Pełna transkrypcja odcinka Improving Treatment Strategies in Acute Myeloid Leukemia (AML)

cell transplant? That's kind of the total treatment package. Manish Shah, MD: That's very helpful and a very good overview. Just very briefly, the symptoms then related to AML are related to bone marrow dysfunction. So, there's bruising and fatigue, infections, bone and joint pain. In your experience, do people have symptoms for three months or years and then they're diagnosed? Are people not thinking of it because it's so rare? Dr. Gail Roboz: So, all good points. I think getting back to my original comment about why it was called acute a century and a half ago, is that there isn't an expectation of having symptoms for years, for sure. It's more like days to weeks, uncommonly longer than that. But what's very interesting is there is an incredible range in such a way that you can have absolutely urgent emergency symptoms related to infection, related to infiltration of leukemic cells where they shouldn't be going. the cells that are starting in the bone marrow spill out from the bone marrow and circulate in the blood, and blood goes everywhere. So if you have hundreds of thousands and millions of leukemia cells that are circulating in the blood everywhere that blood goes, you can imagine a very emergency situation of patients coming in with signs and symptoms from the brain or from the heart or from the lungs. But actually, what's crazy, and it does scare people a little bit when I say this, is that sometimes people are quite asymptomatic. And it's a diagnosis that can get tipped off because somebody goes in for routine blood work and something is seen that's abnormal. It's less common. Most of the time people do have some signs or symptoms of something. But I always talk about the athletes. Athletes really know their body. So for example, if a runner can usually run 10 miles and now can only run nine, they're very, very sensitive to it, and they may come in for attention sooner than somebody who's sitting around, maybe not doing that much, maybe feeling a little bit tired, maybe has a couple of bruises. It's pretty easy to say, "I've had a tough week. I don't feel well. Maybe I bumped my arm." So, you might take a couple of weeks in that scenario before you're actually coming in for some attention. Manish Shah, MD: that makes a lot of sense. So, more than a decade ago, I seem to remember there were eight different types of AML, but now we think of it differently based on molecular testing like FLT3 or IDH. Do you want to talk about that? Dr. Gail Roboz: In oncology, the molecular age has just been stunning. We used to just throw rocks at cancer cells and hope that they died. So, chemotherapy was a hammer, and cancer cells were nails, and we tried to throw the strongest ones that we had to just kill the cells. Now, actually, in most areas, I would say, of oncology and AML included, we have diagnostic tools that allow us to be much more specific in the targeting of the bad cells. So, this includes molecular diagnostics, things that we call next-generation sequencing or the identification of mutations that may be relevant either for the prognosis of the disease or as a potential target for treatment. So, very important. Some of that testing doesn't pick a drug, but it tells you how badly or how well the disease may behave. Some of the results of mutational testing may say, "Oh, I have a FLT3 mutation or an NPM1 mutation or something that we have a direct therapy for." In AML, it's really a complex diagnostic picture of putting together what you see under the microscope with next-generation sequencing or mutational testing. There is still another technology called flow cytometry. There is yet another way of looking with cytogenetics. And the bottom line is that the integration of all of the inputs of these different data points that tell us about the cells and how they're going to behave and what are the best treatments have completely changed the landscape of this disease It's evolving incredibly rapidly. And in AML, the pre-2017 era versus the current era, it's simply stunning. I mean, prior to 2017, we had hardly anything that was FDA-approved in the previous 30 years for AML as opposed to 14 different therapies since that time. It's been an absolute tsunami of good things happening in the field. Manish Shah, MD: and congratulations to you. We're going to talk about your recent article you've been right in the middle of that, so I am really excited to hear more about that. So, just like in solid tumors, the idea is that splitters. We're not grouping big diseases together. We're actually splitting them apart and then refining our treatments to those individual diseases. And Dr. Roboz mentioned there are different chemotherapy regimens for different types of AML and different strategies. I remember not too long ago, there was a treatment of retinoic acid for one of the AML types. Was it APML? Dr. Gail Roboz: Yeah. And ATRA or all-trans retinoic acid is very central to the treatment of APL. It's a story that kind of sets up the audience for understanding how the entire trajectory of AML is going. So, APL, acute promyelocytic leukemia, was one of the absolute worst of the worst. It's an exploding, dangerous, horrible presentation that people might even only live for hours. It used to be one of our most feared subtypes, to the point that actually patients would die so quickly that we didn't even know that they had it because they had died without a diagnosis. So with that backdrop ATRA or all-trans retinoic acid, which is a vitamin A derivative, starts getting tested, changes the entire landscape of that disease, allows us to add that to chemotherapy. So, you take chemotherapy, you take a targeted agent and add it to chemotherapy. And all of a sudden, the survival curves are changing. But wait, there's more. Then, you add a second newly discovered—even though it's a thousand years old—agent, arsenic trioxide, miraculous effects in combination with ATRA. So, we're getting rid of chemo,

