Activity Transcript

Eunice S. Wang, MD: Hello, I'm Eunice Wang, chief of leukemia at the Roswell Park Comprehensive Cancer Center in Buffalo, New York. Welcome to this program, titled Acute Myeloid Leukemia (AML) and the Role of FLT3 Inhibitors: Best Practices for the Interprofessional Care Team. Joining me today are Alexander (Sasha) Perl, who is an associate professor at the University of Pennsylvania Perelman School of Medicine in Philadelphia, Pennsylvania, and Anthony Perissinotti, clinical pharmacist specialist and team leader at the University of Michigan.

Let's begin our discussion with a little background on the treatment of AML and on FLT3-mutated disease in particular. As you know, since its introduction in the early 1970s, the standard of care therapy for AML has been seven days of cytarabine and three days of an anthracycline drug, commonly known as 7+3. For the over 40 years from 1973 all the way to 2017, 7+3 remained the gold standard for treatment of patients with AML. This intensive regimen, however, was associated with significant mortality and morbidity, particularly in the elderly patients who make up the majority of patients diagnosed with this disease. Starting in 2017 up until now, we have had an explosion of novel targeted therapies which are based on the underlying biology and identification of molecular abnormalities in this cancer.

Several gene mutations have now been identified and associated with significantly different prognoses and potential treatment outcomes in patients with AML. Because of the importance of these gene mutations and identifying and selecting the most appropriate and effective treatment options for patients with this cancer, it is now recommended by the NCCN and other panels to perform a standard of care baseline mutational testing in all patients with the new diagnosis of AML. Multiplex gene panels and comprehensive next generation sequencing (NGS) panels are now recommended for selection and ongoing management of these patients. Mutations that need to be tested for in all of these patients include mutations in FLT3, specifically internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations, NPM1, CEBPA, IDH1, IDH2, RUNX1, ASXL1, TP53, BCR-ABL, and PML-RAR alpha. To appropriately stratify therapy options, the test results of molecular and cytogenetic analyses of these immediately actionable genes or chromosome abnormalities should be expedited, and ideally, should be resulted before selection and initiation of any therapy.

In 2022, we saw updates to both the classification of the biology and pathology of AML, as well as updates to the European LeukemiaNet (ELN) recommendations for genetic risk classification of newly diagnosed AML. In particular, we saw that patients who had FLT3 mutations, either ITD or TKD mutations and with or without co-occurring NPM1 mutations, were reclassified in this new system. There is now a three-group classification, rather than the previous four groups. There was elimination of the prognostic or classification importance of high and low FLT3-ITD allelic ratios, with the FLT3-ITD allelic ratios no longer considered part of the risk classification for this disease. This relates to the fact that we do not have a standard method in which to measure FLT3-ITD, and we know that the prognostic and therapeutic implication of having a high or low allelic ratio has not been established in this current era.

I would like to turn to my colleagues, Anthony and Sasha, and ask them what their thoughts are on the impact of this change in how we classify risk factors for AML. Is this important to you? Does this make sense to you? Are you utilizing this in your clinical practice?

Anthony Perissinotti, PharmD, BCOP: Yes, absolutely. For us, this was a welcome change, and functionally actually had no impact for us. If anything, the ELN now better reflects what we have been doing in practice. We always believed the data suggesting the allelic ratio and co-occurring mutations like NPM1 could affect prognosis, but we also understood the limitations of accurately quantifying the allelic ratio, and therefore, what we essentially did was just said, "Everyone that has FLT3-ITD, you need a transplant." We just put these patients into a transplant bucket. So, to us it did not matter whether a patient was intermediate or poor risk, because functionally, it meant that our patients needed a transplant.

