artificial T-cell receptor modified to target a tumor marker in this case CD19. So without going into too many details but as the name implies, chimera is the head of the antibody like what we're using in blinatumomab but has a body and tail of a T-cell receptor. So the one limitation of blinatumomab and inotuzumab, because it's not a living drug, it's not living cells, you do need multiple infusions to get the benefits. You're never done by just giving one week of it or one dose of it. You do need cycles and many months of therapy in order to get the sustained benefit from the treatment. Now what if we get the T-cells just like the vaccines then other things that we do get, what if we can generate a good response from our own immune system so they can live with you long term and providing the constant surveillance against rising cancer cells. That's the whole idea of T cell immunotherapy. And somewhat similar to bone marrow transplant too.

So here we are about to find your own- patient's own- T-cells to insert into these artificial T-cell receptors. Now these powerful CAR T cells will have kind of receptor or antenna or kind of this new structure they did not have before that's trained to target and go after cancer cells. So how does that work? And I'll show you some animation hopefully this will display. So the T-cells, you take it from the patients, you insert this modification method and you typically use kind of the viral DNA, your own T-cells that have taken up this viral DNA will then express these CARs that's now kind of expressed into the surface. We manufacture these cells out of your body in a kind of manufacturing facility. It takes about two weeks or so. We infuse the cells back to you as if you're getting a blood transfusion. But these are again your own cells. Now once it's infused back into you, because they now have the receptor I told you about this CAR they go after because they're searching for the CD19, the marker that's expressed on leukemic cells as they see each other engage with them, the T-cells actually multiply, get activated and excited and then kill all the neighboring tumor cells and this whole idea beside CAR T-cells. It sounds all science fictiony. And it was at the very beginning when what was first developing 15 years ago. And this is our old photo at our facility at MSK that when we are beginning to manufacture these T-cell before commercialization. So this is how the cell manufacturing should look like. We take the T-cells and in this open clean facility, the T-cell has to be manufactured. Now it's a kind of automated system. Many companies are doing it and we have several approved products which I'll get to.

Because it has a few steps for these CAR T-cells because I told you before, we collect the T-cells from you, the patient, and then we take the T-cell to manufacture. I told you it takes about two weeks and then the patients, when the T-cells are ready, literally a bag of your T-cells. Sometimes it's actually a syringe, so sometimes it's as low as 10 cc, that's is all it takes to cure the leukemic cells. And that's how powerful immune cells are and these CAR T cells are. Once those are infused back into you, you do receive some chemotherapy plus T-cells what we call LDC or lympho depleting chemotherapy which consists of two chemo, fludarabine and cyclophosphamide for about three to four days, depending on the product, a few days or one or two days before the cell infusion. So it's not completely chemo free. You get chemo for three days plus again the day of rest and then the T-cell infusion.

So how well does this therapy work in real world setting? So this is our first data that I told you show the pictures from the cells that were manufactured from it. The single infusion of a CAR T resulting in about 85% complete response rates. And some of these patients already had blinatumomab, inotuzumab the other therapy that I showed you before because they were already available prior to CAR T-cell therapy. And for those unfortunate patients who had a recurrent disease afterwards we try CAR T-cells, and we were still able to get the response of 85% and that's pretty remarkable. And you know previously, for those patients using just conventional chemotherapy, we would've expected response rate of about 20%. Then this will be the survival curve, meaning in over two years very few of these patients would've had a long-term survival. We have moved the needle up quite a bit that now we can cure about 60% of the patients who have failed those inotuzumab, blinatumumab and chemotherapy. So not perfect but still remarkable for those patients who otherwise have not had a lot of other options. And obviously the next thing that we would like to do is raise the 60% even higher - 80, 90, hopefully close to a hundred percent.

So, but the result of all this series of clinical trials have led to three different CD19 CAR T-cells that are FDA approved for relapse refractory patients. And these are those three products. The first one that was approved in 2017 is called Tisagenlecleucel or Tisacel or Kymriah. That is only approved for children and young adult patients up to age 25. And for adult patients 18 and older we have a Brexucabtagene that was approved in 2021 and then the latest one that was approved in November of 2024 is Obecabtagene, it's another CAR T-cell. They all target CD19, the same B-cell markers but slightly different kind of product and different characteristics. Just want to emphasize it is approved for pediatric and adult patients. There's no upper age limit so anybody even older than 80 or 85 could potentially receive a CAR T-cell therapy even after initial chemotherapy after blina or inotuzumab. You don't have to fail all of those but even if you do, you're eligible to receive them and even if you had a bone marrow transplant and had unfortunately had a disease recurring, you can also get CAR T cells at that time, too.

