Eytan Stein, MD
Memorial Sloan Kettering Cancer Center
Interview Date: February 2nd, 2022

There is a tremendous amount of progress being made in AML. It was remarkable to see the significant work being done in the field of AML at the recent American Society of Hematology (ASH) conference in Atlanta in December 2021. 

In this show, AML expert and Director of the Program for Drug Development in Leukemia at Memorial Sloan Kettering, Dr. Eytan Stein, shares his top abstracts of 2021 that were presented by himself and his AML colleagues at the 2021 ASH conference. He covers a breadth of topics such as treatment options in the newly diagnosed and relapsed setting, what's been learned about maintenance therapy and MRD status, how COVID-19 is affecting AML patients and the advancements of various immunotherapies. Dr. Stein summarizes topics to consider at each phase of AML in a clear and concise way. He ends by providing us his thoughts on what AML advancements and research to look out for in 2022. 

Thanks to our episode sponsor

Katie: Welcome to today's episode of HealthTree Radio for AML, a show that connects patients with acute myeloid leukemia researchers. I'm your host, Katie Braswell. We'd like to thank our episode sponsor, Genentech, for their support of this HealthTree Radio for AML show. 

Before we get started with today's show, I'd like to mention a few upcoming events that we will be hosting throughout the month of February. Next week on February 7th, at 1:00 p.m. Eastern, we will be hosting a radio show titled "Targeting FLT3 Positive AML with New and Improved Therapies with Dr. Margaret Kasner from the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, Pennsylvania. Dr. Kasner will summarize key developments and clinical trials currently underway for FLT3 positive AML and take your questions at the end. 

Also, on February 16th at 1:00 p.m. Eastern, we are excited to announce that we will be hosting our very first AML caregivers chapter event titled "Lessons Learned as an AML Caregiver." Kerith Amen, who is a caregiver to her husband, Rob, will join us to share the top lessons she learned while supporting her husband in navigating his AML diagnosis with time for discussion at the end. You can register for both of these events by visiting our website, www.healthtree.org/aml.

As a reminder for today's show, if you have joined us online and would like to be able to ask Dr. Stein a question during our Q&A period at the end, you will need to call in via telephone to 515-602-9728 and press 1 on your keypad when you're ready to ask your question. Now on to today's show. 

There's a tremendous amount of progress being made in AML. It was remarkable to see all the significant work being presented at the recent American Society of Hematology, or ASH for short, Conference in Atlanta last month. Dr. Stein and I met in person for the very first time at ASH and agreed that doing a radio show to summarize the AML presentations at the conference would be an excellent idea to inform you of the top AML research of 2021 that was performed by himself and his AML colleagues.

Today, Dr. Stein will cover a breadth of topics such as treatment options and the newly diagnosed in relapsed setting, what's being learned about maintenance therapy, how COVID-19 is affecting AML patients, and the progress on various immunotherapies and targeted therapies. He'll be in the show by providing us his thoughts on what AML advancements in research to look out for this year in 2022. 

We are so pleased to have you here with us on the show today, Dr. Stein. But before we get started, let me provide an introduction for you. 

Dr. Eytan Stein is Assistant Attending Physician, Clinical Investigator, and Director of the Program for Drug Development in Leukemia on the Leukemia Service at Memorial Sloan Kettering Cancer Center in New York. He conducts Phase I clinical trials of compounds that target the genetic and epigenetic basis of myeloid cancers. Dr. Stein led the clinical studies of the IDH2 inhibitor enasidenib and the IDH1 inhibitor ivosidenib in patients with relapsed and refractory AML that led to their FDA approvals in 2017 and 2018. His current research focuses on explaining mechanisms of resistance to IDH inhibitors and the use of menin inhibitors in patients within MLL-rearranged acute leukemia. His work has been published in many prestigious journals. 

Thank you so much, Dr. Stein, for joining us today. 

Dr. Stein: Thank you so much, Katie. I'm really excited to be here, and it's always nice to have an audience of patients and caregivers to chat about AML. 

Katie: Yes, so happy to have you. But before we get started and talk about any AML research, I'm wondering how was it for you actually being at an in-person conference? ASH was only held virtually in 2020, right? 

Dr. Stein: Yeah, it was so. So it was great, actually. I used to travel a fair amount to meetings and conferences, and I hadn't been to an in-person meetings in probably a year and a half. So going to ASH, to the American Society of Hematology meeting and interacting with colleagues in sort of a formal and informal way, which is something that you just don't get when you're looking at each other on little boxes in Zoom was very, very refreshing, and I really enjoyed it. It actually reminded me why I like doing research in this area being at the meeting and being able to participate in person. 

Katie: Yeah, I was so happy to get off to Zoom for a little bit and have some real-life interaction. I was so glad to have the opportunity to attend in person. It was actually my first ask ASH Conference. And while I felt like I needed to be in a hundred places at once from that huge conference center, it was just such an amazing experience. I learned so much and there was so much presented on AML that I just can't wait for our listeners to hear all about it from you today. 

Dr. Stein: Yep. 

Katie: Can you start by just telling our listeners what the ASH annual meeting is and why it's so important?

