Acute Lymphocytic Leukemia: Latest Treatments

Leukemia Research Foundation:

Hello and good evening. Thank you for joining us for the second of, sorry, the third of four sessions of the Leukemia Research Foundation's New + Emerging Treatments conference. The topic tonight is Acute Lymphocytic Leukemia. My name is Lindsey Whyte and I'm the Director of Programs & Partnerships at the Leukemia Research Foundation. I would like to take a moment to thank our supporters of this conference. AbbVie, Astellas, Daiichi Sankyo, Kite, Merck, Novartis, and Pfizer. We also would like to thank our webinar partner Patient Empowerment Network.

The Leukemia Research Foundation's mission is to cure leukemia by funding innovative research and to support patients and families. The Foundation has raised over $87 million in support of its mission since our founding in 1946 and has funded research grants to over 600 new investigators worldwide. Our support programs for leukemia patients and their loved ones include information and resources, education programs, financial assistance, and a directory of helpful organizations on our website.

Just a few quick housekeeping items for the program this evening. All participants will be muted through the program. If you have already submitted a question at registration, please know that we have your questions. We received quite a few questions, so we will do our best to cover as many as possible. You can also type a question into the Q & A box at the bottom of your screen. After today's program, you will be sent a brief evaluation through email. Please just take a moment to complete the evaluation so we can improve future programs. Also, this program will be recorded and sent to all participants after the program.

We are grateful to have Dr. Shira Dinner from Northwestern University with us tonight to present on ALL. Dr. Dinner is a clinical researcher with an interest in novel immunotherapies and molecularly targeted therapies for leukemias in particular acute lymphoblastic leukemia.

She is currently the principal investigator for an NCI and ECOG sponsored phase two trial of Daratumumab for minimal residual disease positive T-ALL. Due to her interest in ALL and adolescent and young adult patients, she was appointed the co-chair of the ECOG AYA committee in 2021. Dr. Dinner received the National Cancer Institute Cancer Clinical Investigator Team Leadership Award to support her research time from 2017 to 2019. She also supports NIH sponsored research in her role as an executive officer overseeing the administration of clinical trials in hematologic malignancies for the Alliance for Clinical Trials in oncology. In addition to her expertise in clinical trials, Dr. Diner serves on the NCCN guidelines advisory panel for MDS, ALL, hematopoietic growth factors as well as the AYA committee. Dr. Dinner, thank you so much for joining us tonight. I will turn it over to you.

Dr. Dinner (03:29):

Great, thank you Lindsey. I will start screen sharing

There we go. Alright, can everybody see that okay? Yes.

Great. Alright, so I am Shira Dinner from Northwestern University. I'm really glad to be here with all of you guys, tonight. I'll be presenting on acute lymphoblastic leukemia updates, new and emerging therapies. These are my disclosures. So ALL has many different subtypes, so it's a bit of a broad agenda to cover. I'll begin with newly diagnosed Philadelphia chromosome negative B-cell ALL, which is the most common type of ALL. I'll review the recent data from the Eastern Cooperative Oncology Group 1910 clinical trial that added blinatumomab to chemotherapy for younger adults. I'll then talk a little bit about inotuzumab combined with mini-CVD chemotherapy and blinatumomab for older adults. And then the alliance AO41703 trial, which combined inotuzumab and blinatumomab as a chemo free approach to treating older adults with ALL. And then moving on to newly diagnosed Philadelphia chromosome positive B-cell ALL.

This is really where we see success with trying to eliminate chemotherapy and we're using drugs like Ponatinib and dasatinib in combination with the immunotherapy blinatumomab. And I'll tell you a little bit about the ongoing clinical trial ECOG 9 1 8 1, which is looking at tyrosine kinase inhibitors with chemo versus tyrosine kinase inhibitors with blinatumamab and then an update on relapsed refractory B-ALL and the newest CAR T-cell that might get approved soon by the FDA. And finally touching on newly diagnosed T-cell ALL, which is more rare. It represents only about 25% of ALL. We'll talk about the children's oncology group study that added nelarabine to chemotherapy.

