Introduction

DR LOVE: Good afternoon, everyone. I’m Neil Love from Research To Practice and welcome to Year in Review, as today we talk about key presentations and publications over the past year in acute myeloid leukemia and myelodysplastic syndromes.

We have a great faculty today, Dr Dan Pollyea from the University of Colorado and Dr Gail Roboz from the Weill Cornell Medical College in New York.

As always, if you have any question or cases you’d like to run by our faculty, just type them into the chat room.

If you’re into audio programs, we know a lot of people end up listening to these webinars, check out our Oncology Today podcast series, including a program with Dr Michael Savona on myelodysplastic syndromes.

We do webinars all the time now. Next Tuesday, we’re doing one on upper GI cancers with Drs Ilson and Wainberg. On Wednesday, we’re doing a program on diffuse large B-cell lymphoma talking about the big ASH paper on the POLARIX trial, upfront polatuzumab changing the standard of care, maybe. We’re doing a program on B-cell maturation targeted therapy in myeloma on Monday, the 7^th. And then on Wednesday, the 9^th, a program on small cell carcinoma. On Saturday, February 12^th, is our first all-day spectacular. We’re doing 6 webinars in a row. Hopefully, Gail is going to attend and get ready for the boards that she’s going to be taking. We’ve got 12 investigators. We’re going to go through about 20 different tumor types in one day. The following week, we’ll be talking about renal and bladder cancer with Dr Plimack and Powles.

But today, we’re here to talk about AML and MDS. I met with both faculty for the program in the last couple weeks to record their presentations. They’re very comprehensive. They go through in detail lots of slides going through many, many papers in this field that came out. What a great year in these cancer types. But today, we’re really here to take it to the next level, get some of the clinical implications of these data and maybe talk a little bit about where things are heading. So we’re really going to go off the 2 presentations that they did.

Acute Myeloid Leukemia — Daniel A Pollyea, MD, MS

DR LOVE: But I just want to start out first by asking the audience a question. So, audience, I want to know when you entered oncology practice? When did you finish your oncology fellowship? The reason I’m curious about that is we know that there are a lot of millennials who end up using our work. I want to find out how many are on tonight because things have changed a whole lot in AML over the last few years. And actually, if I think back to it, and let me see, do we have the poll answers up here? If you could put those up for me. So reflecting back on when I first started to hear about it was from Dr Rich Stone.

As you may remember, I think AML, to me, really started to change about 5 years ago. There was a paper on sorafenib and then a year later, Dr Stone did a paper, a presentation at ASH and midostaurin became standard of care. But I was doing an interview with him and he started talking about venetoclax/HMA. And I’m like, oh that really sounds encouraging. What do you think? And he goes, well I’m using it. I’m like, really? He’s a very conservative evidence-based doc. I had barely heard about it. And then a few months later, I interviewed Dan and I kind of saw what was really going on. Gail, to me, this is one of the most dramatic changes in our field ever. Any thoughts about for, again, the millennials here, we know about 40% of our audience, in general, has only been in oncology less than 10 years. Can you kind of paint a picture of what things were like kind of before and how that changed? And also, how that changed the involvement of general medical oncologists in community-based practice in terms of AML?

DR ROBOZ: Absolutely. I was having fun watching your video roll before you got started. And first of all, I was seeing all of these mask-less people in ballrooms with other people and I was wondering what planet they were on, but okay. So Rich was my attending when I was an intern. Just putting it that way. And I have known him for ages and ages. And to some of the people on the phone right now, or on the webinar right now, are just not going to understand the wasteland that we’ve been in. So if you go back to 7 + 3, so the biggest paper on 7 + 3 came out my birth year which I will reveal as 1968. That was 7 + 3.

DR LOVE: Wow. You’re a baby.

DR ROBOZ: And that’s what I was talking about straight through until recently. And the answer to every board question and the answer to everything was 7 + 3, 7 + 3, 7 + 3 and it still is today. But venetoclax/HMA has revolutionized therapy. If you look at the last several years though, it’s targeted agents, it’s changed therapy for older patients, but we still have a lot of uncured people out there. And I think Dan and I have a lot to share on this talk today that we still have a lot of work to do. So it’s fantastic and different and better, but we’re not there yet.

DR LOVE: And, Dan, reflecting back on that first — I didn’t know anything about it hardly when I first talked to you and as you got into it, you presented to me, I think, it was an 80-year-old woman who had been in remission for several years and it’s something we never saw before. Before we sort of jump into some of the clinical data, any thoughts about some of the basic research that was done that sort of led up to this and your vision about how venetoclax works, Dan?

DR POLLYEA: Yeah. Thanks, Neil. I think this has been a work in progress for decades and it seems, you know, maybe to some, based on your perspective, to have all happened really, really fast. But BCL2 as a relevant gene was discovered back in the 1980s and it has been decades of work to try to make inhibitors to this and many, many failures along the way. It’s really a pretty incredible story of an entire community working together to change the landscape of this treatment. And so this has been many, many years in progress. One thing that excites me so much about this regimen is its ability to target the stem cell population, the primitive sort of roots of the disease that have been pretty allusive for a really long time. And by having the ability to do that, we can get to deep and durable responses, not for everybody, but for, like you mentioned, for some people. And so I think understanding that mechanism better and more has been a mission of ours and mine here and figuring out other ways to do this to compliment venetoclax or even do it better with other regimens I think is a big focus of ours and should be for the community.

DR LOVE: So one other sort of practical thing before we start going through all these papers and what we’ve learned and where we’re heading. Gail, you were commenting to me, we were chatting before we got started, you know, in terms of this whole issue of having oncologists in community-based practice getting involved with AML which is really a new thing. You were talking about how often you’re hearing from general oncologists asking you questions, so many questions. And I’m curious, what I hear a lot is a lot of questions about cytopenias in AML with HMA/venetoclax. What are some of the common questions you get? And what are your usual answers?