Dr. Stein: Sure. So the ASH annual meeting is the major international meeting that covers all things related to blood. So it covers malignant hematology, so cancers of the blood, including leukemias and lymphomas and multiple myeloma and bone marrow transplants. It also covers what's called benign hematology and those are disorders related to blood clotting and other diseases like thalassemia that people can get. It's so important because it's where really the world comes to learn about and present new data for all of those diseases and particularly for acute myeloid leukemia. I mean, in a normal year, so this year wasn't really a normal year because a lot of the international folks weren't allowed to travel. But in a normal year, I mean, you're seeing people from every country you can possibly think of who are there and like the most preeminent researchers from around the world who come in. 

And then in addition to sort of the academic researchers from academic medical centers, it offers the possibility that you also get to interact with pharmaceutical companies, with companies that are sort of more established, and then new companies and have new ideas about how to attack acute myeloid leukemia. That's what makes it so exciting. I mean, it's like the Super Bowl of blood cancers, which sort of like sounds a little weird, but that's what it feels like when you're there, when you're like a science nerd and someone and a doctor who takes care of blood cancers, it feels like the Super Bowl. Not that I've ever been to the Super Bowl, but I imagined that's what it would feel like. 

Katie: I've never been either, but I could imagine. Yes, that's a good way to represent it. Can you give us kind of a high-level overview of some of the major themes that were presented in the AML sessions? Maybe in your opinion, what were some of the top maybe two or three most notable abstract presentations that you listened to? 

Dr. Stein: Yeah, so I think there were two major themes that were exciting. The first is around new targets and new drugs against new targets for patients with AML. I think one of the most exciting ones was actually when I presented about a target, which we're going to talk about I think a little bit later, and against the target called menin. Menin is a protein that is very, very important in the development of a specific subtype of acute myeloid leukemia. We now have a number of drugs that are in clinical trials that target this menin protein. Data that was presented last year and then some data that I presented this year show that targeting this meant in protein really leads to very profound clinical activity and responses in patients with these special subtypes of acute myeloid leukemia.

I think the other things that were exciting are that as many of you may know, we sort of have a new backbone for especially older patients with acute myeloid leukemia, which is the combination of an old drug called azacitidine with the combination of a newer drug called venetoclax. That's now been established as probably or as the standard of care in. In older patients with acute myeloid leukemia, the combination of azacitidine and venetoclax. What a lot of the research that's going on now is looking to, instead of just doing two drugs, adding a third drug to the combination of azacitidine and venetoclax to see whether adding a third drug actually leads to better outcomes than just doing the two drugs. 

So in the world of leukemia, we call the two drugs a doublet and we call the three drugs, when you add a third drug, a triplet. A lot of the research that's being done is to see how well triplets might work. I think the last abstract that or maybe high-level thing that I was pretty excited about was a combination that seems to be very effective in patients with another subtype of AML that has a mutation in a gene called IDH1. When patients have AML as a mutation in IDH1, there is some very good data presented showing that the combination of azacitidine with an IDH1 inhibitor is actually very, very effective and much more effective than just giving the azacitidine alone. 

Katie: Yeah, and I want to kind of break down each of those three themes that you talked about in a bit more detail as we go throughout the show. Those are all really important. But first, maybe we can have a conversation about COVID. I feel like we can't really talk about 2021 without talking about COVID, which has just affected all of our lives in so many ways, and I felt like it definitely was a topic of conversation at the annual meeting. Can you speak about any research that was presented about how AML patients are impacted by COVID, and maybe how they're responding to vaccines? 

Dr. Stein: Yeah. AML patients specifically are actually doing fairly well with the vaccines. The reason is because when you have acute myeloid leukemia, the part of your immune system that produces antibodies actually remains largely intact. So AML patients, generally speaking, who get vaccinated, will mount an immune response and therefore be protected to some extent from getting COVID. When you're in the throes of having active AML, though, or if you're getting chemotherapy, that knocks down your immune system. Those patients are, of course, going to be more susceptible maybe not to getting COVID, but when they get COVID, maybe being more susceptible to having complications from getting COVID. 

We recommend to all of our patients and sort of the national recommendation is that all of our patients should be vaccinated with two doses and then boosted with a third dose. I think the good news about COVID is that we have these new treatments beyond the vaccines that are very, very effective, even in patients with AML. So those are the monoclonal antibodies. There's one that's being given now called sotrovimab and then the antiviral drugs, one that's being given now called Paxlovid. When I have patients now with AML that call me up and say, "Hey, I was exposed to someone, and I just took a rapid COVID test and it turned positive," I immediately bring them in for either the monoclonal antibody or for this antiviral medication.

The good news is we've got people probably from across the country on the call. But in New York, I just got an email actually from the New York Department of Health saying that they actually have much more in terms of supply of these drugs than they did even three weeks ago. I think these things are really going to make a real difference for AML patients who may get COVID either because it's a breakthrough infection or because they're immunosuppressed. 

Katie: Yeah, that's great to have our listeners kind of hear how you're approaching it currently. It's so ever-evolving and changing. So that's really good insight to have. 

Dr. Stein: And because of that, there are a lot of my patients haven't seen -- so AML is a disease of older people, right? The median age for people who get it is 68 years old. A lot of my patients have grandchildren, and a lot of my patients haven't seen their grandchildren for two years. They call me up and they say, "Can I see my grandkids now?" I actually have been, with certain restrictions, I've been saying it's okay to see grandkids as long as people are fully vaccinated and boosted, and that's because we have these treatments if people get the virus that are very, very effective. 

Katie: Yeah, that's good to also talk about the precaution side, not just the vaccination side. Are you still recommending mask wearing?

