Dr. Jane Liesveld
University of Rochester
Interview Date: June 29, 2022
The FLT3 gene mutation is the most common mutation seen in acute myeloid leukemia patients, occuring in up to 37% of adult cases. FLT3 mutations have historically been harder to treat with poorer outcomes, however, with combination therapies using targeted drugs such as FLT3 inhibitors, outcomes have improved. In this show, Dr. Jane Liesveld, an AML expert from the University of Rochester, shared with us the FLT3 inhibitor options currently available and in development, as well as research from several recent clinical trials exploring new FLT3 inhibitor drugs.
Thanks to Our Episode Sponsor
Kerith: Welcome to today's episode of the HealthTree Podcast for AML, a podcast that connects patients with acute myeloid leukemia researchers. I'm your host, Kerith Amen. We'd like to thank our episode sponsor, Abbvie, for their support of this HealthTree Podcast for AML episodes.
Before we get started with today's show, I'd like to mention an upcoming event that we will be hosting. On July 14th at 11:00 a.m. Eastern, we will host another HealthTree Podcast for AML episode. We will be joined by Dr. Rory Shallis from the Smilow Cancer Center Hospital at Yale New Haven Hospital. Dr. Shallis will be discussing the complicated and difficult-to-treat TP53 genetic mutation, where we are with current treatment options, and research from current clinical trials.
Also, I'm excited to announce that on July 19th at 2:00 p.m. Eastern, we will be hosting a virtual HealthTree Round Table for AML event. We have invited two AML experts to join us – Dr. Uma Borate from the James Comprehensive Cancer Center at Ohio State University, and Dr. Naval Daver from MD Anderson Cancer Center. They will be joining us to give a mid-year update on AML news, emerging treatments, research and clinical trials. I hope you all join us for this informative discussion.
As a reminder for today's show, if you have joined us online and would like to be able to ask Dr. Liesveld a 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 are ready to ask your question.
Now, on to our show today. The FLT3 gene mutation is the most common mutation seen in acute myeloid leukemia patients, occurring in up to 37% of adult cases. FLT3 mutations have historically been harder to treat with poorer outcomes. However, with combination therapies using targeted drugs such as FLT3 inhibitors, outcomes have improved.
The development of FLT3 inhibitors has progressed in recent years, and there are currently two FDA approved options – midostaurin and gilteritinib. There are also several FLT3 inhibitor drugs in development and being tested in clinical trials.
Dr. Jane Liesveld is here with us today from the University of Rochester to discuss the FLT3 mutation, FLT3 inhibitor drug options currently available and in development, and share the research from a few of the clinical trials exploring new drugs. We're so pleased to have you here with us today on the show, Dr. Liesveld. But before we get started, let me provide an introduction for you.
Dr. Liesveld is a Professor of Medicine in the division of Hematology and Oncology, and Clinical Director of the Blood and Marrow Transplantation Program at the University of Rochester. Dr. Liesveld's research is focused on all types of leukemia, myeloproliferative disorders, myelodysplastic syndromes, multiple myeloma, and stem cell transplantation. Her work has been published in many prestigious journals. Welcome, Dr. Liesveld, to the show.
Dr. Liesveld: Thank you, Kerith. It's my pleasure to be here with the HealthTree AML community, and to have this discussion over the next hour.
Kerith: Thank you so much. We're happy to have you here. Let's go ahead and jump into our questions today. Dr. Liesveld, can you briefly tell us about the FLT3 mutation, how patients are tested for it, and why it has historically been a hard-to-treat mutation?
Dr. Liesveld: Sure. I think that's a great place to start. As was mentioned in the introduction, this is the most common mutation that we see in our patients who have acute myelogenous leukemia. It's one of the mutations that is recommended to be tested for in all patients at diagnosis that goes along with other mutations like NPM1, IDH1 and 2, TP53, and a few others that are part of routine panels. It's so important to test for this because this does have impact on treatment now, not only in the upfront setting, but later in our patients that would have relapse as their course unfolds.
The FLT3 mutation is present, as was mentioned, in about 30% of cases with AML. What's interesting about it is that while it's common in those who are middle aged, it can be seen throughout the age spectrum. There are children who have FLT3-positive AML. There are also older patients who have these mutations. It's also important to remember that these mutations are of two types. We'll talk about that in a bit.
