Dr. Naval G. Daver: So, let me open it up. I mean, obviously, a lot of choice, which is great compared to 10 years ago where we were all a bit depressed and just having to decide the dose of the anthracycline and how to modulate the cytarabine. Now, we actually have a better discussion about what targeted therapy and where to use it. So, let me ask Dr. Fathi and then Dr. Kasner. So, QuANTUM-First, positive, published Lancet data looks good. Quizartinib, yes, I think is tolerability wise a little bit better in my opinion. But what is your approach? Let's say quizartinib gets approved, we hope it will in the next few months. You see a new FLT3 50-year-old patient in your clinic, ITD mutated. What's your process going to- thought process in that patient?

Dr. Amir Fathi: My thought process is always agree with Eunice, that's my though process.


Dr. Naval G. Daver: There we go, easy answer.

Dr. Amir Fathi: Thought process two is right now the quizartinib is not approved, so the choice for that patient who is sure functionally fit is obviously seven and three in midostaurin. I do agree that midostaurin is tough, man. I mean, lots of GI toxicity, lots of nausea, liver enzymes are an issue. So, it is difficult. I probably compared to some of the other folks on this panel have less experience with Quizartinib. And when that- in general, when that happens with these drugs, I'm very eager to start using them, so I gain experience. Because the data that's emerging and has been recently published is very promising in my opinion. And quizartinib is cleaner, it is very potent, more so than midostaurin, and selective. And for an ITD patient, maybe more suitable and maybe something that they can continue to take without constant challenges. Now, one of the things that came up briefly here is much of the success around FLT3 inhibitors is in my view, at least, the duration and longevity of treatment. And in order to have success with these drugs, you need patients to take them. So, if you have drugs that are better tolerated over time and patients can take them and won't have issues with them, I think the chances of longer term success are higher. Of course, we don't have necessarily data to demonstrate quiz versus midostaurin versus gilteritinib quite yet, but we may in time.

Dr. Eunice S. Wang: So, I have a question. So, one of the major- So, would the age of the patient matter? Here this patient is 50 something, but they're 70 some, 71. So, the RATIFY data was only up to 59. So, if the patient was 71, would you prefer more quiz data, be quiz, or did that not make a difference?


Dr. Amir Fathi: It depends how hardcore you are about the rigorous of the data. I'm not that hardcore. So, I actually rely on- I shouldn't probably have said that. But I rely on the biology-

Dr. Naval G. Daver: You're very hard- you're hardcore, Amir's hardcore. We'll get him back to hardcore.


Dr. Amir Fathi: I rely, and I'm sure- I suspect some of you do as well, we rely more on more these days on the biology. So, choosing, for example, a FLT3 inhibitor or maybe CPX versus traditional seven and three. I think most of us would look at a 70-year old who is robust and fit and not worry as much whether they are 60 something or 72.


Dr. Eunice S. Wang: But what about the cardiac toxicity? The one thing with crizotinib is it does have that side effect of the QTC prolonging data.


Dr. Naval G. Daver. So, I'll make a- So, a couple of- One is there is data that they didn't show, and I think that's why people aren't very familiar. But it's in the paper, in the supplement is the age cutoff, so below 60 and 61 to 75. Actually, when you look at that data, I personally am actually very less excited to give anybody intensive chemo FLT3 because the 61 to 75, the median survival is around 14 months. It's not impressive. And the early drop off is very steep, almost 25% die within that first two and a half month-

Dr. Eunice S. Wang: Because of toxicities?

Dr. Naval G. Daver: Just intensive chemo. I think it's just showing, again, that intensive chemo in the older AML population is a tough sell. Even in academic centers, in a clinical trial controlled setting, the early mortality is not that different from a decade ago. It's about 25%, 60 to 80-day mortality. So, I really think that if I had this older patient population, and we'll get into discussion whether you do azifine, you do azifine, gilt, do you sequence them, do you combine them? But I personally am really away from intensive chemo in that population. The other point I think that's very important is that the one thing I really like about the quiz is that when you look at the survival in patients who go to transplant, everybody benefits. With RATIFY, the survival was great. With quiz, the survival is great. But the thing that we saw with quiz that was not seen with the mido was that even in those who don't go to transplant, because the reality is even in ultra-large academic centers, the best we can do is 60, maybe 70% go to transplant. There are always hurdles, logistics, finances, patient choice, donor. But there, quiz showed a benefit in survival in that subset, which was not seen with the midostaurin.

Dr. Eunice S. Wang: That's because the duration.


Dr. Naval G. Daver: That is because of the duration is-

Dr. Margaret T. Kasner: So, that's going to- What I'm really interested in seeing is does the FDA say, as opposed to with midostaurin, we are approving this as kind of a package deal, upfront consolidation maintenance. Because if you pull the data apart, it's not clear-

Dr. Margaret T. Kasner: -how long they really need. But in the non-transplant patients, they do better.


Dr. Margaret T. Kasner: So, they need it- They need it for some duration of time that maybe we can't tell from the quiz. The allo patients, it's not as clear because maybe what they got was enough. Maybe they've got enough FLT3 inhibition plus an allo, and they're all set. But those other patients- And so I'm curious- But I think it will be approved that way, package deal.

Dr. Amir Fathi: A couple of comments. I don't pretend to know something I don't. I mean, I think in general when you look at data, and again, it's hard to look at subsets. And I think in general the survival advantage applied to the group as a whole. And obviously, if we divide them, we may see differences. The other thing I would say is we don't really know the true advantage or disadvantage of midostaurin because many of these patients that we've treated with midostaurin in recent years, I've ended up getting post-transplant maintenance. They end up getting gilteritinib-

Dr. Eunice S. Wang: With gilteritinib. Where I think that data's coming out, I mean, that data-

Dr. Naval G. Daver: We'll get to that, that EHA.

Dr. Amir Fathi: So, EHA. So I think- I agree completely, I think much of the advance and revolution in terms of the therapy of these patients with FLT3 mutations who used to be so ugly- not the patients, the disease- in terms of how people did, it's due to post-transplant maintenance therapy. I mean, I think it's-

Dr. Eunice S. Wang: Well, I think that's part of a whole package. If you are- if you have a FLT3 inhibitor and you can- If a patient's FLT3 mutant, you should add it to every stage of their treatment, the induction through maintenance, if they go to transplant what is your rationale not to do it, is potentially if we have, you know, MRD, that shows us that it's not there anymore.

Videos

Discussion centered around optimal strategies to effectively treat, and improve outcomes for, patients with FLT3-ITD AML.


Optimizing Treatment Selection for Patients with FLT3-ITD AML

Dr. Naval G. Daver: So, then of course getting into the actual treatments and how all of these molecular cytogenetics will help us select these treatments, so we're going to talk about current and emerging frontline treatment options for acute myeloid leukemia. So, I'll start with what we call the patients who are suitable for intensive chemotherapy. I think, to just start with this word fitness, I'm not a big fan of because fitness usually means the patient's fitness who's sitting in front of you. But now we actually know that the biological fitness may actually be more impactful. So, if I have a 40-year-old who's healthy and very robust and fit, but he has a TP53 with a high VF or complex cytogenetics, I don't know if I really want to give intensive chemotherapy to that person. And the same with if I have a 71-year-old, a 72-year-old who has core binding factor or isolated NPM1 and my potential five year cure rate could be 80%, I may actually consider giving intensive chemotherapy. So, I think more and more the mutation cytogenetic or biological suitability of the disease is what many of us are using to determine treatment. Of course, there's always some component of fitness. We would not give an 80-year-old intensive chemotherapy and for younger patient who does not have clearly adverse-


Dr. Amir Fathi: You haven't been to Boston.