Dr. Stein: I am. It's a little bit of a, you know, depends on the patient and on the family members they're seeing. I mean, if everybody's vaccinated and it's a small group of people and people take a rapid test beforehand, then I think it's okay for people to be indoors with others without a mask. For people who are mingling with others that are not vaccinated, I still say that that should really be done outdoors. I think it's just a little bit too risky to do it indoors if you've got AML. But with that, when everyone's vaccinated, if it's a small group of people, you're not at big concert somewhere, I think it's okay to be without a mask. 

Katie: Yeah, yeah. Great. I want to talk a little bit about AML biology and what we know about the disease itself before jumping into drug research and development. I'm wondering, was there any new information presented at ASH that progress or knowledge about AML just as a disease and how it affects people? 

Dr. Stein: Yeah. I mean, there's a lot of basic science research that gets done about AML. I mean, all the therapeutics, which we're going to talk about in a second, all the drugs that we have now really come from a place of understanding how the biology of AML and how AML develops from the very beginning. There's a fairly large amount of papers that are being published now and data that would that is presented or was presented at ASH, really trying to understand how do stem cells become leukemic? That is how do those immature blood cells that give rise to the blood system, how did they get affected by genetic changes that can lead to the development of leukemia? Once those happen, how can one attack those vulnerabilities to lead to better outcomes for the patients? 

I think that's where a lot of the research is being done now. A lot of research is being done into what are called leukemic stem cells. Then other research is being done to try to understand how certain genetic mutations lead to the development of AML. Because if you understand how genetic mutations or specific genetic mutations lead to the development of AML, it then allows you to target whatever that genetic mutation, whatever abnormality that genetic mutation is causing. 

Katie: Yeah. While we're on the topic of AML biology, were there any notable new molecular genetic characteristics that we recently become aware of that could maybe change the way we classify AML or approach treatment? 

Dr. Stein: Yeah. One of the things that -- we have a fairly good idea of the genetic mutations that occur in patients with AML, but what we haven't been as good at understanding until very recently is how those genetic mutations lead to outcomes. I think there is a better understanding now that certain mutations lead to perhaps a higher chance of the disease not responding to certain treatments and therefore needing to give other treatments. I'll give you an example of this. There's a whole class of mutations in genes that are what are called splicing factors. So what those actually do are probably less important right now, but there are a variety of splicing factor mutations. Until relatively recently, we haven't really understood how splicing factor mutations lead to the development of AML, but now we have a much better understanding based on research that has been recently presented and published of how splicing factor mutations can lead to the development of AML, and that leads the development of new therapeutics that are actually being tested now in the clinic. 

Katie: Yeah. Okay, so let's move on to the initial phase of treatment and talk about induction strategies. To me, with all the many new drugs available, it sounded like doctors right now are focused on figuring out which combinations of these therapies are most effective, as you mentioned, the doublets and triplets and in which specific groups of patients. I even heard you say something very interesting during your Friday talk, which was that the combination of azacitidine and venetoclax might take the place of 7 + 3 in fit newly diagnosed patients and that 7 + 3 might be saved as a later line of therapy. That was really interesting to me, and I'm wondering if maybe you can expand on this and talk about what's going on right now with research on treatment for the newly diagnosed. 

Dr. Stein: Yeah. Thanks for reminding me of what I said on Friday. I'm always a little bit nervous of what I say. I'm going to -- sometimes I reverse myself. I'm not going to reverse myself this time. Because to me, you have to go a little bit out on a limb to make things interesting. And when I go out on a limb, maybe it's not even going out on a limb so much, right now we give younger patients with AML, newly diagnosed younger patients with AML intensive induction chemotherapy with 7 + 3 in the hospital. I really believe that within five years, that intensive induction chemotherapy, like you just said, is going to go away. We're going to be replacing intensive induction chemotherapy with azacitidine and venetoclax, which is now the standard of care for older patients with AML. 

So why is that? So that is for two reasons. One is that azacitidine and venetoclax is extremely effective and getting patients into remission. It seems to be effective in getting patients into remission even when 7 + 3 doesn't work. So in patients that have certain high-risk mutations that 7 + 3 is likely not going to be effective, azacitidine and venetoclax can get those patients into remission. So that's number one. Number two is even if azacitidine and venetoclax was not better than 7 + 3 but was only equally as good as 7 + 3, it is much, much less toxic to patients. You don't have to be admitted to the hospital for a month. It doesn't cause all the side effects that people associate with intensive chemotherapy like hair loss and nausea and lead to fevers and infections. It's just a much, much easier treatment to tolerate. 

So even in a situation where it's equivalent to 7 + 3, as a doctor, I would want my patient to get something that even if it's not better in terms of the efficacy, if it's less toxic, that's what I want my patient to get. And that's why I really think that azacitidine, venetoclax is going to replace 7 + 3. I think the one situation where that might not occur is there are certain patients who have very or what's called favorable risk acute myeloid leukemia. In that situation, we know that in favorable risk of acute myeloid leukemia, 7 + 3 works extraordinarily well. So in that patient with favorable risk AML, we might still give people 7 + 3 just because it works so, so well. 

Katie: Yeah. So 7 + 3, kind of the concept of saving it as a later line of therapy, is that kind of the instance that you're thinking it will be used in the future? 