So a large portion of my talk is going to focus on immunotherapies and I think that's really what's been new and emerging within the last five to 10 years for ALL and has shifted how we're approaching treatment. So an immunotherapy is really using the idea of the immune system to attack the cancer or the leukemia. And so what this is typically is an antibody. And an antibody is a Y shaped protein that's made by the immune system to identify, bind and neutralize harmful things which we call antigens. These are typically infections in the body, but in this case it would be the cancer cell Immunotherapies typically use antibodies that are manufactured or created in the lab and then they are targeted to recognize and attack the cancer or leukemia cell.

So there are many antigens or these proteins on the surface of the malignant B-ALL cell that we can potentially target with different antibody based immunotherapies. On the left-hand side of the cell, you can see CD 19 that is targeted by blinatumomab. It's also targeted by several of the CAR T cells, CD 20 just below that is targeted by rituximab. CD 20 has been shown to have a more adverse prognostic feature in B-cell ALL. But when giving rituximab it kind of reverses that or overcomes that. And down at the bottom is CD 22, which is targeted by inotuzumab ozogamicin as well as some newer CAR T cells that are in development.

So to start with, I'll talk about blinatumomab. This is a bispecific T-cell engaging antibody. And so what that means is it consists of a CD 19 antibody, which you guys see at the bottom here as well as a CD3 targeted antibody linked together. The CD 19 portion binds to the surface of the malignant B leukemia cell and the CD3 portion binds to the T cell and it essentially activates the T cell and recruits it to the malignant B cell in order to attack and kill the leukemia cell. So because of the way it's activating the immune system, it can cause side effects like we call cytokine release syndrome, which is very similar to having a severe infection because we're upregulating the immune system. So patients can have fevers, low oxygen, low blood pressure, and we often have to manage them in the hospital at the beginning of the infusion to make sure that they're tolerating it okay.

It also can cause some neurologic side effects, which could be like confusion or tremors, sometimes even rarely seizures. So that's also monitored in the hospital. And blina was first approved for relapse disease in late 2014. More recently in 2018 it was approved for what's called minimal residual disease, which is when a patient is in remission having less than 5% blast but still there is something detectable in our pathology lab at that less than 5% level. And we know it's associated with a higher risk of relapsing and blinatumomab can help treat that.

So knowing how effective blinatumomab could be in relapse disease and also for this minimal residual disease, the Eastern Cooperative Oncology Group conducted this 1910 clinical trial which in patients between the ages of 30 and 70 years old had them initially receive induction chemotherapy as a standard of care. After they got into remission, they were randomized if they were minimal residual disease negative to continue with standard of care chemotherapy alone, which you see on the right hand side. So that's about six months total of intensive chemotherapy and then moving on to about two years of maintenance chemotherapy, which is very standard in ALL treatment. And then on the left hand side, the patients were randomized to the investigational arm to receive four cycles of blinatumomab added into their chemotherapy, which really does add about six months of additional treatment to their therapy.

And so what they showed in this study is that it did help to improve the overall survival, so meaning how long the patients lived, if they were minimal residual disease negative from the chemotherapy and then we added in blinatumomab they lived longer. So in the graph on the right hand side, the black line at the top is the patients who got blinatumomab and chemotherapy and you can see that they are living longer. The red line is the patients who got chemotherapy alone and it's dropping down lower because their rates of survival were going down. So the median survival had not been reached for blinatumomab and chemotherapy versus it having been reached at about 72 months for chemotherapy or approximately six years. So this was a big landmark study. It is expected to be published in full in the coming months and also it's expected that it will lead to an FDA approval for blinatumomab in newly diagnosed disease.