Dr. Naval G. Daver: You may not- I don't know what happens in Boston, but yeah. But I think more and more I think the underlying molecular cytogenetics is dovetailing into the decision making. So, what are the standard approaches for fit patients below 60? I think this is where we can really highlight the use of cytogenetic and molecular data. So, we check a FISH for PML-RAR APL. If we find that we're very happy, this is the best subset, not just of leukemia, maybe of all malignancies cure rates above 95%, chemotherapy free ATRA arsenic, that's great. Then we also check a FISH for inversion 16821. This is called a group of core binding factor AML. If we find this, this is where we add gemtuzumab to the induction regimen. And with this, we're seeing close to 80% or greater survival. We don't need transplant for majority of them. So, another good subset that we don't want to miss identifying. If you don't have those, then in parallel, of course, we're sending and waiting for molecular data. The big mutation that is going to change potentially your treatment is FLT3. So, if there's a FLT3 mutation, either ITD or TKD, then incorporating a FLT3 inhibitor. This was already established with a RATIFY phase three study midostaurin. But now there's also data with QuANTUM-First quizartinib that was published recently in the Lancet. And one can debate the different drugs, but it's great to have both the options. Quizartinib is very potent, second generation, drug targets ITD. And then the midostaurin does target ITD as well as TKD. So, we would definitely add a FLT3 inhibitor and consider allogeneic transplant. Just to highlight what Dr. Wang also said that it's very nice that- And actually because of the use of FLT3 inhibitors that we no longer use the ALLELIC burden co-occurring NPM1. If you have a FLT3, all of those are intermediate, use a FLT3 inhibitor to get those people a transplant. It simplifies the trajectory of treatment. And then I think the other one that we do look at, and others I know are also looking at frequently is TP53. So, if you have a TP53 in a younger patient- And with TP53, there is a little bit nuance. Usually, it's patients who have high allelic burden or associated adverse cytogenetics with TP53 that are the real TP53-driven disease. There's about 15, 20% that may just have a low TP53 VAF deployed cyto, we would probably give them intensive chemo. But for the majority, you have a high burden or adverse cyto, we really are moving away from intensive chemo. We would of course like to put a trial, if they have an option, CD47. APR will talk about those. But even if they don't have a trial, we are moving more towards the HMA-VEN based approach, try to get them to transplant without too much toxicity. So, I think that no longer is the frontline standard of care just anthracycline cytarabine for at least 45, 50%. We're doing something different, adding something or switching treatment. At MD Anderson, as many of you know, we are doing a trial where we are using a frontline more intensive regimen of FLAG IDA or CLIA-Venetoclax, which is showing very high responses. And early data looks like it may be improving survival. I think this has to be confirmed in randomized study, and those are being planned. So, that's kind of, I think the way we are looking at younger fit patients. But maybe here, just to kind of turn the question a little bit, and maybe I'll start with you Dr. Kasner, how do you view fitness? Is it similar to what I'm saying or do you look at different factors? What do you do for your patients?

Dr. Margaret T. Kasner: Well, I think that really the complication is that it is the disease that is making patients unfit. Or rather the question is, is it the disease that's making the patient unfit? So, for me, the assessment is what were they like a week ago, a month ago, six months ago? As opposed to a patient who may walk in with a breast cancer and whose performance status, which is what we are really talking about here is in- can be independent from their disease. But here, it really cannot be independent from patient's disease. If they come in with a hemoglobin of 5.5, I also would not be able to walk up the stairs.

Dr. Margaret T. Kasner: And so- and we see this all the time in the trials of patients who are deemed unfit for a transplant, and suddenly treating the disease makes them fit. And so, I think it is a more complicated question in AML than in some other diseases. And for me, it is really an assessment of who they were. But also organ function. So, if their EF is 20%, then no matter how functional they were before they got this disease, I mean, I can't give them the same kind of treatments or offer them potentially a transplant as I would otherwise. So, I do think, yes, it certainly comes into play, their performance status, but not just who they are today or a week ago while they have this acute leukemia. But rather trying to assess what their functional status was some reasonable distance in the past, a few months ago. And sometimes they really are that 72-year-old who was- noticed this when they were out on their 10-mile jog. And so even though they can't walk up the stairs today, that's OK because that's who they were a few months ago.

Dr. Naval G. Daver: And I think that's really important, the dynamic nature of what we use as fitness or performance data because we see this all the time. Even with the HMA-VEN where there were patients who were completely unfit, he's a 69-year-old with pneumonia, creatinine is 2.2, has some bilirubin, fatigued, hemoglobin is low. And you give this patient HMA-VEN or some lower intensity therapy, they go into remission, hemoglobin is good, pneumonia is gone, creatinine normalizes, and that patient will go to transplant. And people say, well, but you said he's unfit, and how can he go to transplant? But we do see this.

Dr. Naval G. Daver: So, I think that one should not make a decision that is going to be pervasive throughout the course of treatment. I think it's a fitness at that point, you choose the best treatment at that point, and then you reassess. And maybe that could be turned into a curative option.

Recommendations for community oncologists concerning the treatment of fit patients diagnosed with AML.

Standard Approach to Treatment for Fit Patients with Newly Diagnosed AML

Dr. Eunice S. Wang: I think some of those genes on those panels actually incorporate inherited predisposition syndromes. And those don't seem very important initially at diagnosis because you're not necessarily going to targetable those. But they become incredibly important for, particularly for those patients with intermediate and adverse risk disease that are going to go on to subsequent allogeneic stem cell transplantation. Because we really want to know, do they have an inheritance syndrome, not only to guide their family members to get additional genetic testing and to identify some of these inherited producers families and clans, but also in terms of planning for transplant in terms of selection of a donor. So that's always something to consider. If you don't have that on your panel, but you are considering a younger patient for transplant, it is probably worth your while if there's a young patient, 30, 40-year-old MDS, AML family, primary history of family members having it or low platelet counts to take that additional step to get the germline testing.

Dr. Naval G. Daver: I think that's something we have at Raheem malignancy clinic, I think other centers are doing similar, where now we're doing more and more germline testing and we are finding germline predisposition that may then change the donor choice. We may be going for a sibling, but now we either have to wait, which could take six to eight weeks to get the germline on the sibling if there is a predisposition found in the patient, or we just go for a match unrelated donor if we can find. So I think this is more like five years ago, I don't think we ever talked about this, but now this is becoming more and more prevalent. So Amir, maybe if you could just talk us through the current NCCN recommendations for molecular testing for the community and others were listening.

Dr. Amir Fathi: I think in general, cytogenetics or FISH, depending on what's available are important in order to identify patients who are favorable risk or adverse risk, but mainly favorable risk because it does impact the choice of treatment for younger patients. Most of us would probably incorporate gemtuzumab, oligomycin in addition to seven and three, and down the road it impacts the choice of consolidation, of course. So cytogenetics is essential for both prognostication as well as choice of treatment. A complex stereotype oftentimes swims in the same lane as a P53 mutation. In general, those patients historically have not done well with honestly anything we have to offer. So some centers, not all, may choose not to go with a very intensive route for patients who have a P53 mutation, although that is still I think open to debate. Mutational testing I think has been mentioned already, by the panel here. You have options, one way is to do PCR testing and generally that's more rapid, can generally get that back in a couple of days, max hopefully. And that can give you information regarding both ITD and TKD-FLT3 mutations as well as an NPM1 mutation, and also the IDH1&2 mutations if that is important. And in older patients, I would argue that certainly IDH1 mutational status is important because you can make the decision regarding azacitidine and ivosidenib, which I assume we will talk about shortly. And FLT3 mutations obviously are also important in terms of choice of treatment, particularly with intensive induction in terms of adding midostaurin and perhaps in the near future, quizartinib as well. I think from my perspective, those are the steps in terms of cytogenetic molecular mutational testing that are essential upfront to get that rapid testing, whether it's by PCR, NGS with those targetable mutations as well as chromosomal data to make decisions regarding treatment.


Dr. Naval G. Daver: So just to wrap up this portion, a lot of times people in the community say, "Well, but is this really practically valuable? What percentage of these patients have this?" So if you take a young patient, if you look for APL core binding factor inversion 6821, FLT3, and TP53, that is about 50% of patients if not more. And these could potentially change your frontline approach, each of these. And then the other mutations may change your approach. Like Dr. Wang was saying, now these splice mutations, AXL1 others may actually start making a thing that this patient may need a transplant where you may initially not have been sure. So I think that this is very real world, this is not just academic centers, academic exercise. It could change 50, 55% of your frontline treatment and then it could also change your transplant decision for another 20, 25%. So I think it's very valuable stuff for us to do.


Dr. Margaret T. Kasner: And I would argue for two other points. One is the only reason we know those things about the slicing mutations is because we've been getting them. And so academics does lead to the real-world, and what was targetable five years ago is very different than what was targetable 10 years ago is just certainly different from what will be targetable five years from now. So even if you are not at an institution where you personally have a trial that might, Dr. Wang's very involved in the MLL and the Menin inhibitors and the MPO1 targeting drugs. And that may not be available at your center, but it may be a referral thing. So you do the testing on your patient, even if you send it and it's back after you started, it doesn't mean it doesn't have value. And unfortunately, the relapse refractory setting is very real for many of our patients. And knowing that about your patient's original leukemia is very important, but also testing at the point of relapse is also very important because they may have been FLT3 when they started and they are no longer, they may not have been FLT3 when they started, and now they are. And so, FLT3 inhibitors weren't in your arsenal for that particular patient, and yet now they're FLT3. So, both having the information about your patient's leukemia and retesting at each relapse, I think is really important.