First of all, to kind of explain what this mutation is. FLT3 stands for FMS‐like tyrosine kinase. What that means is that this is a protein that binds to a cell membrane and signals into the cell so that it gives the cell a signal to grow or proliferate. It has impact on differentiation of cells. All these blood stem cells that need to eventually form red cells or white cells or platelets, it has impact in that. It also helps cells to prevent undergoing a programmed cell death. It has importance in normal blood cell production.
In some of our patients with leukemia, this particular receptor becomes mutated or changed so that it is always firing continuously. That gives the cells that have this change in the DNA or a mutation a proliferative advantage over other stem cells and that can contribute to the leukemia.
These mutations are of two types. One is called internal tandem duplication. What that means is that there's a change in the part of the protein that signals through the membrane. It causes this to be active all the time so that it doesn't have to join with another part of the receptor, but it can just keep signaling constantly.
There are other mutations that are called tyrosine kinase domain mutations. They're in a different part of the receptor. There, again, this mutation which is usually just a point change in the DNA of this particular gene will cause this protein to be able to resist any controls that the cell would normally have in place for this.
As a result of both of these mutations, the leukemia cells have a proliferative advantage and can grow. The internal tandem duplication mutations are the most common. As was mentioned, about 30% of patients with AML can harbor these mutations, and about 20% to 25% have the ITD mutation, whereas only about 5% to 10% have that tyrosine kinase domain mutation. It is important to distinguish those because they do have different influences on the eventual outcomes of treatments.
As a result of these mutations, a lot of patients with the mutation will present with very high white counts because, again, these cells have this proliferative advantage. The marrow can be packed with leukemia blasts, and these often behave in a very proliferative fashion. That isn't always true because particularly in some of our older patients, we can find this mutation, even in some AMLs that have evolved from a condition called myelodysplastic syndrome. Some of those may behave in a more indolent or less proliferative state.
That's why looking for this mutation is important. It can be tested for in a couple of different ways. One test that can be done in most centers that care for leukemia is a polymerase chain reaction assay. This usually has a fairly rapid turnaround because as you can guess, this presence of mutation can dictate how we might want to treat our patients initially. It's important to have an assay that you can get a result on within a few days of the patient appearing.
There's also testing through next generation sequencing which can be more sensitive, but it often takes a longer period of time, and for many centers, would involve a send-out test. That would be how the mutation is assayed for.
This is a mutation that has been known about for some amount of time. It's important now because it truly can influence how we treat our patients. It doesn't necessarily influence the percentage of patients that are going to go into a complete remission, but it does influence the risk of relapse of the disease. That's why it's so important to know that upfront.
Kerith: That was a really great overview. Thank you for all that information. You laid that out really well for us. A follow-up question on the internal tandem duplication or ITD, versus TKD, tyrosine kinase domain, the two different mutations within FLT3. You mentioned ITD has a 20% to 25% occurrence, and TKD was about 5% to 10%. You said that possibly one was more difficult-to-treat than the other. Can you tell us which one is harder to treat than the other and why that might be?
Dr. Liesveld: Yes. We can get into that. I think that it's not so much the difficulty in treatment, but it's just the prognostic importance that the type of mutation carries. It's primarily the ITD mutations that are associated with the increased risk in relapse. Because of that increase, many hematologist-oncologists would recommend that many of those patients undergo stem cell transplantation after they get into remission.
Whereas, with the tyrosine kinase domain mutation, many patients will not necessarily have that mutation impact their overall prognosis. The effect on prognosis and outcome is much less definitive with that particular type of mutation, but yet it is also targetable by some of the inhibitors of the FLT3 mutation that we'll talk about later in the program.
Kerith: Great. Why don't we start discussing the two FDA approved FLT3 inhibitors that we currently have which are gilteritinib and midostaurin? Do you want to start there for us?
Dr. Liesveld: Sure. Gilteritinib and midostaurin are the current two inhibitors that are approved by the U.S. FDA. Each of these inhibitors has a little bit different array of approvals based on the European approvals. One that we'll talk about later called quizartinib is approved in Japan, but not in the U.S. or in Europe.