Dr. Stein: Yeah, I think it would be used for patients who, for whatever reason, don't respond to azacitidine and venetoclax. The parallel here with diseases like multiple myeloma or a chronic leukemia called chronic lymphocytic leukemia. In those diseases 10 years ago, we used to always give chemotherapy as the initial treatment, and then we got better treatments that are not intensive chemotherapy. The intensive chemotherapy either is not given at all, or really is reserved for patients where the new treatments aren't working. I think that's what we're going to have happening with AML also. 

Katie: Can you talk to us about these, well, the doublet, more of like the triplet, what we're looking at in the upfront setting? What are some of those combinations that are being studied? 

Dr. Stein: A lot of the triplets that are being studied are azacitidine and venetoclax in combination with a targeted therapy. So there are trials that are studying azacitidine and venetoclax with IDH inhibitors in patients who have an IDH mutation. There are trials that are studying azacitidine and venetoclax with FLT3 inhibitors in patients who have a FLT3 mutation. There are studies that are studying a drug called magrolimab, which is an antibody therapy, in combination with azacitidine and venetoclax really in all patients, but perhaps primarily in patients with mutations in a gene called p53. 

So really, what we're doing, if you think about it in a more general sense, is we're taking a backbone of azacitidine and venetoclax, which seems to work pretty well in everyone, and we're trying to enhance the effectiveness of azacitidine and venetoclax by adding on targeted therapies for specific subsets of patients with specific mutations. That's where all of the research is now being done. 

Katie: I briefly saw a headline about magrolimab. Was there something halted in the studies? I didn't read too much into it, but I'm sure you know. Did something happen? 

Dr. Stein: Something did happen. So there's a study of magrolimab for myelodysplastic syndrome, and that study in myelodysplastic syndrome is magrolimab plus azacitidine, which is standard of care, versus azacitidine and placebo. And the FDA put a partial clinical hold on that trial because there's -- I mean, the press releases are a little bit, you know, they're not completely transparent -- well, transparent is the wrong word. They don't completely say what happened, but it seems that the FDA is concerned that in the group of patients who got magrolimab and azacitidine there might be a higher rate of side effects. So this kind of thing happens in clinical trials, and it's actually a good thing it happens. It allows the people who are doing the clinical trial to take a look, see if there's anything really that's problematic, and if there is, to fix it, and if there isn't, then the trial proceeds. 

Katie: Thanks for clearing that up. I was going to go and read back on it, but now I don't have to. Moving into these targeted therapies, I do want to briefly touch on FLT3 mutated AML. And for those of you listening who may have a FLT3 mutation, as I mentioned earlier, I am doing a full radio show this coming Monday with Dr. Kasner all about FLT3 mutated AML. So we'll go into a lot more detail then. But can you share with us the highlights of what was presented on FLT3 mutated AML at ASH?

Dr. Stein: Yeah. I think there are two highlights. I will tell you the -- we'll start with the exciting. So the exciting is that when you give FLT3 inhibitors as a triplet, meaning you take a backbone of azacitidine, venetoclax, and patients with relapsed and refractory AML with a FLT3 mutation and you add on a FLT3 inhibitor like gilteritinib or there are other drugs, there's another FLT3 inhibitor, which is not FDA approved but is under investigation called quizartinib. It seems to be that you get clearance of the leukemia at a higher rate than if you gave the azacitidine and venetoclax alone.

I think the question that still needs to be answered about that triplet is it seems to clear out the leukemia, but it's a little bit unclear how long it takes for the normal healthy blood cells to come back because when you have leukemia, there are two things that have to happen. You have to get rid of the blasts, which are the leukemic cells, but you also have to wait for normal blood cells to come back because if normal blood cells don't come back, then the patient remains transfusion dependent, then they're still at risk of getting infections.

I think that's something that the researchers are still working out is how do you give the triplet so that you don't get low blood counts for too long of a period of time? But the initial data is very exciting and very encouraging and shows very, very high rates of blast clearance upwards of 70%. There was another trial that was done in newly diagnosed patients where the combination of azacitidine and the FLT3 inhibitor gilteritinib was compared with azacitidine alone. And really somewhat too, I think everyone's surprised, the combination of azacitidine and gilteritinib didn't really seem to be much better than giving azacitidine alone when it came to lengthening people's lives. 

That was surprising because I think there's this general feeling that by adding another drug, especially a targeted drug, you should get better results. But it shows you that sometimes the world doesn't operate the way you think it's going to work and giving this doublet of azacitidine and gilteritinib didn't seem to be any better than giving azacitidine alone. There are various caveats to that trial that they're a little bit too complicated to get into now, but I think that was somewhat surprising.

I think one trial that I should mention that was not presented at ASH but should be presented sometime soon was a trial that combined this FLT3 inhibitor called quizartinib with induction chemotherapy with 7 + 3. There was a press release showing that combining quizartinib with 7 + 3 seems to be better than giving 7 + 3 alone. I think we're all eagerly awaiting to see the results like the real results of that trial outside of just getting a press release. 

Katie: Yeah, yeah, that'll be really exciting to hear. We interviewed Dr. Wang on the Lacewing trial, the gilteritinib plus azacitidine versus azacitidine alone, which is on our website, on our YouTube channel. So if anybody wants to hear about that in more detail from her, you can certainly watch that video there. 

On the topic of targeted therapy, you've mentioned IDH inhibitors a little bit so far. So I want to have you share in a little bit more detail the research highlights for IDH1 and IDH2 mutations. We have two drugs now that are FDA approved for certain indications, but what's next for this group of patients? 

