AML: Latest Treatments

Leukemia Research Foundation:

Hello everyone. Thank you for joining us for the Leukemia Research Foundation's New and Emerging Treatments. Tonight's topic is Acute Myeloid Leukemia, AML. My name is Lindsey Whyte. I am the Director of Programs & Partnerships at the Leukemia Research Foundation. I'd like to take a quick moment to thank our supporters of this conference, AbbVie, Astellas, Daiichi Sankyo, Kite, Merck, Novartis, and Pfizer. We also want to thank our webinar partner Patient Empowerment Network. The Leukemia Research Foundation's mission is to cure leukemia by funding innovative research and to support patients and families. The Foundation has raised over $87 million in support of its mission since our founding in the 1940s, and has funded research grants to over 600 new investigators worldwide. Our support programs for leukemia patients and their loved ones include information and resources, education programs like tonight's, financial assistance, and a directory of other resources on our website.

 

Just a few quick housekeeping items for the program this evening. All participants will be muted throughout the program. If you have already submitted a question at the registration, please know that we have your questions. We received quite a few, so we will do our best to cover as many as possible. You can also type a question at any time into the q and a box at the bottom of your screen. After today's program, you'll be sent a brief evaluation through email. Please do take a moment to complete the evaluation so that we can improve our future programs. Also, this program will be recorded and a link to that will be sent to everyone who registered after the program.

 

We are grateful to have Dr. Matt Christopher from the Siteman Cancer Center at Barnes Jewish Hospital in St. Louis with us tonight to present on AML. Dr. Christopher completed his MD/PhD at Washington University in St. Louis in 2010, and he joined the faculty there in 2017 as an Assistant Professor in the Division of Oncology, Section of Leukemia and Bone Marrow Transplant. He divides his time between taking care of patients with blood cancers and developing immunotherapies for patients with AML. He also was the recipient of a New Investigator Research Grant from the Leukemia Research Foundation in 2021 for his project titled Resensitizing Relapsed AML Cells to the Graft Versus Leukemia Effect after Allogeneic Hematologic Stem Cell Transplantation. Dr. Christopher, thank you so much for joining us tonight. I will turn it over to you.

Dr. Christopher:

Okay, thanks. Let me share my screen here. Everything look good?

Leukemia Research Foundation:

Yes.

Dr. Christopher:

Okay. So we're going to talk about AML and we're going to talk a little bit about some of the slow but steady progress that's been made in treating AML over the last seven or eight years. So AML is, if you look down here at this red bar here about every year in the United States, there's about 20,000 cases of AML acute myeloid leukemia. So it's about, it's not nearly as common as breast cancer or lung cancer. It's about the same, but it's about as common as say, ovarian cancer. It's one of the more common blood cancers. The other kind of acute leukemia is called ALL. So this is this kind of acute leukemia as most common in kids, and AML is the one that's most common in adults. So acute leukemia.

 

So what that means is if you have leukemia, that means that your blood and your bone marrow are filled with bad cells. Leukemia cells, sometimes they're called blasts. And what happens when your bone marrow fills up with these, is it crowds out the good cells in your bone marrow. So the good cells are the good white blood cells that can fight infection, the red blood cells that carry oxygen around your body and the platelets, which are the little cells that could prevent bleeding. So when patients with AML come in here, let me make a little pointer here. When the symptoms that you have, if you present with AML, are the symptoms of your bone marrow failing because it's full of all these bad cells. So patients will come in with just profound fatigue. Sometimes they have some bleeding or some bruising. Often a patient will come in with an infection because those good white blood cells are also being crowded out by the bad cells. And because these are white blood cells that are expanding, they cause an inflammatory sort of situation in your body.

 

So a lot of patients will have bone pain, sometimes fevers and just malaise. People don't want to eat, people don't want to do anything. And these are the symptoms that people have. And so typically they'll go to their doctor and the doctor will run a simple blood test, look at the blood counts, and they'll say, oh my goodness, your blood counts are not right. You've got too many white blood cells or not enough, sometimes not enough white blood cells and not enough of the other good cells. So why do you get AML? How does it happen? We've learned that AML, like every kind of cancer is caused by genetic damage to cells. And in the case of AML, it's genetic damage to your blood stem cells which live in your bone marrow. Now, when I say genetic damage, I don't mean inherited damage. I mean this is damage that happens to your life during your life to your blood stem cells. In most cases, it's not inherited. Most of the time patients do not have a family history of AML, but there are exceptions and there are families that sometimes can pass a predisposing mutation from parents to kids.