So the next antibody based therapy that I wanted to talk to you about is inotuzumab ozogamicin. And this is a little bit different. It's a CD 22 targeted antibody and then it is linked via this protein to a toxin that we call calicheamicin. And what happens is it binds to the surface of the leukemia cell, it gets taken inside the cell and then it gets kind of metabolized or broken down in the cell such that this protein is dissolved and then the toxin or the chemical calicheamicin is released directly into the cell. So it's like a way of delivering a payload or a chemo in a sense directly into a cell and not just into your general body circulation. Inotuzumab was FDA approved for relapsed ALL and is very effective in that setting and based on that, they're now interested in using it similar to blinatumomab in the frontline setting.

So this is a clinical trial that's ongoing in older adults based out of MD Anderson and the regimen is called Inotuzumab Mini CVD. And essentially what they're doing if you look on the left hand side here is they're doing four cycles of inotuzumab in combination with chemotherapy. And the chemotherapy is significantly dose reduced compared to what we would give in standard intensive ALL therapy. And they also remove the doxorubicin, which is an anthracycline chemotherapy and it does have risk of causing damage to the heart. And there are certain patients who have things like coronary artery disease and really it wouldn't be safe for them to get those kinds of drugs at all. After the four cycles of chemotherapy and inotuzumab, the patients then got four cycles of blinatumomab as sort of a consolidation and then a maintenance where they were getting some oral chemotherapies and after every third cycle they would have an additional cycle of blinatumomab added in. They saw that the patients 70 and older were still having a hard time with this regimen and were having high rates of sepsis or infection. And so they amended it and they decreased it further to having only two cycles of chemo with inotuzumab and then they removed the maintenance chemotherapy altogether and gave eight cycles total of blinatumomab as consolidation and maintenance.

This is just to show you how the patients did overall. Notably the five-year progression-free survival, which they're showing in the graph on the left hand side was 44%. So that's meaning that over the course of five years, 44% of patients did not have their leukemia come back or have complications or death related to their leukemia. I know that seems kind of concerning and discouraging, but I think to put it in a historical context with many of the prior intensive chemos, they were very difficult for patients to tolerate and we would've been looking at something like a progression-free survival closer to 20% and then also the five-year overall survival was thought to be good at 46%. Once again, I know it's not as good as we would hope for, but still doing much better than we have done previously. And I will also say they did look at the differences between patients 60 to 65, 65 to 70 and 70 and above. And I do think that part of the drop off there is the patients 70 and above still did have more of a difficult time.

And that's sort of what I'm highlighting here. So there was notable toxicity seen in the patients 70 and above. There were deaths in remission, so meaning that their leukemia was gone, but unfortunately they were having complications of the treatment. So prior to the change in the protocol, there were seven deaths due to sepsis. There was one additional death even after they changed the protocol and decreased the amount of chemotherapy further due to infection. So it's really tough in the older adult population to sometimes get through some of these treatment regimens. But interestingly, they also saw that there were nine patients who died due to what we call a therapy related myeloid malignancy or neoplasm, which would be something like a myelodysplastic syndrome or an acute myeloid leukemia.

So that means that the chemotherapy that they got as part of this regimen for the ALL actually did cause some DNA damage and cause them to develop a second leukemia. And we also see this with solid tumors where patients are getting treated for a solid tumor and they might have consequences of developing something like an MDS or an acute myeloid leukemia. Unfortunately, as we age we are more susceptible to DNA damage like that and at risk of developing this, but that also stresses why minimizing the amount of chemotherapy in these patients is particularly important. Otherwise in the table on the right I highlighted some of the common side effects that patients saw, things that we would expect, constipation, nausea, vomiting, low blood counts like thrombocytopenias, low platelets, neutropenias, low neutrophils, and then there are liver side effects that can be seen with inotuzumab. In particular, there's something called veno-occlusive disease of the liver, which can even cause liver failure. This was very rare in this study. It was only seen in 8% of the patients.