Dr. Stein: Yes. I think the next thing, number one is that, as I mentioned early on in our conversation, the combination of the IDH1 inhibitor, ivosidenib with azacitidine in older patients shows a very, very high rate of complete remission and an improvement in overall survival compared to azacitidine alone. That was a very, very exciting result that we saw at ASH this year. Now, the problem is that we now give all of our older patients with AML the combination of azacitidine and venetoclax. And the clinical trial that I just mentioned didn't look to see if azacitidine and ivosidenib is better, worse, or the same than azacitidine and venetoclax. It's just unclear. So it becomes a real clinical conundrum now, which is that if I have a patient with newly diagnosed AML who's older who has an IDH1 mutation, should I give that patient azacitidine and ivosidenib, or should I give that patient is azacitidine and venetoclax. 

That's something that we're trying to work out. There's a lot of discussion amongst leaders in the field about sort of what the best first line treatment is going to be. Me and my colleagues and a variety of other people are trying to design a clinical trial that is really going to answer that question so that we know what the best frontline treatment is. So that's for an older patient with an IDH1 mutation. 

There is another clinical trial that wasn't presented at ASH but is ongoing, looking at for younger patients, whether giving IDH inhibitors with 7 + 3 is better than giving 7 + 3 alone. That's a trial being conducted in Europe primarily and also Australia, and we hope to have results from that trial in a few years. 

And finally, just getting back to the azacitidine, venetoclax, one of my colleagues down at MD Anderson is doing a clinical trial doing, as I mentioned earlier, a triplet. So we know that azacitidine and the IDH1 inhibitor ivosidenib leads to very long survival. We know that azacitidine and venetoclax leads to very long survival. So what if you combined the IDH1 inhibitor ivosidenib with azacitidine and with venetoclax, would that lead to even better survival than either of the doublets alone? So we get all these clinical trial results and sometimes they, you know, they all, I think, help patients, but they also obviously lead to more questions that we then have to answer. 

Katie: Yeah, absolutely. Are there any new IDH inhibitors that are in development, or are we mostly just looking at the two that we currently have? 

Dr. Stein: No, there are new ones in development. There's actually a drug that we've been working with from Eli Lilly, from Loxo Oncology, which is the cancer arm of Eli Lilly. And they've got a drug that blocks both IDH1 and IDH2. So right now, what's FDA approved is one drug for IDH2 mutations and one drug for IDH1 mutations. This new drug seems to have activity against both IDH1 and IDH2. That's interesting. The other thing this new drug might do is it might be more potent than the currently available IDH inhibitors. This is sort of like a standard development pathway, right? You have one drug that is really good. But then, as time goes on, people try to develop drugs that maybe target the same pathway but are even more potent. 

Katie: Yeah. Is it kind of like the same concept with what we have with FLT3 inhibitors, like we have first generation, second generation? 

Dr. Stein: Exactly. So like midostaurin is the first generation and gilteritinib and quizartinib are second generation and then someone will decide that there need to be a third generation drug. Yeah. 

Katie: Yeah, very interesting to hear that there's one that would target both. I wasn't aware. That's pretty cool. Okay, so maintenance therapy was another topic of interest to me at ASH, especially with the recent approval of oral azacitidine. I once again learned something from you that I did not know, which was that IV azacitidine or Vidaza and oral azacitidine Onureg are not equivalent. Can you talk about what we're learning about maintenance therapy, how it's being used, and maybe touch on why IV and oral azacitidine aren't necessarily the same? 

Dr. Stein: Yes. I think we have to define what maintenance therapy is first. Maintenance therapy -- and by the way, I sat in a room at ASH for like two hours sort of having an endless discussion about what maintenance means, so I'm going to tell you what I think it means. So maintenance is you've gotten your treatment for AML. Your AML has gone away and maintenance therapy, it means giving a drug that maintains you in remission and keeps the leukemia from coming back. The reason maintenance therapy is a hot topic is because there has never been any FDA-approved maintenance therapy for acute myeloid leukemia. There's maintenance therapy that's approved for other kinds of cancer. But for acute myeloid leukemia, despite a lot of effort and a lot of different drugs that have been tried and a lot of different strategies that have been tried, maintenance therapy had never really worked. 

So oral azacitidine, which is otherwise known as CC-486, or the tradename is Onureg, is really the first drug that has shown an increase in overall survival as a maintenance therapy in patients with AML, and it's restricted to those patients who have not had a bone marrow transplant. So in a patient who got induction chemotherapy with 7 + 3, got consolidation chemotherapy was 7 + 3, and then does not have a bone marrow transplant, those patients who got maintenance therapy have a better survival than patients who got placebo. 

Now, everyone knows about IV azacitidine because that's what we give for older patients with AML and for patients with MDS, and it's not just IV. It can be given under the skin as an infusion also. So the thing is that the way the body absorbs the oral azacitidine is not equivalent to the way the drug gets into your body when it's given under your skin or intravenously. So the concentration of the drug in the bloodstream when it's given orally is different than the concentration of the drug when it's given intravenously or subcutaneously. And because of that, you really can't mix and match the oral azacitidine with the IV azacitidine.

So if a doctor wanted to give maintenance therapy with IV azacitidine in newly diagnosed AML who had gotten intensive chemotherapy, that probably would not be the right thing to do. And similarly, in a patient who's getting azacitidine and venetoclax, giving the oral azacitidine with venetoclax might not be the best thing to do. We still need to work out sort of the drug levels with oral azacitidine with venetoclax. 