Dr. Naval G. Daver: I think you bring a very important point, and NCCN does as well as the ELN panel do recommend retesting at the time of initial relapse, especially for targetable mutations, FLT3-IDH1, 2, maybe in the very near future, hopefully so MLL NPM1. So, I think this is also something to highlight. I mean, you're going to-

Dr. Amir Fathi: I just wanted to briefly just echo that both of those actually, I think FLT3 particularly plays a lot of peekaboo, comes and goes. So, I think it's important for us to sort of keep track of it. But it is true also, like for example, the DDX41 mutation, which is a familial predisposition, we didn't really know to sort of test for that or to identify patients. When it showed up in our NGS panel and we started to test for it, all of a sudden, we're starting to detect it. And it's really impactful because siblings can have it, family members can have it, impacts your donor, impacts the choice of how aggressive you want to be. So, certainly these mutations and their discovery and their application, even a little bit further down the road as we're sort of inducing patients, I think is very valuable.

Eunice S. Wang, MD opens a discussion with other panelists concerning the benefits of germline testing in AML, NCCN guidelines for molecular testing, and how molecular testing in AML is advancing over time. 

Clinical Insights Concerning Molecular Testing in Patients Diagnosed with Acute Myeloid Leukemia

Expert Amir Fathi, MD, reviews recent clinical data with ziftomenib in patients with relapsed/refractory acute myeloid leukemia. 

Activity, Tolerability and Resistance Profile of the Menin Inhibitor Ziftomenib in Adults With  Relapsed or Refractory NPM1-Mutated AML

Dr. Naval G. Daver: So in your practice, which mutations are you requesting? Do you get all of them together? Do you get a rapid panel first, then the others later? And then are you doing this all as NGS or do you sometimes for mutations specifically request PCR initially? So when you see a patient, how do these data come to you? And then importantly, what's the turnaround time for these? And which ones can you wait for before starting?

Dr. Eunice S. Wang: Well, that's an excellent question, because I think now in the era of precision targeted therapy for AML, you need to have the data in order to select the therapies. So many panels have been recommending a comprehensive mutational profiling of patients at the time of diagnosis. For example, the ELN 2022 has recently put out new prognostic classification systems that are largely based on cytogenetic and mutational features and incorporate many, many more mutations than we think are probably on most of our panels. For example, they incorporate a whole number of what they call secondary mutations, SRSF2, U2AF, etc., which previously many of us were not looking at because they seem to be just for academic purposes, but now seem to prognosticate and be associated with an adverse outcome. So there are now a number of these mutations which are important for therapeutic purposes. What we have been focusing on our center initially was a rapid heme panel that included NMP1, FLT3, ITD, FLT3-TKD mutations, IDH1, IDH2, also included P53 and KMT2A or MLL. We've now expanded that to a larger panel, including many of these secondary mutations and other mutation types, which probably now incorporates about 75 mutations. So our turnaround time in-house is an admirable three to five days. But many centers still use PCR for FLI3-ITD because patients who have very large internal gen duplications can be missed on a next-gen sequencing panel. So many of us will still do PCR for FLT3-ITD of note, the FLT3- ITD allelic ratio, which was a prognostic category in and of itself for the last European leukemia. Net classification is no longer considered a prognostic factor. So anybody now with FLT3-ITD is considered intermediate risk because of the advances we've made with incorporation of our FLT3 inhibitors. So I think even ideally, the many panels have recommended NCCN, ELN, a turnaround time somewhere in the range of five to seven days. We have three to five days, but we are really encouraging people to use that to better tailor and select therapy for patients.

Dr. Naval G. Daver: That's very impressive. So you get the whole 75 gene panel in three to five days?

Dr. Naval G. Daver: That is really good. So just- at MD Anderson, we do a rapid panel that covers about 10 genes, the ones you mentioned, NPM1, FLT3, TP53, IDH1 and 2, MLL, JAK2, some of those for which targeted therapies are there, those usually come in about three to four days. And then the broader panel, 81 gene panel takes about seven days. So I think that is great. But as you said, I think for most centers and especially community and outside, this is not the reality. I still see a lot of patients coming to us and they've come to me two, three weeks later after their diagnosis and the molecular data is still not available to the referring community doctor or physician. So I think this is one of the big challenges that we are seeing a widening in the gap in the management of AML where the larger academic centers are moving more and more rapidly towards getting the data. But in the community, I think in the last four or five years, I don't know if that timeline has shortened at all. So I think this is one of the big problems. Any thoughts on that?

Dr. Margaret T. Kasner: So I think one of the things that I would talk about frequently is that there was a paper, the abstract was originally published, I think at ASH in 2019. And then subsequently the paper was published that really said, outcomes in AML patients remain equal no matter how long you wait and are better as long as you wait, as long as the patient is stable enough to do so. And we all know that to be the case. And so I think if FLT3-ITD, because your patients are going to present with very high white counts and very sick, those patients need to come to academic centers where it's going to be turnover very quickly. And if ideally I think the most of the panels or most of the guidance is saying seven to 10 days, and ideally it's not taking three weeks, but patients who can wait seven to 10 days are by far going to do better. And actually the BAML trial said the same thing, which is all those patients waited to be categorized. And every patient who either joined BAML or another clinical trial that matched their target did better than patients who got standard of care or supportive care. And so I think the summary version is faster is better, but waiting is best. So if the patient can wait and the data will be available in 10 days, that is the best possible option for the patient. And when they can't wait, which we all know, there are some patients that truly can't wait and they're like five seconds from a ventilator or even on a ventilator, for those patients, we do the best we can.

Dr. Naval G. Daver: And I think that's really important to highlight. Because I think a lot of community and smaller academic or even fellows when you talk to them, this is a different message that was told to us 20 years ago. The motto was the sun should not set on AML. It was like appendicitis. So now I think a lot of times we call people and we say, oh, it's OK, you can wait 10 to 14 days. And I think that is because now we actually have treatments that have a bigger impact on changing the course of the disease than just rushing in with Anthracycline Cytarabine and hoping it works. Now, I do think it's important, like you said, to make sure that the patient is appropriate. Because the study you mentioned, Kristof Roleg [ph] in the German AMLSG group, they published that. But those were all patients who actually made it onto the AMLSG trials. So they were actually patients who were reasonably stable. And I think for 80, 90%, that's probably true. But of course, if you have somebody with the new FLT3 proliferative, you start and then you have to tailor the therapy later to whatever you find is a mutation.

Experienced clinicians highlight the role of biomarker testing in AML for optimal patient care and treatment selection.

An Introduction to Biomarker Testing in Acute Myeloid Leukemia 

Dr. Naval G. Daver: Welcome everyone and thank you for joining me. Today, we're going to discuss recent updates in the treatment of acute myeloid leukemia. We will discuss the data in the context of guidelines, the treatment landscape, and its impact on clinical practice. So let's get started. So the first section we're going to cover is incidence diagnosis and classification of acute myeloid leukemia. So I'll take a start here. We all are aware AML is the most common of acute leukemia is about 20,000 patients or so a year diagnosed with AML. The recent data statistics published in 2022 show that we are making some progress. The survival is now around 32% for five year, but this is still quite dismal. We still need to do a lot of work. And I think there's a lot of importance and focus now being put on understanding the molecular pathogenesis of acute myeloid leukemia. So maybe I'll turn it here to you, Dr. Kasner, to just talk through what you do in your practice when you see a new patient, what are the cytogenetic factors you're looking at and what you expect as the presentation for new AML? 

Dr. Margaret T. Kasner: So that's a big question, right?

Dr. Margaret T. Kasner: Because AML is a broad range of diseases and presentations. We have patients who might present in a more indolent fashion where maybe they saw their primary care doctor even for routine visit without any real symptoms, or some fatigue and have pancytopenia. And on the other side, we have patients who may present acutely ill from any of the complications of AML. So they may have infections, they may have a very high white count that leads to leukostasis. They may have easy bruising or even overt bleeding, all the things that can happen when your white count is too high or low and your hemoglobin is low and your platelets are low. So I think all of them though, in terms of diagnosis, we take a very similar approach, which is that we start with the oldest of the morphology. We look under the microscope to classify the patient, but really flow cytometry. So flow cytometry describes the cells that we're looking at and helps us classify a patient into a myeloid leukemia. And we may be able to sub classify them into a monocytic, but at any rate, that's going to be the first step in our diagnostic process. After that, we're going to be looking for important cytogenetic factors. And some of them, like 15, 17 translocation will put patients in a completely separate type of AML that we treat so differently from what we're going to talk about today. And others may just be, not just, but they may prognosticate for us. So a minus five or a minus seven might tell us, we have a patient with a poor risk. Then things like PCR able, which will also categorize our very initial presentation. Then we're looking at molecular factors. So, FLT3 ITD mutations are sort of its own in terms of testing because they're a PCR-based test as opposed to a genetic panel of molecular tests. And then there's a whole range of genetic things that we look at. I think we're going to get into the molecular biomarker testing in a moment, but I think that's the range of tests that we look at for every patient, no matter how they present.