putting in targeted therapies. But wait, there's more. The testing goes deep, deep, deep on a molecular level, getting down to one in 10,000 cells, one in 100,000 cells, one in a million cells. And the story gets put together that we take the worst subtype of the disease, get targeted agents, get rid of the heavy-duty chemotherapy, molecularly monitor it so that the disease is gone, and we turn tragedy into cure. And it is an absolute stunner of a story in the space of acute myeloid leukemia that we are trying very hard now to do with other subtypes. We're not there yet, but in subtypes of AML, for example, with a FLT3 mutation, with an NPM1 mutation, are we moving toward exactly the story that I told you? Find a targeted agent. First add it to the chemotherapy, and things get better. Then you realize, wait a minute, I can start pulling away some of that chemotherapy, and the patients are still doing well, and I can measure it down to one in a million cells so that I know that it's gone. It's not done. AML is not cured. I'm not out of business yet. I have plenty of work to do, but this is the way that the field is going. And what I can take you to in the article that you wanted to talk about, which is brand new, is not only are we doing this for people who can have intensive chemotherapy, which was the entire subject matter of AML for decades, that you had to be able to tolerate intensive chemotherapy, otherwise you wouldn't have a chance at survival. And yet the median age of this diagnosis is 67 years. So, there were tons of patients in their 70s and 80s who couldn't possibly tolerate intensive chemotherapy, and therefore had no shot at surviving mostly beyond six or eight months, not years. In addition to all of the stories that I'm telling you about the molecular age, adding targeted therapies, monitoring down to one to a million cells, what we have been able to do is have breakthroughs in the administration of the chemotherapies in such a way. And this is a dataset that I have recently been involved with that we're very excited about, that for patients who are not receiving intensive chemotherapy in the hospital, we are able to administer the agents orally to maximize quality of life and minimize time in the hospital for many, many patients who would previously have been spending weeks and weeks and even months of their life in the hospital. So, the switch to all oral, I'll just open by saying it doesn't make AML an easy disease to treat. There's nothing easy about AML. And even though there are patients that I can actually give you your entire treatment orally, they are surprised when I say to them, "Yeah, it's all pills, but I still want to have you in the hospital for three or four weeks until I get you into remission, because you're 85 years old and you have many other medical problems and medications. And I want to get you safely in remission with us in the hospital while we're watching you closely." But then, the prize is that when you

get out due to the all-oral therapies, and this was published recently in The New England Journal, we have the ability in the post-remission setting for patients who are not going on to get a transplant to give ongoing cycles of pills and keep them out of the hospital, which has just been really fantastic. Manish Shah, MD: So what I'm hearing is that the chemotherapy historically was aggressive therapy that had side effects, and you had to be well enough to receive it, and many people who were in their 70s and 80s were not well enough to receive it. it was associated with risk of infection and bleeding and other toxicity that required hospitalization. Now, and let's dive into the article, this new regimen, which is an all-oral regimen of treatment is able to achieve remission in about 50% of the patients and in a way that is safer for people who are older, but it's not a walk in the park. Dr. Gail Roboz: I want to emphasize not a walk in the park because people definitely tend to say , "Oh, it's a pill. How bad could it be?" So, AML is still a very dangerous disease and all medications have side effects, whether they're pills or not. So, I think it's important to get that out there. However, the combination of what's called a hypomethylating agent, in the case of this article we're talking about decitabine, but decitabine and azacitidine are game-changing hypomethylating agents which when combined with venetoclax, which is arguably the most important thing that has happened to acute leukemia possibly ever, but certainly recently. That is a game-changing, paradigm-shifting medication that is a pill that basically gets at the exact mechanism that these awful leukemic cells use to keep themselves alive. I like to tell people remember The Incredibles movie, which has girl in it, who had a force field around herself. Leukemic cells have a force field around themselves called BCL-2. Venetoclax actually takes down that force field and allows leukemic cells to then get killed by, in this case decitabine. And what we did in this paper was turn the whole thing into pills because decitabine can be given orally. It's oral decitabine combined with another drug called cedazuridine so that it doesn't break down in your stomach so that it's powerful. Venetoclax is a pill. And when you put these two things together, the side effect