So what can we do to further limit chemotherapy? Well, the Alliance for Clinical Trials in Oncology is currently conducting this study AO41703, which is giving two cycles of inotuzumab followed by approximately three cycles of blinatumomab as consolidation and then there is no maintenance chemotherapy given after that. This study is pretty new and it's ongoing. They've only followed patients for approximately 22 months. At one year they did report an event-free survival of 75%, meaning patients living without leukemia coming back or death. And the overall survival at one year was 84%. So patients living and not dying related to any complications of leukemia or other issues.

So where we've really had success with not using chemotherapy interestingly is in Philadelphia chromosome positive ALL. And so these are patients who have a translocation between chromosomes nine and 22, and that leads to this BCR-ABL gene mutation and that can be targeted by drugs that we call tyrosine kinase inhibitors. Imatinib was the first generation of this. It was discovered approximately 20 years ago, and when it was added to chemotherapy in Philadelphia chromosome positive ALL, it significantly improved outcomes. Those were patients historically that would've been dying even with things like a stem cell transplant and now we're having much longer survival and lower rates of relapse. And so seeing that 20 years ago, what we've done over the course of time then is to slowly decrease the amount of chemotherapy. And the other thing is in that time we've had the approval of blinatumomab for relapse disease and minimal residual disease. So again, now we're looking at blinatumomab in the frontline setting and rather than combining it with chemotherapy, like the earlier study I presented to you we're combining it with Ponatinib, which is a tyrosine kinase inhibitor that can block the Philadelphia chromosome or the BCR ABL mutation.

And so this is a trial that gave ponatinib and blinatumomab together as a so-called induction and consolidation. Patients got up to five cycles of blinatumomab with the Ponatinib and then they continued Ponatinib by itself in the maintenance phase for up to five years. I should say that not all patients can tolerate Ponatinib. It does have serious cardiovascular side effects including risks of heart attack and stroke up to 30%. That is decreased by lowering the dose of the Ponatinib once patients are having a response. There is another tyrosine kinase inhibitor called dasatinib that has also been studied in combination with blinatumomab and also had promising results and does not have those cardiovascular risks. So would be something important to discuss with your physician potentially.

So this is just to show you that at the top line here we can see that the complete remission rate was very good at 96%. That's the number in the parentheses and what we call the complete molecular response was also quite good at 87%. So that's the number of patients who not only got into remission like looking through the microscope, we're not seeing the leukemia cells, but also when we use other laboratory tests to check for the BCR ABL mutation, that was negative and that's important because that also can be used as a marker of minimal residual disease. They did also, you can see at the bottom, do what's called next generation sequencing for minimal residual disease. And that was also negative in 88% of the patients. And we know that that predicts for a better prognosis, a lower likelihood of the leukemia coming back.

And then here they're showing you the survival of the patients, which is extraordinarily high. This bar on the left is showing you that it's going up to a hundred percent and you can see that the event-free survival is close to a hundred percent. They reported two year event-free survival of 92%. So meaning that patients are surviving without the leukemia coming back or having complications. And then here the overall survival at two years patients being alive was 95%, which is also quite good. And I will say the dasatinib and blinatumomab trial has had a longer follow-up. They followed the patients for about four years now and they reported a four year survival of 80%, which is also very good.

Should we just say that Ponatinib and blinatumomab are absolute standard of care and we don't need chemotherapy anymore for this disease? Well, the answer is that we don't know. We still have data showing that chemotherapy and Ponatinib for example, has very good outcomes, a 75% survival at six years. And so there is a clinical trial that is randomizing patients, which I highlighted here in the red box between chemotherapy with ponatinib or dasatinib versus blinatumomab with dasatinib or ponatinib. And it's looking to see if the survival will be the same if potentially blinatumomab and the tyrosine kinase inhibitor will be better. And I think that will really give us our answer as to whether or not we can truly say that we can go without chemotherapy for Philadelphia chromosome positive ALL.

