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Targeting FLT3 Positive AML with New & Improved Therapies with Dr. Margaret Kasner
Targeting FLT3 Positive AML with New & Improved Therapies with Dr. Margaret Kasner image

Feb 07, 2022 / 01:00PM EST
HealthTree Podcast for AML

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Episode Summary

Margaret Kasner, MD

Sidney Kimmel Cancer Center

Interview Date: February 7th, 2022

About 30% of acute myeloid leukemia patients have developed a mutation in the FLT3 gene. Up until recently, this specific mutation usually resulted in poor treatment outcomes. Today, we have several drugs designed to directly target this mutation and even more progress is occurring with newer drugs and various treatment combinations in clinical trials.

In this show, Dr. Kasner, an AML expert from the Sidney Kimmel Cancer Center at Thomas Jefferson University, summarizes key developments and clinical trials currently underway for FLT3 positive AML. 

Thanks to Our Episode Sponsor

Full Transcript

Katie: Welcome to today's episode of HealthTree Radio for AML, a show that connects patients with acute myeloid leukemia researchers. I'm your host, Katie Braswell. We'd like to thank our episode sponsor, Jazz Pharmaceuticals, for their support of the HealthTree Radio for AML Show. 

Before we get started with today's show, I'd like to mention a few upcoming events that we will be hosting throughout the month of February. Next week on February 16th, at 1pm Eastern, we will be hosting a virtual event within our AML Caregivers Chapter, titled, Lessons Learned as an AML Caregiver. Kerith Amen, who was a caregiver to her husband Rob, will join us to share the top lessons she learned while supporting her husband in navigating his AML diagnosis. There will be plenty of time for discussion at the end. Also, on February 23rd, we'll be hosting a virtual event within our Adult AML Chapter, featuring AML survivor and patient advocate, Ilana Massi, who will share her journey of physical and emotional healing after stem cell transplant. You can register for both of these events by visiting our website, 

As a reminder for today's show, if you have joined us online and would like to be able to ask Dr. Kasner question during our Q&A period at the end, you will need to call in via telephone to 515-602-9728, and press “1” on your keypad when you're ready to ask your question. Now onto today's show. About 1/3 of acute myeloid leukemia patients have a FLT3 mutation. Up until recently, this specific mutation typically resulted in poor treatment outcomes. Today we have several drugs designed to directly target this mutation and even more progress is occurring with newer drugs and various treatment combinations in clinical trials. 

Today, Dr. Margaret Kasner, an AML expert from the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, will summarize key developments in clinical trials currently underway for FLT3 positive AML. This show will provide those who are FLT3 positive, a deeper understanding about targeted treatment options and which clinical trials to consider as part of your care. We are so pleased to have you here with us on the show today, Dr. Kasner, but before we get started, let me provide an introduction for you. 

Dr. Margaret Kasner is associate professor and chief of the Leukemia Program in the Department of Medical Oncology at Sidney Kimmel Medical College. She is also the co-Medical Director for the Clinical Trials Office at the Sidney Kimmel Cancer Center. Her research focuses on the use of novel agents in myelodysplastic syndromes and acute leukemias. She has participated in many clinical trials for FLT3 positive AML, including the ADMIRAL trial which showed improved overall survival with the oral FLT3 inhibitor, gilteritinib, versus chemotherapy in patients with relapsed or refractory FLT3 positive AML. She currently has quite the list of open clinical trials with several of them being for newly diagnosed or relapsed/refractory FLT3 positive AML.  

You are the perfect person to speak to us on this subject today. Thank you so much, Dr. Kasner, for joining us today. 

Dr. Kasner: Thank you so much for having me. I really appreciate the opportunity to talk to you about the FLT3 mutation today and all our new therapeutic options. 

Katie: Yeah. I just want to say that I'm just absolutely amazed at the willingness of AML experts to participate in these programs. I reached out to Dr. Kasner after hearing her moderate in AML session at the annual ASH meeting in December, and she responded to me the very same day and was so open to participating. We're just so very grateful for your time today. Let's go ahead. 