So while it is great it has its own side effects too. It's actually very similar side effects as I mentioned to blinatumamab. Because blinatumamab I told you about T-cell activation kind of fever-like or the flu-like syndrome you get the same thing because we are again activating T. But this you may get a little bit more because we are infusing more CAR T-cells. So these are a kind of souped up version of immune system that's super activated. So you may get more of these syndromes and more severe. In fact when we were first doing CAR T-cells in ALL, about quarter of our patients, 25% of the patients needed to go to the intensive care unit because they were so sick enough to need to go there to receive care. Luckily those side effects are transient, reversible. So while you could get sick but you know these are reversible side effects and managed with some steroids and other things as well too. But I told you that I will tell you very soon that it's gotten even better than what we had previously but that's how sick the patients can get from this very activated immune cells and then you know the leukemia cells are being wiped away.

The one nice thing is that because of this unique side effects that can last for you know one week or so we are required to have patients close to our treatment center for 28 days, for about a month. And that was kind of the one limiting factor to get more patients for CAR T-cell therapy because you need to sometimes relocate to live close to treatment centers which is mostly in the urban setting. So if you're traveling far, two or three hours away, although we do provide housing and so forth, it's still away from your home for quite some time. But now that therapy has gotten so much better and side effects from the 28 days the window has gone down to 14 days. So you still need to be close to the center to safely get this therapy but at least it's not a month of time, it could be as short as two weeks. And I told you that the side effects has gotten better. So with the Obecabtagene, which is the newest CAR T-cell therapy that got approved in November 2024 that even though the efficacy is exactly the same or maybe a little bit better, that I told you about a quarter of the patients need the intensive care unit. Here I highlight in the orange box without going into details is about two or 7%. So it's dramatically less from 25% to essentially about 5% of the time they get there.

But the other thing that I'll show you is that there's all patients that's graph on the right but if you actually get CAR T cells when your disease burden is lower, meaning you have a low leukemic cells in your bone marrow, your side effects is even better. So that's the orange box on the left. It's showing 0% of the patients got grade three and higher. Grade three or higher is ICU level of care. So nobody needed to go to ICU if you actually got the CAR T-cells in the lower disease burden setting. And although I'm not showing you the data, not only the safety is better but the efficacy, long-term efficacy is better when you get the CAR T-cells in lower disease burden setting.

So you know CAR T-cells and some of the things, where are we going with this therapy in the future? Kinda the one of the first thing that a lot of our patients do ask and we ask is, since 80% of the patients can get into remission, the leukemic free state, then what? Do we still need to go to bone marrow transplant afterwards? That question still remains to be answered. We do not have a perfect question just yet, but I can tell you that about 20% of the patients do go to bone marrow transplant after CAR T-cell therapy but that also means 80% do not and then some of these patients could be cured without bone marrow transplant. The trouble they were having or the problem they were trying to figure out is can we predict who those patients might be that do not need a transplant or who do need a bone marrow transplant? We have some tools to decide, you know have a lower disease burden.

Other markers that we do follow, these are kind of quite complicated questions that we also have to put our heads together but that's kind of the what we are doing. The second is that there is some cost of a labor for the CAR T. The one thing is that I told you the CAR T we need to collect the T-cells from you. So if you're too sick to begin with in the middle of your chemotherapy you have no T-cells to give because you just got wiped out immune system because of the chemo or you had bad infections you and those are challenging times. We cannot safely collect the T-cells and here, this long diagram is just to illustrate about 17 to 20% of the patients in a clinical trial do not make it to CAR T-cells even though they're referred to treatment center for CAR T referral. Because for those reasons we see those patients sometimes a little too late to say oh they have way too much disease or we have no good tools to control their disease and not safely make it to CAR T because it takes time from the time that we see them, collect the T-cells, make the T infusion. That's about four week period of time. One month you know may not sound like a lot but if you're actually getting these patients way too late at the end of life, which is sometimes what has happened, we just simply don't have enough time and tools to do that. So we always emphasize both to the referring doctors and the patients, think about this therapy early. It may not be right for you but at least we can decide together what is a good time for this therapy. Because if you get too late then we may not be able to infuse those cells later on.