Alexander Perl, MD: I would echo everything that Anthony just said. I would say that when we do incorporate a number of agents into the therapy of patients who are FLT3-ITD positive, their outcome really has been much better. We are not seeing as many patients who have relapsed disease, or that is just totally refractory to therapy and hard to get to a transplant. With advanced disease, that used to be quite common before recognizing to give FLT3 inhibitors in the frontline, to make sure patients get aggressive induction chemotherapy and go as quickly as possible to transplant in first complete remission (CR1). We also understand the importance of checking for FLT3 mutations after relapse and to get those patients to transplant in second complete remission (CR2), using FLT3 inhibitors both in frontline therapy and in post-transplant maintenance. I think this has been very important in improving patient survival, and we see a lot fewer relapses from these patients. Outcomes really have been better, so I agree that this lumps better with the intermediate risk group when these patients are treated appropriately, but we do not just give them 7+3 and four cycles of HiDAC, because we see really bad outcomes with that, so you have to treat them appropriately.

Dr Perissinotti: You brought up a really good point about some of the limitations, and one of those is that in the community setting, or even some academic medical centers, they are not always testing for FLT3, especially on relapse. We often get patients, even in the frontline, that come to us for recommendations on transplant, and we say, "Well, I don't know your FLT3 status. I don't even know your cytogenetics." So, I think one limitation we need to continue to educate on is testing, testing, testing, especially in relapse, but of course in the frontline setting.

Dr Perl: I think a polymerase chain reaction (PCR) test at initial diagnosis is really important because you get an answer quickly, and that helps you modify or really refine your induction strategy to include a FLT3 inhibitor on day 8, when we should be giving it, rather than waiting three weeks to find out that the patient could have benefited two weeks ago, had we known the data then, because the NGS takes a really long time to come back.

Dr Wang: Just to highlight that point, I think that now that we have targeted therapies, particularly for example for FLT3 mutant disease, the question comes up whether we can use things like a FLT3 PCR not only to select initial therapy but also to monitor the disease status over time. Additionally, whether we can use this test to determine who needs transplant, what would be the ideal time for transplant, and how long to continue FLT3 inhibitor therapy? I know that there has been recent developments in this regard, with questions about the use of molecular FLT3 analysis with tests such as a highly sensitive PCR or NGS, to detect minimal or measurable residual disease (MRD). Anthony, could you tell us a little bit about whether this is coming to the forefront now? Is this something that in addition to just diagnostically and selection of therapy, this might be something that we could use to guide treatment of these patients?

Dr Perissinotti: Absolutely. I think whether or not it is coming to the forefront clinically right now, it is already live and in action, because the intriguing aspect of this is that ELN recently changed their prognostication of FLT3 mutation-positive AML. One of the reasons they did this was because of the emerging role for MRD, in that MRD can perhaps better prognosticate a patient's risk for relapse and overall survival. This was one of the reasons why they changed their classification, among other many reasons.

There are several different ways that we can quantify or identify MRD. You mentioned PCR. We also have multi-parameter flow cytometry, and of course NGS. Unfortunately, there is not a universally accepted standard, either in clinical trials or clinical practice. I think our European colleagues are a step ahead of us here. At our center, we are not universally checking for MRD. There were some recent intriguing data from the HOVON group that seemed to suggest that NGS could be the way to the future, especially for FLT3-ITDs. It seemed to perform better than the ELN risk stratification, better than flow cytometry, and in fact, better than NGS-based platforms that looked at the co-occurring mutation NPM1.

This group used a platform with a single-amplicon NGS library panel that covered exon 14, and their limit of detection depending on the sample, was anywhere from 10^-4 to 10^-5, or 1 in 10,000 to 1 in 100,000 cells. What they showed was, not surprisingly, MRD is bad. For MRD-positive patients, the 4-year relapse-free survival (RFS) showed that essentially 75% of patients were relapsing at year 4, which is very high. Comparatively, in MRD-negative patients, it definitely discriminates, but still 33% of patients were relapsing, so I think there is still some room for improvement. Clearly, from a prognostic perspective, it is useful I think. I will turn it over to my colleagues, but I think there is still an open question of, can we use it to make treatment decisions? Can we de-escalate therapy? Can we escalate therapy based off of this? These are open questions that I do not have answers to right now.

Dr Wang: I would like to turn to Sasha, and ask if you could review for us some of the data on FLT3 prognoses, and just give us an overview. I think people know that there are FLT3 inhibitors for treatment of this disease, but I know that there are first generation inhibitors and second generation inhibitors, and the way that we are using these inhibitors sometimes can be a little bit confusing in different patient populations. Would you be able to provide an overview to us, and just remind me of the differences between some of these FLT3 inhibitors?