 

So what causes this genetic damage? Well, we don't really know most of the time, as far as we know, it's bad luck. But there is one thing that happens to people that definitely can raise your risk of getting AML, and that is getting any kind of chemotherapy or radiation for any other kind of cancer. We know that something like five to 7% of patients who get chemotherapy for let's say breast cancer or lung cancer, even if they're cured from that other cancer, they can down the road develop what's called therapy associated AML or t-AML. We also know that patients who have a history of bone marrow failure syndromes, so other bone marrow problems that can happen, which also happen because of genetic damage to your blood stem cells, those people can, sometimes their bone marrow problems can sometimes turn into AML evolve into AML.

 

And so those are called secondary AML. But about 70% of AML is what's what we call de novo. It's not secondary, it's not therapy associated. We don't know why it happens. And typically when it happens to a patient, it hits you like a ton of bricks. Patients are well, and then over a period of just weeks, often they will develop symptoms and they'll ultimately receive this terrible diagnosis. So AML is, it's a bad actor, it's a bad disease, it's frequently fatal. So this is a special plot. So we're going to look at a lot of these plots in this talk. This is a way that the doctors and other medical people like to show outcomes in a disease. It's called a Kaplan-Meier plot. And on this left axis, you see the percentage of patients that are alive at different time points and the time points are plotted on this axis.

 

And so if you just kind of focus on this purple line here, this is survival in AML, and it just kind of shows us two things. The first is that only 50% of patients are alive with AML in this purple line at 11 months after diagnosis. That means by 11 months, about half of the people who've been diagnosed with AML during this time period have died. The other thing that it tells us is if you kind of look out further out to 36 months, 48 months, these are people, the line kind of becomes steady, so no more people are dying. And so these are people that appear to be cured from AML. And so if you look at the purple line, you can see maybe 30 or 40% of patients can be cured. Now, the different colors of lines here in this sort of retrospective study show outcomes in AML throughout the years.

 

So the most recent years in the study, 2010 to 2017, this is what the cure rate was. And as you go back through time, it gets lower and lower. So there's been some slow improvement in our outcomes in patients with AML. Well, so one of the things about AML and outcomes in AML is that it depends on the age of the patient. So for example, in the most recent cohort, about 60 or 70% of patients in this purple line are being cured if they're under the age of 40. But with each decade as patients get older, this cure rate seems to go down. And patients that were older than 70 up until recently really had pretty poor outcomes altogether. And so this is one point about AML is that AML outcomes worsen with patient age. And unfortunately, the median age at am ML diagnosis is 68. That means in the disease, half of the patients who are diagnosed with AML are older than 68. So more than half of our patients are falling into this category that's very difficult to treat successfully.

 

So part of the problem with AML outcomes historically has been that we've had this traditional approach to AML treatment that really hasn't changed since the 1980s. So when patients are diagnosed with AML, sort of traditional way to treat them is with something called induction chemotherapy. So probably people listening right now are familiar with this seven plus three. So a patient is admitted to the hospital, you're usually in the hospital for a whole month and you get this chemotherapy called seven plus three.

 

It's called seven plus three because one of the drugs cytarabine is given is a constant infusion over seven days. And the other drug, there's a second drug that's given over a period of three days. So these are bad old fashioned chemotherapy drugs that've been around since the eighties. And they can cause all of the things you think about with chemo, they cause nausea. They cause diarrhea, they can cause mouth sores. They make your hair fall out, they make you tired. So it's a hard month that you're in the hospital during that induction. And so what happens after that month? Well, after that month hopefully you're in remission. And then we ask the patients and the doctors ask, can this patient be cured with chemotherapy only? And in a subset of patients that we think we can cure them, and we think these patients that we think we can cure, this is based on our experience with patients who have certain mutations, certain mutations with AML have better prognosis and we think we can cure you with chemotherapy only.

 

And if we do, then you get a few more rounds of consolidation chemotherapy and then you're done. But the majority of patients though, we don't think we can cure with chemotherapy only. And if possible, if they're in good enough shape and if they have a donor and if they're up for the rigors of a hematopoietic stem cell transplant from a donor, then that's the recommended course of therapy. So these stem cell transplants, these used to be called bone marrow transplants in the old days, that might be what some of the people listening know these as. And then of course, some of the people who we try to cure with chemotherapy only they relapse. And if they relapse, then they have to be treated with salvage chemotherapy followed by a transplant. That's the only way to cure them.

 

So there's a couple problems with this traditional approach to AML treatment. The first is that it's kind of a one size fits all approach and it treats every patient the same way while we've learned over the last 10 or 15 years that patients' AMLs are all different. The second problem that we sort of alluded to before is that many patients with AML are older or they have other medical problems and they can't safely receive these intensive treatments. So this is what I'm talking about when I say AML is really many different diseases. These lines show patient outcomes classified by different mutations, right? Each of these different colors is a different mutation that is found in the AML. And you see that some of these patients have cure rate of 80%, 60%, 55%. So these patients do quite well with the traditional chemotherapy, but then there's others that don't do well at all. This blue line here, these inversion three patients, so only a 3% cure rate that is really dismal.