The first FLT3 inhibitor that was approved was midostaurin. It was initially not developed as a FLT3 inhibitor per se, because it also inhibits a lot of other growth pathways that can be important in oncologic diseases and also in blood formation. For example, something called the VEGF receptor and some other similar tyrosine kinases are also inhibited by that. Whereas, gilteritinib was developed later and more specifically as a FLT3 inhibitor.
Some of the first FLT3 inhibitors that were developed like midostaurin were found to inhibit FLT3 just in the context of being examined in other cells types or other malignancies. They tend not to be totally specific for the FLT3 mutations. With time, some of the later inhibitors that have been developed are more specific, and those are given. They're called second-generation FLT3 inhibitors because they are more specific, and they have fewer what are called off-target effects. They also tend to be more potent in their ability to inhibit the FLT3 receptor, and to target the mutation.
The first-generation ones are less potent and less selective, but you might also think that because so many growth pathways are involved in AML. Sometimes, that lack of selectivity may actually benefit a patient. We’re, I think, still trying to understand that completely if some of these other so called off-target effects might also lend some benefit in AML treatment as those agents are further examined in treatment of AML.
Midostaurin is a first-generation FLT3 inhibitor. Gilteritinib is one of the second-generation FLT3 inhibitors. There are also some differences in the inhibitors that have been developed in terms of how they interact with the binding site for these proteins. There are some that interact with the protein when it's in both an active and inactive form, and then others that only interact with it when it's in an inactive form in a little bit different site.
There are a lot of different inhibitors that are under development, but gilteritinib and midostaurin are the two that we have available to use clinically in our patients at the present time.
Kerith: Are you using those, gilteritinib and midostaurin, in the same fashion? Can you use them in the same way to treat AML patients , are they used at the same time during treatment?
Dr. Liesveld: No. They're actually not. That leads into discussing how these received FDA approval. The first drug to receive FDA approval as a FLT3 inhibitor was midostaurin. The trial that led to its approval was the RATIFY trial. That looked at the use of these inhibitors in newly diagnosed patients.
Whereas, the trial that led to the approval for gilteritinib was called the ADMIRAL trial. It examined the use of this inhibitor in patients who had already had relapse of their disease or who had not responded to their initial treatments.
Currently, if one uses these as they are approved by the FDA, midostaurin would be used in upfront treatment of the AML. That is at the time of diagnosis. Gilteritinib would be used in a relapsed or refractory setting. The trials that led to these approvals were quite large trials. Particularly for the RATIFY trial, I think because it was really the first trial to look at FLT3 inhibitors, it took a long time to accrue the over 700 patients who eventually got randomized to use of the midostaurin versus use of a placebo.
The midostaurin was combined with the standard upfront treatment for AML which is an anthracycline, daunorubicin, and cytarabine. In the randomization, it was found that the midostaurin gave a superior length of survival. It was about 70-some months for those who gotten midostaurin versus only about 26 months for those who were randomized to the placebo.
The patients did equally well whether they were on the placebo or the midostaurin arm in terms of their count recovery, but there was a reduction obviously in the risk for relapse and an overall survival benefit for those patients who received the midostaurin along with the anthracycline and the cytarabine. That's what led to the FDA approval of the of the midostaurin.
Interestingly in that trial, they did include patients who had both the ITD mutation and the other tyrosine kinase domain mutations. Both types of patients benefited from this treatment. It appeared to be active in both those mutations as would have been expected. The midostaurin was also able to be used in what's called a consolidation phase of treatment after patients go into remission.
As many of you are aware, that isn't enough to maintain the quiescence of the disease, so patients need to have additional chemotherapy usually with high doses of a drug called cytarabine, which is the same drug that's used in lower doses in the induction treatment. The midostaurin or placebo was also looked at during consolidation.
Then in this trial, many of the patients did go on to transplant, and after transplant could also either stay on the midostaurin or a placebo in a maintenance fashion. It did look at the use of a FLT3 inhibitor at all phases of AML treatment.