And then finally, to focus a little bit on relapsed B-cell ALL and what's new there? So chimeric antigen receptor T cells I think has been one of the hot topics in the last five to 10 years for B-cell ALL. And so what this is is that they take a patient's immune cell called a T-cell. They collect it through a process called apheresis, which is very similar to someone doing a blood donation or a platelet donation. The cells are then sent to a laboratory, typically at a pharmaceutical company and the T-cells are engineered and they use viruses actually to help with engineering them. And what they're doing is getting the cell to recognize the antigen that's on the surface of the leukemia cell. So that would be CD 19. So the same thing that blinatumomab is going after, but they're basically sort of retraining the brain of the cell and having it have an antibody on its surface that can go after the surface of the leukemia cell.

They grow these cells in the laboratory, they send them back to the medical center and then they infuse it into the patient. And then inside of the patient these CAR T cells go to work and they recognize the leukemia cell, the CAR T cell gets activated and then it kills the tumor cell or the leukemia cell. Now similar to what I described to you about with blinatumomab because this is an active immune reaction against the leukemia cell, patients can have symptoms like when they're infected, so they could have fevers, low oxygen, low blood pressure chills. We call that cytokine release syndrome. So this is typically done in the hospital and we can give medicines to limit that reaction. And then also the same neurologic toxicity that I talked about with blinatumomab can occur more severely with CAR T cells.

So we have currently two FDA approved CAR T cells. The first is the tisagenlecleucel, which is approved up to the age of 25 years old. And then there's brexucabtagene autoleucal, which is approved for 18 and older. What I'm showing you here is a newer one that's called obecabtagene autoleucel or Obe-cel for short. This was presented at the American Society of Hematology meeting and the reason I mostly wanted to highlight it here is this is the one that is currently applying to the FDA for approval. And what the company feels sets this one apart scientifically, is that it binds- the CAR T cells are programmed to bind quickly and let go of the leukemia cell quickly as well. And they think that by doing that it's preventing the CAR T cell from getting exhausted and worn out and potentially then it will be more effective in the longterm to keep working against the leukemia cell.

So here you can see that 76% of the patients who received this CAR T product got into remission, which was quite good. And 97% of the patients who got into remission were considered to be MRD negative by a technique called flow cytometry, which is also very good. And they did show that 61% of the responders had an ongoing remission without subsequent anti-cancer therapies, although I will acknowledge that they've only followed them for approximately 10 months. So it is still a relatively new therapy and we need to learn more about it to know if it's going to have a durable response. They did say that 13% of responders went on to stem cell transplant and that they sort of took those out of their analysis at the time of transplant.

I will say that I don't believe CAR T-cell is a replacement yet for stem cell transplant. I feel like that's a question that sometimes comes up. It's still relatively new technology and we don't yet know that they're persisting long enough in the body to have that long-term efficacy. Just briefly, this is just to show you the cytokine release syndrome and also the neurologic side effects that can happen. One thing to note is for patients who had more than 20% blasts in their bone marrow when they got their CAR T cells infused had higher rates of the cytokine release and the neurotoxicity at 82% and 33%. And just to remind you, we can treat those side effects. Tocilizumab is a drug that we can use for the cytokine release syndrome that kind of quiets down the immune response and then steroids can be used for both cytokine release syndrome and for the neurologic complications.

And then last but not least, T-cell ALL, which is more rare and we haven't had as many successes just because I don't think it's studied as much as B-cell ALL. The children's oncology group did a study AALL0434 where they added a newer chemotherapy called nelarabine, which is currently FDA approved for relapse T-cell ALL. And they took it and added it to intensive chemotherapy in newly diagnosed T-cell ALL. And what they showed with this was that it improved what we call the disease-free survival. So meaning living without the disease coming back when the nelarabine was added to the chemotherapy. They didn't see a difference in how long the patients were living, overall. The overall survival was similar, but they also saw that at five years the rate of having a central nervous system relapse was much lower when patients got nelarabine added to their chemo rather than just the standard chemotherapy alone. And that is important because it is very challenging when patients have central nervous system relapses. We have very limited treatment options for that.