Dr. Naval G. Daver: So it's a big question, and as we get more and more cytogenetic molecular information, I think we're integrating it more and more into practice. So Dr. Fathi, can you just walk us through the different subtypes of acute myeloid leukemia? What classifications are you using? Are you still focusing on morphology at all in your institution, or is it all now molecular cytogenetic-based when you see a new patient?

Dr. Amir Fathi: I think a lot of this has evolved over time. And broadly speaking, we have become accustomed to categorizing patients according to favorable, intermediate, and adverse risk. And we incorporate chromosomal data as well as mutational data in making those decisions. And that has really carried over the course of the last, I would say, decade. There have been iterations over time in terms of what falls into what category, but generally we do use cytogenetic and molecular features to make those determinations. In our institution, we use all of the above. So we look at the patient, look at their age, look at their comorbidities, we look at AML and whether it's de novo or arose from an antecedent myeloid disorder like MDS or CMML or CML. We look at the cytogenetics. So cytogenetics are quite important. If somebody has a core binding factor alteration, they generally have a better prognosis. If they have something ugly like inversion three or an MLL translocation, they in general have an adverse risk. And many of the alterations fall into the intermediate risk category. And in which group we don't really can establish whether they're more favorable or more adverse, hence the larger category. Mutations, initially we had just FLT3 and NPM1, one was unfavorable, one was favorable. But in recent years, there has been a floodgate opening of all these new mutations that we know about that underpin AML. Some we think are more favorable, some we think are less favorable. So all of this data comes together for us to get a better sense of what the AML looks like. So if you have a younger patient, for example, who has an inversion 16, a core binding factor alteration in general, we feel pretty confident that we can treat those patients with intensive chemotherapy and perhaps consolidate with additional rounds of therapy in an effort to cure them without the need for transplant. Let's say you get an older patient, and I'm just providing examples here, an older patient who has a long history of MDS and after many rounds of treatment for MDS has now progressed to AML. You know you're dealing with a more challenging subtype. Maybe they have a P53 mutation, maybe they have complex carrier type or a deletion seven. Those patients in general are going to have a tougher course, a tougher biology in terms of responsiveness to treatments. So those are important for you to gather together so you can have a good nuanced informative discussion with the patient and come up with a management plan.

Moderator Naval G. Daver, MD introduces expert panelists and leads an overview of Acute Myeloid Leukemia, focusing on the importance of timely diagnosis and risk assessment for patients with AML.  

An Overview of Incidence, Diagnosis, and Subtype Classification in Acute Myeloid Leukemia 

I want to thank all of you for this rich and informative discussion. Before we conclude, I’d like to get final thoughts—a few minutes only, not a dissertation; don’t pretend you’re Harry Erba and go on for a half hour—from each of you on exciting new developments and emerging agents. I’m going to start with Dr. Fathi to discuss what’s exciting him about immunotherapies like ADCs [antibody-drug conjugates], and BiTEs [bispecific T-cell engagers], and things like that.

Just briefly to answer your question, Harry, I think it’s an exciting but early field. There are a whole host of targets that are potentially relevant in AML [acute myeloid leukemia]. The oldest targets are CD33 and maybe CD123. There’s a range of antibodies, antibody-drug conjugates, novel bispecific agents, novel DARTs [dual affinity retargeting molecules], CAR T [chimeric antigen receptor T cell] therapies that are now actually looking at additional targets in addition to those I mentioned, such as CD7.

CD47, a naked antibody, seems to have some legs, at least in combination with hypomethylating therapy in MDS [myelodysplastic syndrome] and in AML. We’ll see ultimately where that data is, but it seems to have some promise potentially in patients who have 

 mutated AML. The surface of the leukemic cell as opposed to the alterations within it may also potentially provide us with novel approaches to treatment.

Thank you. Mark, give us your thoughts about moving the second-generation FLT3 inhibitors in combination with initial intensive chemotherapy.

It’s nice that we have lots of choices but we really need to move into refining what we have and how to use them. Is there an advantage to using a more potent selective inhibitor up front and transitioning to a type 1? Is there a reason to be using maintenance, a FLT3 inhibitor after transplant? In whom and using MRD [minimal residual disease]? In other words, we actually have the drugs, I think. We have to learn how to use them. We have to go back to good old-fashioned discipline and do very careful large-scale trials with very specific molecularly defined questions. There’s still lots of work to do but progress is being made.

Dan, 1 of the most difficult subsets of patients to treat are those with 

-mutated AML. Anything besides 10 days of decitabine out there?

Gosh, I hope so. But you’re right: t’s been a long time, and this has proven to be resistant or refractory to most of what we’ve thrown at it. There’s some hope now. APR246 is something we’ve seen several presentations on, a specific 

-directed therapy for patients with that horrible mutation. Both in MDS and AML, there is some real promise.

The biology of the way that drug works is really exciting and different, and we’re all anxiously awaiting to hear more. Some of the stem cell–directed therapies may have the ability to neutralize, to some degree, 

. When you look at venetoclax combinations, response rates are in the 50% range—lower than non-

-positive patients probably, although statistically we still haven’t quite seen that. But certainly the response durations are not as long for sure with 

-positive patients. But venetoclax is still certainly an option to consider, and then other stem cell–directed therapies. Amir mentioned magrolimab, a CD47 antibody that has some stem cell–directed therapeutic potential, seems to maybe have some activity in the 

-positive subset. Around the corner I’m hopeful this will be something we can work on solving soon.

Thanks, Dan. Gail, you get to talk about the hottest topic that we have right now on our inpatient service, and it’s not COVID-19 [coronavirus disease 2019]. It’s CAR T cells. CAR T cells in AML—is there a future there?

Well, we want there to be a future there. With CAR T cells, the appeal has been, “Hey, wait a minute, that’s curing some people.” So we have cures with CAR T-cells. What can we do to move curative therapy to patients with myeloid disease, patients with AML? Our most powerful immunotherapy is transplant. We cure some patients with transplant, but transplant is a pain. We don’t cure a lot of patients with transplant, so what about CAR T cells? The land of the myeloid hasn’t come to full bloom yet. I’ve been particularly interested, as you know, in looking at allogeneic CAR T cells.

Definitely 1 of the glitches with CAR T cells, which is profound, is that the patient has to be able to hang out until the cells are manufactured, and they also may have some extensively beaten up cells that may or may not survive what’s needed. Neither the patient nor the T cells may be adequate to get them to CAR T. We haven’t had this available for younger patients. It’s not worked in myeloid. What about taking really robust, fantastic cells from somebody else and hitting the right target. We’re looking at CD123, but as was already mentioned, there are numerous targets in AML. What about having those cells eliminate the possibility for graft-vs-host disease? We want to overcome issues of T-cell persistence. But that would be a very hot topic for AML, with at least the allure of potential cure since CAR T cells have cured other patients with other hematologic malignancies.

Thank you again, and thanks to our viewing audience. We hope you found this 

Progress in the Treatment of AML

Gail, a couple of other things that came from the QUAZAR study that caught my attention. Unlike the last German study of 12 months of parenteral azacitidine, where those patients just got induction and then got maintenance or observation, in this study, 80% actually got consolidation. These were correctly treated patients with intensive chemotherapy. But I would also point out that in terms of that transplant option, the median survival was clearly better. But those survival curves, unfortunately, come right back together down around 2 to 4 years. It’s not a very good outcome. I personally wouldn’t replace transplant with this without a properly controlled study showing that.

My final point before I let you jump back in is that I’m really happy to hear you say that your patients tolerated it, because quality-of-life assessments make me a little anxious because I‘m not really a QoL [quality of life] kind of expert. I was worried about the grade 1 GI [gastrointestinal] toxicity, a few more infections, especially in older patients populations. But if you tell me your patients are tolerating it, and that’s New York, so they must be really tolerating it.