The FDA approval for midostaurin is just for its use in induction and in consolidation. In the U.S., it's not approved for maintenance treatment although many physicians are able to utilize it in that setting if insurance approvals can be obtained. The European agencies did approve the midostaurin for maintenance treatment. There's a little bit of difference between the U.S. and Europe, but the important thing is that whether this was used in induction or consolidation or maintenance, it appeared to have benefit for patients. Also, it was able to be quite well tolerated. That led to the approval of midostaurin which is what we now have for use in upfront treatments in a standard of care fashion.
Speaking about relapsed refractory disease, the ADMIRAL trial, all the trials with gilteritinib have butterfly names interestingly. ADMIRAL was the one where they looked at gilteritinib as compared to other chemo therapies that would normally be used for patients who have their disease in a relapse setting. They compared that.
In this study, gilteritinib was used as a single agent. Whereas, many of the patients who got the standard chemo therapies had combinations of various chemotherapy drugs. Again, in this trial, the gilteritinib did result in an improved overall survival. That led to its approval as a single agent in the relapsed refractory setting. It's the drug that we have available to use in those patients who’ve had relapse of their disease or for whatever reason, have not responded to their upfront treatment.
Kerith: Was there additional information that was gleaned from the ADMIRAL trial since gilteritinib is a second-generation FLT3 inhibitor, just in regards to first-generation versus second-generation?
Dr. Liesveld: Yes. As regards that, I would say that midostaurin of itself as a first-generation inhibitor really has not a lot of activity as a single agent. Whereas, in the ADMIRAL trial, gilteritinib, as a single agent, given orally in a dose of usually 120 milligrams a day as a single dose, was able to outcompete with some fairly intensive chemotherapies. I think that does have to do with its being a second-generation inhibitor that is able to inhibit both the ITD and the tyrosine kinase, and probably has a little bit more potency and a little bit more of an untargeted effect in the patients who have FLT3 mutations.
One thing that I didn't mention earlier that's important, I think, to remember for patients and physicians is that unlike some other mutations when they're present at the start in leukemia, they stay with the patient throughout their course. With the FLT3 mutations, they can be lost after a patient goes into remission and then relapses, or there are some patients who don't have this mutation when they're first diagnosed, but then when they relapse, the FLT3 mutation can appear.
It's important as one goes through the course of the treatment to keep assaying for the FLT3 mutation to see if it is present because obviously, at a relapse setting where we often have difficulty getting patients back into a remission, if there is a FLT3 mutation that's appeared at that time, it gives us additional treatment options such as adding in gilteritinib or other inhibitors that might be available on clinical trials.
Kerith: With FLT3 in particular, are you repeating the PCR assay at all bone marrow biopsies? Can you have multiple -- I think I read you can have multiple ITD mutations. Are you repeating the testing to make sure that even from the outset, the FLT3 mutation isn't changing?
Dr. Liesveld: Yes. That's an excellent question. I think that a lot of centers wouldn't necessarily assay for that at all of the bone marrows that are done to assess response. For example, the so-called day 14 or day 21 marrow after the patient has gone through their induction therapy, and their FLT3 inhibitor, if they were FLT3-positive. But many would assay for that certainly, again, at a time of relapse.
We won't get into this in a great deal of detail today. But a lot of centers are looking for clearance of the FLT3 mutation, for example, at the end of consolidation therapy. Sometimes, that requires a more sensitive next-generation sequencing assay, then might compare with a PCR assay which sometimes really isn't able to pick up that minimal or measurable residual disease as might the NGS type assay.
I think that's an evolving area, but I think that clinically right now, the important thing is if a patient is in a remission morphologically and by looking at other parameters, but then has the blasts reappear either in the blood or the bone marrow, it's important at that time to reassess with usually a PCR assay to see if the mutation is still there or has changed, because not only can these come and go, but as you imply, the type of mutation, even between an ITD or a TKD mutation, can change as the disease evolves.
Kerith: I see. That makes sense. Have there been studies comparing gilteritinib and midostaurin? Or is that not really necessary because it's first-generation versus second-generation?
Dr. Liesveld: There are studies that are underway that are making that comparison. It's not so much that they are different generations, but I think that what people are trying to ascertain is would a second-generation FLT3 inhibitor like gilteritinib be more effective in upfront treatments than a first-generation FLT3 inhibitor like midostaurin.