profile for anybody, for a younger patient, for an older patient, is easier than taking our historical chemotherapies. But this particular trial that I'm talking about was for older patients and also for younger patients who could not tolerate, for whatever reason, due to their current condition or medical comorbidities, intensive chemotherapy. Nobody's going to say walk in the park, but I will tell you that my patients both on the trial and who are getting this therapy now that it is available not on a clinical trial are literally thrilled that they don't have to keep coming back over and over and over to get therapies intravenously or as injections in clinic because the key point is that for this combination, for venetoclax combined with this special type of chemotherapy called a hypomethylating agent, it gets repeated over and over and over again every six weeks, four weeks, depending on how the patient is doing. Patients will ask me, "Oh my God, am I going to be on this forever?" Yeah, you might. Because if you have a really dangerous disease that's in remission, we want to keep it that way. And for many patients, and it's beyond the scope of this discussion today to say who needs ongoing therapy versus who doesn't, but for a lot of AML patients on this combination who are in remission, we don't know yet when it's safe to stop. So when you are getting ongoing maintenance treatments, potentially for months or years, again, high-class problem because the survival used to be only a few months and now it's measured in years, we want to make sure that we can give the drug safely and conveniently at home without dragging people into clinic, and that's what this has done. Manish Shah, MD: So the standard treatment used to be chemotherapy, , and it was cytotoxic, fair amount of side effects, given as an inpatient. And you would do that for a few cycles to get people into remission. And then, once you're in remission, you would follow that up with perhaps a bone marrow transplant or other treatment to try to eradicate all of the blast cells. Here, Dr. Roboz and colleagues developed a regimen, which is an all-oral regimen using venetoclax, which is a game-changing drug, and a hypomethylating agent, decitabine, given with cedazuridine, which allows it to be given oral. venetoclax is given every day, but the decitabine is given five days every month, and you monitor patients. And then, you can get a large number of them, about half of them, into remission, and then maintain them in remission without the need of further therapy like a transplant. Induction refers to the first cycle of treatment. And with standard intensive chemotherapy protocols that require hospitalization generally of around a month, most patients, about 70% of patients who are offered intensive chemotherapy induction will go into remission with one cycle. About 22% to 30% of them may require two inductions to get into remission. But the standard paradigm for an intensively treated patient has been induction to get into remission, followed by either three to four cycles of intensive chemotherapy consolidation or a stem cell transplant. Whether the patient gets consolidation or a stem cell transplant has depended on what the prognosis is if you get chemo versus what the prognosis is if you get a transplant. Dr. Gail Roboz: Now, that paradigm has typically been offered to patients who are young and healthy. In the past, when you were 65, when you were 70, when you were 75, that treatment that I described would be the only way that you would have any kind of a long-term cure or a long-term remission. So, some of those

older patients were in fact and can still be offered that type of an intensive approach. However, back in the day before venetoclax, if you weren't fit to get a lot of chemotherapy with or without a transplant, you would be given a drug like decitabine alone, and that had a poor chance of remission and a poor chance of keeping you alive for more than about a year. The addition of venetoclax made things better. You had a higher chance of getting into remission and a higher chance of living for more than a year. But many patients still without intensive chemotherapy and without a transplant, median survival of about a year to 18 months. So, better than six months, but still very, very far off of cure. If you are getting a combination of these non-intensive drugs, that is typically given on and on and on in ongoing cycles in order to try to keep you in remission as long as possible. I think it's important to make a note that this therapy is so much more tolerable than what we used to do, transplants have been getting better and better over time, there are actually older patients who get this type of a regimen either orally or intravenously, the less intensive regimen to get in remission, but are then in such good shape because they haven't been beaten up with intensive chemotherapy, that once they're in remission, they may in fact be offered a stem cell transplant. And we at our program just took an 81-year-old gentleman into a stem cell transplant. So, the ability to transplant older patients is better because transplants are better, but it's also better because we have more effective chemotherapy approaches like the one we're talking about today with oral decitabine and venetoclax to get you safely in remission and without so many side effects that you're so beat up that then you can't get a transplant. It used to be two separate tracks. You're either getting intensively treated and you might have a shot at long-term remission or even cure, or you're getting non-intensive therapy and you're going to live a few months. That is what we have gotten