A couple of things. First, I definitely agree with you that we are not prepared to say do this instead of transplant. But there are lots of nuggets of interesting things. For example, we know from Chris Hourigan’s data from EHA that if you’re an older patient and you’re going into a reduced-intensity allotransplant with MRD [minimal residual disease], that’s not going to go well. You’re not going to get cured of that. We have some data, both from this study and from others looking at azacitidine that might you be able to reverse MRD. Can you go from MRD positive to MRD negative? We are working on looking at those data.

If you have a patient in their late 60s who would be eligible only for reduced-intensity transplant, who has a significant proportion of MRD, for example, by next generation or by flow, you know that that patient’s outcome in transplant is not going to be what you want. Might you think about a maintenance approach in that patient? Again, these were questions that were not definitively answered by QUAZAR, but in putting together what we know about MRD, about the reduced-intensity transplant option versus a myeloablative transplant option for some of these older patients, it’s thought provoking.

From a quality-of-life perspective, we have to present the data exactly as they are. But let’s look into the nuances of it. First, the quality-of-life measures. We really worked hard on this. There were multiple significant tests. They were done throughout the entire follow-up period, which was long. What we saw on the GI [gastrointestinal] toxicity, it maybe took a couple of cycles for patients to straighten out. If you talk to my patient who’s been on it forever, she’ll tell you, “Oh, on those days, I might take an extra Pepto-Bismol, or I might not eat cheese on those days.” People work out what they need to do to manage the GI toxicity, and then it gets better. If you look at the cycles where it happens, it’s incredibly well managed.

Similarly, and this is not completely clear unless you dig into the weeds, but yes, there is some myelosuppression. But the significant myelosuppression occurred in the study at the time when patients were relapsing from their disease where the toxicities were because there was leukemia there, not so much because of the drug. So I actually was very, very encouraged and reassured that this is a feasible long-term ongoing therapy that doesn’t wreck people’s lives.

Gail, those insights from an investigator on the trial are very important in considering maintenance where we know quality of life is going to be important for these older patients. There were a couple of follow-ups to QUAZAR. One of them was the quality-of-life data that Farhad Ravandi-Kashani presented. The second is that in the study, patients for whom the blast count started to go up between 5% and 15%, they went to a 21-day schedule from 14 days, and about 25% of those patients responded, and their survival looked to be better.

Yeah, there were 3. Ravandi presented, so I presented the quality of life. That’s actually in a talk which is I believe available for eternity on video. Then Farhad did a poster on the patients over 75 years old.

He did a great job. It’s 1 of these interactive posters that I found to be a fun aspect of the virtual meetings. Somehow, when you’re in a poster hall with 9000 people and bad beer, bagels, and stuff, you can’t focus as well as when the author is walking you through it. But he will walk you through that poster if you look at it on the EHA site. You can see that these are older patients. These are exactly the patients you would like not to do a transplant on, and they actually had a survival benefit, tolerated the drug, etc.

The third data set was regarding the salvage option of patients who had from 5% to 15% blasts who look like they were in early relapse, and actually by increasing from 14 to 21 days in those patients, we were able to get some of those patients back on track. That goes along with Uwe Platzbecker and some of the RELAZA2 data suggesting that staving off relapse is a potential concept of application of HMAs [hypomethylating agents]. They were not using CC-486. They were using regular azacitidine in that.

The benefit in survival in the MRD-positive patient subgroup—there’s a lot here. I agree with you: This is going to become a new standard of care. Imagine that, maintenance in AML after all this time. Hints along the way, but you’ve shown it now.

Implications for Treating AML With CC-486

 Gail, you’re going to lead the last section before we get to concluding remarks. I would like to preface this, maybe controversially, by saying maybe this is the next practice-changing thing that’s coming for AML [acute myeloid leukemia]. Tell us about CC-486, also known as oral AZA [azacitidine].

 I don’t think it’s controversial. I’m going to just go out there and say that this is going to be practice changing in AML because I’ve been working for so long that it has to be practice changing in AML, otherwise it will be too depressing. But we had some very gratifying data that were released at ASH [the American Society of Hematology Annual Meeting], and then we had some follow-up data that were presented at the EHA [European Hematology Association Congress] looking at CC-486 in the QUAZAR study. This is an oral formulation of azacitidine. I want to say quickly and out there in front that it’s not just the same thing. It’s not going to be a 1:1 easy substitution, and there’s lots of discussion about where CC-486 could potentially be used instead of currently available formulations of AZA [azacitidine]. But that’s not what this study was.

What this study looked at were patients who were treated with intensive induction chemotherapy, older than 55 years old, who were deemed ineligible for stem cell transplant. Patients were in remission. Patients were in remission, CR [complete response] or CRi [incomplete count recovery], and then they were randomized to CC-486 versus placebo. It’s a clean study, hundreds of patients, international, placebo controlled, all the good stuff. Basically there was a very clear overall survival benefit for the patients treated with CC-486.

Some of the additional data, which were really gratifying, showed, first of all, the patients were in pretty good shape in terms of health-related quality of life when they started the study. They were reporting solid measures of quality of life in remission. For the ongoing therapy, we’re talking 12 cycles of therapy. A lot of these patients were on it for a long time. I actually have the longest patient on it in the United States. I think we’re at 7 years at this point.

These patients were able to maintain their very good quality of life, so this was feasible to administer. It was also feasible and tolerable in older patients, in patients more than 75 years old. For those patients, yes, you can do transplant, but it’s a struggle. A lot of patients over 75 years old don’t want to do a transplant even if they can do it.

Maintenance has not shown an overall survival benefit to date in AML. This is a first. It’s with a tolerable agent. I think it’s going to change practice. It’s going to be stressful initially to figure out who should get this. If the question is, should I not do a transplant, should I get this instead, this study didn’t answer that question. This wasn’t a head-to-head study that do you do maintenance or do you do transplant. But we’re digging very hard into the data to try to answer as many questions as possible about which patients will benefit from maintenance. In combination with other studies that have suggested a maintenance benefit for hypomethylating agents [HMAs], this is suggestive that ongoing treatment with an HMA might be a good thing. After regular chemotherapy, it might be a good thing to have ongoing cycles, for example, of HMA–VEN [venetoclax]. Will you be able to substitute CC-486? I’m not sure.

Of course the post-transplant azacitidine is another interesting area to investigate, since there have been some data suggesting restoration of chimerism and staving off relapse by using azacitidine post-transplant. I find these very encouraging data, very thought provoking, and I can easily envision another decade of study to figure out what we can actually do here.

CC-486 Maintenance Therapy in AML

 Let me, for the sake of time, move on and turn it to gemtuzumab. How do you use gemtuzumab? In June the FDA approved gemtuzumab for pediatric AML [acute myeloid leukemia].

 I didn’t know that. Thank you. I should know that, but I didn’t know that.

 I can’t comment on that, but the answer to your question is that I use gemtuzumab sparingly. The scenario in which I definitively do use it is in patients who have core binding factor AML and who are younger. We know you generally combine that with chemotherapy. One of the challenges with that of course is getting those results back, so you have time enough to incorporate the treatment. But I do use gemtuzumab in that setting. I also use it in consolidation as well in an effort to cure them. In other scenarios, I have not used it in older patients as single therapy. I know it’s approved for use in that setting. I have not used it in intermediate-risk AML.

I have used it a handful of times for relapsed/refractory disease when I don’t have anything else. I have nothing against gemtuzumab, but it’s not the easiest agent to give. There are infusional reactions in patients who have relapsed disease. You have to worry about the history of transplant. You can dose at a lower dose and decrease that risk, but you’ve still got risk. And I’ll be honest with you, the rates of remission, rate of response is very modest, with a high potential for toxicity in certain patients. So my use of gemtuzumab is very low.

 The other place you haven’t mentioned, I’m sure you’ve probably used it here, would be the high-risk APL [acute promyelocytic leukemia] patient. Instead of using an anthracycline, using a single dose of gemtuzumab for a count reduction.

 It’s hard to get around the meta-analysis showing a survival benefit of gemtuzumab when added to chemotherapy. We’re talking over 3300 patients, a subset with core binding factor [CBF] leukemia is clearly doing better. Some have argued that they didn’t do so well with just chemotherapy, but actually core binding factor leukemias, the overall survival is only around 50% to 60% at best without gemtuzumab. In that study, in that meta-analysis, it was in the 75% range. I think there’s something there.