There are a couple of trials that are underway right now that are similar to what I described with that RATIFY trial. Patients received a standard 7 and 3 chemotherapy, and then they are randomized either to gilteritinib or to midostaurin. The object here is to compare whether the gilteritinib will be more effective than the midostaurin, not so much in achieving complete remission, but in terms of survival-free of the disease, relapsing, or in overall survival.
There are a couple of studies that are underway. Nationally, one is through the ECOG cooperative group which involves a lot of centers nationally. Another one is underway. It's through what's called the HOVON cooperative group which is centered in the Netherlands and Belgium and has more of a European-Australian participation. Both of those trials are underway.
We don't know the results yet in terms of the comparison of these two drugs with combination with the anthracycline and the cytarabine in upfront therapy, but it's hoped that in the next couple years, we will have that information to see if there will be increased advantages of using some other inhibitor beyond midostaurin in the upfront setting.
As I mentioned, because midostaurin hasn't really had much activity as a single agent, I don't think there are a lot of studies that are underway comparing midostaurin, for example, to gilteritinib in a relapsed refractory setting. Most of these comparative trials are going on in patients who are newly diagnosed.
Kerith: That makes sense. I guess what would happen if you have both gilteritinib and midostaurin for use in the upfront setting? Is there a reason why you would choose then one over the other? Would it have to do with the mutation like ITD versus TKD? How would you be choosing if you had both to choose from?
Dr. Liesveld: Yes. With those two agents, the midostaurin and the gilteritinib, I think there it would be determined primarily by what these studies might show in the way of efficacy in terms of preventing relapse or even death later. I think that would be an important consideration. I think it also would be important to compare side effects perhaps if for example, they turned out to be equally efficacious and we have them both to choose from upfront.
Both are really quite well tolerated, but midostaurin, for example, can have some gastrointestinal toxicities. Some patients get a lot of nausea because when they open the blister pack that has the midostaurin, there’s an unusual odor initially, so some people have difficulty overcoming that. Whereas, for example, gilteritinib can cause some liver or heart changes occasionally.
I think one will have to just look at the individual patient in that setting and decide what might be the best upfront treatment if, for example, these studies don't end up showing a lot of difference between them in terms of overall outcomes.
Kerith: I did hear that the midostaurin has a very strange odor to it which I found interesting.
Dr. Liesveld: Some patients say that if they open it and leave it open to air for a while, I guess like letting a wine breeze up, that it gets lessened with time, but others are bothered by it no matter how long they open it in advance. It's not a major consideration, but it may be that when we have a multitude of these agents to choose from that, even little things like that may start to become important.
Another factor is that, and again, this isn't so important in the upfront setting in what's called induction treatment because most people are in the hospital, the midostaurin is twice-a-day dosing, the gilteritinib is a once-a-day dosing, but once patients get in the outpatient or get in this prolonged maintenance time after transplant where they're having to take these medications for, again, we don't know the right duration, will it be a year or two years? Whether you take something once a day or twice a day may have an impact for certain patients in terms of ease of administration. There'll be a lot of variables like that that go into those types of decisions.
I guess a parallel example would be in what we call chronic myelogenous leukemia. We now have four or five different inhibitors to use in that disease. Many of them are equally effective, but we just have to choose between them based on side effects and what comorbidities our patients already have, and what we anticipate their tolerability will be for those agents. It'd be great if we could get to that point with the FLT3 inhibitors, if we had enough of those to choose from to be able to make decisions on those, but we're not quite there yet.
Kerith: I guess that would be a good problem to have. Let's talk about other FLT3 inhibitors that are in development and have shown to be promising in clinical trials. Can you discuss other ones that are in development?
Dr. Liesveld: Yes. The two that are in a lot of trials right now are quizartinib and crenolanib. I should also mention that there's another agent that is, I wouldn't say it's fully developed, but it has been utilized in patients with FLT3 mutations. That's a drug called sorafenib.
Again, it's another first-generation inhibitor. It was developed initially as an inhibitor of an oncogene called RAF. It's used in some other solid tumors also, but it’s still is used in some settings in patients with FLT3. There are still some trials ongoing in upfront settings. There have been some trials that have been completed in maintenance settings with that particular agent. I wouldn't say it's under development, but it's still under study.