Nelarabine does have neurologic side effects, things like neuropathy, also sometimes even things like seizure and they did not see that that was increased when nelarabine was added to chemotherapy. And also early T precursor is a subtype of T-cell ALL that typically is known to do worse. It takes longer to respond to the treatment and to get into remission. Many of them are MRD positive after the initial induction. And these patients who were able to get MRD negative with early T precursor ALL had comparable disease-free and overall survival to the more favorable risk T-cell patients. And that's really nice and important to see.

I just wanted to highlight an ongoing trial that I'm leading for the Eastern Cooperative Oncology Group, this 9213 looking at daratumumab for MRD for T-cell ALL. As I mentioned earlier, blinatumomab is FDA approved for MRD in B-cell ALL, but we don't have something yet for T-cell ALL and daratumumab is a drug that targets CD 38. It's another monoclonal antibody and it's currently FDA approved for multiple myeloma. There's a lot of CD 38 antigens on the surface of T-cell ALL cells and so that was the thought process behind investigating it here in T-ALL. It's also been studied in the laboratory with T-ALL as well as in some case studies and has been effective for MRD. So we decided to do a larger clinical trial. So if that's something you might be interested just let me know. In terms of other things going on in T-ALL, I didn't include slides, but Venetoclax is a drug which is currently FDA approved for CLL and AML and it does have clinical laboratory studies that suggest it's effective. There are also some very small clinical trials showing efficacy in T-cell ALL and then also CAR T cells are currently in very early first in human trials for T-cell ALL. It's obviously a little tricky scientifically to take a good T cell and get it to appropriately recognize a bad malignant T-cell. So it's been a little hard to find an appropriate target for those cells.

So just to summarize, adding blinatumomab to chemotherapy in the ECOG 1910 trial showed an improvement in overall survival for patients who are MRD negative after chemo. When we look at long-term follow-up of the mini CVD with inotuzumab and blinatumomab in older adults, it suggests that chemotherapy can be minimized when it's combined with novel agents. But we did see that there were relatively high rates of secondary malignancies or leukemias that raises concerns that maybe we need to even further reduce chemo in older adults. The early results of AO41703 suggested that inotuzumab followed by blinatumomab is a promising chemotherapy free approach, but limited follow-up has been done so far. It's only one year of following these patients, so we need to see them longer.

And then similarly, early results of ponatinib or dasatinib and blinatumomab are promising for pH positive ALL, so maybe we can treat those patients without chemotherapy. But once again, we have that ECOG 9181 trial going on comparing that to chemotherapy and we are essentially wanting to see that we're not having higher rates of relapse when we're removing the chemotherapy. Obe-cel had a high complete remission rate and a good duration of response during the short follow-up that they've reported to date. If this is a new CAR T cell that gets approved, we're going to then have three CAR T cells that are FDA approved. Two of them would then be available for patients 18 and older. That would be the obe-cel and the brexu-cel that I listed here. And it's not clear how would we pick between them. It might even be come down to insurance and which one is authorized by the insurance.

There are other CAR T cells in development for B-ALL. Some of them target CD 22, the ones that are currently approved target CD 19 and some of them will have multiple targets. There are also molecularly targeted drugs that are in development. I didn't touch on menin inhibitors which target KMT2A, which is a rearrangement that can occur in B-cell ALL and is associated with a worse prognosis. So those are drugs that are on the forefront. And then nelarabine improves outcomes for newly diagnosed pediatric and young adult T-cell ALL. And in terms of more novel things currently in clinical trials I showed you the Daratumumab trial for minimal residual disease. There's also BCL2 inhibitors like Venetoclax, other ones that are in development by other companies that aren't quite as far along as Venetoclax. And then there are also CAR T T-cells that they're working on for T-ALL. And with that I'm happy to take any questions.