DR ROBOZ: So I would say that we’ve had this tremendous proliferation of drug approvals over the last several years. We hadn’t had anything to talk about and then all of a sudden, we’ve got all these drugs and wait a minute, they’re pills. I can do a pill. And not only that, then we have pills, we have therapy that actually works for older patients and then we have COVID. And you have a perfect storm feeling like, okay, AML has to be treated everywhere. It has to be treated at home. You can’t have people traveling in the middle of a pandemic. And all of a sudden, you have a lot more treatment of AML patients going on. And look, this is a rare disease, the subtypes in particular, if you look at the targeted agents like the IDH inhibitors, these are rare diseases. So you’ve got docs dealing with drugs and patients who are rare patients who are all of a sudden in their practices.

And to be honest with you, these therapies haven’t made AML an easy disease. AML is AML. It’s bad, it’s dangerous, there’s neutropenic fever, there’s cytopenias, you’ve got patients starting off with a platelet count of 2. So they’re not going to be getting better for the next 4, 5, 6 weeks and then there’s myelosuppression, there’s tumor lysis, there’s differentiation syndrome. There are very specific and difficult toxicities that aren’t the usual stuff in a practice because they’re rare. So I would say that people are psyched to use the drugs. They want to keep the patients home. They want to keep them safe, especially during COVID and not have them traveling too much. But there’s not a complete instruction manual despite Dan’s fantastic paper in leukemia and how to actually manage some of these cytopenias and how to change the dose and the schedule. We don’t have the right cookbook which is why I think his and my cellphone keeps going off every 5 seconds.

DR LOVE: And, Dan, another issue is the overall global management of HML. And one other sort of general clinical point I’m curious about where you see it heading is sort of the eligible for intensive chemo, but older. So 60 to 75, for example. I’m starting to hear about the possibility or the thought of using aza/HMA — I’m sorry, ven/HMA in that situation and maybe going to transplant as opposed to 7+3. Any thoughts on that strategy?

DR POLLYEA: Yeah. It’s been interesting to watch. Ever since you spoke to Rich Stone and he told you he was essentially using this off label when it was only approved for CLL, I think the tentacles of venetoclax sort of get in there and they really do get on the ground in practice. It starts to get used in many areas where it’s not on label. And I think when I see that in our country and parts of our country that get more familiar with it and now you can see it more and more around the world. And so I think you’re right. I think that is an area that many of us are reaching for the venetoclax instead of intensive chemotherapy even if a patient technically would be fit for that and know that that’s a very controversial discussion and assessment anyway. And in particular, some of the emerging data that you referenced about outcomes from patients who get into a remission from a venetoclax-based regimen and then move on to a transplant and how they are, you know, that is a practical, feasible strategy that is leading to an early days, early analyses, some good outcomes. I do think that that is going to change, is changing the treatment landscape. And I think it’s going to continue to change in a lot of different ways the way you described, Neil.

DR LOVE: So one more question and, Gail, we’re going to get into specific papers, but here, I’m just kind wanting to get a little bit of a global overview, particularly about ven/HMA because there are just so many questions about it. We’re going to get into the research on MDS. It’s an obvious question. But can you kind of in a capsule sort of tell us where we’re at right now with that strategy in MDS?

DR ROBOZ: So, look, ven/HMA has transformed the standard of care for AML. It has taken patients who have very poor chance of remission and very poor chance of survival beyond 6 or 9 months to crossing not only the sound barrier of the year in 18 months, but actually having MRD negative remissions. There are patients who are being treated who are getting into durable remission with therapy that works in AML who didn’t have that before. So what we want is for that to be in MDS too. And if you look at the path report and you say, oh 15% well that’s almost AML, AML is 20. So if you look hard enough, you can find those blasts. But I think we all know that AML and MDS are just not the same disease. And the cautionary tale is that while I think it’s very clear, and I’ll show some of the data, that response rates are higher with the addition of venetoclax to HMA in many patients with MDS.

What we don’t yet know is, do we have those survival data? We’re waiting. The trial is, thankfully, accrued and we’re going to get those Phase III data. But also, the dose, the schedule, not the same. Even in AML, there’s a lot of backpedaling from the 28 days to the 21 days to in the post-remission setting, things like 14, 10 and 7 days of venetoclax. We don’t want to have crushing cytopenias. In the AML setting, we kind of know how to do this. In MDS though, we don’t know the dose, we don’t know the schedule and I would say that the direct transplant of doing the exact same thing in AML needs more information and more data. We all want this to pan out to be that Phase III survival benefit in MDS because we’re not having it. There are a lot of doublets out there. I’m reporting on yet another unfortunately negative trial in a Phase III in MDS that we wanted to be a positive with the addition of pevonedistat and that didn’t work. So we’re looking for it, but the finish line is not crossed yet.

DR LOVE: All I’m going to say is if you think this is complicated, there’s 5 lines of therapy approved for metastatic bladder cancer so image being a community-based general oncologist. Gail, you better learn that for your boards. There are 2 antibody drug conjugates, Gail, for a metastatic bladder cancer. But anyhow.

DR ROBOZ: I’m terrified. Thank God for your webinars. I am terrified. And I do not know — I have friends and colleagues in general oncology and I tip my hat every single day. I only have to know about a couple of things. I literally don’t know how it’s done. It’s terrifying.

DR POLLYEA: I agree.

DR LOVE: Well I will say one thing. I took the boards 2 years ago just to see what it was like. I didn’t have to. And it’s — everybody was saying our stuff — it’s case-based. It is very, very case-based. Anyhow. Let’s get into some papers. I know we’ll never get through all of these. I’m just going to stop halfway through and flip over to your papers, Gail. But let’s start out with Dan’s. And what I did, in his talk, one of the things that I really liked a lot was he interspersed data slides with sort of conceptual text slides. And I’m going to really emphasize those. So, Dan, do you want to comment a little bit about this issue about MRD negativity in the VIALE-A, the classic trial, looking at azacitidine and venetoclax?