In terms of the quizartinib, it has been examined in both phase II and phase III trials. It is also a second-generation FLT3 inhibitor, but it is the type that only inhibits the inactive configurations so it is not effective in those patients who have a tyrosine kinase domain mutation. It's only effective in those who have an ITD mutation. In fact, when it's used even in patients with the internal tandem duplication mutation, some of them will, with time, develop a tyrosine kinase domain mutation just in the presence of that quizartinib.
The crenolanib is also a second-generation inhibitor. It also is fairly specific for FLT3. It also inhibits another entity called platelet-derived growth factor receptor, but it's really also quite specific and quite potent. It also is being examined in several different phases of leukemia with both. It's able to inhibit both the ITD and the TKD. Those are the two main ones that are in later phase trials at this point.
Kerith: So far as comparing those two drugs, is there one that's showing more promise than the other? Or how are they different as far as when you might use those?
Dr. Liesveld: That's a great point. I think right now, we don't have a lot of direct comparison between them. In fact, the quizartinib is right now being involved in a trial that's called QuANTUM-First. It's being compared with, again, that 7 and 3 chemotherapy. Patients either get the quizartinib, or actually, a placebo.
The results of that trial are just starting to emerge in abstract form. It is looking like the quizartinib, again, just as the midostaurin did in the Rydapt study, is going to have a benefit in terms of reduction of relapse and reduction of death.
I think the effect on overall survival is less clear right now, although as I mentioned, this is just in abstract form at this point. I think, again, the key difference there is that this will not be effective necessarily in those who have the TKD mutation.
As far as the crenolanib goes, it also is in trials where it's being compared with midostaurin in an upfront setting along with the 7 and 3 chemotherapy. Patients received that chemotherapy backbone and then are randomized to either get midostaurin or crenolanib. Those studies are also still in progress.
We don't really have a lot of data in terms of any comparative fashion. We just have phase I, phase II data to go on the crenolanib. Some of its phase II studies, it actually had over an 80% long term effect when combined with 7 and 3. The quizartinib has also been evaluated in some relapsed refractory settings. Again, compared to chemotherapy regimens didn't meet FDA approval in that setting, but it's possible that with this new trial where it was examined in an upfront setting against a placebo that it may eventually get FDA approval in that setting.
Kerith: For the crenolanib trial, when will this trial be completed? Do you think an FDA approval on crenolanib is coming?
Dr. Liesveld: That's a great question. I think that some of these trials got a bit delayed in terms of their accrual rates during the COVID pandemic. I think right now, I'm told that the accrual is picked up again and is steady. One would hope that the accrual might be finished perhaps toward the end of this year, but then, it's going to take a longer period of time for the analysis to be completed because they will have to wait for relapse events or other events that will determine the endpoints of those studies.
It could be a couple of years yet before we have the results of that study. I don't foresee necessarily a quick FDA approval on that at this time. It will take a little while for all of that to mature. I think the important point is that these are all being examined in fairly very well-designed careful studies where they're being directly compared to another FLT3 inhibitor or to a placebo.
Those types of trials do take time which I know is hard for patients and for providers to have patience with sometimes, but it's important that these be done well and that we understand at the end what endpoints have been met; that certain safety standards have been met. It will take a little while to get some of these randomized trials completed, not only with the crenolanib, but also those with the gilteritinib and others that are ongoing.
Kerith: There's really quite a few out there being tested right now. It's a flurry of activity it seems.
Dr. Liesveld: Yes, it is. That's great. We have to hope that that activity will translate into benefit for our patients. I think it just also raises the issue that participation in these trials for patients who have FLT3 inhibitors is very important if they're available at the centers where they're being treated.
Kerith: If crenolanib were to get approved, would that be a situation where crenolanib would replace midostaurin or just become again, another drug in the arsenal that you have to choose from?
Dr. Liesveld: I think either is possible. I think if the randomized study shows that it's much more effective than the midostaurin, we should get that information because it's being directly compared. The design of that phase III crenolanib study was really paralleled fairly closely to the RATIFY trial that led to the approval of midostaurin so we should have a lot of comparative efficacy data there.