And so you can't really, what we're trying to get away from is treating everyone with AML the same way because the traditional therapy works well in some cases, but it doesn't work very well in other cases.

(00:14:59):

So this is another analysis. This analysis was done here at Washington University about 11 years ago. It was published. We looked at the AML genomes in 200 patients with AML. So each one of these little columns is a patient with AML. And on this left hand side, these are the most common mutations in AML. And so you can kind of go down patient by patient. Some patients have just one mutation, but most patients will have - so this guy here has got this mutation here, he's got this WT1 mutation. He's got some other mutation down here. Well, it turns out that when we looked at 200 patients, over 70 different genes are mutated in multiple patients with AML, and most patients have two or three of these 70. So as you can imagine, there's a lot of different combinations of mutations that can drive a given patient's AML.

 

The most common mutations are this gene here called NPM1. It's found in about a third of patients with AML. The other two most common commonly mutated genes are DNMT3A, and then FLT3, which we're going to talk about. So each of these genes is mutated in about 30% of patients with AML, but sometimes they're mutated in the same patients. And so that can affect how many patients we can treat. These IDH1 and IDH2 genes I'm going to talk about those a little bit later too because we also have new treatments that target these mutations.

 

So traditional AML therapy is too intensive for many patients, like I mentioned. So in the past, some patients who couldn't take the intensive chemotherapy, they received what I sort of describe to people as light therapy with these other drugs azacitidine and decitabine a kind of chemotherapy, but they don't have the same side effects. They don't make your hair fall out, they don't make you sick to your stomach. They don't really have too much by way of side effects. And so they are appropriate treatments for patients that maybe have other medical problems and cannot tolerate the intensive chemotherapy. The problem with these treatments is they've been around a while, but they don't work particularly well. So here's the outcome. Patient outcome curves in patients treated with this decitabine versus patients with basically treated with supportive care. So this is really no treatment at all other than blood transfusions. And so if you go out two years or so, there's really only about 10% of patients are alive at that point and the patients treated with decitabine aren't really doing much better.

 

Historically, a lot of patients, even the majority of patients diagnosed with AML, never even received any therapy at all. So this analysis here is kind of pooling these different scientists' reports. So if you go back to the year 2000, this is the proportion of patients not treated in these different reports. Different people went back and looked, and 60 or 70% of patients with AML were not even treated with anything at all back in 2000. And that's because AML patients tend to be older, they tend to have other medical problems. When you present with AML, you're not at your best physically. And the doctors just thought that these people were not suitable for the intensive chemotherapy. You'll notice that over as time has gone on, this number of patients not treated has gone down. And this study ended in 2016. But the number of patients not treated nowadays, as I'm going to tell you why this is actually very low. Most patients nowadays get some kind of treatment with AML.

 

But there's sort of two main goals that we've had for the last seven or eight years within the field of AML. And the first is that we want to develop therapies that targets these specific molecular subtypes of AML. So no more one size fits all. We want to have different treatments for different people, and we hope to improve outcomes for all patients this way. The second is that we definitely need new AML therapies that can be used safely in older patients or patients with other medical problems. This is a real unmet need.

(00:19:42):

And so lemme tell you about the first breakthrough that happened. This is about seven years ago or so. There was a drug called Venetoclax. This was a pill that was invented about eight or nine years ago, and it's a pill that inhibits this protein called BCL2. BCL2 is a protein that cancer cells use to prevent cell suicide. So if you're a cancer cell, you don't want to commit suicide. And so they actually express high levels of this BCL2. Venetoclax was invented to treat certain kinds of lymphoma and chronic leukemias where it works quite well. It was tested in AML and by itself it doesn't work very well. But somebody had the bright idea of combining it with one of these light chemotherapy agents and treating patients with Azacitidine plus Venetoclax together. And in this study that was published in 2020 in the New England Journal of Medicine, this was a study of older patients or patients with medical problems who couldn't receive that intensive traditional induction therapy. And some of the patients received AZA were treated with Azacitidine alone. And you see it two years after treatment, as we expect, as we've shown before, about 10 or 20% of patients are still alive. If you add Venetoclax to this, well, this is more like 30, 35, 40 even 40% of patients are still alive with two years. So that may not seem like much and it's still far short of what we need. But I'll tell you from experience that this is beautiful when it works out. I've got some patients in my clinic in their eighties who were diagnosed three, four years ago with AML, and they knew it was a terrible diagnosis, but here they are, three or four years later, they come into clinic, they get outpatient treatment with this light chemotherapy. They come in about every eight weeks or so, and then they go home and they travel and they see their grandkids and they live their lives. And so when it works, it's a great treatment. It just doesn't work often enough.