And I'll end with this one because the CAR T-cells are great and I told you that we, the trend is effective therapy is already approved in those patients with the recurrent disease relapse refractory. And then I told you the Blina Ino is already moving to earlier lines of setting, newly diagnosed setting. With CAR T the one big difference is, is just one single infusion. So as opposed to blinatumomab which is cycles, inotuzumab cycles, chemotherapy cycles, these T-cells the biggest benefit is that these are living drug or the living cells and they can provide this continuous surveillance even when nothing else is happening, we don't have to give additional treatment. So now we're actually testing this hypothesis a little bit in a bold way that what about those patients who get chemo for two or three months and they have no detectable disease or may have a little detectable disease. What if we gave CAR T-cells for those patients in an earlier setting and can we then get durable remissions without any subsequent therapy? If this were, so this is an ongoing study that's currently open at Sloan Kettering and it will open at other centers in the near future as well too. So we're concentrating older patients like 40 and older or 30 to 39 who are not able to continue on those three years of a chemo that I just told you about. The CAR T might be able to replace their block. So if this, and we obviously have to see this as ongoing study, we need to see is it successful or not. If it is successful we might be able to reduce months and years of a chemotherapy with a single dose of a CAR T-cell therapy. And then we're also trying to maximize delivery of therapy to most patients by seeing these patients early when we can optimally choose the time when the CAR T-cell therapy might be most effective. And it's not just CAR T- it includes blinatumomab and inotuzumab as well, too. And I told you that we still don't know whether bone marrow transplant is needed after CAR T-cell therapy because we're only testing in those patients who have failed a lot of different things. But if we use CAR T earlier we probably will have the best chance of a sparing transplant afterwards because we're starting from a healthier T-cell from you when you did not have years of chemotherapy in you already. So we're you know, trying to test those questions in this clinical trial. So hopefully in the near future we can share some positive outcome from this.

Okay, this is the you know the last slide and I told you about the BiTE and the one thing is that I told you about the blinatumomab continuous infusion but there are now several products that's out there to make it easier now more potent version of those antibodies, a higher response rates than IV blinatumomab. There's actually a subcutaneous version. So instead of carrying the bag and IV lines you can actually get this injections like getting an insulin injection like three times a week or once a week. And that could be as effective if not better than kind of what we have currently. So you know just AstraZeneca, there's Merck and there are many other clinical trials actually farther along, hopefully in the next couple years actually coming to the market to be approved. Lastly, all the therapy that I talked about today is for B-cell ALL and there's subset of an ALL called T-cell subtype ALL which is is rare but it's about 20% of ALL will be in this category. We have not seen much of immunotherapy in these categories but luckily there are actually now several clinical trials undergoing right now targeting same CAR T-cells against different marker CD7 for relapse refractory T ALL patients across the country. So for those patients who have failed the chemotherapy, this will be a great option which we did not previously have about two years ago. So this is kind of new and upcoming therapy for those rare subset of ALL patients.

So where are we? Tremendous progress has been made for our ALL patients. We have a very effective treatment. We may not even need to use chemotherapy at all for some subset. The CAR T-cell therapy, which is one of the most effective therapies we do have has improved significantly with less side effects. In some cases kind of the zero the rate of a patient's getting sick and it could be outpatient therapy, they don't even have to be in hospital and most of these patients could be outpatient and you don't have to spare as much of a time away from home. So I think it's important because that you may not remember all of those and that's why we are here. So do ask your doctor about different therapies and seek second opinions. First treatment, especially the first time because the cure we have the best chance of a cure the first time we're delivering the therapy. So formulating the best treatment plan at the beginning, I do believe is critical so I think it's getting, it's good to get a second opinion even if you don't necessarily get the treatment at the referral centers, at least you can get a better sense of what the disease trajectory might be, what therapy options might be there should you need some kind of tertiary care center help. MRD I told you about that it is kind of good to think about them.