Leukemia Research Foundation (33:51):

Okay, great, thank you. We do have one question already that was submitted. I don't know if you can see this. It says are we exploring opportunities to use inotuzumab for additional recurrence? For example, it may be used for the initial recurrence, but when it is successful and a patient is then cancer-free for a couple of years, is there consideration to use it again?

Dr. Dinner:

Yes, that is reasonable to consider. And it was reported in the original clinical trial of inotuzumab compared to chemotherapy. They did have a handful of patients that were treated, got into remission and then recurred and were treated again at a later date and did have responses. The most important thing that we look for is to see if the leukemia still has that CD 22 antigen on the surface of the leukemia cells because then it's very likely that we can target that with the inotuzumab.

Leukemia Research Foundation:

Okay. I have a question that was submitted in the registration. What does MRD positive at the end of induction chemo of 29 days mean? Does this reduce the survival rate and what is the best treatment for such a patient?

Dr. Dinner:

So optimally a patient would be minimal residual disease negative at the end of induction. And so what we're talking about is not only being in remission, having less than 5% blast when we're looking through the microscope, but also that when we're using other laboratory techniques, we're not detecting a very low level of disease. However, I will say that it takes some patients until about day 84, which is after consolidation chemotherapy to clear their minimal residual disease and there is data that if they can become MRD negative at day 84 that they can still have a good outcome without a stem cell transplant.

Leukemia Research Foundation:

Okay. How about one patient said they have been in remission for six years, had 30 months of chemo. If ALL came back, what new treatment would you suggest?

Dr. Dinner (36:18):

So if it's B-cell ALL, which I presume because that's the most common then one could consider blinatumomab or inotuzumab or even CAR T cells. Most likely if it's relapsing we would then recommend a stem cell transplant. So I think if a transplant was a feasible option and there was a lower level of disease, blinatumomab tends to work well in that situation. Usually if there's a higher burden of leukemia blast cells, especially once we're getting up to like 50% blast cells in the bone marrow, blinatumomab doesn't always work as well or there's a higher risk of that cytokine release syndrome and neurotoxicity occurring and then we often have to stop the blinatumomab infusion. So in those instances I usually favor using inotuzumab. CAR T-cells take a lot more time and effort. So blina and INO are both drugs that are what we would call off the shelf, they're already manufactured and we can get insurance authorization for them and treat the patient pretty quickly within a day even if we have to.

With CAR T-cells as I showed you, we have to collect the cells, send them to the company, have them manufactured and then get them back and infuse them into the patient. We also have to deal with real world problems like getting insurance authorization before we can do any of those things. So the reality is that many CAR T cells will take several weeks before we can treat the patient and obviously sometimes patients don't really have that time for their leukemia to wait. Now sometimes what we can do is get the cells collected and then give the patient a treatment and then give them the CAR T cells. But essentially all of these would be options and I think some of it would just depend on how your disease is behaving and how urgently you need treatment and sometimes what is the plan for a stem cell transplant for you.

Leukemia Research Foundation:

Okay, thank you. So before we move on, I wanted to remind participants that if anybody does have another question, you're welcome to submit it in the q & a. I don't see any questions there right now. I'm just going to refer back to the questions that were submitted previously to see what we haven't touched on already. How about how long have ALL patients been known to stay in remission?

Dr. Dinner:

So that is a little tricky because there are different types of ALL and so I think every subtype is a little bit different. I did present to you some data for example with the INOTUZUMAB and mini CVD and that the progression-free survival and disease-free survival were approximately 50% at about five years. So I would say in today's day and age with using some of these newer treatments in older adults, that's what we're seeing in the younger patient population like what we would call adolescents and young adult patients, 18 to 39, I didn't present it today, but there was a study called the CLGB 10403, which basically used an intensive pediatric regimen in these young adults and it had I would say a progression-free survival of about 60 to 70% at three years. So not giving you an exact amount of months or years necessarily, but I think giving you a sense of what is the likelihood that someone might be in remission after about two to five years.