 

But the really exciting thing about Azacitidine and Venetoclax together is that we're realizing we can add other drugs on to the Azacitidine and Venetoclax because they don't have such strong side effects. So for example, there's another drug called Ivosidenib that was developed about seven or eight years ago, was approved for AML, and it inhibits this protein I mentioned called IDH1. This is one of the mutations that can be seen in a subset of people with AML, and it turns out that you can add ivosidenib to azacitidine. And this is a study published a couple just two years ago. Again, some of the patients were treated with just azacitidine alone. And as we've seen before, maybe 20% of them or so are still alive two years after treatment. But if you add ivosidenib, you double the number of patients really that are still alive two years out.

 

Even more excitingly, you can put three drugs together so you can add the ivosidenib to azacitidine and Venetoclax. Now, this is a very preliminary study. Not very many patients, only six patients, six 13 patients in these different arms. But if you look at this blue line and this purple line, these are patients who got all three drugs, Ivosidenib, Venetoclax and Azacitidine, and these are two different doses of Venetoclax that they were given. But look at this. I mean, if this holds up, then it would be amazing if we could cure 80% of people two years out or have that many people in remission. So like I say, it's very preliminary. It's not very many patients, and we haven't followed them for very long, but it certainly is exciting.

 

What other drugs can be added on to Azacitidine and Venetoclax. Well, I mentioned one of the three most commonly mutated drugs is called FLT3. I'm sorry, one of the three most commonly mutated genes in AML is called FLT3, and there's been a lot of interest for many years in developing inhibitors to FLT3. At this point, there's actually four drugs, sorafenib, midostaurin, quizartinib and Gilteritinib that are all FDA approved FLT3 inhibitors. And so we're learning how to use these to treat patients with AML. So this was a small study, only 12 patients in this arm, 13 patients in this arm. If you just look at the blue, think about the blue line. These were newly diagnosed AML patients, 12 newly diagnosed AML patients that were treated with a FLT3 inhibitor plus decitabine plus Venetoclax. And again, look at this. Look at how many patients are still alive 24 months out. Again, it's preliminary and it's not very many patients at this point, but it's intriguing. This is a study from MD Anderson where they did a very similar thing. They used a different FLT3 inhibitor called Gilteritinib. They added it to Azacitidine, they added it to Venetoclax. So three drugs, and again, this is 30 patients, but 80% of them are still alive two years after the treatment starts. So these are much better outcomes than historically we would've expected.

 

I should mention that when you add these three drugs, even though each drug doesn't have too much by way of side effects, the three of them together, the more drugs you add, the better your results are. But you can sometimes have more side effects, especially in terms of suppressing these drugs, suppress your good blood cells. And so patients who are going through this need careful follow up with their doctors and nurses and other medical people, they'll need frequent transfusions and they need frequent monitoring to make sure they're not developing infections.

 

Well so those are using these targeted drugs with decitabine or Azacitidine. But what about is there a way to use these targeted drugs along with that traditional intensive chemotherapy in younger patients? This is something that we're also very interested in doing and we're starting to learn how to do this. So this was a study where these patients got standard seven plus three induction chemotherapy, and then they were either added this IDH1 inhibitor or this IDH2 inhibitor, and this was a pretty good size study. There were about 150 patients altogether, and it shows that the, although there's no, it's just a one arm study, everybody in this study got the targeted therapy, but it's very, very impressive survival two years out.

 

Another study that came out where intensive chemotherapy was used alongside a targeted drug was this study from 2017 where patients got standard induction chemotherapy plus a FLT3 inhibitor called midostaurin. And you can see that there's improved survival even five years out. There's more patients alive in the midostaurin group than the placebo group. The I will say that this improvement here is real, and this was done in a high number of patients, but it's modest, and we definitely want to find ways to get even better outcomes than this for sure.