 I actually have been surprised by the seeming lack of knowledge about those particular data. I guess CBF leukemias are rare. People may not see them much, but it’s important to emphasize on a call like this that those are resoundingly positive data. Most of us view the addition of gemtuzumab in the CBF, the core binding factor leukemia scenario, as in fact standard of care. I still get consults for transplant, consults for all kinds of things for CBF patients who have not received those. In particular, when core binding factor leukemias are combined with many other cytogenetic abnormalities and/or a 

 mutation, which are scenarios that happen, those are the particularly confusing ones that then result in, well, does this patient need a transplant? Does this patient need this, that, or the other?

I think we want to keep it pretty pure. If you have a core binding factor patient with or without other cytogenetic abnormalities, with or without 

, you probably do have a good shot of curing that patient with chemotherapy and gemtuzumab without doing a transplant and without switching that patient. We’re asked very frequently, should that patient get 7+3 and midostaurin, or 7+3 and gemtuzumab, or 7+3 and both of those drugs? Mark is here, but I believe the best answer to that is to focus on the core binding factor and not on the 

 We get our FISH [fluorescence in situ hybridization] back for core binding factor within hours, so the GO, gemtuzumab ozogamicin, is already hanging before we know the 

 status. Our usual decision is they’ve had 7+3, they’ve had GO [gemtuzumab ozogamicin], and they say, “What do we do with the 

?” And we often throw it on if the patient is still talking to us.

 I actually think people are much more—it’s somehow much more prominent in their mind to be looking for the 

 FISH [fluorescence in situ hybridization].

 Our algorithm is find that core binding factor fast.

 We have to emphasize that point, that these are your curable patients. These are the ones you want to call.

 Some of your neighbors up there don’t do that, Gail.

 I moved to the Duke University School of Medicine 2 years ago and I’ve taken a little heat for giving GO [gemtuzumab ozogamicin] to the CBF patients as opposed to giving midostaurin alone to those patients if they’re 

 positive. But they’re getting used to me, and I’m hoping they’re not going to kick me out. I kind of like Durham, North Carolina. It’s beautiful here.

Gemtuzumab for AML

 Chemotherapy isn’t dead. It still has a role. CPX-351, the liposomal daunorubicin cytarabine, has been approved by the FDA for patients with secondary AML [acute myeloid leukemia], those who had previous MDS [myelodysplastic syndrome], CMML [chronic myelomonocytic leukemia], patients with de novo AML [acute myeloid leukemia] with complex karyotypes or MDS-like karyotypes, and treatment-related AML. And this was based on a large phase 3 study that actually validated the results of a prior randomized phase 2 study, showing improvement in overall survival but also CR [complete response] rates and not at the cost of higher induction mortality. It was actually lower.

And I think what was most impressive about that report to many of us is that the patients who went on to allogeneic transplant for this very poor-risk AML following CPX-351 had a much better survival than those who went on to allotransplant after 7 and 3. We’re not really sure of the reason for that. It could be that we induced a deeper level of minimal residual disease with CPX-351. It could be that they weren’t as beaten up from CPX-351, but we really don’t know the answer. The question is: What populations are really benefiting?

And I think at the ASH [American Society of Hematology] meeting, R. Coleman Lindsley, MD, PhD, presented data where two-thirds of the patients, we had mutational data, and what he showed was no response benefit, no survival benefit in the 

-mutated patients, which was a third of the population. But in patients with the secondary AML mutational profile, those are both those patients with a spliceosome mutation, chromatin modifiers, and that 1 cohesin mutation, 

, those patients did have an improvement in survival in that subset with CPX-351 versus 7 and 3. But, of course, we have a lot of questions about how to use CPX-351. I want to throw those open to the group. And the most obvious one to start with is: Does anyone use CPX-351, or is everyone giving AZA [azacitidine] or HMA [hypomethylating agent]/venetoclax [VEN] combinations now? Dan is smiling. You’re the first to smile, so you’re on.

 I’m giving a lot more venetoclax combinations to patients that would have probably, in most places or in a recent era, felt to be pretty decent intensive induction chemotherapy candidates. And there’s a variety of reasons for that, and there’s a lot of extrapolation that goes into that. But that has eroded my use of all chemotherapy, including CPX-351. What you brought up about the presentation at ASH [American Society of Hematology] , the Coleman Lindsley presentation, is somewhat concerning because if you are now removing the 

-positive patients from the secondary and treatment-related AML population, you’re starting to leave yourself with very little. There’s not much left if you have to subtract those patients out. And so I think it’s a commentary about disease resistance subtypes against chemotherapy approaches that maybe aren’t so dramatic or set in stone for nonintensive chemotherapy approaches.

 Harry, I would take a stab and say we use about 10:1 HMA/VEN to CPX, if I had to guess.

 So, Mark, as long as you chimed in, let me ask you. So let’s say you have somebody in the labeled indication for CPX-351, a secondary AML, someone who had received an HMA before, even, or a therapy related, and they have a 

 mutation; would that be a patient you would consider CPX-351 with a FLT3 inhibitor?

 When I’m considering CPX, I look at fitness. It’s not a drug for the unfit, even though it sort of has that reputation, uh-uh. You’ve got to be fit enough to tolerate it. And so then it’s on that paradigm, and the AZA, as you know, if they’ve had AZA before, their response to anything is less good. As far as the FLT3 inhibitor goes, no. If they’re fit enough to get CPX, I’m more likely to give 7 and 3 in a FLT3 inhibitor than CPX. We’re doing that trial investigating that.

 I would just bring up the point that we clearly are using a lot more HMA/VEN. But I actually believe in pharmacologic optimization of chemotherapy, and I think that I’m interested in knowing is this better, 7 and 3, and what about younger patients or patients. I mean, most patients with AML are cured with chemotherapy. We haven’t cured anybody yet, really, with the venetoclax-based or IDH-based therapies. We’re doing well, and we want to avoid, we wanted to avoid intensive chemotherapy in those patients to begin with, so we’re excited to be able to do that.

But the question is: Can 7 and 3 be replaced with CPX? And I still wonder about that. Because if it’s just plain better, if it’s better tolerated and sort of better pharmacologically, that’s still an open question that I think we have to study. I definitely feel that we have the over 70 or over 75 in bad shape doing well with HMA/VEN, begs the question that if you’re 62 and in great shape, why can’t that regimen be for you, too? And I think that has shifted the use of HMA/VEN to what is clearly the off-label setting of better patients who could theoretically target, be treated with CPX as an on-label.

 To that point, we would, for the 62-year-old fit enough, we would not offer HMA/VEN; we would offer CPX if they have secondary AML.

 That’s the question that how, exactly, what is the calculus in that, and I think it’s hard sometimes. That’s a little bit in the eye of the beholder.

 And those clinical trials are being designed to look at those fit patients. Because I agree with Mark: CPX-351 still is chemotherapy with a very same profile of toxicities, maybe a little bit less mucosal toxicity but for more prolonged myelosuppression. But let’s come back to the fact Jeffery Lancet, MD, our friend from Moffitt Cancer Center, presented the 5-year update of that phase 3 study. And there’s a true plateau on the survival curve with CPX-351, much above 7 and 3, or double 7 and 3 is what I should say. We have a lot of room for improvement, and I would imagine I think most of those patients out in the tail of the curve were patients who were able to undergo allogeneic transplant. So I use CPX-351 for that fit, younger patient where I know that the goal of therapy is cure, and I’m trying to get them to transplant for a secondary AML or therapy-related AML.

CPX-351 in Newly Diagnosed Secondary AML

 I’ll come back to Courtney DiNardo, MD’s presentation at the randomized phase 2 of an enasidenib and AZA [azacitidine]. The azacitidine arm probably looked good because 20% of those patients got enasidenib. But that’s the only data she had. I wonder how many of those patients actually got venetoclax combinations and did well.

So your point is well taken, Amir, that, you know, I’m not saying that the survival of patients is that AZA alone was going to be 22 months. I’m saying that we now have choices for these patients, and we can add these therapies in.

 But I think it’s worth it to note that we’re probably never going to really know the answer to that study for the exact reason that choices evolved as those studies were trying to accrue. So, I mean, if it becomes really difficult, you have to go outside of the United States to complete the accrual because there was complete contamination with venetoclax. I think it’s just been; I think that those companies have had a very tough time accruing and have definitely broadened the net with respect to participating trial centers.

 Amir, I want to come back to you. You published in 

 the enasidenib experience with differentiation syndrome [DS]. Do you want to talk about IDH DS?

 Thank you, Harry. So we published about 14%, 15% of patients who received enasidenib monotherapy on the original phase 1 dose expansion, dose escalation and dose expansion study.

