Welcome to The AML Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Naval Daver, Amir Fathi, Jessica Altman and Eunice Wang, who debate key updates in FLT3-mutated AML.
“I think we’re at a really interesting time in FLT3-mutated AML. We have gone from looking at agents in combination with induction chemotherapy, that’s midostaurin and now have an approved agent in the relapsed space, that’s gilteritinib, and looking to further improve upon those..”
– Jessica Altman
“Some of these novel FLT3 inhibitors, if they are able to improve overall survival for that patient population, then we may be starting to think about not transplanting all of our patients if we can get those survival curves up far enough”
– Eunice Wang
Mechanisms of resistance
“We’re working on trials on how mutational escape is going to change when you combine venetoclax and gilteritinib or even if you give azacitidine, then gilteritinib… Are there optimal sequences for these agents so we don’t put too much therapeutic pressure upfront?”
– Naval Daver
“Drugs like gilteritinib, in my view, are very well tolerated usually in terms of long-term maintenance. Sorafenib you can run into some issues as we were just talking about in terms of GvH, skin issues, liver issues, but overall, relatively well tolerated in most. So when possible, I, Amir personally would recommend indefinite treatment.”
– Amir Fathi
Naval Daver: Hi, my name is Naval Daver, and I’m very glad you could join the sessions today with the VJHemOnc team. We’ll be discussing the updates on FLT3-based therapies in acute myeloid leukemia from the recent SOHO and EHA meetings.
Naval Daver: It’s a great pleasure to have some of our top FLT3 leading expert colleagues of mine here. We have Dr. Jessica Altman from Northwestern, Dr. Eunice Wang from Roswell Park, and Dr. Amir Fathi from Mass General with me today. We’re looking forward to a good session, and I’m just going to go ahead and start with some questions here.
Naval Daver: So let me ask Jessica, she’s been working a lot on some of the novel combinations, especially with gilteritinib, which currently is one of the two FLT3 inhibitors approved in the relapsed space. The other one being midostaurin in the front line. So Jessica, with gilteritinib, what are the future directions you’re excited about and new combinations, et cetera?
Jessica Altman: Thank you Naval. It’s a pleasure to be here, and it’s great to be here with colleagues and more importantly, friends. I think we’re at a really interesting time in FLT3-mutated AML. We have gone from looking at agents in combination with induction chemotherapy, that’s midostaurin and now have an approved agent in the relapsed space, that’s gilteritinib, and looking to further improve upon those.
Jessica Altman: There are studies looking at adults with newly-diagnosed acute myeloid leukemia, who are fit for intensive chemotherapy and receiving an agent other than midostaurin. Looking at randomized studies of midostaurin and gilteritinib for instance, or crenolanib and additional trials that are being done in the upfront space for both those who are fit and deemed inappropriate for intensive induction chemotherapy.
Jessica Altman: I think more specifically, you were probably getting at what are the novel combinations that are being studied in the relapse space. For instance, gilteritinib has been combined in an ongoing study with venetoclax. We’ve presented data already at ASH, and we look forward to hopefully presenting updated information shortly. We’ve demonstrated, as you well know, that there appears to be an increased response rate. We’re really interested in trying to garner more information about overall survival. Likewise, gilteritinib has been studied in combination with immunotherapy. Those trials are ongoing and of interest. I’d be interested in seeing what the rest of our colleagues think about other therapeutic combinations.
Naval Daver: So let me turn it over to Eunice on that note. Eunice, you’ve been doing the frontline studies, crenolanib randomized study, and there are others of course ongoing with the HOVON group of gilteritinib versus mido with induction. And then quizartinib, which is actually the one that is the first one to complete its randomized study, although that was only against 3 + 7 and we hope to have data sometime next year. So what are your thoughts on the frontline space? Do you think we will beat midostaurin? Do you have any preference for particular drugs? How do you see in the next two years, let’s say, frontline induction FLT3 moving?