If that's the case, and it is superior, then I think it could replace it, but as you say, if it turns out to be just the same in terms of response rates and relapse rates and overall survival, then I think it would just be another medication in the arsenal.
We would have that opportunity to choose between them based on dosing considerations, potential side effects, potential drug-drug interactions. We would be able to just choose which one we felt would be best for our individual patient as they sit in front of us.
Kerith: Also, I have a question about, can a patient begin to show -- or can they have resistance to a FLT3 inhibitor? Would you want to try another FLT3 inhibitor if they showed resistance to one FLT3 inhibitor? Is that possible?
Dr. Liesveld: Yes, that is possible. I think that we're just learning about that, but there are certainly multiple means by which patients who are on FLT3 inhibitors can develop resistance. Sometimes, just the changes that happen in the marrow microenvironment where these blast cells grow can be altered by the presence of the inhibitors so that there are increased support for stem cells irrespective of the FLT3 inhibitor.
There are mutations that can occur within the FLT3 domain itself that render the protein no longer affected by the inhibitors. There's one mutation called a gatekeeper mutation that can arise particularly in the presence of a Type I inhibitor and that prevents binding of all these inhibitors to the protein. There are actually some inhibitors under development that are being specifically designed to overcome that, what's called gatekeeper mutation.
What also happens is leukemia cells are so smart that because the FLT3 mutation is interacting with a lot of pathways in the cell that are what are called downstream or beyond the effect of the FLT3 inhibitor, some leukemia cells are able to find ways to bypass that FLT3 mechanism and to grow independently of the FLT3. There can be clones that evolve that are really no longer dependent on FLT3.
There are multiple means of method of resistance that can develop. Whether one inhibitor will be effective were another one wasn't in terms of resistance acquisition, I think we're still learning that. I think what a nice view of that is that we know that there are some patients who received midostaurin in their upfront treatment during induction, and then they relapse and they go on to receive gilteritinib.
Obviously, they have the FLT3 mutation in both settings, and yet, the gilteritinib seems to be effective in a large proportion of those in a relapsed refractory setting even if they've had prior midostaurin exposure.
We have to hope that we will be able to use these sequentially, but I don't think we have figured out all of the resistance mechanisms well enough yet that we really know how to sequence them well or what ones will be effective when others haven't.
Kerith: Yes. Sounds like there are a lot of questions still to be answered.
Dr. Liesveld: Yes, I think. As you say, there's a flurry of activity, but every time we have answered something, it seems like there are more questions that are raised. I think while that sounds like a quandary, it also is a great thing that more and more is being learned about these diseases and about how to treat them.
Kerith: I have a couple more questions. I want to make sure I save some time for caller questions as well. What do you think is next for the FLT3 inhibitors so far trials or new drugs in development? Is it refining the mutation target? Or do you think it's different types of drugs to address the mutation?
Dr. Liesveld: That's a great question. I don't really know the answer to that. As I said, there are a lot of these inhibitors under development. They're all a little bit different. It's going to take us a while to learn about where each one is going to be most effective.
I think that in terms of where things are going with this field, one thing that we didn't touch on is that both the midostaurin and the gilteritinib were approved in combination, at least the midostaurin upfront is in combination with intensive chemotherapy. The majority of our patients with AML are older, above 60 years old.
We really need a lot of trials to look to see how these FLT3 inhibitors that we already have available can be combined with less intensive treatments like five azacitidine or decitabine, or those drugs in combination with venetoclax. There are a lot of trials undergoing to address that. We're still not completely there in terms of understanding how best to combine all of those in either a doublet or triplet fashion. I think there'll be a lot more to come regarding that in the near future.
Kerith: This is just a general question. It seems that the care of AML patients has evolved so much in the last five years based on all the drugs that have become available, and it seems that now, you really need to work with a specialist and receive a highly personalized treatment plan that's based on specific mutations and your own specific genomic profile. How much has this changed your practice and the way you care for AML patients on a day-to-day basis?