And so differentiation syndrome in that setting mainly manifested as a vague constellation of symptoms–unexplained fever, respiratory symptoms, pleural effusions, pericardial effusions, rash, mild generally azotemia, boney pains, adenopathy. And we tried to go through every single case that had that constellation. And, as you can imagine in a patient who has AML [acute myeloid leukemia], who is marrow suppressed, who has potential cardiac pulmonary symptoms, it’s difficult to tease out what’s what.

Courtney DiNardo and Stéphane de Botton, MD, we came across approximately 15% or so of patients who we could easily or fairly well rule out other secondary causes of those symptoms and signs and could say that the likelihood of differentiation syndrome was possibly or likely related to the actual process, meaning that the differentiation syndrome was caused by the drug. There wasn’t a secondary cause for those symptoms, that it was related to differentiation syndrome.

Differentiation syndrome can be severe. It can be potentially life threatening, and so our recommendation has generally been that if you suspect it and worry about it, and secondary causes cannot be immediately and quickly ruled out, that you should start treatment with dexamethasone and we recommend 10 mg twice a day. And then once, and if, patients get better, and they should if it is differentiation syndrome, then there should be a tapering down dose over time.

On occasion, differentiation syndrome is accompanied, but not necessarily so, but on occasion it is accompanied by leukocytosis. So hydroxyurea may be necessary if there is concurrent leukocytosis. Similarly, other phenomena can be a co-occurrence such as DIC [disseminated intravascular coagulation], which can be potentially life threatening, as well as tumor lysis syndrome.

So, again, it is hard to necessarily tease out differentiation syndrome in the patients with AML. But when secondary causes are ruled out or cannot be ruled out in a timely manner, I think initiation of steroids is important because these conditions can escalate. And if you look at study after study after study with IDH inhibitors, either as monotherapy or a combination with induction for HMA [hypomethylating agents], you’ll see this weight of approximately 12% to 20% of patients getting differentiation syndrome. So it is a real entity, and it is to give up that closely in patients who get treatment.

One other important point I would just say is that the timing of developing differentiation syndrome can be somewhat delayed as opposed to a differentiation syndrome that you get with ATRA [all-trans retinoic acid]. The differentiation syndrome with IDH inhibitors, typically we found that the median time of loss was around 12 weeks. So anywhere between 10 days to 6 months, you can potentially get it. Especially if you stop treatment and resume it later, you can get recurrent episodes of differentiation syndrome.

 I agree, Amir. A couple other important distinctions between IDH and APL [acute promyelocytic leukemia] differentiation syndrome is 100% of patients with APL who developed differentiation syndrome, if they survive, will achieve a remission. That is not true with the IDH inhibitors. And partly because I think some of these patients really, truly had progression and pneumonia and heart failure and things like that. But also it may be that you’re differentiating 1 clone, but then a 

-positive clone grows out. And so you may see some differentiation.

 I completely agree with Harry on this one. APL is about the cleanest disease that we treat, right? Generally, it’s only 1 alteration that causes the disease. On occasion, you’ll get a 

 mutations, you get the ugly AMLs, but you know, the multiple clones, the other mutations, you might have a potential efficacy. And training the 

-susceptible clone with an IDH inhibitor, that might be why not everybody with treatment with IDH inhibitors gets to the differentiation syndrome and certainly not, well partly the reason why patients don’t respond, some patients don’t respond to IDH inhibitors.

But also keep in mind that about 100% of patients treated with ATRA arsenic trioxide these days also get remission anyway, so… we’re kind of comparing something that is good with something that is outstanding. So it’s a little bit challenging and not perhaps the comparison for IDH Inhibitors.

 Harry, I wanted to jump in with 1 comment that, you know, AML used to be an inpatient disease, right? And now there are lots of aspects of AML therapy that are being handled as an outpatient. And one of the things that we’ve actually worked on with the company is surrounding differentiation syndrome is I think a little bit of patients’ education and advocacy so that they understand, also, this toxicity. Now you have an APL patient coming into the hospital, you’re not necessarily giving them a lecture on differentiation therapy if you’re watching them in the hospital. If they get it, you’ll tell them about it—if they don’t, they don’t.

But a lot of these patients, we were thinking as we were trying to prepare some of the educational materials for patients, they might end up in a local emergency department where somebody has never heard of the medication that they’re on; they don’t know what to look for. And I think that there actually has been an explosion of articles for internal medicine doctors, for emergency department physicians, on various oncologic complications of therapy, both for solid tumor therapies and also increasingly for heme malignancies, to just alert doctors that if you have somebody coming in with leukocytosis and infiltrates, it may not be pneumonia. You might have differentiation. So I just think it was a whole other axis of this particular toxicity to kind of warn the public, if you will, warn the patients, warn so that people were not getting really down the wrong path as they presented to the emergency room.

 Yeah, early intervention with dexamethasone, 10 mg twice daily, is very important, admitting them for monitoring. I will say that I have a dot phrase, a smart phrase in my Epic notes that go into the patient instructions as to when to call, how to monitor their weight, if they’re getting more short of breath. And I talk to my nurses as well. If someone on an IDH inhibitor calls in with shortness of breath, yeah, most leukemia patients, that means you can set them up for a transfusion in a couple days. The IDH inhibitor patient, we need to see. And so there is a lot of education there.

I want to move on to our last topic. So, before I get there, I want to mention a couple of other important toxicities that we do manage with the IDH inhibitors—hyperbilirubinemia is seen with enasidenib. Quite frankly, I don’t do dose adjustments because of hyperbilirubinemia from inhibition of UGT1A1.

 Harry, it’s a measure of patient adherence.

 But it is a mistake to stop the therapy, and I think you want to get that in your smart phrase, which, by the way, please send me because that will save me a lot of work. But I think that point also, you don’t want to stop the effective therapy for an irrelevant bilirubin value.

 QT prolongation has been associated with ivosidenib, and then not many people know this, but in our phase 1 experience, you all may remember Guillain-Barre in 2 out of about 250?

Differentiation Syndrome and IDH Inhibitors in AML

Let me come back to Mark’s point about picking ivosidenib for the previously untreated patient, maybe an older patient who couldn’t tolerate a myelosuppression. How about the patients who’ve had MDS [myelodysplastic syndrome] and been on a hypomethylating agent [HMA]? Is that another niche for the IDH inhibitors?

 So, I can’t comment from trial data. There are trial data looking at, for example, IDH inhibitors, as you know, in MDS. You all have used it; I know you have, I have. And, actually, it works. It’s highly effective. It’s the same disease. Who cares if it’s 9% blasts; it’s going to be the same disease. In fact, my impression is it works a little better than if it’s AML [acute myeloid leukemia]. If you’ve got an 

-mutant high-grade MDS, I love an IDH inhibitor in that setting, to be honest.

 But that’s basically what I’m asking, though. This is an MDS patient progressed to AML, and now you find an 

 mutation. Do you add VEN [venetoclax] to an HMA? Do you add an IDH inhibitor to an HMA?

 No, I would probably go with the IDH inhibitor at that point. That’s been my practice.

 I mean, there are some data that Amer presented at ASH [American Society of Hematology], Amer Zeidan, MBBS, Yale School of Medicine, showing the utility of addition of venetoclax to a hypomethylator failure MDS situation. And they were pretty promising data. It’s still early, but I think it’s a bit of a dealer’s choice at that point.

 Yeah. AZA failed, so then add VEN. IDH failed; add AZA/VEN, it worked great. AZA/VEN failed; add IDH. I mean, we have choices.

 But I want to be very clear about Amer Zeidan’s presentation about adding venetoclax to HMAs, and HMA failure patients who still have MDS. You know what was most impressive to me about those responses that he saw was that these were mostly more marrow CRs [complete responses] with an AML we would call a morphologic leukemia-free-state. In his ECOG presentation, he tried very hard to say that there is some hematologic improvement, which he showed. But I would say that the real benefit there is if you have, these are high-risk patients, right? MDS progressing to AML. Their only long-term outcome is going to be good with, if they undergo allogeneic transplant. So it may be a way of cytoreducing the marrow and making your transplanter happy that the blasts are gone even if the disease isn’t.

 Yeah, I just did it with a guy who failed 3 cycles of AZA who was sent to me; we added VEN. Great; his counts normalized. He looked like he was in CR. The marrow still shows MDS. He’s going to transplant, but this is a high-risk transplant.