DR POLLYEA: Yeah. So this was from Keith Pratz on behalf of a lot of the VIALE-A investigators, published in JCO. I think we knew from the New England Journal paper that there was a high response rate. We didn’t know what the depth of the response was or could be and that’s why this publication was so important. I think the message that I took away is that a low-intensity regimen, and it depends, we can quibble of how intensive venetoclax is. It’s certainly a lot less intensive than intensive induction chemotherapy. But there is a percentage of patients that can achieve a very deep response. And I think that that translated into a better outcome with respect to survival. So I think MRD is really an important metric in our field because it does translate into better outcomes. And I think the message here is that effective targeted low-intensity regimens can achieve super deep responses. And I think that the important issue going forward is, how do we predict who these people are? How do we take this into standard practice? And we should be looking at this in other fields as well. Gail just published on the ability of patients getting maintenance therapy with oral azacitidine to get into MRD negative remissions. And so we need to all be looking at this, thinking about it, valuing it and not writing it off as a possibility for patients who are not eligible for intensive approaches.

DR LOVE: So, Gail, any thoughts on this? And also, I’m curious about what patients who from their performance status, et cetera, would be eligible for intensive chemo, younger patients, et cetera, where you go to aza/HMA, for example, complex cytogenetics?

DR ROBOZ: Okay. So there were a bunch of questions at the same time in there. I want to make sure that I unpack them. So you brought up the transition zone patients of 60 to 75, but I would expand that a little bit and I would say that AML isn’t an age thing anymore. AML is, what therapy is going to work for you? So I would submit to you that if you have a 29-year-old with a TP53 mutation and 12 cytogenetic abnormalities, that patient can get any kind of therapy and yet we know that our therapies don’t work. So the 60 to 75-year-old group was unpacked a lot at ASH with major datasets including from my group, I am proud to say, looking at some real-world data of giving, for example, CPX-351 as intensive therapy, which is FDA approved for patients with antecedent MDS, bad kind of AML, versus HMA/ven. And how does all of that come out in the wash? So I would say that right now, look at biological fitness. There are certainly rationales to consider the application of non-intensive therapies for patients who could achieve them. It’s a whole topic by itself, but it’s not an age thing and don’t look at age.

The second thing is that intensive versus non-intensive, what’s going to actually work? And what is going to take you to 2 years of disease free survival? So that’s where the whole maintenance thing comes in, right? Because if you get into remission, up until now, if you get into remission, the only that we were doing for anybody who could possibly tolerate it would be a transplant because that was the only way that you were getting to 2 years of any kind of survival. Well not so much now because the oral azacitidine data suggests that if you can’t get a transplant, or if you don’t want one you might also be in this group, there are certain groups who might be able to get to that 2-year and even beyond, there are patients well beyond that, who might not actually need to go on to transplant. The study was for patients who didn’t have the ability to go on to stem cell transplant. So MRD negativity sounds good. It’s important, but it’s not easy in AML. How do you measure it? When do you measure it? With what technique do you measure it? Dan tells me you’re MRD negative after HMA/ven, you’re 82 years old and MRD negative. I’m not exactly sure what that means with respect to overall survival. Does that mean another year or less than a year? We don’t know. So there are a lot of unknown questions and I can dig a lot into MRD, but you’re going to kill me for doing that. So you’ve got to tell me when to stop.

DR LOVE: Okay. That’s good. Really what I wanted to do tonight is just say, well here’s Gail and Dan, I’ll be back in an hour and let the 2 of you talk. But I’ll try to get involved somehow. Anyhow. Dan, another thing you talked about in your talk and I want your thoughts on, when daratumumab came out in myeloma, they were saying, well this is the rituximab of myeloma. So I want to know whether venetoclax is the rituximab of AML because now I see you’re starting to use it in the younger patients with intensive chemo. What have we learned about that so far, Dan?

DR POLLYEA: Yeah. That’s a great, maybe, way to think about it. I think, you know, we have a couple of inside jokes. You’re not relapsed in AML until you’ve relapsed and failed venetoclax. I think we use venetoclax in the relapsed setting and the upfront setting, like we described, kind of off label. So it is extremely pervasive. But strategically, how should we be designing clinical trials and stuff like that? I think we’re getting some early data of a lot of different scenarios. One of which was this MD Anderson experience of looking at their intensive chemotherapy regimen of choice, FLAG-IDA, with venetoclax. And it’s going to be hard without randomized clinical trials, which by the way are ongoing, to really suss out, do you need the venetoclax? Do you need the intensive chemotherapy? What is sort of adding to what? And I think the goal should be to de-intensify regimens if we have really potent therapies that we could add.

And so if we do think intensive chemotherapy to some degree is beneficial with venetoclax, I would hope we could turn down the volume of that, you know, of the intensity of that intensive chemotherapy a bit to allow venetoclax to do its thing. Realistically, everyone’s doing everything right now. And I think there’s a lot of good in that. Every — venetoclax, for whatever reason, preclinically, it looks good with every therapy. So in vitro, venetoclax makes every drug look great. And so that’s caused a lot of excitement and a lot of clinical trials that are ongoing and pairing venetoclax with everything is happening. I’m a little more skeptical that it’s going to go down exactly like that. And I think the bar is going to be high to beat just venetoclax/azacitidine, at least for the so-called unfit newly diagnosed patients without adding a bunch of toxicity. So that’s going to be an important trade off to watch carefully. I think when we see reports at ASH with a few dozen patients with really high response rates, I think that’s great, but we definitely need to see more before this is adopted widespread in practice. And I’m certainly not doing this routinely.

DR LOVE: So, Gail, Dr Malladi in the chat room has a 74-year-old man with a FLT3-TKD who ended up on ven/gilteritinib and developed severe hyponatremia down to 111 requiring hospital admission. Dan typed in the chat room that he hadn’t seen this. Have you seen that with either of these drugs, hyponatremia? Do you ever see hyponatremia for other reasons with AML?