Leukemia Research Foundation:

I'm glad that you mentioned that. And I know that in your intro we said that you're involved quite a bit in adolescent and young adult patients. Can you talk a little bit about how you approach an AYA patient versus how you work with the patient who's a little bit older? Maybe just talk about the differences in approach there.

Dr. Dinner:

Yeah, so I think for one thing it's a very different social situation. The young adults are just at a critical point where they might be leaving home, whether it's for a job, whether it's for college or graduate school. It might even be that they are already on their own and have a job, but they've already started to have young children of their own. They're typically not as financially established as older adults are. They might not have a spouse that can serve as a caregiver for them. And so I think it creates a lot of social disparities that are very challenging and I think it can be very frustrating for the patients to deal with. They're also facing issues like fertility and whether or not they will be able to have children if they haven't had children yet. So that's also daunting things to think about for them.

So I think we try to encompass addressing all of those issues for our patients. It's not just about the treatments but also needing to balance these social factors I think in the adolescent and young adult patient population. In terms of the treatment itself, as I mentioned for the B-ALL, we usually give these pediatric based regimens. We're doing the same thing for T-ALL. That's what I did present at the end of my talk with the nelarabine regimen that was studied by the Children's Oncology Group, but they did extend it up to the age of 30 in their clinical trial. And so that is typically what I am treating with up to the age of 30. PH positive ALL is more common in older adults than in young adults. But we definitely do see it and we don't know exactly what the right approach is for a young adolescent, young adult with PH positive ALL. And that is why I think something like the clinical trial that's looking at chemo with the tyrosine kinase inhibitor versus chemo or excuse me, a tyrosine kinase inhibitor with blinatumomab is an important question to be addressed.

Leukemia Research Foundation:

Okay. It looks like there was a follow up to the previous question regarding inotuzumab. I don't know if you want to take that offline. And then another one you mentioned flow cytometry for MRD testing, any benefit in using clonoSEQ testing for MRD instead of flow cytometry?

Dr. Dinner:

Oh, I think that these days I use both flow cytometry and clonoSEQ testing to do minimal residual disease testing. ClonoSEQ is FDA approved for minimal residual disease testing, but it is newer and I will say that patients don't always have sequence that can be tracked reliably. So it's not something that can necessarily be used for all patients. There is a report from MD Anderson that did compare flow and clonoSEQ MRD testing and seemed to indicate that clonoSEQ was more sensitive. So clonoSEQ is an NGS based modality of MRD testing. It's the only one that is technically FDA approved. I just usually try not to necessarily favor one test company over another, but in this instance, they're the only ones who do it. But I think they both have benefits and I think it's actually nice to have the information together because then you can kind of try to correlate them. And as I said, for some patients it's not easy to use clonoSEQ, it's not readily trackable.

Leukemia Research Foundation:

Okay. Let's see. We don't have any others. Did you want to go back to the follow up question to the Inotuzumab?

Dr. Dinner:

I know this person, so maybe Lauren, would it be okay if we talk offline about it?

Leukemia Research Foundation:

Okay. In that case, I think we've covered everything unless anybody wants to very quickly enter something else into the q & a and unless we see something come up, I think we're going to wrap things up for this session. Hopefully everyone found this to be useful. I think you covered a lot of information today. Thank you very much for all of that. I'm just going to put our sponsor slides back up one more time and acknowledge the support that we received to be able to host these events. And I'm going to also encourage everyone to complete the survey that we're going to send out separately after this event so that we can get some feedback on what is most interesting for patients and what you find helpful in these programs. And just want to say thank you once more to Dr. Dinner and wish everyone a great night and be sure to look out for the replay. We'll also, in addition to sending the survey out, we'll be sending the link out for the replay to this so that people can watch it again and again, catch all of those long words that you missed the first time. So thanks everyone. Thanks Dr. Dinner and have a great night. Thank you. Thanks.