Dr Perl: Let's start with the target itself—FLT3 as a gene. It is a receptor tyrosine kinase, with mutations relatively common in AML. If we look gene by gene, it is the most heavily mutated gene in all of AML by NGS of whole exome or targeted panels, with up to about 35% of patients with newly diagnosed AML having a mutation in FLT3.

There are two major types of FLT3 mutations that we see, and they have somewhat different prognoses. The more common of the two are insertions of FLT3 sequence into the juxtamembrane region, and this is called an internal tandem duplication, or an ITD for short, and these are the ones that when we think of the bad prognosis of FLT3 mutations. This is the group that has been identified as the really high risk group. FLT3-ITD traditionally had been the one that had the shorter CR1 duration, the greater likelihood of relapse, and really aggressive disease if it ever did relapse, and hard to get back into remission or stay in remission with short survival. The second kind of mutation that we would see were tyrosine kinase domain (TKD) mutations, that would activate the kinase, but had probably a weaker role as a driver mutation in AML, and it was less clear that they impacted prognosis alone. They do not fit into the ELN classification in terms of modifying risk at all, and they can be associated with favorable genotypes, such as core binding factor (CBF) rearrangements or NPM1 mutation. We often see FLT3 mutations in patients with diploid karyotype, normal karyotype, and they often are co-mutated with NPM1. They can be associated with acute promyelocytic leukemia (APL), and in that setting they are not at all prognostic and we do not target them with these drugs.

The type of mutation may actually indicate which FLT3 inhibitor is relevant for therapy because there are different chemical classes of inhibitors. Type I inhibitors are active against either the FLT3-ITD or the FLT3-TKD mutations, and type II inhibitors are only active against FLT3-ITD mutation. In fact, a FLT3-TKD mutation can render the patient resistant to type II inhibitors.

So, which are these drugs? Midostaurin and gilteritinib are currently the approved FLT3 inhibitors. These are both type I inhibitors. Included in the FLT3 inhibitors are drugs that happen to hit FLT3 as an off-target effect, and one that is approved and used off-label is sorafenib. Sorafenib really only can be used for patients who are FLT3-ITD positive, and not really for FLT3-TKD, at least when used as a single agent. There are also investigational agents such as quizartinib, that are type II inhibitors.

In terms of prognosis, the FLT3-ITD mutation is one of the more common reasons that patients are referred for transplant. A FLT3-TKD mutation, if it is not associated with NPM1 or core finding factor rearrangement also may be a reason to refer a patient for transplant. Again, both of those mutations can be targeted by the approved drugs midostaurin or gilteritinib.

Dr Wang: Anthony, do you want to tell us a little bit about the differences between midostaurin and gilteritinib, because those are the two FLT3 inhibitors that are really approved right now for clinical practice.

Dr Perissinotti: I think the major take home point is that midostaurin is FDA-approved in combination with intensive chemotherapy, such as 7+3, in the frontline setting. Gilteritinib is approved as a single agent in the relapsed/refractory setting. From a side effect profile, midostaurin, in my practice, can lead to a significant amount of discontinuations because of the GI intolerances, especially nausea and vomiting. This was not really shown in the RATIFY trial, but in clinical practice, it can be very challenging for patients. Gilteritinib, in my practice, tends to be a little bit better tolerated. We certainly have patients that can have some myalgias, and the myelosuppression can be an issue in some, especially because it is administered in the relapsed/refractory setting. We do see elevations in LFT abnormalities. Usually it is a “watchful neglect”, as I like to call it, and I do not hold the drug I just watch patients. We can also see a little bit of differentiation syndrome with gilteritinib.

Dr Wang: Well, now let's take a look at some of the data supporting the use of these FLT3 inhibitors in clinical practice. I would like to start out by discussing a case of a patient, and this patient would be one that we would think would be in general considered fit for intensive chemotherapy, potentially with that 7+3 standard backbone.