DR ROBOZ: Yeah. There have been reports and I have seen significant orthostatic hypotension. That comes up, but I’ve never seen anybody with hyponatremia like this. And I would actually — anything can happen with anything, but I would be suspicious about what else might have been going on simultaneously with that patient.

DR POLLYEA: Sometimes we see it with aza. I don’t know if you’ve seen that a whole lot, Gail. But I think this was just gilteritinib, not just — gilteritinib and ven.

DR ROBOZ: And ven. Yeah.

DR POLLYEA: Nothing stood out there to me. But I have seen a couple bad cases of hyponatremia with aza for whatever reason.

DR ROBOZ: Yeah. This case, I’m trying to look at you and the camera and the case at the same time. So I don’t know where my eyes are looking right now, but I’m trying to read the case. So the doc wants to know what to do. So the IDH1 is also positive on that patient. So yeah. So there are a lot of options for the treatment of that patient. I would just say out of the gate though that to answer the question that, no, that is not a common toxicity that I have seen. I don’t think I’ve admitted anybody with, I don’t think ever, with a sodium of 111, but certainly not on this regimen and I’ve used a lot of these drugs.

DR LOVE: So hopefully, we’ll get some follow-up in the future from Dr Malladi. So I was about to ask you about a paper you discussed with magrolimab, but I was all excited about Dan and then I saw this press release. I think this was yesterday. I don’t think there’s a whole lot of information in there, but maybe you can just comment on the fact that the magrolimab/azacitidine trials have been put on hold. Not an uncommon thing to see in trials. And, Gail, you’ve been involved with this as well. Any thoughts about this press release?

DR ROBOZ: Sure. Yeah. No. I’m treating patients on the trial. So first of all, I think that if you ask the bankers and the analysts, they got nuts when there are holds. I think studies go on hold because we have to look at safety related issues and I think this is just a look to stop and take a look at safety is what the press release is. I think that it’s always a cautionary tale with new drugs. You’ve got to get — new drugs have new toxicities and have new issues and you have to learn about them. One thing with magrolimab is that CD47, the don’t eat me signal, is highly expressed on red cells and it’s very well-known for CD47 drugs, in general, that they have to be managed carefully because of their on-target red cell activity. You can get hemolytic anemia. It can make it difficult to bank in the blood bank. So these things are known and I think that certainly as this drug moves forward, which we hope and anticipate that it will because it’s looking good in some hard to treat patients, we’re going to need to learn how to manage that and docs are going to have to learn about that specific toxicity.

DR LOVE: Actually, last night on our lung cancer program, Dr Garon from UCLA, we were talking about the antibody drug conjugate, T-DXd, the ILD that was out there, concerns about that. He was saying that when cisplatin came out, people could not give it. It was not deliverable until they figured out how to give fluids, et cetera. So as you say, not uncommon with new drugs. Dan, in terms of what we know about magrolimab, again, I was real excited about what I was seeing with the efficacy there. Of course, we’ll have to see with a Phase III study. But can you talk a little bit more about what we’ve learned about magrolimab in AML, particularly in combination?

DR POLLYEA: Yeah. I think we’ve been really excited about magrolimab for several years. The mechanism is really fascinating. And we, in single arm studies, have been seeing some really promising outcomes. This was sort of a little before venetoclax approval, so a lot of these studies were done with azacitidine or even before that, single agent. We did a single agent magrolimab study for mostly for some relapsed AML patients. I think a couple of exciting signals there. There appears to be some increased, more than expected, activity against the TP53 mutant AML and MDS patients. That is an enormous problem that we face. It’s a subtype of these diseases, these myeloid malignancies, that we have no effective therapies for. So we’re pretty excited to explore that a little bit further and see if that holds up. And then like everything else, could it synergize with the venetoclax/azacitidine regimen or have additive properties there?

I think there’s some reasons to hope that, for instance, upregulation of CD47 with the target of magrolimab by the backbone therapy might allow for some synergy there. So it’s a super rational combination. We saw some early data for it in AML in the upfront and relapsed settings. So these trials are hopefully going to be able to continue soon and we’ll learn more about it. And then like Gail said, any new therapy that we are privileged enough to have comes with new side effects. We’ve got to learn how to manage these. And same thing in the clinical trial setting. And like you were saying, we all learned that the average life of a red blood cell is 120 days and the reason for that is because of CD47. So your body uses CD47 to regulate the lifespan of a red blood cell and knows to take out the old ones. That whole thing is mediated by CD47. So if you’re going to manipulate CD47, you have to account for this. And in the early days, in the clinical trial, this was done by giving smaller priming doses of the drug to prevent a largescale hemolysis. And so we’ll have to see more information, but it may be that that wasn’t done properly or something else to account for some concerns over anemia. But like Gail said, hopefully, we can keep going with this really promising drug.

DR LOVE: So, Gail, I just want to flip over to your talk real quick and we’ll come back to Dan’s because you also talked about magrolimab and azacitidine, this Phase III study. Can you comment on that?

DR ROBOZ: Yeah. I think that we were, you know, you always want more and faster and especially for MDS and especially for TP53. And I think that these were not totally new data that were presented at ASH. So what we are waiting for, obviously, is completed results. But basically, the mechanism of action is here and everybody likes to say don’t eat me signal. So the CD47 action is an interesting one. And we think that, as Dan had mentioned, that there might be specific synergy with azacitidine. But the data here are not totally new. So what we’re seeing in this is just the outline of the trial which is the randomization to placebo plus azacitidine versus magro plus azacitidine. And this isn’t done yet. It has a strong mechanism of action and we’re looking for a little bit more than just the few patients with high response rates that were presented.