Eunice Wang: Thanks Naval. I appreciate the opportunity to chime in here. As you know, the newer generation FLT3 inhibitors are more highly specific and more potent against mutant FLT3 than what we call the multikinase or pan kinases, midostaurin and sorafenib. Those original first-generation what we call FLT3 kinase inhibitors were really designed to target a broad range of kinases or in fact developed for their ability to target tyrosine kinases in a variety of tumor types.
Eunice Wang: When we just look at the early Phase I/Phase II data with some of the newer combinations, gilteritinib, quizartinib, and crenolanib in combination with 7 + 3, what we notice right away is that each one of those agents has been shown to result with into a 80 to 90% overall response rate in combination with standard 7 + 3 for the treatment of upfront, newly-diagnosed FLT patients with FLT3 disease.
Eunice Wang: Now, as you recall, the RATIFY trial really only showed about a 50, 55% CR rate with the combination of midostaurin and 7 + 3. So improving the overall response rate by 20 or 30%, we think realistically could translate into better overall survival. We have some early data from a Phase 2 study of crenolanib in combination with 7 + 3 foundation chemo, and about two-year follow-up on that study shows an overall survival of over 70%. I do think that given the very, very high response rates with the newer generation FLT3 inhibitors that we will see improvement, hopefully. But the answer to that question really lies in the results of ongoing Phase 3 trials.
Eunice Wang: We’ve been fooled before by high response rates in very small numbers of patients, single center or limited center studies. We’ve really seen overall response rates and overall survival rates drop when placed into a broader population of patients across many, many centers. I think we’ll have to wait and see, but think there’s a lot of optimism for these newer inhibitors really changing the paradigm and becoming the new standard of care for upfront treatment of FLT3 mutant disease.
Eunice Wang: That being said, right now when we use midostaurin in combination with 7 + 3, the recommendation is always to proceed to an allogeneic stem cell transplantation in first remission if you are able to, and then results of that RATIFY trial are intricately linked to the use of transplant. Some of these novel inhibitors, if they are able to improve overall survival for that patient population, then we may be starting to think about not transplanting all of our patients if we can get those survival curves up far enough.
Naval Daver: Yeah, that’s great. I think the other important practical point that I’ll open to all of you is we know that of these combinations, the first one that we’ll read out will be probably QuANTUM-First, which is 3 + 7 quizartinib versus 3 + 7. It was designed in 2013 before midostaurin had approval. That time, this design was considered to be reasonable, and of course the FDA probably will still hold a statistical design. But let’s say it is positive, which I would be surprised if it doesn’t beat 3 + 7 how do you think you, and more importantly, community doctors will view that? Will they say, “Well, yeah, but it didn’t beat midostaurin so I don’t use it.” Or will we just try to do cross trial comparisons? You think randomized trials will be needed eventually? What are your thoughts on that? Because I think that’s a very realistic thing that’s going to happen in the next eight to nine months. Any of you. Amir, Jessica? Maybe Amir. You want to start?
Amir Fathi: Yeah. I mean, I think if the Phase III randomized study ends up being … By the way, hi everybody. Good morning. I hope everybody is safe and well. Thank you for having me. I think if the randomized study ends up being positive, I think more and more people will start to use the drug. Midostaurin is a good FLT3 inhibitor, but it has side effects. It’s not the most potent, it’s not the most selective as Eunice was just saying. I think if quizartinib ultimately shows that it is superior to 7 + 3 in combination in the frontline setting, it probably will increasingly be accepted and used. As I’m sure all of us know though, quizartinib is fairly potent and selective against ITD, whereas midostaurin and gilteritinib and some of the other FLT3 inhibitors also inhibit the most common PKD variants.
Amir Fathi: So it is important, I think, if this drug gets approved, that we disseminate that there is a possibility that some patients won’t respond as well and that we should be thoughtful about using it. Also, there is this chance of secondary mutations that arise when you use FLT3-ITD inhibitors, specifically such as sorafenib or quizartinib so I think that is a consideration. But for a FLT3-ITD newly-diagnosed patient, if that study ends up being positive, the drug gets approved, I think it will be increasingly used. I don’t think that people will wait for a comparison to 7 + 3 with midostaurin. That would be my opinion.