Having said that, I do think we are going to come to a time, probably in the next year or two, where this is going to be worked out, and we will, at some point, be giving some formulation of oral azacitidine with venetoclax so that hopefully we're going to have all oral regimens for patients with newly diagnosed AML. I mean, think about that. I mean, if you just think about that, I mean, I know I'm sort of like going on and on here, but like it's really amazing. This is a disease where the standard of care now is like, for younger patients is putting them in the hospital for a month. Can you imagine if we now have a time where we're giving people treatment as an outpatient orally? I mean, that's an amazing change in our treatment paradigm. 

Katie: Yeah, absolutely amazing. It would be life changing for patients to be able to do that and the hospital. In addition to azacitidine being used as maintenance, are researchers also -- or even being used in clinical practice now using targeted therapies as maintenance, is gilteritinib one of the ones that are being used or with that now? 

Dr. Stein: I think in patients who have FLT3 mutations, we're sometimes using midostaurin as maintenance if you don't have a transplant. After a transplant, we're often using sorafenib as maintenance. Some people are using gilteritinib as maintenance. There's a big clinical trial comparing gilteritinib with placebo for patients to FLT3-mutated AML post-transplant. 

Katie: So much to learn in this area, definitely. That's a really great overview. 

Dr. Stein: Yeah, and it's actually become, you know, when I started -- I mean, I started this probably 10 years ago, right? And it was like really simple. There were basically only two drugs you could give. So I can't say it was really good for anybody, but it was easy to understand. And now, even since I sort of got into this field, there's been such an explosion of drugs and new things that it does become really complicated, which is good. It's good. 

Katie: Yeah, it's definitely good. It seems like it'd be a very short podcast back in those days, whereas now we could do four, five, six podcasts if you really -- 

Dr. Stein: We could do a mini-series. We could do a mini-series. It would be like dropping something new on Netflix, right? We do like seven episodes and then next year do another seven episodes. 

Katie: Yes. So let's talk a little bit more about some of the research that you're specifically working on. Tell us a little bit more about your abstract on SNDX-6532 and what the next steps are for your work on menin inhibitors. 

Dr. Stein: Menin is a protein that's very important in the development of two subtypes of AML, AML with mutations in a gene called NPM1, so Nancy, Paul, Mark, NPM1 and AML with a specific chromosome abnormality called an MLL-rearrangement. And we did a clinical study, or we're in the midst of a clinical study with this drug called SNDX-5613, which is a targeted inhibitor of menin. And what we showed in the abstract that we presented was that if you give this menin inhibitor -- by the way, the menin inhibitor is an oral drug. You take it twice a day, or this particular menin inhibitor is an oral drug that you take twice a day, really very, very few side effects, it leads to complete remissions in 55% of the patients that were studied. In addition, those remissions were very, very deep, meaning that even by the most sensitive methods and the patients who went into a complete remission, we were unable to detect any residual AML. 

So we think that's really exciting. This trial has now sort of expanded into an expansion phase where basically we've got the right dose of the drug now. We're looking to give the drug to many, many more patients to hopefully see how well it's working in a larger group of patients. And then assuming it does continue to work, which I think it will, the next step is really to do what we do with all these drugs, which is that you don't, you know, this drug is now being studied in patients with relapsed leukemia. But obviously, you don't want to wait for someone to relapse. I mean, no one wants to relapse. We want to cure patients from the get-go. 

So the development strategy, as we say, is going to be to combine menin inhibitors generally and this menin inhibitor specifically with standard of care treatment, like aza-venetoclax, like intensive chemotherapy. There are a variety of other menin -- this works really well, so a lot of different companies are trying to get into the menin inhibitor field. I'm aware of five different menin inhibitors and different companies that are in various stages of clinical development. So this is a really, really hot area, and I think is going to make a really huge difference for patients with these specific subtypes of AML. 

Katie: NPM1 is a fairly common mutation, right? This would impact a lot of patients. What percent of patients have this mutation?

Dr. Stein: NPM1 is found in 30% of patients with AML, newly diagnosed AML. Now what's interesting is that NPM1 occurs, will often occur with FLT3 mutations. So you can imagine a scenario where now maybe, instead of giving a triplet, maybe you're going to give a quadruplet. So maybe you're going to give azacitidine, venetoclax, a menin inhibitor and a FLT3 inhibitor, or maybe you're just going to do a FLT3 inhibitor with a menin inhibitor. And these are all the things that I'm really excited about. I mean, I think this is really where the fields going and where we're going to get the most bang for our buck.

Katie: I thought my head was spinning with triplets and you add on another one. Other than menin inhibitors, are there any other projects you're currently working on?

Dr. Stein: Yeah, so I mentioned earlier the splicing factor mutations. We have a variety of compounds that we're working on the target mutant splicing in patients with AML. A lot of patients with AML will have splicing factor mutations. In fact, in patients with IDH mutations, or at least IDH2 mutations, about 50% of those patients will have splicing factor mutations. I think that there are drugs that are being developed and that are currently in clinical trials that target mutant splicing. That's something I'm very excited about. I think we're going to see results from those trials in the next two to three years. 

Katie: Great. So this more is its own show, but immunotherapy was obviously another hot topic presented. We don't have a ton of time, but maybe you just -- can you give us what you're most excited about in the immunotherapy area? 