The ven which you had moved to a slide of, I think it just goes to show that everybody is trying to combine. So standard of care for myelodysplastic syndrome is azacitidine or decitabine as an HMA backbone and then what can you add to that to make it better? So in AML, you add venetoclax to azacitidine. Aza alone does very poorly in AML. Aza plus ven does great. Can we have that in MDS? Waiting for it. What else can you add to aza? You can add magrolimab. We don’t know what it does yet, but we hope it’s better. You can add pevonedistat. That didn’t make it better. Didn’t hit the OS benefit. And we can add, and I’ll talk about this later if we get to that slide, you can add sabatolimab which has yet another mechanism of action that is interesting. That actually has both an immunologic and an anti-stem cell mechanism of action. Is that going to make aza better? So when you’re thinking about the MDS landscape, we know we have aza. Aza is limited in what it can do for people. It’s way better than doing nothing, but it’s not taking us across that remission or significant move to significant overall survival benefit with adding something else is what we really want from these ongoing Phase IIIs.

DR LOVE: So we picked papers from this past year that we thought are particularly relevant to general medical oncologists who is our primary target audience for our CME work. And, of course, as we’ve been talking about, venetoclax and HMA, a very important topic. But the other thing that’s come out in the last few years that has been so explosive, getting back to my initial conversation with Dr Stone, has been what I would call targeted therapy, particularly FLT3 and IDH. And Dan talked a bit about FLT3 in his talk. Maybe you can kind of go through what your thoughts are in terms of where we are now and where you see things heading, Dan, and what some of the papers are that came out this year that were most important in this arena.

DR POLLYEA: Yeah. So we’ve known about the results of the ADMIRAL study for a couple years now and are fortunate in our field to have a super specific FLT3 inhibitor in gilteritinib for patients in relapsed refractory FLT3 positive AML. And thank God we don’t have to give these patients these horrible, intensive salvage chemotherapy regimens over and over again that just kind of beat our patients to a pulp. It’s so much better, so much nicer to have these much better tolerated therapies. I think what we now know is that there was a nice report at ASH, a large randomized Phase III study very similar to the ADMIRAL study that was conducted in Asia that really recapitulated the results really nicely. So it just gave us more confirmation from another part of the world that we should be doing this over salvage chemotherapy or any other sort of standard of care for these patients.

But I think the other take home message is we’re not doing great with these patients. You can see it’s better than the control, but we’ve got to do better than what we are doing. And then this here shows with a couple extra years follow-up from what Sasha Perl presented, the data hold up in terms of the patients getting gilteritinib do better than those patients getting chemotherapy. This is, I think, with 2 additional years of follow-up. This is from last year’s ASCO. So it persists but, again, pretty dismal long-term survival even with a super specific targeted therapy. So we’ve got to do better. We’ve got to maybe take advantage of other vulnerabilities of these diseases to really move the needle even further. But I’ll tell you, having a pill for these patients to give them a better therapeutic outcome than with making them miserable for a month in the hospital with chemotherapy is really, really advantageous.

DR ROBOZ: Neil, could I add one point to that?

DR LOVE: Sure.

DR ROBOZ: Just because it includes your faculty member on the chat who was bringing up the difficult hyponatremia case. But I wanted to use that just as an excuse to say that all of these data are also bringing to the spotlight rechecking patients and looking for their mutations. And I have had surprise after surprise that FLT3 mutations do pop up. So I think it’s really getting out there that it’s market now. It is standard of care. Check again. I’ve had — it’s not curing everybody. It’s not fixing everything, but it is a huge moment when you pick up that IDH mutation. And don’t forget, audience, when you have those NPMs that are percolating, there are IDH mutations buried in there. There’s IDH1 and 2 in some of the patients who have been sitting around with even an MDS NPM overlap. So searching for the mutation and carving out those patients who can benefit from a much better quality of life on a well-tolerated drug, I think, has been incredibly important.

DR LOVE: So, Dan, when Gail gets ready for the lung cancer part of the boards, of course, she’s going to hear about osimertinib which succeeded gefitinib and erlotinib. And oncologists see a drug like gilteritinib and they want to move it up, cleaner, more effective. Any thoughts about whether that’s going to happen? And also, Dan, the very common question of how you manage patients who are not eligible for intensive chemo with FLT3 alterations.

DR POLLYEA: Yeah. Well as far as the first question, I think we’re doing really well with super specific FLT3 inhibitors. And I don’t know that any sort of better more specific FLT3 inhibitor is exactly what we need. As Gail suggested, because these mutations are a bit transient and can pop up or go away, they also don’t make for the best long-term therapeutic option. And so I hesitate to say that we need to find an even better, even more specific FLT3 inhibitor that that will change things. I worry that the disease being driven by FLT3, we’re doing a pretty good job with these new generation of FLT3 inhibitors and I don’t know how much further we can get with that.

As far as the question as, should we move more specific FLT3 inhibitors up earlier into the treatment process? I do think that that is something that we should be working on. The midostaurin example suggests that that’s the best way to use a FLT3 inhibitor in the newly diagnosed setting with intensive chemotherapy for those patients. And so those studies are ongoing and reading out with drugs like gilteritinib, quizartinib and even maybe crenolanib. A different question though, and thanks for the slide, the cue, what happens if you push a FLT3 inhibitor into the upfront setting for a so-called unfit population? So Eunice Wang showed us with the LACEWING study that she presented that adding gilteritinib plus azacitidine versus azacitidine alone didn’t move the survival needle there. There may have been some explanations for that. It was certainly a better regimen with respect to response. But we don’t necessarily see that same pattern that we saw with midostaurin, for instance, in the RATIFY example and that we hope to see moving more specific therapies upfront and with intensive chemotherapy. So I think it remains to be seen. And then there’s the question, well what about adding it to a venetoclax-based regimen? And we got some data on that as well. I think just very early preliminary sort of suggestions there. I think the principle is strong. I think it’s something we should try to do. I don’t know that we should assume it’s going to move the needle the same way in the unfit population, but I don’t know. Gail, what do you think about the FLT3 opportunities?