Dr. Liesveld: Yes, that's a great point. I would say that even though we have so much more work to do, because even for example with the FLT3 inhibitors that we've talked about today, the long-term survival, for example, in the Rydapt trial, was still only about 50% of patients alive at four years. That was a number of years ago and we've made progress even since then.
When I started caring for patients with leukemia, we basically made the distinction between myelogenous and lymphoid leukemias andmMost of our patients with myelogenous Leukemia just had the option of doing what we call supportive care or getting the standard 7 and 3 chemotherapy.
Now, with knowledge about mutations that are important in terms of either driving or sustaining the leukemia, and having several of those that are targetable with agents that are either FDA approved or are under evaluation and clinical trials, it has really improved the outlook for patients and has made this disease much more, I guess, interesting to treat.
It makes us all really aware of the great heterogeneity that there is in this disease and that really no two patients if you do a wide array of mutation profiles, have exactly the same leukemia, yet there are these recurrent mutations that are themes within that spectrum of AML that we can target and that have, I think, already and certainly for the future will make a big difference in treatment outcomes for all of our patients.
In parallel to that, improvements have happened in stem cell transplantation and in how we are able to support our patients with antibiotics and transfusions, so there have been improvements on so many fronts, but as I said, still, so much work to do to overcome this disease for so many of our patients.
Kerith: Yes, it's such a complex disease, but it does sound like you have made great progress, but so much more progress to make too as well.
Let me just open the lines up for callers to see if there's any questions.
If you have any questions about anything Dr. Liesveld discussed today, you can call into 515-602-9728. Once you are on the call and ready to ask your question, press 1 on your keypad.
It looks like I have a question from a caller that ends in 0653. I will unmute you and ask your question. Actually, there's a caller that ends in 5272. I'm going to unmute you. We'll take your call first. Go ahead, caller.
Caller: Hey, doctor. Thank you for taking my call. It's not so much a question as I guess I can add to the data of your studies. I was diagnosed two years ago, March of 2020, with AML with FLT3 along with four other mutations that I can't remember off the top of my head. After my initial chemo which was the 7 and 3, I was given midostaurin, two pills in the morning, two pills in the evening for 14 days. After each consolidation, was given the same dose of 14 days through that September. I was in remission a month after I was diagnosed.
Then last year, May 28th, I was transferred to the Nashville VA, and worked with the Vanderbilt doctors, Dr. Savani, and got my stem cell transplant, and then back on midostaurin, taking two in the morning, and one in the evening as maintenance. As of my last checkup for my first annual post-transplant checkup, they said that if a doctor didn't know my medical history of looking at my labs, they would never know.
Dr. Liesveld: That's great.
Caller: They never know I had cancer. None of my gene mutations were present in my last bone marrow biopsy. I'm 100% donor.
Dr. Liesveld: That's fantastic. I think you described very well the course with the midostaurin that many patients with FLT3 mutations would take through the induction and then through the consolidation, and now your post-transplant maintenance. It sounds like this has worked really well for you. That's fantastic. Thank you.
Caller: Yes, ma'am. Like I said, if you want to access that information, Dr. Savani at Vanderbilt Hospital was my transplant doctor. Also, Dr. Michael Ashigby at UT Health East Texas HOPE Cancer Treatment Center. Them and the VA would have all those records. If they contact me to release it to you, I would be more than happy to.
Dr. Liesveld: Thank you for sharing your story with us.
Caller: You’re welcome.
Kerith: Thank you so much for sharing. Thank you for asking a question. We appreciate it. I think that's all we have time for today unfortunately, but if you have a question that didn't get answered that you would like to ask Dr. Liesveld, you can email the question and I'll pass it along. My email address is email@example.com.
Let's see. That's all the time we have today. Dr. Liesveld, thank you so much for joining us today. We're so grateful for your generosity with your time, and your willingness to share your incredible expertise with us. We would love to have you on the show again in the future to share more updates on your research and clinical trials. We wish you all the best in your clinical practice and your future research endeavors.
Dr. Liesveld: Thank you. It was my pleasure to spend the hour with you.
Kerith: Thank you so much. It was wonderful.
Dr. Liesveld: Okay. Great.
Kerith: Thanks for listening to HealthTree Podcast for AML. Join us next time to learn about what's happening in AML research and what it means for you.
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