rid of because if you're only able to get non-intensive therapy, you're still doing better than before because of regimens like the one in this article. You're not probably going to be cured, but you're living longer than you would have a few years ago. importantly, it's safer and better than what we had in such a way that, well, if you're on the margin and we're not sure, we can give you something easier to get you into remission and then actually consider stem cell transplant for cure even in patients in their 70s and, dare I say, beyond. Manish Shah, MD: Dr. Roboz published this all-oral regimen and it made it to the New England Journal of Medicine. That's the top journal in the medical field in the world. congratulations. I found it very interesting. There was a phase 1 portion, a phase 2A, and a phase 2B. And I don't think the details matter so much in terms of the differences in those portions. But as I was reading it, what I found is that the phase 1 was very regimented, as most phase 1s are, and very proscriptive as to the dosing and the timing and things like that. And I feel like by the time you were in phase 2B, it was intentionally written in a way that you had more nuanced ability to make alterations. And by doing that, it seemed like patients got lower doses of treatment in the different cycles, but they actually were able to survive longer. Is that fair, the way I read it? Dr. Gail Roboz: Yeah. I think it's actually several super important points that you're bringing up because people aren't used to reading about the different phases of a study in this way. And yet, we specifically brought it forward in this way to get at a really important point. And this is super important for patients, for caregivers, and for doctors. So, if you buy, I don't know, Duncan Hines, and you're trying to make a chocolate cake or chocolate chip cookies, the stuff is in the box. You do exactly what it says in the box, and you will get the exact cake or the exact cookies unless you really don't know what you're doing. This isn't that. And what's super important is the realization that for individual patients, the nuances of tailoring the dose and the schedule of oral decitabine cedazuridine, and the venetoclax is incredibly important. And we are still learning a lot about this because it's very hard for patients and doctors to say, "Well, okay, what am I doing? How many pills a day am I taking next month?" Well, it depends on how you did this month. So, it's actually pretty hard sometimes to give a sense of what the next three to four months might look like in terms of how many pills, how many times do I need to get my bloods checked, and what kind of adjustments in the schedule might be needed. Because we still have tolerabilities that need to get worked out for individual patients so that the post-remission ongoing cycles are tailored to be strong enough to keep the leukemia away, but not so strong that blood counts fall super low and put the patient at risk for side effects while they're in remission Both decitabine and venetoclax, and especially together, they make your blood counts worse before they get better. In the beginning of treatment, when we are in the so-called induction phase or the first part, we are trying to wipe out everything that we can reach because almost all the cells are leukemic, and we want those normal ones to grow back. However, once you are in remission and you have beautiful blood counts and you're feeling really good, you don't want me to wipe all of your blood counts to kingdom come because then all of the risks of bleeding and of infection and of complications from having a non-working bone marrow come back. So, there is nuance to giving the patients in remission enough to make sure that these nasty leukemic cells that are hiding, and they do hide, and they are still there. We can't stop because they'll come back, but we

have to tailor the amount of chemotherapy that's given after remission so that it's a little bit Goldilocks, not too much and not too little. And that can take a few cycles of careful monitoring to figure out that for that individual patient, what's going to be the sweet spot to accomplish those two goals. Manish Shah, MD: That's how I read it. And thank you for explaining that because it actually gets to the art of medicine. And why even in this era of AI, we will always have jobs because it takes thought and time and skill to make these adjustments. The protocol was written in a way that you did a bone marrow at day 21 and then made adjustments even based on that, which I hadn't seen before. amazing. So, congratulations on this work as well. A couple follow-up questions. What proportion of patients with AML will this benefit? And then, would you offer it or use it in young people? Does the paradigm now translate to them? Dr. Gail Roboz: Since you used the word paradigm, the trial that is trying to answer this question which is going to be published soon, is called Paradigm, literally. So, the Paradigm trial was actually a randomized trial comparing for all-comers, for patients older than 18, not the oral version, but an agent, either azacitidine or decitabine plus venetoclax versus the standard. And so, the question is, okay, well, if this is so great, and if the remission rates are so great, and it's higher safety profiles, better safety profiles, safer delivery of patients to transplant, why are we giving this only to older patients? Why shouldn't younger patients get this too? And the answer is, maybe they should. So, the Paradigm trial is looking at this, and there are definitely going to be certain subgroups of AML where we are no longer able to demonstrate the