Dr. Kasner: Really happy to be here.

Katie: Great. Let's go ahead and jump into our discussion, all about FLT3 positive AML, and let's start with the very basic. Can you tell us what a FLT3 mutation is, and talk about how this mutation affects patients with AML? 

Dr. Kasner: Sure. Even though you'll probably never hear it called anything but a FLT3 mutation, it stands for FMS-like tyrosine kinase 3. That's because it's a member of the class three receptor tyrosine kinase family. A lot of other members of this family can also be an issue in the development of different cancers, and many, many large studies have identified FLT3 as the most common mutated gene in both adult and pediatric patients with AML. As you said in the introduction, about 30% of adult patients with AML have consistently activating mutations, and it's quite as common in pediatrics. 

There are two types of FLT3 mutations. Most commonly that you will see, the letters ITD or internal tandem duplicate. This is an interesting structure for mutation in that what happens is the same set of abnormal genetic material repeats itself, over and over and over again, gets longer and longer and longer, and that's how it causes problems. We sometimes see the same structure in genetic disorders that are passed from generation to generation. Sometimes, as it gets longer and longer, it gets worse. Sometimes we see it younger and younger, in future generations. This is that type of genetic mutation. There's also what's called a TKD or a tyrosine kinase domain mutation, and that is what's called a point mutation, when a single letter in the genome, a single nucleic acid in the genome is altered. 

Clinically, the ITD mutations are the ones that are associated with earlier time to relapse and poor overall survival in AML patients. More recently, it's become clear that patients who have a higher number of mutant copies compared to the wild-type, and you'll hear that called the allelic burden or the allelic ratio, the higher that number is, the worse the clinical outcome. In the European LeukemiaNet Classification, people with lower ratios are not considered to be as high risk. In the AML community in America, we usually treat all FLT3-ITD patients as high risk.

Katie: Excellent, excellent overview. Do we have an idea of why this mutation occurs? Is this something that runs in the family? Is there anything environmental we're aware of? 

Dr. Kasner: What we know about these mutations is that, clearly, they're not random. The same types of mutations occur in lots of different people's AMLs, and that's because they provide a survival advantage to the leukemic cells. They make it easier for them to grow, and better, but we don't know what actually causes them in the first place. It's not, as far as we know, passed genetically through families, and there isn't a specific environmental risk that's associated with it. We know that if we give somebody radiation for a cancer diagnosis, it increases the risk of AML, but not this type of AML. For now, we don't have a specific cause for FLT3 mutations. 

Katie: How would a patient know if they have a FLT3 mutation? 

Dr. Kasner: It is standard, when someone is diagnosed with AML, when they come to me, that we look at the genetic and molecular makeup of their AML, and this always includes a PCR for FLT3 mutation. Now, as I said, there are two different kinds of FLT3 mutations, and it actually requires two different types of testings to look at the two different mutations, but we standardly do that for all patients at the time of diagnosis and also at the time of relapse. Because FLT3 mutations can appear when they weren't there before, and they can also disappear after people are treated for their initial AML. 

Katie: This is something that's being done on everybody as a standard of care. It's not necessarily something a patient would need to ask for. 

Dr. Kasner: Right. That's correct. Everybody should, every patient with AML should have this tested, both at diagnosis and potentially at relapse. If there's a patient who has a diagnosis and hasn't been told what their FLT3 status is, that's likely because it's negative, but it's always appropriate to ask. 

Katie: Got it, yeah. I was going to ask you on some stats about FLT3, which you have already gotten into, but what about the difference in prevalence between the two that you mentioned, ITD versus TKD, which one's more common?

Dr. Kasner: FLT3-ITD mutation is much more common. I actually don't know the numbers, but it is the more common mutation. When we get down to talking about treatments, not all FLT3 inhibitors cover both types of mutations, but again, the FLT3-ITD mutation is the one that is associated with the worst outcome. The TKD mutation is less common and also is less bad, if I can use that phrase, but it does allow us a target for therapy to add to standard therapies if a patient has that mutation. 