This is a 57-year-old gentleman. He presents at a local emergency room or urgent care with progressive fatigue, spontaneous bruising, and bleeding from his gums. He has not seen a doctor for a little while because he has been very busy working, and just has not been able to take a day off, so he appears at the urgent care. They do a quick lab work-up and they discover a white blood cell count of 75,000, hemoglobin of 9 g/dL, and a platelet count of 47,000. However, what triggers a referral to the medical center oncologist is the presence and noting of circulating peripheral blasts. The patient quickly gets transferred to an inpatient center, and is admitted. He receives hydroxyurea, as obviously a white count of 75,000 with circulating blasts is very concerning for clinical diagnoses of hyperleukocytosis. The hematology consult is called, and the patient undergoes a bone marrow biopsy, which reveals AML with 60% myelomonocytic blasts and normal diploid karyotype. The NGS panel then reveals the presence of mutations: NPM1, DMNT3A and FLT3-ITD. So, in thinking about this gentleman, what would be the ideal therapy for this patient, Sasha, based on the clinical evidence to date?

Dr Perl: This is a classic presentation of FLT3-mutated AML, presenting with hyperleukocytosis, very symptomatic, and often these patients go from well to sick really quickly, and their doubling time is fast. This is very typical for what we see in this patient population. I think it is imperative to quickly get these patients diagnosed and on therapy with cytoreduction. Initiation of intensive chemotherapy in a fit patient is what I would typically do. And the standard therapy for these patients is 7 + 3, plus a FLT3 inhibitor.

This was first shown by the RATIFY study, which evaluated the use of midostaurin given for a 14-day course after 7 + 3 therapy in a randomized, placebo controlled trial, in which patients 18 to 59 years of age were screened for the presence of a FLT3 mutation, and if present, they were randomized to either receive midostaurin for a two-week course during up to 2 cycles of induction, and then if in remission, up to 4 cycles of high dose cytarabine plus continued midostaurin, and then a year of maintenance therapy. There was a placebo matching on that study, so the control arm got 7 + 3 plus a placebo.

The study convincingly showed that midostaurin improved the overall survival of these patients. A large number of patients on that study went on to transplant, and if we look at the outcomes from the transplanted patients, the survival was better when censored at the time of transplant. Even when you looked at the transplanted patients, those who went to CR1 transplant and received midostaurin prior to transplant looked like they did even a little bit better than those who had been treated with placebo, so there seems to be an important role for the early initiation of a TKI in frontline intensive therapy. This study convinced the world that FLI3 inhibitors were for real, and they were the preferred therapy.

The question has arisen now that there is more than one FLT3 inhibitor available, what should we be using? We are starting to get data from other trials about other FLT3 inhibitors. Midostaurin really was one of the first FLT3 inhibitors, and it is a relatively weak drug with more limited single agent activity in the relapsed/refractory setting than some of the more recently developed drugs.

One such agent that was recently studied in a similar trial is a drug called quizartinib, which is a more potent FLT3 inhibitor. It is a type II inhibitor, so it is only active against FLT3-ITD positive patients. The QuANTUM-First study was just presented at the European Hematology Association (EHA) meeting, and then updated at the American Society of Hematology (ASH) meeting in 2022, that showed that it had very similar findings in FLT3-ITD-positive patients up to the age of 75 years. So this was a higher risk population, both because it was older than RATIFY and also only included FLT3-ITD positive patients. A statistically significant improvement in overall survival was seen with adding a two-week course of quizartinib to induction, consolidation and maintenance. On that study, if patients went on to transplant, they could restart their quizartinib after transplant and use that as post-transplant maintenance, which has come into vogue in terms of using FLT3 inhibitors of late, which I think we are going to discuss later on.

So, frontline therapy I think is really to do what has been done on these studies, which is to get this patient treated with intensive chemotherapy, to add a FLT3 inhibitor to that, to look to go to transplant, if at all possible, and to look at giving post-transplant maintenance therapy with a FLT3 inhibitor afterwards. I would point out that this patient’s genotype of DNMT3A, NPM1 and FLT3-ITD is actually a relatively common tri-mutation combination that is associated with really dismal prognosis (even though it is NPM1-mutated) and that has come out of studies from several different groups. These patients really do badly if they just get chemotherapy only, and we really need to treat them aggressively, and I really do think these patients do benefit quite a bit from transplant.