 

And the last new drug I'm going to talk about, it's sort of an exciting class of drugs making a splash in AML are these menin inhibitors. So menin is a protein that's certain kinds of leukemia, leukemia with certain mutations, mutations in this gene called MLL or mutations in this NPM1 gene, they depend on menin. They're addicted to menin to survive. And so if it turns out some scientists figured out that if you inhibit menin with a drug, then the leukemia cells can die. So this is a very preliminary and early sort of results published in Nature, the journal Nature, just last year, each line here is a patient. So they treated 60 patients, and this is how long the patient has been on the drug shown on this axis. So the blue lines are patients with the MLL who had the MLL mutation, and the pink line is patients who had the nucleophosmin - the NPM1 mutation. These little white diamonds here - this is when a patient has had a complete remission. A complete remission means that all of the bad cells are out of your bone marrow and your good cells, the good cells have come back, and most importantly, you feel better. So that's a good outcome in somebody with AML. And so you see how many of these little white triangles there are. Now, one of the problems is that these were all patients who had had some kind of standard therapy before and they relapsed. And so they're being treated with this menin inhibitor. So on the one hand, it's impressive that we were able to get this many complete remissions. Unfortunately, these little pluses here mean that the disease came back. So the patient was in remission for a while, but the disease came back.

 

So it's a mixed kind of good news, bad news, these drugs. And there's other companies that are making different menin inhibitors that might work better. The other thing is we're trying to figure out how to use them better. And there's clinical trials now where this Revumenib is actually given upfront in newly diagnosed patients where we think it might work better. There's another study where it's being given as maintenance therapy in patients who have gone in remission with these mutations, but we're trying to prevent the disease from coming back.

 

(00:30:23):

So this is kind of the last slide I wanted to show. Each of these little yellow circles is a new drug that was approved by the FDA for AML. And so if you kind of just going back to 2017, so we haven't even talked about some of these like this one or this one, and some of these drugs that we did sort of briefly talk about, but there've been 11 new drugs approved since 2017. And if you go back, it was only, these are 1, 2, 3, 4, 5, 6, 7 drugs approved all the way from 1969 to 2005.

 

So to conclude, I would say that the last seven years have seen more drugs for AML approved than the prior 50 years, and that's exciting. I would say that each of these drugs I've shown you that they have improved patient outcomes a bit, but not as much as we would hope. So patient outcomes still remain behind where we'd like them to be.

 

But I think that as we learn to use these new drugs better, we'll hope to improve the survival and decrease the side effects and toxicity that patients have to live with. Finally, one thing I didn't really talk about because there haven't been really any that have been shown to work very well in AML, but there's immunotherapy. Some people listening might be aware that in the other acute leukemia, ALL CAR T-cells, bispecific antibodies are very effective and we're trying to develop those now for AML.

 

That's all I had to say today.

 

Leukemia Research Foundation (00:32:12):

Wonderful, thank you. I think that was a very good overview of where things stand in terms of the approach to patients right now with AML, it sounds like a very important takeaway is this knowing kind of what your sort of personal profile is in terms of the genetic mutations. And for patients that are on the phone, hopefully they are able to have conversations, productive conversations with their clinicians to understand what their profile is and make sure that the treatment they're receiving is consistent with that.

 

So we're going to open it up for questions. I don't see any right now in the Q&A. I want to remind everyone that if you have a question, please go ahead and click in this Q&A at the bottom of the screen and enter your question and you can enter it anonymously, if you prefer, and we can cover the questions that anyone has. And in the meantime, I'm going to just bring up some questions that were submitted during the registration process. So one person specifically asked, and I think you touched on this briefly and early in the presentation, the individual said his wife had AML and he has a daughter who is 16 years old and was wondering if he should worry for his daughter. Or maybe you could just comment on that.

Dr. Christopher:

Yeah, so this is something who wouldn't want to know. Of course, first I'd say I hope she's doing well. This of course is a terrible diagnosis, but it is a curable disease and I hope your wife is doing well. It's the most human thing in the world to worry, since we know that some kinds of cancer do run in families. I alluded to before the idea that most of the time AML is not inherited most of the time it's just something that happens to the patient and their children are not at any risk. But I'll say that nowadays, I'm sure the patient that we're talking about has had all of her genes sequenced and the doctors have probably identified which are the genes that have mutations. Most of the time just by looking at that, they can tell if that's a gene that might've been passed down to your children or if it's one that's probably not passed on, if it's one that just happened in some of the cells in your wife's bone marrow. So if you talk to your doctor, they can look at those and sort out whether there's any chance that this could have been an inherited gene. And if so, then they can do further testing to see if that gene has been passed down.