DR LOVE: And, Gail, before you comment, can I throw another question on top of that so you can pound up the questions? I think I heard in that case we heard before that the patient had both IDH and FLT3 and I know that’s not rare and I’m curious how you approach those patients. And also, Dan’s question.

DR ROBOZ: Okay. So I’m going to try to hit all of those. So the first thing, the first part of the question is, I think, what makes all of our European colleagues just apoplectic and angry with us all the time because we — I love having all of these choices. I think it’s fantastic. And, yes, I dabble in them. I will confess. But we are making a bit of a mess because the problem is, and MD Anderson is absolutely leading the way in many of these exciting doublets and triplets and quadruplets and quintuplets and whatever, but the problem is that we really, really, really already have a rare population of patients within further rare subsets and we don’t exactly know how to combine all of these things. So I would encourage for right this minute, just coloring within the lines correctly for AML right now really matters for patients and gets them to better outcomes. And if you have 5,000 patents in your practice with colon cancer and 1 with AML, adding on 5 different agents, as Dan was saying, upfront. We know why we’re doing it. We’re doing it because even though azacitidine and venetoclax has very significant benefits across subgroups, there are certain ones, FLT3 mutated patients, TP53, RTK pathway mutations, who we know are not going to have that long-term durable benefit. So we are trying to get into those subgroups and add stuff upfront. We don’t know yet if it works.

That leads to the second part of your question which is that there are co-mutated patients, right? You send your mutation panel in, uh oh, there are a whole bunch of things. What do I do here? So, in general, for the co-mutated patients, I have to say that there is a practice in many cases to throw on the triplet, for example, if you have a concomitant FLT3 mutation or an IDH mutation. And that might be the best thing to do, but it might not. A sequential approach might actually make a lot of sense too. And I think that a lot of practices are working on getting the FLT3 portion under control initially and then seeing what to do with the IDH or even considering an inhibitor for the IDH afterwards rather than the other way around. And that tends to be, if you’re not throwing all of these agents together, the way to go. What I wouldn’t start doing is start taking brand new drugs of azacitidine plus venetoclax plus an IDH inhibitor plus a FLT3 inhibitor and just mixing them all together because we don’t have data to do that, it will be more toxic for the patient and ultimately, it may not solve your problem because you’re just selecting for other clones potentially.

DR LOVE: So here’s a little palate cleanser before we go on to MDS. We’ll just cut the AML in the middle, I think. But, Dan, agree, disagree? With all we’ve learned about the technology of communication as evidenced by what we’re doing right here, it would be really great if there was more connection between docs in practice and investigators managing patients with AML. If I had AML and I was going to be managed in the community, I’d like to at least see that case run by somebody like you all just briefly. And we can do that. Agree or disagree, Dan?

DR POLLYEA: Agree. Agree. I think it’s getting to the point where these therapies, the nuances behind them, I think a patient is best served with having people who’ve had quite a bit of experience with this specific area and at the very least, having a partner at an institution that takes care of high volumes of this relatively rare malignancy, I think, makes a difference. So I totally agree.

DR LOVE: So if anybody out there in the audience has a way to do that, contact me. We’re trying our best anyhow.

Myelodysplastic Syndromes — Gail J Roboz, MD

DR LOVE: Okay, Gail, let’s get into a little bit of — do a tasting in some of the papers in MDS. And this first one, I think, really is important and I want you to go through it. I didn’t put the slides up. I just want you to explain it verbally because it’s so interesting and it seems really relevant, this new prognostic scale.

DR ROBOZ: Absolutely. Look, all of MDS is not the same. You can have a waiting room full of MDS patients and they sit and talk to each other and they come in saying I don’t know what’s going on with that lady, but that’s not what I’ve got at all. So MDS is complicated and I think that docs have gotten used to it and patients have even gotten used to it to use an IPSS calculator. I hope that they’re not using it to tell how long they live because that’s horrible. But what they get used to is that there are certain components. You look at hemoglobin, you look at neutrophils, you look at cytogenetics. And you’re not supposed to use the IPSS to tell you how long you’re going to live, but you are supposed to use it to get a sense of, is this disease going bad like now, tomorrow, in 2 years? Something to put it on the map. And what it doesn’t include at all is, first of all, it is not personalized, it’s not individualized to a patient. What if you’re missing one piece of data, but you have another? And it doesn’t include, most importantly, any mutational data.

So what the paper at ASH, the presentation at ASH, talks about is the IPSS-M or the addition of molecular information to the IPSS. And what the publication is going to result in is going to be actually a web calculator that allows, if you have some missing data, it allows you to put in some mutational information and it actually takes out neutropenia from the equation interestingly. But it’s a new modern way of trying to categorize MDS that I do think is likely to become our way. And I sit down with MDS patients and I plug into the calculator with them. I show them what do I think this is telling, what do I think it’s not telling me. And I think it’s going to be very important to incorporate the mutational data because up until now, we’ve looked at it. You get back a list depending on what center you’re at. You get back 200 mutations. You have all kinds of weird things that you’re trying to explain whether they matter or not. And I think this is going to really help to try to get an assessment for the patient that is, again, more personalized. And this came out for myelofibrosis too, a different type of calculator incorporating mutational information. And I think a lot of the patient advocacy groups have latched onto that to try to educate people about how to use this information.

DR LOVE: And here’s Gail’s summary of this. And please consult her talk as she goes through all the details. Really interesting. Dan, any comments?

DR POLLYEA: I can’t wait for this to be live and for us to be using it. It just gives an extra important degree of granularity to these important decisions and helping patients sort of understand their disease and prognosis. And so I’m really — we’ve been waiting a long time in the field for this and I’m really excited about this.

DR LOVE: I’m looking for a tool that goes through PD-1 levels in upper GI cancers which we’re talking about next Tuesday which suddenly is the most — and, Gail, wait until you get to this for the boards. The most confusing — forget it.