benefit of more toxic chemotherapy even for younger patients. But there is a lot of work to be done here because again, the cure fraction of patients, those patients with AML that we have a good chance of curing with standard intensive chemotherapy, we're slightly nervous about messing with that too much because this is a hard disease to cure. But there absolutely is, and the way of the future is to try to figure out—and when I say future, I mean, like, next week. We are trying really hard to pull away the patients who clearly do not benefit from intensive chemotherapy no matter what their age is. For example, TP53 mutations, which are incredibly difficult-to-treat mutations across all of oncology, AML is no different. TP53 mutations should very rarely be given ultra-intensive chemotherapy as opposed to something like decitabine and venetoclax, because the intensive chemotherapy is just harsher. It doesn't work better. So, there absolutely are patients that we already know, "Okay, you're 28. You can handle anything that I can give you. But just because you can handle it doesn't mean it's better for you." And I think that that nuance and what the Paradigm trial is trying to get at is, "Okay, is the world moving away from intensive chemotherapy altogether?" Well, maybe, but we need to go subgroup by subgroup, it's incredibly important. I think from a use case scenario, what I would tell people is that we understand that, okay, I've done this a million times. I was part of the trial. I know what I'm doing when a patient comes in. But if I want to teach a fellow, the fellows are losing their minds because they will say to me in clinic, "Well, how come you did it this way for this lady, but that way for that lady?" We don't want to be doing anecdotal medicine. We don't want to be doing things in such a bespoke way that you literally can't figure it out from patient to patient. So, this is a plug on this podcast. The patients want this. Stay on the clinical trials. My patients who are on this clinical trial, they want to know, like, "Do I actually have to take this forever? Can I take five days instead of seven days of venetoclax?" So, the patients are actually incredibly beating the band, not only for additional clinical trials to try to figure out, "Now that I'm on this therapy that works, fine, great. How do I get off it?" So, that is very important. And the second thing is to make sure that the real trend, and I hope this is going to be AI-assisted too, but there is an incredibly important trend in oncology to publish real-world data experiences. This used to be the crappiest data that was relegated to some terrible journal that nobody would read. And now, real-world data, because data collection is better and because electronic medical records are available, is allowing us to see, okay, what happens outside of the clinical trial? How does this look when hundreds of patients get this in community settings and in other settings? And how can we put together guidelines for families, for patients, and for doctors that say, "Hey, by the way, you may want to use the following tricks of the trade when you're trying this, new recipe"? Manish Shah, MD: For our listeners, participating in clinical trials is really incredibly important for all the reasons that Dr. Roboz mentioned. And it helps us advance care. But there are lots of criteria that people need to pass to get into a trial. And the benefits of real-world data is that it allows us to now see what a drug or a treatment regimen will do where you don't perfectly fit into the trial, if the creatinine is a little bit elevated or the liver test is a little bit elevated, or whatever reasons. And sometimes it doesn't matter, and sometimes it does. And we won't know that unless we capture this information. Thank you so much for this. What are you most excited for in the future? Dr. Gail Roboz: I want the APL story for as much of AML as I can. I want my molecular target with a better tolerated targeted drug with better monitoring in remission so that I can get in and get out. Get in with therapy that is more targeted, wipe out the cells in a super strategic way, and then measure it so that I can tell the patient, "Okay, it's clean. They're gone." We're chipping away at it. Not every mutation has a target. Not every mutation can be monitored in this type of a one-in-a-million way. But this is the way the field is going. And I would say the cherry on top is that the mixture together of increasingly targeted but more tolerable agents is hopefully moving us away from some of our most harsh and not honestly most effective standard chemotherapy drugs. Manish Shah, MD: we get farther with a more targeted, specialized, nuanced approach. Well, thank you so much for your time today. Dr. Gail Roboz: Thank you for having me. Manish Shah, MD: You can download, subscribe, rate, and review CancerCast on Apple Podcasts, Spotify, YouTube, or online at weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments, and topics you'd like to hear us cover in the future. That's it for CancerCast: Conversations about New Developments in Medicine, Cancer Care, and Research. I'm Dr. Manish Shah. Thanks for listening. disclaimer: All information contained in this podcast is intended for informational and educational purposes. The information is not intended nor suited to be a replacement or substitute for professional medical treatment or for professional medical advice relative to a specific medical question or condition. We urge you to always seek the advice of your physician or medical professional with respect to your medical condition or questions. 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