The last thing I would leave with an impression the future is bright for ALL treatments, many ongoing research for B-cell ALL, younger and older. We're trying to reduce the amount of chemotherapy we need to administer because now we have some effective tool and different immunotherapy by combining those that we can get a better state for our patients with an ALL. With that I will turn it over to Lindsey.

- Wonderful, thank you so much. That was very, very informative. And can I just ask you on the, you had a slide a couple slides back about alternative deliveries for blinatumomab. Yes. And one question that came in through registration and also a question that I had, isn't there a genetic, a gene therapy option currently in trials for blinatumomab? It's basically like a one time, yeah and that's through a clinical trial if I recall.

- That is a clinical trial. So I'll talk -the two things there. One is that the blinatumomab is given IV continuously, but there's a subcutaneous version of it actually for that blinatumomab drug itself for newly diagnosed older patients and for younger patients as well. So that is kinda the one thing that's happening but it's still in multiple injections you do need to get. The second thing which is what the question is kind probably related to there's what's called in vivo CAR or in vivo BiTE. What is that? That is a form of a gene therapy. So it's kind of vaccine trial but you know they're getting this vaccine or mRNA delivered your own cells to make you you basically you’re training or you're making your own cells or your own T-cells to make this BiTE within you. So it's a kind of in vivo pharmacy or in vivo cell therapy. That is very early but having said that, there's many clinical trials ongoing. So there is such trials ongoing very similar to the blina kinda the in vivo blina, it's not quite blina but in vivo similar structures BiTE what we call it that's happening there too. So in, there's in vivo CAR as well. So instead of making the CAR T-cells and collecting and taking four weeks, we can just inject those kinda mRNA vaccines and can make the CAR itself within your body too. So it's the same technology but one is making CAR T-cells one, the other one is making blina or the BiTE. So those are actually being investigated but those are clinical trials not yet approved but quite exciting.

- Okay, great. And I really appreciate the message that you closed on about asking for alternatives from your provider, your clinician and seeking a second opinion if, you know, possible because given the fact that there are other options out there, sometimes it's good to know that you have those alternatives and you don't necessarily need to go with the first thing that came along.

- Correct and I think that's a very important for especially rare disease like this because ALL, while it may be very common for pediatric hematologists, for a lot of adult oncologists it's a very, very small portion of what they will do and we are very fortunate to practice in a very specialized center and I have a research focus strictly dedicated to ALL but many do not. So, and that's the reason and the same thing is true for me for other disease and I'm not the expert and I have to ask for opinions and second thoughts also too. So I do think it's good to ask those questions before it goes too far. It's never too late. Even if you're far along you can still ask questions, am I on the right track? If this were to fail, what other therapy options are out there? I have you know, this small disease right? Should I worry about this or not? So those questions and the referring doctors don't, they don't mind. I think all of us should encourage second opinions so that you know that we can ensure you guys get the best care.

- Yeah, I'm so glad you mentioned that because you know rare disease day is coming up on

- Oh yes the 28th of February. And a lot of people don't realize, as you said in pediatrics in kids ALL is seen more frequently, right? But in adults ALL is seen less frequently and for patients who aren't at a major academic medical center in a big city, the doctor that they're seeing may not see very many people with ALL. So it's a very important point to mention. Okay, so let's get to some of these questions. One of the first questions that came in was why can't inotuzumab replace maintenance?

- That's a good question. So it has, it's been studied I think the whole maintenance question is being, is being studied now. So maintenance part and it's unique to ALLs and very few curable leukemia have this two year long of a maintenance therapy. Maintenance typically consists of steroid, oral chemotherapy such as mercaptopurine, methotrexate and then IV vincristine kind of this four drug combo is the kind pillars of these kind of maintenance therapy. So first this maintenance was out there for when we only had a chemotherapy and for the induction and consolidation. And at that time the maintenance was necessary for two or three years because if we didn't get those relapse rate is high. What we don't know is now that we are using blinatumomab and inotuzumab in the induction and consolidation, which is a much more effective therapy than the chemo, do we still need the maintenance therapy? And we did not have any MRD tools before. And so what if the maintenance is only beneficial for MRD positive patients and not so much MRD negative, we also don't know that question too. So the point is that it's been questioned but what's being done currently is that there are efforts to shorten the duration of maintenance by incorporating this new therapy and adding blinatumomab during the maintenance part, too. The inotuzumab, the maintenance has not been, it's also been studied before but because of this liver disease with the liver side effects, because if you get too much of this dose, at least the dose that we're using currently for relapse refractory in the frontline patients, the risk of liver disease may go up. So because of that we are trying to be very mindful of how much total doses of inotuzumab that we're giving to our patients. So if you got any during that consolidation, we may not need to get that many during the maintenance. But post-transplant maintenance inotuzumab has been also been studied so that drug is being also being studied but blin and others also being studied in the maintenance setting as well too.