Katie: Okay. Why is FLT3 positive AML historically been known as a difficult-to-treat type of AML? What are your thoughts about this idea today? 

Dr. Kasner: Well, it turns out that patients with and without FLT3 mutations go into remission at similar rates. The issue is that they don't stay there long. Patients who go through mutations without the addition of FLT3 inhibitors tended to relapse very early, tended not to be able to make it to allogeneic stem cell transplantation, which is our road to cure, because if their disease relapsed too quickly, then maybe they weren't even able to make it there. Even if they could make it there, they might not do or they definitely did not do as well as patients without the mutation, in transplant. Of course, that's not a good scenario. Certainly, the statistics showed that it was in fact more difficult to treat, but the truth is that FLT3 inhibitors are changing that. 

If you look at other diseases in the leukemia arena, for example, Philadelphia chromosome positive ALL used to be the one that was the worst and difficult to treat, but then when we started using all of the great drugs that we use for CML, in that disease, it turned out that not only was it not worse, but now there's evidence that maybe we could even treat these patients without a transplant. That's how I see, or at least, that's how I hope FLT3 positive AML is moving. Now we have very targeted inhibitors that aim at this mutation, and when we use them, especially in combination with chemotherapy, people's outcomes are greatly improved. We have a lot of hope that if we can figure out the right combinations, the right timing, that we can maybe make FLT3 positive AML not only not worse, but maybe better. 

One area that this is particularly true is actually in older patients, patients who can't maybe undergo very intensive chemotherapy or maybe can't undergo a stem cell transplant because of their age or other medical conditions. In the past, having a diagnosis of FLT3 positive AML and being one of those patients was really a very poor position to be in. Now, because of our targeted, much less toxic agents, we are potentially able to treat, put into remission, extend the lives of patients who previously might have died very quickly from their disease. Honestly, my thought is that we’re very much moving in the right direction in that, like I said, it used to be kind of a doom diagnosis, but now, I think it's really changing, and it's changing rapidly. 

Katie: That's amazing. It's really exciting and gives a lot of hope to hear your thoughts on that. Thanks for sharing. I want to talk a little bit more about the conversation of transplant, and you mentioned that getting into remission is definitely doable, but staying in remission without a transplant is probably the area of conversation. I'm wondering, is transplant always recommended for those who are deemed appropriate, with FLT3 mutations? 

Dr. Kasner: Right now, yes. Right now, to the best of our understanding, we still believe that people with FLT3 mutations are best served by an allogeneic stem cell transplant if they can undergo one. Now, again, if we take lessons from Philadelphia chromosome positive ALL, which, not that many years ago, the answer to, should we transplant those patients, was 100%, yes, all of the time. Now, it’s not at all. Now, there are groups of patients that we recommend potentially don't go to transplant. We follow along and look for their mutations. We might take them to transplant if we need to, but not by definition. Again, this is a little bit further behind in that pathway, but I am hopeful. I'm hopeful that we might be able to find the right combination of inhibitors and chemotherapy for people who not just don't have to undergo transplant, but who really can't undergo transplant. 

Katie: Yeah, that would be amazing. Let's move more into treatment options. Can you talk to us about what FLT3 inhibitors are and when, during the course of treatment, they're used?

Dr. Kasner: Absolutely. Now is where I really wish I could show you all the pretty PowerPoint picture of the FLT3 inhibitor, of the actual tyrosine kinase and what it looks like. Basically, there are two forms of the FLT3. There's an inactive conformation, and then when two of them come together, that's the active conformation. We have a number of inhibitors, some of which affect only the ITD mutation, and that is present in the inactive conformation, and then some which affect the TKD, and some which affect both. 

The first generation FLT3 inhibitors actually were drugs that were used in solid tumors in other diseases, for example, sorafenib and sunitinib. Now sorafenib is a type two inhibitor. It only targets the ITD mutation. Then there's midostaurin, which, I think, anybody who knows a little bit about FLT3 has heard about because it was the very first approved FLT3 inhibitor. It is a type one inhibitor. It affects both ITD and TKD mutations. Actually, I think now is a good time to talk about midostaurin because, again, it is the first FLT3 inhibitor approved in AML. It is approved in the upfront setting, and the trial that demonstrated benefit was something called the RATIFY trial. 