Dr Wang: So, just highlighting a couple points. In this particular patient case, I think it would be really important, now that you have started the patient on hydroxyurea, you would recommend, that we should wait for that FLT3 mutation result. We should do FLT3 testing on that patient. Once we get the FLT3 testing, then we initiate therapy, because otherwise we will not know whether to initiate that inhibitor or not, right?

Dr Perl: Yes, that is right.

Dr Wang: In both the RATIFY and the QuANTUM-First trial, the TKI, midostaurin or quizartinib, was started after induction chemotherapy was complete. So, you could theoretically start the 7 + 3 and then get your results back. This would give you enough time to choose the FLT3 inhibitor to be starting after induction, so I think that is an important point I just wanted to highlight once again.

You talked about the QuANTUM-First as well as the RATIFY trials. There were some differences in the patients that were enrolled on those two trials. As you mentioned, quizartinib really is only utilized in patients with FLT3-ITD, right?

Dr Perl: Right, right.

Dr Wang: So that is, I think, an important difference. Anthony, any other differences you would like to highlight between the two trials?

Dr Perissinotti: Yes, and herein is the challenge. We now have two randomized controlled trials of two FLT3 inhibitors. We have never compared them directly, and so I think having to figure out how to operationalize this in practice is going to be challenging. Obviously, it is easy for the FLT3-TKDs. We are going to continue to give them midostaurin, but for the FLT3-ITDs it remains an open question. I think some will say, "Well, because QuANTUM-First included older patients, maybe we should give it to them." But at the same time, the Germans have great data that suggests that midostaurin is safe and effective. We have been using it in clinical practice as well, so I do not know that should be a deciding factor. I am compelled to use the newer, fancier, more potent, more selective FLT3 inhibitor, quizartinib, but I honestly do not know if it is any better than midostaurin. There is certainly prolonged myelosuppression, and QT prolongation that we have to worry about. But here is the thing. Bottom line, if my patient cannot tolerate midostaurin, I think it is going to be nice knowing that we have additional options for patients.

Dr Wang: Sure. And it is important, as Sasha mentioned, that the results of both of these trials is somewhat integrated with the use of transplant in first remission. If you look at least at the RATIFY trial and the QuANTUM-First trial, the standard of care for patients that have this FLT3 mutation with either intermediate or poor risk disease is to go to a transplant in the first remission, in conjunction with a FLT3 inhibitor. This is an important step in trying to cure them. Similarly, as was mentioned previously, it is now considered standard of care to, after a successful allogeneic stem cell transplantation, to utilize or employ some maintenance or post-transplant therapy. Now obviously, waiting for the results of the phase 3 MORPHO trial, where patients with FLT3-mutated disease were randomized to receive gilteritinib or placebo, will be important. We currently have some data, in trials with sorafenib, showing a clear advantage in an improvement in relapse-free and overall survival with incorporation of sorafenib in the post-transplant setting. There are similar data with midostaurin as well.

Now let's turn our attention to talk about older patients. The median age of presentation of AML is 67 to 70 years old. Many of our patients are not going to be fit to receive intensive induction therapy, so what about those patients? So I want to discuss a different case. This is again a man, but could easily be a woman, 70 years of age, with hypertension, hyperlipidemia, has arthritis, and is not very mobile, needing some elective knee surgery. He comes in for a pre-operative analysis and has a CBC done that shows a white count of 3000, hemoglobin of 10.2 g/dL, and a platelet count of 82,000. Looking back at the blood work from a few years ago at his primary care office, this represents a decline. The hemoglobin was 11.5 g/dL a couple years ago, and platelets were 120,000.

Review of the smear does not show that many abnormalities. However, because of the pancytopenia, the patient is referred to a hematologist. A bone marrow biopsy is performed, and low and behold the patient has AML with 25% myeloblasts. Again, a normal karyotype, which is what we see in half of patients that have a new diagnosis of AML. And again, now the presence of a NPM1 and a FLT3-ITD mutation.