Leukemia Research Foundation:

And I'm going to share in the chat a link to an organization called Facing Our Risk that focuses specifically on questions to ask your doctor about those specific concerns. If you are an individual or you have a family member who is affected by any kind of cancer and you want to understand, is this something that could potentially impact other family members? And this organization focuses on that. In the meantime, let's also,

Dr. Christopher:

I'm just going to interrupt you. I want to kind of touch on one of the things you mentioned before, Lindsey, about talking with your doctor and working as a team. I mean, I have patients who sometimes apologize to me because they've been doing research. They will say, oh, I know I'm not supposed to be going online and finding out things. And then they'll proceed to ask me some very good questions that they've researched and figured out. So I want sort of put out there to everyone who's watching this that doctors like it, and we sort of depend on you guys and expect you guys to do some research and to ask some good questions. Because our job, when you have a diagnosis with a disease like this, it's overwhelming and it's usually not something that you've ever thought of before. And you probably don't know anyone who's ever gone through this before, but our job is to help you get perspective. We're the ones who know about what it's like to live with these diseases. And so yeah, please always, no question is it is really true. There are no bad questions. Okay, sorry about that.

Leukemia Research Foundation:

On that topic, there's a question in the Q&A. Are there any statistics on the success rate of Olutasidenib?

Dr. Christopher:

Yes. So I mentioned ivosidenib and enasidinib. These are IDH1 and IDH2 inhibitors. So this new drug that the listener is asking about is another, it's a new IDH inhibitor. It seems to work a little bit better some than the older IDH inhibitors. So this [pointing to the timeline slide in the presentation] is ivosidenib that was approved by the FDA in 2017. This is one of the newest, one of the more recently discovered drug. So right now it's only approved as a single agent, patients who have had other AML therapy and then relapsed. But like I say, we're hoping to be able to, as we learned how to use these drugs better, we're hoping to use them in combination with other drugs to really improve those patient outcomes.

Leukemia Research Foundation:

Okay. Another question that was submitted during registration. What are the true long lasting effects from chemo, physical and mental? I'm almost two years post-diagnosis and, while physically I feel okay, mentally I'm not.

Dr. Christopher:

Yeah, so this is a great question. It's something that I hear all the time. So we focus, I spent the entire talk focusing on cure rates and survival and how we are working hard to make those better. And one issue though that comes up with this question is the people who do survive, what kind of things do they live with? It's very common. I've heard so many patients say that after 1, 2, 3 years after the chemotherapy, they still don't feel normal. They really don't feel normal like they did before. There's a lot that we don't understand about this. You'll hear patients talk about chemo brain or brain fog. They just don't feel like their thinking is the way it was before. We don't know a lot scientifically about this, and it's something that people are researching and trying to learn more about. One of the things that we've done at Wash U and that every cancer center really around the country is doing, are having these survivorship clinics. So survivorship means dealing with medical problems and the patients who've been cured of the original disease but are still having medical problems. And we've learned a lot through experience about some of these things. Patients who've got chemotherapy for AML, they're at a higher risk for heart disease down the road. They're at a higher risk for memory problems and other things like that. They're ironically, they're at a higher risk for getting another cancer because of all the genetic damage that the chemotherapy can do.

 

What I tell patients who have noticed that their thinking is not the same as I say, that we don't really have any good treatments for that or a ways to fix that. It's something that a lot of patients notice have noticed. So you're not alone. What I recommend patients do is they work with whatever their problem is. If they're having memory problems, then they should go see one of those specialists. If they're having heart disease or something like that that's been accelerated by their chemotherapy, then we try to make sure that they're just plugged into all of the best medical care that exists. But unfortunately, until we figure out a better way to cure these diseases than chemotherapy, this is just something that patients are going to have to live with, I'm afraid.

Leukemia Research Foundation:

Okay. We have a question in the chat. I was diagnosed with AML at age 68 and was part of a clinical trial for my induction therapy with Venetoclax, to which I responded very well. I had a subsequent bone marrow transplant. I'm 20 months after bone marrow transplant. My question, did any of the patients in your studies have subsequent bone marrow transplant or were they only treated with the various chemo treatments?

Dr. Christopher:

Ah, that's a great question. Yeah, I was showing those patient outcomes and some of those patients went on to get bone marrow transplants and some didn't. So it just depends. It just depends on the study. The first ones I showed were patients that were older and had some medical problems and they were treated with Azacitidine plus some targeted therapy. And on those studies, some of those patients, it varies with the study, but in each of those studies, a minority, like let's say maybe one fourth or one third of those patients went on to get a stem cell transplant. Of the latter studies I showed where patients got induction chemotherapy plus a targeted agent just like this patient who's asking this question, who got induction therapy plus Venetoclax? Most of those patients went on then to get stem cell transplants. The bottom line in AML is most patients, if they can go through a stem cell transplant, we give them a stem cell transplant. Because I mentioned at the very beginning, it's only a small number of people that we think we can cure with chemotherapy only.

Leukemia Research Foundation:

Okay. There was one question in the registration that was asking about a very, it seemed like kind of a rare form of leukemia cutis.