This trial was for relatively younger patients who were able to get upfront aggressive chemotherapy. We call this combination, seven and three, because we give seven days of one drug and three days of the other. They added this oral FLT3 inhibitor called midostaurin to this combination of chemotherapy, and then they also added it to later stages of therapy, to consolidation and then sometimes after transplant. What they demonstrated was a survival benefit for all types of FLT3. The biggest benefit was actually shown in TKD patients, but there was also a benefit in ITD patients, both high and low allelic ratios. 

Now sometimes people talk about midostaurin as what they call a dirty inhibitor. It inhibits a lot of things, not just FLT3, so its benefit may be not quite as clear as a more specific FLT3 inhibitor, but it is our current standard of care for upfront patients who are able to receive intensive chemotherapy. We'll talk about some trials in that area a little bit later, I think. Then there are second generation FLT3 inhibitors that are much more specific, and that include gilteritinib, lestaurtinib and crenolanib. 

Gilteritinib is like an oral drug approved by the FDA for relapsed and refractory AML patients, and that was because of the ADMIRAL trial which is something you mentioned upfront. We participated in it here at Jefferson. It was a phase three trial that compared oral, easy-to-tolerate, that's my editorial, FLT3 inhibitor versus physician’s choice salvage chemotherapy, and it showed an, in four months, improvement in overall survival, and so this led to FDA approval. 

Now, there was another study with crizotinib, called the QuANTUM-R study, which also randomized patients to single agent versus salvage chemotherapy, and also showed an improvement in overall survival, but it showed an increased risk of cardiac toxicities. I think, partially because gilteritinib was also already approved, the FDA denied approval of the crizotinib, based on that study. 

There's another big study that just came out with quizartinib for the upfront setting, called QuANTUM-First, and we're all eagerly awaiting the results of that trial to be announced. The announcement that was already made is that it reached its primary endpoint, meaning, it improved survival in combination with chemotherapy in the upfront setting, but we're waiting to hear all of the details of that and then the FDA review. I know that was a lot of information, but it turns out, there's actually even more information about FLT3 inhibitors and what's on its way.

Katie: Yeah, yeah. We mentioned before the show even started that 60 minutes is definitely not enough to cover everything here, and it's very obvious there's a lot going on. That was a really good rundown. I'm glad you brought up quizartinib. I was going to talk a little bit about it later on. I did a show with Dr. Stein last week, from MSK, and he said that we might see FDA approval for it sometime this year. I was curious, your thoughts, if you were anticipating that as well.

Dr. Kasner: I am. I think we were both on the same meeting with the company where we got to hear the sneak peek for what that trial showed, because we both participated in the trial. I, in fact, I do think that there will be approval forthcoming, and I'm eager to see the data in its completion. I think that the real question, and this moves into what trials are out there, but the real question is, how do these drugs perform in comparison to what we now consider the standard of care, which is midostaurin plus chemotherapy? 

Because neither of the studies were done, there was no standard of care, there was no midostaurin plus chemotherapy, so neither of the studies were done in comparison. We're left with both ongoing studies that will really look at the question the way it should be looked at, which is comparatively, but also we'll have this freestanding study. We can't help but compare it. We can't help but try to figure out which will be the better option for our patients, and that will include both, which one will provide a bigger benefit, but also managing the risk because these drugs do have different risks, for sure. 

Katie: Yeah. If we have drugs that specifically target the FLT3 mutation, why is there still such an issue with resistance? Can you talk to us a little about what researchers are currently working on, to try to overcome this resistance?

Dr. Kasner: Yeah, absolutely. A little bit cynical and, I guess, a little bit sad answer to why we're dealing with resistance is that AML is very smart.  It knows, when you give it a therapy that, if it wants to survive, it needs to find a way around that therapy. There are many mechanisms for FLT3 resistance, unfortunately. One is clonal. What I mean by that is that AML actually develop, we used to think that all cancers developed as one single cell that grew up into the cancer. Actually, what really happens is that there are multiple little pockets of cells that are a little bit different from each other. 