Eunice Wang: I would agree with that. I mean, I think what we were going to see when that data comes out, when we go to the conferences is, is what we see now is the graph of the RATIFY trial here on the left-hand side, and the right-hand side of the same slide we’ll see the graph of the quizartinib first trial, the QuANTUM-First trial, that people will try to extrapolate by putting the two data. You say, well, A as compared to B and then C compared to B, so then A compared to C is this. I think they’re all going to do that. Invariably community practitioners are going to do that extrapolation. So I don’t know that people are going to wait for another Phase III trial to come out to really address that.
Eunice Wang: I think one of the questions that people are going to look at very closely given that quizartinib was not approved for relapsed/refractory FLT3 mutant disease, is the toxicity of the combination, particularly the QTC prolongation. How many patients had that? What are the dose adjustments? Are people going to feel safe giving quizartinib in the upfront setting with a cardiotoxic agent, given all of the negative connotations that led potentially to it not being approved in the relapse/refractory setting.
Naval Daver: Yeah, I think that’s a good segue to these mechanisms of resistance. I think in the last few years, there’s been a lot of data coming out from different groups, showing different mechanisms of resistance. For a long time we knew the TKD is one of the main mechanisms of resistance to the type 2 FLT3 inhibitors, sorafenib, quizartinib. The argument was maybe the type 1 are going to be in general just better because that doesn’t happen, which is true. But then we now know that Ras-MAP kinase signaling mutations can occur in about 35, 40% of the people who get gilteritinib. We don’t know yet for crenolanib, but some of the preclinical data suggests that may be the same pathway.
Naval Daver: Our fellow, Dr. Alotaibi had a poster on this and the papers hopefully will be out where we looked at type 1 and 2. And we find that, yeah, that there is a mechanism of resistance and escape on both and it’s just different. And what was also interesting that we found is that we do see TP53 emergence. Now, I don’t know if this was true acquisition or this was actually just enrichment or enhancement. I think it’s the latter. That it was probably there. We just couldn’t detect it with NGS sensitivity. We saw about 10% TP53, 10% IDH1 and 2. But to me, I think this is getting interesting like CML. Where maybe five years from now, we’re going to actually look at the mutation profile and do some very sensitive digital droplet PCR, others at baseline, and then select drugs. Do you think that, that’s kind of the future, and that eventually we’ll use all of these drugs, even if one is better than the other? What are your thoughts on that? Jessica, maybe you want to-
Jessica Altman: Sure. I think you brought up some great points. There are a couple of other mutations that are also identified. There’s the gatekeeper F619 mutation that can occur as well with gilteritinib and there are occasionally BCR ABL mutations that occur. I think the more we utilize these agents and the more clinical experience we have in following these patients at the time of relapse, the more we’re going to understand what mutations occur and which ones need to be targeted and when. I think we don’t know, obviously don’t know yet, what to do. I kind of wonder as we’re thinking about these patients, if when we combine combination therapies, if we’re going to see less resistance or we’re going to see even a different mutational profile that occurs. So whether we’re utilizing combination of chemotherapy and targeted therapies or novel, novel combinations, I think really, really remains to be seen.
Jessica Altman: I also want to piggyback on something that was mentioned previously that not all tyrosine kinase domain mutations at diagnosis are also targeted by midostaurin. There are some TKD mutations that midostaurin is not predicted to hit. For instance, if we’re in a situation where in the future gilteritinib is approved in newly-diagnosed patients, there are a couple TKD mutations that gilt hits that mido doesn’t, and as we have more information, that may be relevant as well.