DR ROBOZ: I’m going to need — I will suck in a Valium after this because every single thing about the boards is making it clear that I can’t do this. I don’t know what I’m going to do, but I can’t take this test.

DR LOVE: What kind of PD-1 level you use. Do you go with the FDA approval or do you go with what the investigators say? Anyhow. Jumping back to new papers. You referred to this before, Gail. We won’t spend a whole lot of time talking about it, unfortunately, a negative Phase III study, the PANTHER study. Nice name anyhow. Any comments?

DR ROBOZ: Interesting mechanism. We wanted it to work. It didn’t work in this setting. We’re still trying to figure out what we can learn from it. Big Phase IIIs, you have to do the work and figure out why it didn’t work and what you learn from it. But I have to say, we all have to have the cautionary tale because we want things so badly for this. And it did look really, really good in Phase II. It’s sobering reality in MDS how hard it is to actually move that overall survival needle.

DR LOVE: So, Dan, before we go on with MDS, I was going to ask you before, anything new in AML? And when we were talking about this before, you brought up something that I don’t think many people have heard about. I’ve heard the name. I don’t know too much about it, which is menin inhibitors. What are they? And do you see that maybe potentially coming into practice?

DR POLLYEA: Yeah. In the last couple years, we’ve been hearing more and more. This started many years ago with an attempt to target basically the abnormality that occurs in AML and, frankly, also in ALL around MLL gene rearrangements. We’re not really supposed to call them that anymore. It’s gotten very confusing. KMT2A is now the gene rearrangement we’re supposed — but it’s the same thing as an MLL. But it’s often — these are translocation events between chromosomes. The most common, 9;11, but also other partners can result in this KMT2A or MLL gene rearrangement. And these menin inhibitors are a targeted therapy for this subset of patients. Also, interestingly, it appears that patients with an NPM1 mutation may have a similar mechanism of response to these menin inhibitors. But the last 2 ASHs, we’ve heard some pretty encouraging data in early phase, you know, Phase I, II clinical trials, of these oral therapies for this targeted subset of patients. And so in a field like ours where we have this history of targeting therapies in the past that’s been genomically targeted gene mutations. This is a little bit different now, but it really looks good. And so I think it’s something we should all keep our eyes on. And certainly, if you have a patient with relapsed or refractory AML with one of these abnormalities, these rearrangements, look around to find a place with one of these clinical trials. It’s really become, I think, one of those destination clinical trials that IDH was at one point. It’s a trial probably worth telling a patient considering relocating or traveling to some distance to get because we are pretty excited about what we’re seeing.

DR LOVE: That’s so helpful. It’s so difficult for docs in practice to figure out — sure, trials, you know, mother and apple pie, but there are trials out there looking at things you can’t get in practice that look very exciting. So, Gail, speaking about new things, we were talking about venetoclax/HMA in MDS and there were a bunch of papers you reviewed including this one. What’s your thoughts?

DR ROBOZ: So I think that what we’re trying to glean is we’re trying to see what can we see other than the bottom line Phase III data which we’re waiting for? And I think the point of that paper that I presented was just to, again, refer to broad spectrum activity of the combination across mutational subtypes. Again, this is, we hope, going back to the original mechanism of action which we’ve talked about a little bit here, but looking at the real synergy between venetoclax and azacitidine and hoping that that translates into actually improved outcomes across molecular subtypes. And it does seem that there are a variety of cytogenetic subtypes and molecular subtypes that are of benefit. We’ll wait and see what the overall survival benefit is which is what this cue slide was kind of looking at. So Rami was looking at his center, what does this look like? And he was basically saying that you have the increased response rates, it looks good, we want this to be good, it might prolong OS, but we’ve got to get there. So I think all of these data are, again, they are both — it’s hard. I guess it’s hard being in practice and listening to this because I’m saying X and the opposite of X. I am saying this looks encouraging, this looks promising, there’s a lot of rationale to imagine that venetoclax plus aza is going to be better in MDS, but I’m also saying in the same sentence, we don’t know that yet. And I just presented a Phase III trial that really looked good in Phase II that didn’t cross the overall survival finish line. So I have to watch that myself that we don’t get too caught up in our initial enthusiasm because it doesn’t always pan out the way we want it to.

DR LOVE: Dan, a very common question from oncologists is the management of a patient who starts out with high-risk MDS, develops AML while on a hypomethylating agent. There are docs who will add in venetoclax. I’ve heard people talk about low-dose Ara-C and venetoclax. How do you think that through, Dan?

DR POLLYEA: Yeah. That’s right. I think adding venetoclax to a backbone therapy is the right way to go there. Those patients, unfortunately, have worse outcomes and it may be because they just have more aggressive disease and it may be because they have been previously treated with an HMA and that sort of does something to the disease to make it respond less well. But regardless, I think, my practice there is to continue their HMA and add venetoclax. But a person who was a real student of the data, they could tell you that the VIALE-A study that used azacitidine excluded a patient such as this who had prior exposure to an HMA and then evolved to AML. And so when you look at the VIALE-A study, you won’t see any patients like that represented whereas alternatively, the VIALE-C study, another randomized study, that looked at low-dose cytarabine plus venetoclax versus low-dose cytarabine alone, it did include those patients. And so you could have a better estimate of how your patient is going to do by looking at that data and giving them the low-dose cytarabine. In practice, we just find it very difficult to get low-dose cytarabine and we just have less experience with it and so I think those are barriers or limitations for us. You’d certainly be well within your rights and, in fact, probably a connoisseur of the data to go that direction, but I think most of us, we’ll just continue the HMA and add venetoclax, but have lower expectations than what VIALE-A shows us in that setting.

DR LOVE: Gail, second opinion on how you manage this situation? But also, what are some of the trials out there that a patient like this might be eligible for that you’d be excited about?