Dr. Christopher:

Oh, leukemia cutis. Yeah. So I said when I was at the very beginning, that leukemia, it's a cancer of the blood that involves too many cells, too many white blood cells in your blood or your bone marrow. Well, it turns out that one of the problems with AML is these cells really do grow. They grow quickly and explosively. And although they mostly are confined to the bone marrow and the blood, they also sometimes, because it's blood, right, it's flowing all around your body. So sometimes they can stick places. So you can actually get collections of AML that form a big lump anywhere in your body. Sometimes they even go to your brain, which is a terrible place to have AML. So leukemia cutis is like the Latin word for skin. And so what that means is that the leukemia is gone into your skin.

 

So it's true that when leukemia, when AML or any leukemia goes into your brain, it's hard. It's a problem. There's worse outcomes. And the reason for that is because most of the traditional chemotherapy agents we use, they don't cross the blood brain barrier very well. And so it's harder to get a patient in remission. It's harder to kill all those leukemia cells. Fortunately though, with leukemia cutis, if you've got leukemia in your skin, it turns out that the chemo that we give you to treat the leukemia that's in your bone marrow and your blood, it gets into your skin really well also. And so if the leukemia is sensitive to chemo, then we just treat 'em with the same. If you've got you've leukemia, cutis, leukemia in your skin, we just give you the same chemo that would give you if you had leukemia anywhere else. And it turns out that the cure rates are about the same.

Leukemia Research Foundation:

Great. We got one more question regarding an individual said he was treated in 2021 with Venetoclax and Vidaza is Vidaza known by some other name because he did

Dr. Christopher:

Not. Yes. Vidaza. So I was showing the Azacitidine plus Venetoclax. So Vidaza is the other name for Azacitidine. Yep.

Leukemia Research Foundation:

Azacitidine. Okay. My husband was just diagnosed at 80, is a stem cell transplant and option? That sounds like a very specific situation for the patient.

Dr. Christopher:

So her husband was diagnosed at age 80 and they want to know if stem cell transplant is an option. Well, it's hard. It's hard to say. I mean to kind of give a historical perspective, if you go back 20 years, 25 years, patients older than 60 or 65 almost never got stem cell transplants. So over time we've gotten better at giving stem cell transplants. There's less side effects, less toxicity from the chemo. We're having better outcomes, fewer complications, less graft versus host disease. And so gradually the age of patients who are getting stem cell transplants safely is going up. And that's really important because I mentioned that the median age of patients with AML is 68, half of patients with AML are older than 68.

 

25 years ago, more than half of the patients with a AML would be too old, would be considered too old for transplant. Well, nowadays at Wash U and in other centers around the country, we're transplanting people in their early seventies safely. We've not ever transplanted someone who's 80 here. Unfortunately at this time, most centers would just not consider that a safe thing to do. The good news is that patients who are 80 who are getting Vidaza and Venetoclax can sometimes have very long and very good remissions. So I mentioned patients in my clinic three, four years out just getting these drugs and they didn't have to go through a stem cell transplant or deal with all of those side effects and the risk of a stem cell transplant. And they're living large traveling and enjoying time with their families. So I would say probably the answer to the question is most transplanters would not consider transplanting someone in their 80 and their eighties because the risk is just too high.

Leukemia Research Foundation:

Okay, great. Well, I don't see any additional questions. If somebody does have a question and wants to enter it very quickly into the q&a, please do so and otherwise I'm going to remind everyone that we'll be posting the link to a replay of this in a few days and it'll be on our website and we encourage you all to take a look at it again. And if you have friends or others you think could benefit from it, please share the link to the replay. And we also will be sending a link to a questionnaire, a survey to just invite some feedback on this program. So we hope it was helpful for you. Do see, oh, here we go. We got a few more questions. Let's just see if we can go through these quickly. How many Venetoclax and Vidaza cycles?

Dr. Christopher:

Yeah, that's a good, a great question. So we don't know. The standard is to continue treating people with it as long as they're not having side effects and as long as it's working. And the reason is that we're not sure. I mentioned that some patients, some of my patients are three or four years out on Vidaza and Venetoclax and still in remission, but we're not sure if we stopped. The question is if we stopped, would the AML come back? So there is some data actually there's some retrospective data from patients who have had to stop treatment for one reason or another who seem to still be in remission. So probably some of these people that we're giving Vidaza and Venetoclax to for many cycles, probably some of these people are cured. The problem is we don't know which ones. We don't really know which ones.