Naval Daver: Yeah. I think that’s a great point. This is something we’re also very interested in and working on trials with most of you in these settings is how the mutational escape is going to change when you combine these drugs. So if you give ven and gilt or even if you give aza, then gilt, my feeling is you’re going to see a lot of TP53 and these high-risk mutations coming out because you’re going to put a lot of frontline therapeutic pressure. But eventually, probably the leukemia finds a way. So that then brings up the whole question and ideas of, are there optimal sequences for these agents so we don’t put too much therapeutic pressure upfront. But I think this is going to be very exciting going forward.
Jessica Altman: I think the other thing just to stress is that it reminds us that at the time of relapse, we need to re-sequence because you’re right, there may be patients who develop an IDH mutation and that’s something that you can target.
Naval Daver: Yeah. Or BCR ABL. So let me ask, go ahead, Amir.
Amir Fathi: I’m sorry. I was just going to say, I think right now, and I think for the foreseeable future, we will probably have many more targets than drugs for those targets unfortunately. But I do think ideally, in the year, I don’t know, 2040, 2050, we will be in a scenario where we will be monitoring these patients over time with serial checking of mutational profiles and making decisions with probably a variety of targeted agents depending on the patient and their tolerability and the side effect profile of those drugs and try and keep them in remission for as long as possible.
Amir Fathi: I’m not one to subscribe to sort of the comparisons of FLT3 AML with CML. I think as you mentioned Naval, I think it’s a different beast, highly proliferative, much higher capacity for mutational changes on secondary mutations and such. So I think it’s a little bit difficult comparison.
Amir Fathi: The other thing I would just bring up and maybe you were going to allude to it before I interrupted you was, a lot of these patients, I think it does matter in terms of their age and their disease status. If they’re newly-diagnosed, relapsed, young old, because ultimately I think the setting in which these drugs are perhaps, in my view, most potent and most impactful in terms of curative potential is the maintenance setting post-transplant. We will see. Obviously the Phase III randomized gilteritinib study is currently, we don’t have the results for that yet. But it is true that to prevent the onset and development of mutations and the resistance of disease, at this time, we try and get these patients who are eligible for transplants or have not been previously transplanted, at least most of them, to get to transplant and then do maintenance therapy to try and fix them if we can.
Naval Daver: Maintenance, I think, is going to be very interesting. I think that you’re right. I think the question is going to be whether this becomes more like Philadelphia positive ALL, where we found a really amazing drug, at least in our experience, ponatinib, which is fantastic and really just covers pretty much everything, and then you don’t get these escapes. Or whether it’s going to be we are going to sequence, and at least what we’re seeing, because we have a lot of these Phase Ib studies open with quiz and combos and crenolanib, and some of these new FLT3 inhibitors and that we’re getting people with failed mido gilt, and then we’re able to put them on some quiz combos and actually they’re still responding. So we’re kind of getting more into this. There’s no perfect FLT3 inhibitor yet, maybe some of them, but we’re just kind of sequencing them more and more, which I guess is fine as long as you end up improving the survival of the patient. So we’ll see which way it goes.
Naval Daver: But maintenance is I think very important, especially post-transplant. So let me ask Eunice, today for your post-transplant FLT3 mutated patient, are you routinely using maintenance or if not, what parameters guide you and then if you do, what drug are you preferring?
Eunice Wang: So that’s a great question. First of all, we do have a number of patients on upfront clinical trials with a FLT3 inhibitor, and most of those trials include maintenance after transplant as an extension of that upfront trial. For patients who are not on clinical trial, we are advocating that all of them go on a FLT3 inhibitor, and that’s really based on the results of the SORMAIN trial, showing that the addition of sorafenib post-transplant versus no maintenance post-transplant, FLT3 mutant patients did result in a statistically significant improvement in relapse free survival.