This patient, I would argue, could meet the criteria to be considered ineligible. Generally, we tend to have a cutoff of 75 years of age, but certainly there could be patients in their sixties, seventies, or even younger that are considered unfit, based on other criteria, and that generally involves some sort of organ dysfunction, a significant congestive heart failure, cardiomyopathy, for example, with an EF less than 50%, kidney disease, liver disease, lung disease, or even mental health issues. These can all be considered contraindications for somebody to be hospitalized for several weeks to receive an intensive regimen. Other examples are people who have active infections, who have any comorbidities, such as severe uncontrolled diabetes, or other cancer diagnoses, and patients that we generally would feel have performance status issues. There are newer criteria that look at the gait time, whether they can walk across the room in a certain amount of time, so any of these factors that you think make the patient unlikely to benefit from intensive therapy. We do know that the mortality and morbidity with 7 + 3 in patients in their seventies and eighties is upwards of 25% to 30%.

So, what do we do for these older patients? We would offer them lower intensity therapy, and we would test them for the FLT3 mutation. Now, it is less common in older patients than in younger patients with newly diagnosed AML, but a certain percentage will also have FLT3-TKD and/or ITD mutations, so what about the incorporation of a FLT3 inhibitor for these patients?

There was a recently published trial in 2022, the LACEWING trial, which attempted to add the FLT3 inhibitor gilteritinib to standard low intensity therapy with azacitidine, as compared with azacitidine alone in these older, newly diagnosed FLT3-mutated patients who were considered ineligible for intensive chemotherapy. This trial originally looked also at the use of gilteritinib monotherapy in this population, but because of various choices and changes in the standard practice, this third arm was dropped. So this was not a placebo-controlled trial, and it looked at overall survival of patients treated with gilteritinib plus azacitidine, versus azacitidine alone.

This trial did not demonstrate a difference in overall survival between the two groups. However, it did show that patients that had a FLT3-ITD mutation did seem to benefit in terms of overall survival from the addition of a FLT3 inhibitor, and patients particularly with that high allelic ratio, or a higher disease burden with FLT3 may have shown some benefit, as one would anticipate, based on the fact that their disease was more FLT3-dependent.

There was however an improvement in the overall response rate. There was a CRc or composite complete remission rate of about 58%, as compared to 26% in patients getting azacitidine alone. Really, it was pretty well tolerated with no significant differences in the amount of patients getting fevers, diarrhea, or febrile neutropenia as compared to azacitidine alone.

However, there was again this negative, or no difference, in the overall survival. And looking a little bit more closely at those patients, it turns out that gilteritinib was approved for the relapsed/refractory patient population during this trial accrual, and it looked as if half of patients who were in the azacitidine group went off-study and subsequently got some sort of FLT3 inhibitor, and about 20% or 30% actually received gilteritinib after azacitidine. So, that clearly contaminated the results looking at overall survival, and so it is not clear whether this regimen would potentially have been something that we would have been recommending, had we gotten, potentially, a more clean control group, or, potentially, the use of a placebo control as was done in other trials like the upfront AGILE trial of ivosidenib plus azacitidine versus placebo plus azacitidine. Regardless, I am not sure that this is a regimen that I will use right now for my clinical practice, just because of the LACEWING trial data. Anthony and Sasha, do you have any comments on that? And then I would like Sasha to discuss where we are currently using gilteritinib, if not in the upfront setting.

Dr Perissinotti: First of all, a wonderfully conducted trial. I now know the primary author here. In a way, this trial actually confirmed what my practice was, and some of my suspicions. That is, it seems as though we can preserve overall survival if we sequentially use our agents, and potentially prevent concomitant adverse effects from both agents at a time. What I mean by this is that my current practice for these patients is using the combination of azacitidine with venetoclax, followed by, on relapse, gilteritinib. Again, the study showed no overall survival benefit, likely because patients received gilteritinib on relapse. So, that is my practice

Dr Perl: Yes, and my approach has been pretty similar. I think what the LACEWING study unfortunately did not show, an improvement in overall survival compared to an azacitidine alone approach, largely because of the reasons that you mentioned. If you add the drug sequentially, you see that benefit then, so the patients who really are FLT3 driven, they can get that added to their therapy and level the playing field at that point. You do not need to use the drug right from the day of diagnosis, but I think what we are seeing is that with almost any standard therapy, that FLT3 dependency increases over time. Patients who do get venetoclax plus azacitidine in frontline and have FLT3-ITD positive disease unfortunately have a high relapse rate, and a relatively short CR1 duration, and that is a similar story of what happened in the days where we would use chemotherapy alone. I am not all that surprised to see it in this setting.