- We did have several questions generally about testing during maintenance. And so one is should clonoSEQ be used during/ after maintenance in B ALL or only after induction? I don't know if you wanna tackle that one quickly.

- Sure. Yes, yes. So MRD monitoring is not just one time portion. There are some critical time points that it is very important and we typically said the minimal time point is after induction or before you go to consolidation, which is typically two or three months from the time they initiate your initial chemotherapy or initial treatment. Because you do want to be in MRD negative setting if you're not, you either have to switch therapy to something else to get into the MRD negativity but that's one time that it may make a treatment decision and the, not only the treatment choice difference, but the second is if you're MRD positive, that also indicates higher risk of a disease for which we were considering a bone marrow transplant even when you do get MRD negative with the subsequent therapy. So that's the reason that two or three month mark is important for an MRD assessment.

But even if you got lucky and the fortunate and then MRD negative, that doesn't mean that you are done. So we do also recommend and monitor MRD continuously and there's no set frequency, the exact frequency does depend on what typical regimen that you are on, but you might be able to get every three to four months in some cases through either the bone marrow biopsies to make sure that you are staying in MRD negative because if you're rising MRD that means your disease unfortunately is recurring and that we also need to think about different therapies. If you don't monitor for those, you don't know when that is coming ultimately. So it is kind of early look and then kind of the prediction of what's coming ahead as well too. So during the maintenance we also do bone marrow biopsy and MRD assessment. Now MRD assessment, the clonoSEQ can also be done in blood as well too. So there's another alternative to sometimes what we do for our patients because it's not easy and they're not the most convenient thing to get a bone marrow biopsy every three months, every four months, every six months even so that you can replace them with the blood. The blood is less sensitive than bone marrow biopsy. But because we are able to, the sensitivity of this testing is so good, picking a one cell out of 1 million that if the blood is a lot less sensitive than bone marrow biopsy, but it could be a good replacement alternative to bone marrow based testing. But it is important to be tested for and monitoring because you know, rather than the disease coming back all of a sudden and then you're not well prepared for it and we're kind of scavenging for another therapy, which you will be able to formulate a plan, you have a little bit more flexibility and time to plan for the next line of a therapy when you pick up a disease at a smaller disease setting.

- Okay, so unfortunately we are running out of time, so I'm going to take a minute just to talk a little bit about some other alternative sources of information we have on the right here you should be able to see the NCCN patient guidelines. I always recommend to patients and caregivers that you take a look at those if you haven't already. We do have a lot of information as I mentioned on our website and I wanted to also mention that we have, Dr. Park did a great job of an introduction to immunotherapy in this session and we have a session coming up in April that is entirely focused on immunotherapy for leukemia. So we will have experts on the acute side - the ALL side as well as the chronic side - CLL and they will be talking exclusively about immunotherapy. So I highly encourage everyone here to keep an eye out for that information. The event I believe is on April 27th if I have the date correct, but definitely keep an eye on our communications and social media, et cetera.

So I want to thank Dr. Park for this great session. I think we all learned a lot and as I mentioned in my original comments, the video will be made available on our website as soon as possible. You also all will be receiving an email from me in a little while with a link to a survey. So please do take a minute to fill out the survey and give us some feedback.

And I also just in closing, wanted to thank again the sponsors Autolus, AstraZeneca, Menarini Stemline and Cycle Pharma. So that's about it for this program. Thank you everyone so much for your participation and thank you Dr. Park and if you had any closing remarks?

- No, thank you for having me here and I think that feel free to ask questions or reach out and you have incredible resources, so I think it's really good to be engaged with the community. So it's my pleasure and my honor to be here.

- Thank you so much. Okay, everyone have a great day.

- Thank you guys. Bye.