 That happens with some frequency, actually. I do think that we should make the point, because you were talking about MDS transformations, there are perhaps a surprising proportion of patients with antecedent MPN [myeloproliferative neoplasms] who also seem to pop an 

 mutation. And those patients have historically been particularly difficult to manage and get into remission. So that’s another scenario where if you have an antecedent MPN, it may be worth it to wait an extra minute and get back your mutation studies.

 Yeah, the responses to the IDH mutant inhibitors in those patients are extraordinary.

 They’re really good. So, yes, that’s a group where other therapies are particularly not good, so there’s no need to rush to launch something ineffective for those patients.

IDH Inhibitors and MDS

 Dan, you published on newly diagnosed patients getting enasidenib. Gail did publish the single-agent IVO [ivosidenib]. Tell us about enasidenib there.

 Yeah. You know, very similar experience, very similar numbers, you know, patients included in that study. Similar sort of a design, in which the patients really came out of the original phase 1 in an arm of patients who had no prior therapy. And very similar outcomes, really, with respect to response rates and survival. So no big surprise there.

 And the responses with both IDH inhibitors seemed to be higher with combination with an HMA [hypomethylating agent] than VEN [venetoclax] alone. So there seems to be something there with that combination in the relapsed/refractory setting and in the newly diagnosed patient population. But I guess 1 of the most interesting things I saw at EHA [European Hematology Association] and ASCO [American Society of Clinical Oncology] was Dr Courtney DiNardo’s presentation on the randomized phase 2 of AZA [azacitidine] alone versus AZA and enasidenib. Higher response rates, but no difference in survival. Getting at what Gail was talking about, we’re starting to see some studies there. These patients are having longer survival than what we expect and have seen before.

 I’ll tell you, though, we haven’t done a good job with the super responders also. And, I mean, Dan and I have been looking at this in some of the data sets. So I actually have on the ENA [enasidenib] single agent, I have the person who would be absolutely the longest. I mean, this is an older patient who was 71. I forget exactly how old he was when he initially went on the trial, was told, “Forget it,” you know, nothing. Five years on single-agent ENA, and now back in remission in a hot minute on AZA/VEN when he relapsed. But the question is: How do we pick; how could we pick the patients who were destined to be those super responders? And this is single-agent initial therapy. So even though you’re absolutely right that the response rates that were just presented for the ENA/AZA were higher, the question is: Some of these patients actually can get single-agent IVO or single-agent ENA and live for a long time on it, but how do we pick them out?

The statement that you were getting to that we’re just getting very good at keeping people alive for longer on azacitidine: I think that that should still be used. Keeping people alive for longer is good. But I absolutely believe that if we could ever study the quality of life, being in remission is better; it has to be better.

 I just wanted to bring up a couple of points that I think are pretty important. One is that if you’re alluding to the abstract presentation from ASCO, I think you’re talking about the one that had 100-something patients who were randomized 2:1. I think we have to keep 68 in 1 arm, 30 patients in the other. The overall survival was, I think, 20 months or 22 months, something like that.

 So, you know, this is not a randomized phase 3 study; we cannot assess, in my view, survival advantage in such a study. And so I worry a little bit about drawing conclusions from that. I do think that HMA plus IDH inhibitor is better tolerated than HMA/VEN, so I agree with Mark. And there are certain patients in whom HMA/IDH inhibitor is the better approach.

But all else being equal, I like to keep my IDH inhibitors in my back pocket because they provide a response rate that approximates relatively the response rate you get in the up-front setting. Meaning the relapsed/refractory patients had a response rate that approximates as monotherapy what you would get in the up-front setting. You know, somewhere in that overall response of 40% to 45%, complete response of around 20% to 25%. That’s what we have generally seen roughly in patients. And because HMA/VEN has such a high response rate, I generally in the younger patient, or the patient who I think can tolerate HMA/VEN, generally go with that first and keep the IDH inhibitor in my back pocket. On occasion, however, if I’m worried about whether a patient may tolerate HMA/IDH inhibitor better, I generally go with that. I’d like to have options so that I can prolong a patient’s survival with sequential therapy. There’s no data, obviously, to guide that, but that’s just been my general approach with these patients.

 When considering how to sequence these agents, HMA/venetoclax versus an IDH inhibitor, let’s remember that the labeled indication for venetoclax is in the treatment-naive older, unfit AML [acute myeloid leukemia] patient. Whereas the labeled indications for the IDH inhibitors were initially, at least, in relapsed/refractory; now, ivosidenib is approved also in the treatment-naїve patient, but if you sequence it with venetoclax first and then the IDH inhibitors, you don’t have to worry about the opposite situation, having to get approval for venetoclax. Having said that, I think most of us on this panel haven’t had much difficulty getting these medications for our patients with AML if they need it. But it is something to consider in terms of the sequencing.

IDH1/2 Inhibitors for AML

 I’m going to have Gail take the lead on this because we’re going to switch gears and talk about the 20% of AML [acute myeloid leukemia] patients that have mutations of 

 Well, the land of IDH, you know, brought us back to all of our nightmares of organic chemistry and Krebs cycle and everybody kind of got through that year where we actually learn this again. And everybody took their medications and learned about IDH inhibitors. Revolution No 1 was the identification of course of the mutations in AML. Then, all of a sudden, wait a minute: AML, relapsed AML, isn’t necessarily completely the land of the lost. We have been suffering so enormously with poor therapies for patients with relapsed AML.

We have been pummeling them for decades with lots of different chemotherapy combinations without success. And then there are data emerging for ivosidenib and for enasidenib: ivosidenib being a potent IDH1 inhibitor, an orally available drug; ivosidenib an orally local inhibitor or mutant 

, showing actually quite high response rates as well as durable remissions, a single-agent, pretty well-tolerated drug in relapsed AML; not curing the patients.

We are not talking years in remission, but we are talking durable remissions in the 6-to-12-month zone, with a single agent. Toxicity profile has been a little bit glitchy for these drugs. You have to watch for differentiation syndrome, which we’ll have to talk about a little bit. You have to look at QT. But basically these are orders of magnitude different from standard chemotherapies. They have better response rates than chemo in these groups, and we thought, “OK, this is huge; let’s move them to the up-front setting.”

So there we also had some interesting data. The ivosidenib trial allowed some patients with newly diagnosed disease to be treated. And actually, there’s the CR-CRH [complete remission and CR with partial hematologic recovery] of about 40% in those patients. Some of those, if you look at the swim plots, were actually durable remissions. These are patients who might not actually have been offered anything. They were the patients that you’re talking about, Harry, who are older and may have fallen into the nihilism trap of, “Oh, you can’t get anything.” And yet here they are in a durable remission. So the data are very similar for enasidenib. So these are single agents that can be used both up front and in relapsed disease to be remitters; they induce remission.

Of course, then the question is: What about combining them with standard chemotherapy? What about combining them with azacitidine? But actually the world was moving at the same time, and what we started seeing as this tremendous success was evolving was that actually venetoclax was particularly affective in the IDH subgroups, in IDH1 and IDH2.

So, this is confusing, and I’m sure you’re going to want to initiate some discussion about this, because now you have choices: “Well, how do I pick a combination of venetoclax and azacitidine, or which ivosidenib and azacitidine, or which 1 if we have a little bit of too many choices?” And I would say the summary that we’ve seen so far out of EHA and out of ASCO [American Society of Clinical Oncology]. So we know that IVO plus azacitidine works. That is an effective regimen for up-front disease.

We think that ENA plus azacitidine might be a little bit less resoundingly good. It didn’t look like there’s a survival benefit over azacitidine alone, but there was still high response rates. So the question on everybody’s mind is: Why would you choose one of those instead of AZA and venetoclax? And I think we can deliberate that a little bit. I think there are individual patient characteristics that may lead to 1 combination versus the other.

But I think the most interesting part is that we were telling everybody, all of us on this call, on this kind of conference—although we didn’t use to use Zoom, but we were all telling people: “Wait, calm down; wait for the mutational profile. AML [acute myeloid leukemia] doesn’t have to be treated for everybody in 5 seconds; let’s apply our inhibitors.” Certainly in the relapsed setting, this is absolutely true, and the last thing we want to be doing is pummeling on chemotherapy.

But in the newly diagnosed patients, I think the question is: Do you wait? Or do you say, “Well, venetoclax kind of fixes everything, and then we’ll see who didn’t get fixed and deal with an inhibitor later.” And I think that’s kind of where we are right now for newly diagnosed patients who are older patients who are not going for intensive induction.

 I might interject, though, that in the really unfit, or the really elderly patients, I kind of want to know if they have an 

Amir Fathi, MD, Massachusetts General Hospital

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