One of the things that happens with FLT3 therapy is that a cell that doesn't have FLT3 in it and therefore is able to grow even in the presence of inhibitor, that will grow. That will be the smarter AML clone. Because, again, all it wants to do is survive, it doesn't really care very much about the fact that it's killing the host. So, what you'll see is that a patient will relapse with a FLT3 negative leukemia, FLT3 negative clone, and then we're no longer able to use the inhibitors, obviously, to treat because that clone never had that particular target. 

The other thing that can happen is that there are specific TKD mutations that provide resistance to the FLT3 inhibitors. They make it so that the FLT3 inhibitors are not able to affect the cells anymore. There are specific TKD mutations that provide resistance for the cell to midostaurin, some that provide it to later generation, like type two inhibitors like crizotinib. There are some that provide resistance to, specifically to crenolanib. Again, these are smart cells, and they're developing other ways of helping themselves grow. 

There are also other mutations, things like RAS mutations, which you see in other solid tumors, that can develop in these cells to help them grow, again, around the FLT3 pathway. One of the simpler things that's happening is to not use these agents alone. When we give them in combination with chemotherapy or with other agents like hypomethylating agents, it's actually considerably less likely, at least we believe, for resistance to develop. So, combining the FLT3 inhibitors with chemotherapy or with lower intensity regimen, is one strategy. 

Another strategy is actually transplant with a FLT3 inhibitor as maintenance. If the patients are not getting a lot of FLT3 inhibitor upfront, and then only a little bit of the disease is left after transplant, and the inhibitor is just being used to kind of prevent relapse; we think that that should help with resistance. Of course, there's the development, the constant and ongoing development of newer generation FLT3 inhibitors that will, hopefully take into account some of these resistance mechanisms and be available for treatment for people who are resistant. 

Lastly, there are other combinations of drugs that aren’t FLT3 inhibitors but may work particularly well in FLT3 positive patients that are also being explored in clinical trials. We know it's a problem, and we're really working hard to try to address and overcome that resistance. 

Katie: Let's go into each of those areas you mentioned, in a little bit more detail. Let's break up the current work going on, by phase of treatment, and talk about the newly diagnosed setting first. Can you talk about the studies that are going on now that are trying to answer the question of which FLT3 inhibitor is best to use in combination with intensive chemotherapy? As you said, current drug is midostaurin, but does this have the possibility to change? 

Dr. Kasner: I do think it does. There are actually quite a number of ongoing trials that are directly comparing different agents in combination with upfront therapy versus midostaurin. There is a trial ongoing, we have it opened at Jefferson, that compares gilteritinib plus seven and three, to the standard midostaurin and seven and three. There are ongoing trials with crenolanib that are sponsored by the company that looked at the same thing, crenolanib upfront with chemotherapy versus midostaurin plus seven and three. 

Now, the quizartinib question, for the record, we're never supposed to compare two trials, but it's just impossible not to. That data will be used, even though they're not in a head-to-head trial. Those are the three currently being developed FLT3 inhibitors. I think we will soon, I hope pretty soon, relatively soon, in trial time, have some answers about which is the best or which are better options for our patients. 

One of the things that is interesting is that the quizartinib trial included patients that were considerably older than the RATIFY trial, so it may come up simply that if a patient is older then they should go on the quizartinib plus chemotherapy, rather than midostaurin plus chemotherapy, just based on the patients that were included in the trial. 

The other things that people are looking at for upfront therapy is, so the standard of care now for upfront therapy, for patients who are not eligible for chemotherapy, is a combination of hypomethylating agents, classically, azacitidine or decitabine plus venetoclax. People are looking at combinations of those two agents with FLT3 inhibitors, and also actually looking at the combination of FLT3 inhibitors plus HMA alone or FLT3 inhibitors plus venetoclax alone. Those are combinations for people who aren't eligible for upfront chemotherapy. These are all trials, but they're very interesting and very promising. 