DR ROBOZ: Unfortunately, if you’ve had a lot of cycles of an HMA, that is just not good news with respect to the initial ability to get into remission and then what happens afterwards. What you have to do is look at, first of all, look at the patient again. Say, did this AML take off? Do I have 100,000 white count now? What am I dealing with clinically? And what is going to be feasible for this patient? So do I have an MDS patient who had therapy-related MDS as a 40-something-year-old and transformed quickly? Do I have — am I dealing with someone who is frail and older? So all of those clinical questions are going to go into guiding this. I actually ran the, at our site, the subQ cytarabine plus ven — when all of the ven trials were going on and it was HMA/ven, we did the Ara-C one. We were on that one. And part of that was I had had a ton of experience with low-dose Ara-C in lots of other trials that I ran a long time ago with things like arsenic and other stuff that we were playing with a long time ago. So I do use that and I do have experience with that. And it is a headache to get, but we kind of know how to get it. And there sometimes is a rationale for patients who might have had a zillion cycles of an HMA prior to the transformation to switch to Ara-C, again, not with great hope, but with a little bit feeling better that I’m not just giving the same thing all over again.

DR LOVE: So, Dan, in a second, I’m going to ask Gail to comment on a paper in low-risk MDS with oral decitabine, but before that, I’m just curious, I get this question from oncologists in the age where we’re very sensitive about oral versus bringing people in, the idea of oral HMA, either decitabine/cedazuridine or oral azacitidine, CC-486, used in maintenance therapy. Outside of a trial setting, would you ever use that strategy at this point, Dan?

DR POLLYEA: Well oral decitabine is an approved therapy and it’s been shown with pretty strenuous parameters to be equivalent to IV decitabine and I think it’s great and I think it’s preferred and I think it’s better for quality of life, et cetera, et cetera. It’s the same drug. You’ve got to monitor it the same way. You can’t be cavalier about it, but absolutely 100% I really would prefer that in any place that I’m going to use an HMA. Oral azacitidine is very different. I think it’s an important distinction for people to understand. Although approved, it is approved in a very different situation. It has not been shown to be equivalent across the board with conventional azacitidine and so you cannot substitute it out anytime you would use conventional azacitidine the way you might do with decitabine. So it’s a really important distinction. It’s not just off label to do that. It’s really — you’re going way off the map there. If you want an oral HMA, decitabine is available. And we’ll have to wait and see if azacitidine has similar equivalence in the oral formulation. But I think moving these to oral therapies is really, really, really great and I enjoy having that option for patients.

DR LOVE: Any comment, Gail? And also, anything you want to add on about CC-486 in terms of maintenance therapy? Any misperceptions? We don’t have any papers in here, but just any thoughts about it?

DR ROBOZ: So yeah. I would say that, in general, patients’ and doctors’ brains are exploding about the fact that, well wait a minute, so there’s an oral decitabine that is the same as decitabine, but there’s an oral azacitidine that isn’t the same as regular azacitidine. Is that just the doctors being a pain in the neck about it and everything is all the same? And Dan’s right and they’re not. So oral decitabine and IV decitabine, PK, PD, are the same and they can be interchanged. I have a lot of experience with those. I have patients who absolutely love being on the oral and not trekking in whether in the middle of Omicron or not. But they’re the same, but they’re different. And there are patients, for example, I have on the IV who never take an antiemetic or any type of stomach anything and on the oral, they might need to. So, again, it’s different perhaps from an individual clinical profile and side effect management might be different, but the drugs are the same.

Oral azacitidine is FDA approved in a very specific setting currently which is the clinical trial was of patients older than 55 with AML in remission who, for whatever reason, couldn’t go on to a transplant. So this was not a randomized trial of transplant versus maintenance. This was people who were not getting a transplant who either got oral azacitidine or a placebo. And the oral aza is better and it is approved in that setting. And I think the main thing to think about there is in the academic medicine talks, everybody says, well we transplant all of those patients. Well, actually, no you don’t because a lot of patients can’t get a transplant for a variety of different reasons. They don’t want it, they don’t have a caretaker for their child, they don’t have the financial resources. So now there is an option that is getting patients better overall and relapse free survival with a maintenance agent.

So I’m not advocating against transplant, I’m just, you know, we have to look closely at our patients because it just isn’t true that absolutely everybody who is supposed to get a transplant gets one. Furthermore, there are patients who are on the margin where you sort of would be wanting to push them on to a transplant, but they have something about them that you’re worried about, maybe they won’t tolerate it well. And now, you’re looking at the CC-486 data, the oral aza data, and saying, hey, wait a minute. This patient has a really good chance of getting to 2 years of disease free survival if I do this pill and has a really high potentially nonrelapsed mortality of transplant for this reason or that. It’s something to think about. And I think that oral agents, in general, are terrific, but I always caution people, patients can barely take azithromycin, okay? It is confusing, confusing and hard to go home on venetoclax, posaconazole, valacyclovir, levofloxacin, all your antihypertensives, all your glucosamine chondroitin or whatever you’re taking for your drugs. So we say oral is great and it’s great for quality of life and then patients are crying because they can’t figure out what their pills are. So be careful.

DR LOVE: Well I just skipped about 10 articles and that’s good because it was all good clinical stuff. But I think we’re going to maybe close things up and let everybody watch your presentation to get into more detail of what we’ve been talking about here tonight. I think you can just see, we kind of just did a little bit of a tasting menu there. But I want to thank Dan and Gail so much for coming tonight and sharing their experience and wisdom with us. Thanks to the audience. Come on back on Tuesday. We’ll see if we can unravel the mystery of upper GI cancer. Hey, Gail, not only that, anti-HER therapy. First line therapy of HER2-positive gastroesophageal cancer, Gail, now includes trastuzumab and pembrolizumab as well as chemotherapy, Gail, so make sure you have that for your boards. Be safe —

DR ROBOZ: I will be there.

DR LOVE: Be safe, stay well and have a great night. Thanks, Gail. Thanks, Dan.

DR POLLYEA: Thanks, everyone.