Dr. Stein: It's so hard because there's so much going on, and we only have a few minutes left, I know, and we don't have time for questions. But I think that there are, I guess, I would put it broadly like this. We know that the immune system is very good at controlling small amounts of acute myeloid leukemia. We know that because stem cell transplants are a form of immunotherapy. So the donor stem cells that a patient gets during a stem cell transplant are what presumably keeps any residual leukemia in the patient's body from growing back.

I think the question is what is the right setting to use immune therapy, whether it's car T cells, whether it's what's called bispecific antibodies, what is the best setting to use these therapies? I actually think that where we should be investigating these immunotherapies are in patients with what's called minimal residual disease or small amounts of leukemia that are left over after getting azacitidine and venetoclax or after getting intensive induction chemotherapy. I think that is the perfect setting to test these immunotherapies, to eradicate this small amount of disease that's left over, and that is where I think the field should be going in these clinical trials. 

Katie: That was perfect, perfect response to a very complex topic. Do you anticipate any new FDA approvals coming our way for AML in 2022? 

Dr. Stein: I think in 2022, probably the one that I'd be looking out for is quizartinib. I think, depending on -- I mean, 2022 is already two months in now. But I think that the quizartinib drug is the drug that we talked about, which is a different FLT3 inhibitor that was studied in combination with intensive chemotherapy. We know from a press release that at least the company says that it's better than giving 7 + 3 alone. If that data holds up in what they actually present, then that might be another FLT3 inhibitor that we're going to have sort of available to us. 

I think looking at 2023 and beyond, I would expect that -- I think menin inhibitors, some menin inhibitor will get approved in 2023 or maybe 2024. I think that's where we are. 

Katie: You've given us so many pearls of wisdom throughout this hour, but maybe we'll wrap up by having you sum up maybe what you think the major focuses for 2022 for AML research will be, and just provide us your thoughts if you feel that there will be any changes to clinical practice in this year. 

Dr. Stein: Yes. I think the major focus of research is going to continue to be on the small molecule inhibitors that we talked about. Menin inhibitors, triplets, that's going to be a major area of focus. Maybe even developing quadruplets is going to be a major area of focus. I think we're going to be focusing on immunotherapies for patients with what we call measurable residual disease in 2022 and 2023. That's going to be another major area of focus. In terms of changes in clinical practice, I think we're going to be seeing that people are going to start giving the IDH1 inhibitor, ivosidenib, with azacitidine, instead of azacitidine and venetoclax in some patients with IDH1 mutated acute myeloid leukemia. Whether that's the right thing to do or not in terms of whether it's better than azacitidine and venetoclax, we just don't know because it hasn't been compared head to head yet. 

And then I think if quizartinib gets approved, that may be another practice change for we may be giving quizartinib in combination with chemotherapy for patients with newly diagnosed FLT3 positive AML. We don't know whether quizartinib in combination with chemotherapy is better than midostaurin in combination with chemotherapy. So that's another area that's going to need to be investigated. 

Katie: Great. All right. So now I'd like to open it up for caller questions. If you have a question about anything Dr. Stein discussed today, you can call into 515-602-9728. And once you're on the call and ready to ask your question, press 1 on your keypad. I see here, I'm going to unmute caller that ends in 1034. 

Caller: Hi, Dr. Stein. Thank you so much for joining and sharing with us today. I have a question about MRD testing. I know MRD testing is becoming more prevalent in AML, and I'm wondering, what's the status? What did you hear at ASH? And when should AML patients get MRD testing and what's the value? 

Dr. Stein: That's a really, really good question. So the best time to test for -- or I will tell you when we test for MRD. Probably the best time to test for MRD is after someone has gotten intensive induction chemotherapy with a drug like 7 + 3 to test after their first round of induction and then to also test after they've gotten one round of consolidation. That testing for MRD can potentially be done from the bone marrow, or it can be done from the blood. But the timing of MRD testing and in what setting I think is still an area of some controversy. I think you bring up or I'm not sure if he meant to, but I think you bring up a good a good point about what's the benefit of MRD testing. 

So the thing is we can test for MRD. We know when someone has MRD. But what we don't have yet is proof that any specific drug can eradicate MRD and that by eradicating MRD with a specific drug, that a patient will live longer because you can imagine that, let's say someone gets in duction chemotherapy, they go into remission, but they still have MRD. So you can imagine a situation where I want to give a patient a drug to get rid of that MRD because I worry that MRD is bad. But maybe that drug has such bad side effects that it actually makes things worse for the patients than making things better. 

I think the MRD testing now is primarily just for understanding the prognosis of the patient. I'm not sure yet whether it impacts the clinical decisions we actually make when it comes to what the next line of therapy might be. 

Caller: Yeah, that makes sense. Thank you. 

Katie: Okay. Caller ending in 7401, you can ask your question now. 

Caller: Thank you. Yeah, I'm just wondering about the treatment of azacitidine and venetoclax. Is it always given as an outpatient drug, or is it ever started first in the hospital to monitor, anything like that? 

Dr. Stein: Yeah, it's a really good question. So I think different hospitals do different things. Some hospitals start everybody in the hospital over the first seven to 10 days and that is to look for -- to make sure that there are no bad side effects. Some people started always as an outpatient. At Memorial Sloan Kettering, I can tell you what I do is I take sort of a risk adapted approach, which means as follows: If I worry that a patient is going to have some particularly bad side effects from azacitidine and venetoclax either because they've got some part of their medical history suggests that they might have bigger side effects. So like, for example, the patient who has kidney problems to begin with or a patient who recently had a heart attack or a patient recently had a stroke, that patient, I might start as an inpatient just to watch them a little bit more closely. 