I’ll try to make this plug often. We're halfway through, and I haven't made it yet. Enrolling on a clinical trial for these combinations is always going to be of benefit. The hope, the great hope is that it's of benefit to the individual person who's on the trial, but it, for 100% certain, is of benefit to the community of AML patients and to the future of AML therapy because this is how we will figure out what the safest and most effective combinations of therapy are. These combinations are being looked at, in the upfront setting, so, relapsed/refractory, same combinations being looked at for relapsed/refractory patients. Then there's a whole discussion about maintenance, which I think we're probably going to have, shortly. 

Katie: Yeah, I think you can make that plug, maybe three or four more times throughout the remainder of this show. I'm totally okay with that. Super important. Let's talk about post-transplant maintenance. What's going on? What do we know about FLT3 inhibitors in this setting? Should they be given to everyone, or do we know the answer to that yet? 

Dr. Kasner: Yeah, unfortunately, we really don't know the answer. I will editorialize my belief, which is that, yes, there is a role for maintenance therapy in FLT3 positive patients. I say this based on a lot of trials that have already happened and that are ongoing. The area of post hematopoietic stem cell transplant maintenance therapy for FLT3 inhibitors is not new. People have looked at midostaurin, sorafenib, gilteritinib. 

The evidence that we have, so far, so there was this trial that looked at sorafenib in AML FLT3-ITD only patients. It did, in fact, show a very impressive risk reduction for relapse and for death. The truth is that sorafenib is not an easy drug to use. There are a lot of side effects and issues with it, but it certainly provided a lot of hope. There was a second randomized trial that was also with sorafenib that also showed impressive one and two-year relapse-free survival and overall survival improvement. Those trials really encouraged us in this area, than the midostaurin, the RATIFY trial. Even though the FDA did not include post-maintenance therapy, the trial included it, and that gives us some evidence that event-free survival is better with patients who get midostaurin maintenance. 

The other agent, gilteritinib, is the drug of choice for what's called the MORPHO trial, which is a phase three randomized trial looking at gilteritinib versus placebo, for 24 months of maintenance after transplant. It's quite a large trial. It’s about 350 people. It is also only ITD patients. We're all eagerly awaiting the results, but it's going to be a bit. I think that we're not expecting those results until 2025. There is a crenolanib trial. We thought we were going to see the results of that trial. We’re hoping to see the results of that trial this year. We thought maybe last year, but we haven't quite seen them yet. 

The QuANTUM-First trial, which I've already mentioned, included 36 months of post-transplant maintenance for those patients. We'll definitely see those results this year in 2022. I think, simply the fact that, if it is borne out that patients were able to tolerate that duration of therapy, is actually very encouraging for the use of these agents in maintenance therapy. Because, again, in maintenance, you need something that patients can tolerate because they've been through their transplant, and now they're in remission. Our goal is to keep them there, but we need to do that in a manner that isn't toxic to them or to their bone marrow. 

There is yet another phase three gilteritinib trial that actually includes upfront and consolidation maintenance therapy. It's against midostaurin, and we're hoping to see the results of that next year. There is a lot of hope for use of FLT3 inhibitors in the post-transplant setting, and it is one of the things that gives me hope that we will be able to say, eventually, that FLT3 positive disease isn't worse than other subtypes of acute leukemia. I think that this particular area will make a big impact. Again, I say this based very much on preliminary data. I really hope that in the next two, three years, that a lot more data will support this. 

Maybe we won't know which agents because maybe all of the agents will show benefit, and that's really ideal because then we have a choice. We can look at what patients are tolerating, what patients have received in the past. Because they aren't identical drugs and so if somebody has maybe an issue with their heart, it would maybe be better for them to be on one than the other. Having choices is always really good. Like I said, I think this is an area of a lot of hope for us, and a lot of research. 

Katie: Yeah, definitely a lot that we'll be learning in the next few years, for sure. Can you talk to us about your ongoing trials for FLT3 positive AML? 