 

And so we're hesitant. I'm hesitant to stop treating patients altogether as long as they're tolerating the treatment and the treatment really doesn't have too much by way of side effects. I'll say one sort of compromise that we do that I do with my patients and most other doctors do as well, is if a patient's having a good remission is we deescalate the therapy. So instead of every four weeks, they might come in every six weeks or every eight weeks instead of 14 days or 21 days of Venetoclax, we give them five days or seven days of Venetoclax so that the period where their blood counts drop isn't so long, they don't need so many transfusions and they feel better.

Leukemia Research Foundation:

Okay, great. And then we have a question here that is initially very brief and then she goes on to clarify, can you comment on when to administer maintenance AZA and Venetoclax after a stem cell transplant? What is the criteria? The original AML was a high risk mutation.

Dr. Christopher:

Right? So that's another thing we're starting to learn more about is after stem cell transplant. The main risk, actually the main complication is that the AML can come back. When a stem cell transplant doesn't work, more often, that's the most common reason why it doesn't work, is the disease comes back and when it does, it can be very bad. It can be very hard to control again because the patient's just been through a stem cell transplant. So more and more we are trying to prevent that from happening because it's better to prevent it than to have to deal with the disease when it comes back. There are a lot of clinical trials here at WashU and elsewhere where patients are being given a hypomethylating agent like Venetoclax or Azacitidine or Decitabine plus Venetoclax as a way to do maintenance. And there've been a number of small studies that have suggested that it might be of benefit in preventing relapse. And so we're all very interested in doing this and testing it out. The problem is that after transplant, your bone marrow is not very strong. And so a lot of patients they don't tolerate even as gentle as Decitabine and venetoclax are or Azacitidine and Venetoclax, they'll have big problems with low blood counts. So it's kind of balancing the complications you can get from having low benefits or from having low blood counts with the benefit that we think is happening of preventing relapse. So it's something we're still learning about.

Leukemia Research Foundation:

Okay. The last question, I'm not sure I understand this one. How soon can one go into a stem cell transplant? Having a donor.

Dr. Christopher:

How soon can you go into a stem cell transplant? What was the last part

Leukemia Research Foundation:

Having a donor.

Dr. Christopher:

Well, I mentioned that most patients with AML wind up getting transplanted unless they have what we consider to be good risk mutations. And so during that long period in the hospital that induction, one of the first things we do is we try to find a donor. And so you could have a donor who's related to you, a family member, or you could have an unrelated donor even if we're not going to transplant. So we wind up not transplanting somebody. We like to have a donor identified that we can use. So whether or not we decide a patient should get a transplant or not, depends on a couple things. The first is it depends on what kind of shape they're in after that induction chemotherapy. It depends on whether they or not they're in remission after chemotherapy because we know that transplants really work the best if you're in remission. And the third thing is if you are in remission, it depends on how fast we get you to transplant. Depends a little bit on how much your risk of relapsing before transplant is.

 

So we try to find it, to answer the question, I would say we try to find a donor as soon as we can in case we need it and then we see how it goes with that induction chemotherapy. If you get in remission but we think you have high risk disease, we'll move you to transplant pretty quickly. And sometimes the donor that we choose depends on how fast we think we have to move. Unrelated donors work really well and they're usually younger and have got great stem cells and everything like that, but it can sometimes take a few months up to a few months to organize to find that unrelated donor wherever he or she is in the world and get their stem cells. So sometimes if we're really in a hurry, if we think the patient has just a narrow window of being remission before they relapse, we'll go with a family member, even just an HLA half matched family member because we can usually organize a family member sometimes in just a matter of a few weeks. I hope that answers the question

Leukemia Research Foundation:

Well, they did add that there's a sister with a 10 out of 10 match and it's an aggressive AML, so it sounds like,

Dr. Christopher:

Well, so it sounds like if there's a sister who's a match, that's a good way to do it. The business of HLA matching, it was something that was very important 20 years ago because if you didn't have a fully matched 10 out of 10 donor, the risk of graft-versus-host disease would go up significantly. We've come up with some new ways of doing transplants that really mitigates the risk of graft versus hosts disease and people still get it. But I even five or six years ago, I would see patients in the hospital, which is terrible life-threatening graft versus host disease. And I won't say we never see that now, but it's much, much less common and it has to do with how we even from unmatched or not fully matched donors since it just has to do with this new technique of giving transplants.

Leukemia Research Foundation:

Very good. Well we are just about at time, so I think it's probably a good time to say thank you and as I mentioned before, we'll be following up shortly with a link to the recording as well as a request for you to fill out a quick survey to give us some feedback on the program. We are very grateful to Dr. Christopher for his time and for sharing all this great information about where things stand currently with AML treatments and research in progress, clinical trials. And we hope that everyone has benefited from this and hope you all have a great evening. Thank you so much.

Dr. Christopher:

Alright, thank you Lindsey. Thanks for inviting. Thank you.