In addition, in a patient with a very high white blood count, I would start that patient as an inpatient. But my general practice is to try to start as many people as I can as an outpatient. I do not like hospitals. I think that people often don't get better in hospitals because one of the problems with hospitals generally is that we make the bed of the hospital room the defining characteristic and people spend a lot of time lying down. I think that, in a lot of cases, people sometimes come out from the hospital weaker than when they went in. So I try to start as many patients as I safely can as an outpatient. 

Caller: Great. Thank you. That's helpful. 

Katie: Okay, I see one more question here. Caller ending in 4085. 

Caller: Hi, thank you. So as a follow-up, you mentioned the side effects with azacitidine and venetoclax with individuals that have major health concerns. What about other people that don't have any major underlying health issues, what side effects are you seeing for them with that combination? 

Dr. Stein: I will tell you the three things that I tell my patients about when it comes to side effects. One of which always happens and two of which don't happen that much. So the one thing that will always happen is that azacitidine and venetoclax will lower people's blood counts to the point that they will need transfusions. They will almost always need platelet transfusions, and they will likely need blood transfusions as well. It also impairs a patient's immune system. It lowers the neutrophils, so the patients are somewhat susceptible to infections, although in my practice, I put people on prophylactic antibiotics to help prevent infections. So that's something that always happens. That's number one. 

Number two is sometimes people can get a little bit nauseous from the azacitidine. The venetoclax itself doesn't typically cause much nausea, but sometimes people get a little bit nauseous from this azacitidine. That can be an issue. The third issue, which is very, very, very rare but I tell patients about because if it happens, it can be serious, is that sometimes as the leukemia cells are dying, because of the treatment, they can release toxins that can damage the kidneys. That's called tumor lysis syndrome. We put people on medications to help prevent tumor lysis syndrome. We tell them to drink a lot of fluids to help prevent tumor lysis syndrome. It's a very rare occurrence, but it's a serious thing, so we watch people very closely. 

Now, of the things I mentioned, the only thing that a patient might experience, though, is the nausea. In general, the combination is fairly well tolerated in the sense that -- and what I mean by that is a patient isn't going to feel completely normal. They're going to feel fatigued. They might feel a little bit down. But I have a lot of patients who feel pretty fine, and they might work during getting this, especially now at a time when a lot of people are working from home, if you can work from home, they feel well enough to work. It's not the kind of treatment which sort of lays people up in bed for 20 days. People really overall feel generally pretty well. There are exceptions to the rule, but in general, that's been my experience.

Caller: Okay, thank you. That's great. 

Katie: Okay, I see one last question here, which we'll end on, from caller 0431.

Caller: Thank you very much for the information. I have a slightly different question regarding the core binding factor AML. I noticed that MSK and MD Anderson are using completely different regimen and they claim they can have 80% to 90% cure rate for the core binding factor AML. This is to relate to the potentially different mutation, also have MRD positive. Could you comment on the two institutions with the such a different treatment regimen there? Thank you. 

Dr. Stein: It's a loaded question, so I have to think about how I'm going to answer it. So I would say that I think that a lot of places in the country for core binding factor AML, which is favorable risk AML, use a backbone of 7 + 3 with gemtuzumab ozogamicin. I think that's the most common thing that is done if you pulled different cancer centers in the United States. You know, at MD Anderson, their backbone, they don't typically use 7 + 3 as their backbone for intensive induction chemotherapy. Their backbone for intensive induction is FLAG, I think it's FLAG-Ida, which is a slightly different chemotherapy backbone. That's what they've done with all of their trials. 

Whether that backbone is better than the 7 + 3 backbone, I think you would get different answers based on who you talk to. I think that FLAG-GO or FLAG gemtuzumab for core binding factor AML, I think it's a very, very good regimen. It seems to work extremely well. There have been studies out of the United Kingdom that shows that it works extremely well. I think whether it's better than 7 + 3 with gemtuzumab I think maybe remains in an open question. You'd probably get a different answer if you talk to someone from MD Anderson, but I'm going to leave it sort of open like that. 

Caller: Thank you. Just a follow-up there. It's GO have been used at all? MSK, is that considered to be out there? It's kind of approved. I noticed that it seems MSK hesitated using that for the core binding factor. 

Dr. Stein: For gemtuzumab, we traditionally have not used a lot of gemtuzumab in our practice. That's for a variety of reasons, some historical, some because the clinical trial that was done with 7 + 3 and gemtuzumab shows an event free survival benefit but not an overall survival benefit. It's something though that we readdress every six to 12 months, and we all fight about what we should be doing. I think we're going to be re addressing it in the next six months or so, so maybe our practice will change. 

Caller: Thank you. 

Katie: Okay, so that's all the time we have for caller questions. Thank you so much, Dr. Stein, for joining us today. We're just so grateful for your generosity with your time and your willingness to share your incredible expertise with us. We're excited for what's to come in 2022 and maybe we can make this post-ASH show an annual tradition. We wish you all the best this year in your clinical practice and research endeavors, and I'm sure we'll be chatting again soon. 

Dr. Stein: Okay, perfect. Nice to talk to you. Thanks so much. Bye-bye. 

Katie: Thanks for listening to HealthTree Radio for AML. Join us next time to learn more about what's happening in AML research and what it means for you.