Eunice Wang: We typically would at this point favor, given the results of the SORMAIN trial, using sorafenib as our sort of off-label maintenance drug of choice. For patients that were obviously on gilteritinib for relapse/refractory disease prior to an allogeneic stem cell transplantation, as much as feasible we do and again in the absence of a clinical trial, continue the gilteritinib post-transplant. The reasons not to do that would be if they have significant active GvHD. That tends to be the major reason. Now with the introduction of BTK kinase inhibitors, as well as JAK inhibitors for treatment of graft-versus-host disease complications, we’re a little wary about adding a second or third kinase inhibitor to patients that are actively receiving those other kinases, although we have done so, and it does seem to be helpful. But it does require a lot of coordination, at least in our service, between the transplant team and ours to avoid toxicities.
Eunice Wang: If somebody develops, for example, LFT abnormalities, is it due to the post-transplant gilteritinib maintenance or is it due to underlying GvHD? So those issues can complicate it. I think the major question that’s come up over and over, and I know we’ve all had discussions and thoughts about this is, if you put somebody on maintenance post-transplant do you stop after 12 months? Do you continue after that? Because given our experience with the Ph-positive malignancies, sometimes we do stop after 12 months, but I think this is, as you said, a very aggressive malignancy, it mutates, there’s clonal evolution. You talked about single cell sequencing being something to pick out those mutant clones that grow out. Is it safe to stop after 12 months? What about 24 months? I’d be interested to know what my colleagues are doing in that situation with FLT3 inhibitor maintenance.
Naval Daver: Since you had the analogy of Philadelphia Positive ALL. I mean, that’s something that Elias Jabbour and Kantarjian in our group are very, very strong believers that actually indefinite therapy is really the way to go, and this based on data that was shown at ASH last year, where we did have about, I think it was 10 or 12 patients who stopped ponatinib not because we requested it, but because of different reasons, financial, logistical, toxicity in a few of them. We actually found that three of those 12, even after having a median of two years, ponatinib, eventually relapsed at three and four years follow-up time point, which is much lower than the about 5 to 8% we see in people who continue ponatinib indefinitely. So again, small numbers, but based on that, we basically kind of are pushing again to do what we initially would suggest, which is to continue.
Naval Daver: Now FLT3 inhibitors, usually at least two years is kind of been what I tell my patients. And then we’ll see, and haven’t had too many yet on two years because we started this maintenance in the last two years. But what I’m seeing is the patients at least are not pushing at that time to come off. If they’re doing well, they’re on a good dose, gilteritinib is quite well tolerated. Many of them say, “Doc, if there’s any concern, even 2%, why should I take that risk?” So I would say we’re doing it long-term but I think that’s where a single cell sequencing MRD FLT3 PCR may help us. We need to do kind of randomized Phase II approaches where you stop at one year, two years, stop the MRD. But I would say at least two years is kind of what we’re seeing, but I don’t know, Jessica or Amir, what your process has been there.
Jessica Altman: Very similar. I think a lot of it’s dictated by patients. For lack of data, based on some of the other maintenance trials, we’ve stopped at two years. At least we’ve told patients that they can stop at two years. But many patients, if they’re not on a clinical trial and are receiving something outside of a trial, they both choose to stay on.
Amir Fathi: As Eunice was alluding to, I don’t think there is data here to guide us. So we’ve done everything in our group. Everybody kind of does what they want, one year, two year. I personally think that AML is worse than CML. So why would you not continue indefinitely? Especially if the patient is tolerating the treatment. Drugs like gilteritinib, in my view, are very well tolerated usually in terms of long-term maintenance. Sorafenib you can run into some issues as we were just talking about in terms of GvH, skin issues, liver issues, but overall, relatively well tolerated in most. So when possible, I, Amir personally would recommend indefinite treatment.
Naval Daver: Well, I think, we’ll kind of close it out there. I think single-cell sequencing, I’ll just mention something. We’re very interested in and in the future, I think we’re going to see a lot of these trials that are going to target early emergence of clones. Already there are some being designed, and I think it’s going to be very exciting, especially now with venetoclax, IDH inhibitors, FLT3 and how we combine or sequence them. So thank you all so much for joining and look forward to talking to you all soon. Have a great day.