But that is something that just tells us we need to refine how we are giving frontline therapy, and if azacitidine plus gilteritinib is not the right answer, perhaps a combination of venetoclax plus a FLT3 inhibitor might be better. So we have looked at that, and we started from the idea of using gilteritinib as its initial development as a single agent in the relapsed/refractory setting, and now we are exploring it in a bunch of different areas. Some of these we have already mentioned. We talked about giving it in combination with intensive chemotherapy. That is being looked at in studies right now. They may show the same thing as LACEWING, that it is no better than other FLT3 inhibitors, but we will see. We are waiting for those data, as it is being compared to midostaurin in randomized studies right now as to answer the question of which FLT3 inhibitor to use for fit patients.

A more interesting question, I think for me, is for patients who are not eligible for intensive chemotherapy, how could we move it earlier in the therapy to improve their outcome? Because I think we really do not have a good answer, and many of these patients canot undergo the rigors of transplant, which we said is so important for younger and fitter patients. There has been a lot of interest in combinations of, say, venetoclax plus gilteritinib as a next logical step. We know that gilteritinib being a pill, and generally well tolerated, it has significant activity in a randomized controlled trial against investigators choice of salvage chemotherapy, enrolling both fit and less fit, unfit patients. Gilteritinib outperformed standard chemotherapy in both settings, and when we looked at the subgroups, overall survival was improved by gilteritinib single agent in relapsed/refractory AML with a FLT3 mutation, either ITD or TKD mutation. That is the ADMIRAL study, and we have recently published a long-term follow-up, which confirms an ongoing benefit of the drug, even years after enrollment to the study.

More recently we have looked at combining venetoclax plus gilteritinib in a single arm phase 1b study. That was found to be tolerable, although associated with significant myelosuppression. We needed to often adjust the number of days of venetoclax, and it is not a “set it and forget it” regimen. We have recently published those results, and they are quite promising, particularly in patients with relapse who need a bridge therapy to go to transplant. That was probably the most effective area for that treatment.

Dr Wang: I know that triplet regimens have been studied, and they are currently ongoing, and it is not just gilteritinib, there are also triplet studies with other agents and other hypomethylating agents (HMAs). Anthony, could you talk to us a little bit about some of the other triplet regiments, and whether the results are consistently being seen across the board?

Dr Perissinotti: Absolutely. I think it is important for the audience to remember what our benchmark is. Our benchmark, as we just described, in our current practice is an HMA with venetoclax. When you look at pooled data from the early trials in the VIALE-A study, specifically for our FLT3 subgroup, you see that our CRs and CRis are relatively high, about 70% to 75%, but unfortunately they are not durable. This is especially true for our FLT3-ITD patients.

Unfortunately, with an HMA plus venetoclax doublet, virtually a majority of patients have relapsed and died within a year, so clearly this is an unmet need. I think this has sparked the interest in the triplets. As Dr Perl had mentioned, you have an HMA plus venetoclax with gilteritinib, and you have an HMA plus venetoclax with quizartinib as well. I think across the board, here is the punchline. You are seeing close to 100% response rates, whether that is complete remission, complete remission with incomplete count recovery, or morphologic leukemia free state. But as also described, the myelosuppression can be very challenging. So, for right now, I do not think that these regimens are necessarily ready for primetime. We still need to do some sorting out with regards to what doses we should be using in these combinations? How long should we be continuing these agents? How do we assess early to determine who can stop therapy and wait for count recovery? And lastly, I think it is very important for us to identify whether a sequential approach is better than giving all three up upfront. Would giving HMA plus venetoclax, followed by the FLT3 inhibitor be better and better tolerated, compared to all three at once?