Dr. Kasner: Sure, of course. We have an upfront trial and a relapsed/refractory trial. I mentioned the upfront one. That is the PrECOG trial. ECOG is the Eastern Cooperative Oncology Group. It's one of the national -- we used to be divided into physical geographic areas of cooperative groups in this country. Now, it turns out that we're actually all one big happy family, but trials can originate from a specific group. This one is the PrECOG. It compares gilteritinib to midostaurin in the upfront setting in a randomized fashion. We've been enrolling to that for quite a while now, and we look forward to the completion. 

The other trial that we have is interesting in that it specifically looks at a non-FLT3 inhibitor drug for patients who are already resistant to FLT3 inhibitors. It is a combination of two different pathways, the MDM2 pathway which is where p53, one of the oncogenes that we have, is involved, and something called a BTK inhibitor. That is a class of drugs that has been shown incredibly effective in things like CLL. We combined those two agents, they’re oral agents, to interfere with cell cycling and to address the needs of patients who have already seen FLT3 inhibitors and are now resistant. 

We are also going to be opening a trial that combines azacitidine, venetoclax and a FLT3 inhibitor in the upfront setting for patients who are not able to get aggressive chemotherapy. That's still being opened nationally. It hasn't quite opened yet, but it's on its way.

Katie: Great. In your opinion, what are some of the major questions that still need to be answered for FLT3 positive AML? 

Dr. Kasner: Oh, I'm going to sound terribly cynical when I say, all of them. The truth is we're really in our infancy. We know that targeting FLT3 is certainly a benefit. The question really is, when, upfront versus in relapse versus maintenance? Honestly, I think the answer is probably yes, all three. We are still, again, in the infancy of our development of FLT3 inhibitors. I think that we certainly have good options, but I really believe, based on the development of other tyrosine kinase inhibitors in the field of CML, that we have much better ones to come very soon. I think that as we develop better ones, we’ll continually have to re-ask the same questions that we've been asking, which is, where is the best place to use, the optimal way to use them. I really do think that, ultimately, the answer is going to be everywhere, upfront, in consolidation, relapsed/refractory and in maintenance. 

Katie: I think we'll end by maybe letting you re-share your plug on clinical trials, so we'll have plenty of time for caller questions. When should a trial be considered, and do you feel that all FLT3 positive patients should consider joining a trial?

Dr. Kasner: I will expand that and say, I think everybody who has AML should consider joining a trial. That's because the very unfortunate truth about AML is that we are still in a place where only about 30% of our patients are long-term disease-free survivors. We all know that is not good enough. We have made incredible strides in terms of new therapies for AML, in the last five to ten years, and that has only happened because our incredible patients have been willing to participate in clinical trials and have worked with us to move the field forward.

We have one standard of care for upfront therapy and one standard of care for relapsed/refractory therapy. If that is what is available and appropriate, that's okay, but that is unlikely to be the end of the story for anybody with AML. There are likely to be next steps in therapy, and I highly recommend that if you don't choose an upfront clinical trial, that you consider choosing one in the next stages of your therapy, for maintenance, for a trial, or if, unfortunately, you relapse. Because, again, we cannot move this field forward without the participation of patients, and I cannot tell you how much I appreciate and how honored I feel to be able to participate in these trials. Because the goal is for 100% of our patients to be with us, five years after their diagnosis, and so we have a very long way to go. 

Katie: Excellent. Now I'd like to open it up for caller questions. If you have questions about anything Dr. Kasner discussed today, you can call into 515-602-9728. Once you're on the call and ready to ask your question, press “1” on your keypad. Let me check our caller list here and see who I can unmute. I’m not seeing any questions come through yet, so maybe I can pose my question while I see people call in from online here. I'm curious if you could maybe go into the differences between the FLT3 inhibitors that we talked about. You touched on that each one is a little bit different in terms of side effects. Could you tell us maybe what the main differences are that you've seen so far? 

Dr. Kasner: Sure, sure. Again, we have only two approved right now, at least for AML. Midostaurin, that drug is the one that's in combination with chemotherapy upfront. I'll tell you, in terms of side effects, that when you're in your upfront first cycle of aggressive chemotherapy, it's kind of hard to notice side effects from this additional pill because you're already in your big complicated cycle of chemotherapy. That's good. When people try to take it in consolidation and in maintenance therapy though, it's not the easiest drug in the world to tolerate. One of the reasons is that, this is interesting to me, it's a pill, but the pill has a scent, an unpleasant scent, and it makes it sometimes difficult to take.

People have issues with, sometimes nausea or vomiting or difficulty eating and some diarrhea. It has some GI side effects. They're not often so hard to take that we can't manage them, but it's also not, again, the easiest tolerate for every patient. Now some patients do completely fine, of course. That's midostaurin. All of the later generation inhibitors, gilteritinib, quizartinib, crenolanib, they're more likely to affect your heart rhythm, and so something that we have to watch very carefully when we give people those drugs is, we get frequent EKGs, at least in the beginning when people first start taking the drugs, and we have to be more careful for drug-drug interactions. 

My experience is that people who take gilteritinib tend to have an easier time taking it, and we just need to be careful with people's hearts. Those drugs like gilteritinib are similar to other tyrosine kinase inhibitors in that they sometimes have these side effects that include swelling. They can be swelling of your legs. It can also be, interestingly, swelling around your eyelids, called periorbital edema. Of course, any drug can sometimes have rashes or other issues like that. I will say that these drugs, they are chemotherapies in that they target cancers. They're not like taking a classic chemotherapy, but they do have their challenges. 

Katie: Great. Okay, I see a caller here, ending in 3280. I'll unmute you now, so you can ask your question. 

Caller: Okay, yes. Thank you for that presentation, Doctor. I had a question about the gilteritinib. I had a stem cell transplant two and a half years ago, and I'm doing really well. I have a FLT3. Then I started me on the gilteritinib for maintenance, shortly after the transplant, and I couldn't tolerate it. I had muscle pains, and then my liver enzymes went sky high. Since that time, I've not been on any maintenance. I don't know. Should they be considering another maintenance track for me? 

Dr. Kasner: Well, let me start by saying congratulations. That's great. You’re two and a half years out. 

Caller: Thank you.

Dr. Kasner: Actually, I can't back this up with any solid data, but I can tell you that, at this point, we don't really believe that adding maintenance therapy, as long as you remain FLT3 negative, will be of benefit. At least all the historic information we have about maintenance therapy says a year, maybe two years, and at the outset, three years of therapy. If you've gotten to that point without any, it's extremely unlikely that you need any.

Caller: Oh, okay, thank you. I've always been negative MRD every time they've done the bone marrow.

Dr. Kasner: Yeah. 

Caller: Okay, thank you. That's very nice to hear. 

Dr. Kasner: You're welcome and, again, congratulations. 

Caller: Thanks. 

Katie: Okay, again, if you'd like to ask a question, press “1” on your keypad, and I'll unmute you. I don't see any additional questions coming through. If I don't hear in the next few seconds, we will go ahead and wrap up. Okay, I guess we'll go ahead and wrap up today's show. Thank you so much, Dr. Kasner, for joining us today. We're just so grateful for your generosity with your time and your willingness to share your incredible expertise with us. We've learned so much today. We're excited for what's to come for you this year in 2022. We'd love to have you again on the show in the, hopefully, near future, to share more exciting updates on FLT3 positive AML. 

Dr. Kasner: Thank you again for having me, and I would be happy to hop back in, with updates when they're available. 

Katie: Great. I'd also like to mention to everyone that Dr. Kasner will be joining us again in May, for an event in our Adult AML Chapter, to talk with us about understanding our AML labs and bone marrow biopsy results. She'll be speaking on this topic to us on May 5th, so go ahead and mark your calendars. Dr. Kasner, we wish you all the best this year in your clinical practice and your research endeavors. Thank you so much again for your time today.

Dr. Kasner: Thank you.

Katie: Thanks for listening to HealthTree Radio for AML. Join us next time to learn more about what's happening in AML research and what it means for you. 

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