Dr Wang: I think that is a great point. When you look at some of the data from the azacitidine plus venetoclax plus gilteritinib trials, some patients take a median of 40 to 60 days to get full blood cell count recovery. You have to remember, these are not younger, fit patients; these are 60, 70, and 80-year-olds. In some medical centers it is standard to admit people for that length of time. My impression is that that can happen at some centers, but in the world that we live in, where there are a lot of community practices, they are not going to be able to routinely admit patients for 30, 40, or 50 days. And those patients are, even as an outpatient, are going to have a more difficult time to come in every Monday, Wednesday, and Friday to an infusion center. Ny experience has been, a lot of those patients have other things that they want to do with their lives. They have lived seven decades, they have grandchildren, they travel, they have retired. So, I think it takes a village, and I think that we need to carefully look at the pros and cons. I agree with you, sequential doublets, or maybe an induction with a triplet regimen, followed by consolidation with a doublet regimen, followed even by monotherapy with one of the drugs, might be something that we should be looking at on a practical basis. We already have enormous trouble dose adjusting azaciditine plus venetoclax, and then adding the third drug on top I think is really hard to do.

I do not know about you, but in my practice, the ability to maintain and monitor these people really depends on having a team approach, having the pharmacist as my best friend, and nurse practitioners, nurses, the transfusion center, laboratory technicians, and overall my clinic. The interprofessional team approach to manage these complex drugs now, in the outpatient setting, is something that is relatively new. We knew we always had an inpatient component, and I think that is probably why some centers are doing this all inpatient, because it is built into the inpatient setting, but we are almost now having to recreate the inpatient team on an outpatient basis, because these patients require such intensive ambulatory management. Do you both want to comment on your centers about that team approach, or what you do for managing some of these toxicities?

Dr Perl: Yes, I do not think this is easy. I think that this is a hard nut to crack. I think the other thing that we have barely touched upon are the other supportive care issues here, like adding azole antifungals, and the financial toxicity of these very expensive medications, which is also a challenge for patients. It is heartening, however, that we are moving towards more and more oral therapy for AML, I am excited about that. But it makes things very complicated and it puts a lot of onus on patients to manage a lot of things if they are trying to do this on an outpatient basis. I totally agree with you, you need a team approach. I have my pharmacist on speed dial on my phone, because I am constantly referring with them to make sure that I am doing things right. I do this day in and day out and I still have to go over these things and double check myself. I think that is really important. And lastly, this is very specialized, and this is not going to be something that's easily done by the community oncologist in terms of these complicated regimens, potentially fragile patients, and regimens that they are increasingly asked to do in the outpatient setting in a busy practice.

Dr Perissinotti: You both definitely warmed my pharmacist's heart, so thank you. And I completely agree. I think beyond the supportive care aspects that a pharmacist can do, I think we should also challenge our pharmacists, our nurse practitioners and physician assistants to also push the envelope and be a part of treatment decisions. I think they all provide unique perspectives when interpreting data, and how to best apply data for patients, so I think it helps elevate our practice to help us be involved in those treatment decisions. Obviously our bread and butter is drug interactions, and as you mentioned, Dr Perl, azole antifungals are the bane of our existence. Unfortunately we do not have great pharmacokinetic or pharmacodynamic data that actually tell us exactly what to do, so most of us are thoughtfully guessing here. I am happy to be a part of the team, and I agree completely, the interprofessional team is incredibly important.

Dr Wang: I think that FLT3-mutated AML has gone from a poor prognosis, universal death sentence, to something that is actually treatable. With upfront FLT3 inhibitor therapy incorporated into a backbone of intensive therapy, followed by transplant, we are now getting 50% of our patients overall achieving long-term remission with potential cure. In the older patient populations, with triplet therapies, we are seeing a hundred percent response rates, albeit with significant toxicity, and we certainly do need to manage that, but those would have been considered unheard of several years ago. And so, we have seen the improvement in FLT3 inhibitors reflected in the newest classification system for AML, and hopefully the goal will be the next time we have this program that FLT3-mutated AML will be considered a favorable risk category for AML. So, with that, I would like to thank you all for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation. And on behalf of myself and my colleagues, have a great day.

This transcript has been edited for style and clarity.