Gabriel Mannis, MD
Stanford Cancer Institute
Interview Date: September 13th, 2021

Dr. Gabriel Mannis of the Stanford Cancer Institute is studying what could become the first all oral therapy for older adults with newly diagnosed AML. The combination of venetoclax and decitabine with cedazuridine (a combination medication called ASTX727 or Inqovi) would provide older adults and those who cannot tolerate standard intensive chemotherapy a much needed alternative treatment option. Dr. Mannis shares details about how hypomethylating agents combined with venetoclax is an effective combination for older adults with AML and how oral therapies can give patients the freedom to live their lives without being confined to a hospital room. Medication options for older adults with AML are significantly advancing and becoming more effective. This exciting trial aims to add another treatment option to a patient's arsenal. 

To learn more about the trial being discussed in today's episode,

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

Before we get started with today's show, I'd like to mention a few upcoming events. On September 30th at 12:00 p.m. Central, I will be doing a radio show with Dr. John Reagan of Lifespan Cancer Institute at Rhode Island Hospital about immunotherapy options for AML patients who relapse after stem cell transplant. He will discuss his clinical trial looking at whether the drug gemtuzumab followed by an infusion of blood cells called leukocytes from a donor can stimulate the immune system to potentially fight AML. It will be an exciting and informative hour-long discussion, and you can call into the show live to ask Dr. Reagan your questions at the end. 

Also, on October 25th at 2:00 p.m. Central, I will be hosting a radio show with Dr. James Blachly of the James Comprehensive Cancer Center at Ohio State, who will be giving us an overview of the current landscape of AML clinical trials, so we can get a sense of what's being studied and what types of new treatments appear to be promising. We will have more information about both of these upcoming radio shows posted this week on our website, and you'll be able to register for them at healthtree.org/aml/community.

As a reminder for today's show, if you have joined us online and would like to be able to ask Dr. Mannis 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. 

Treatment for newly diagnosed older AML patients is improving dramatically. We've always thought of the standard of care being 7+3 intensive chemotherapy. And if someone could not tolerate that due to their age, health status, or other medical conditions, then there wasn't much else left to offer them. Fortunately, there have been many new drugs recently approved for older individuals, and researchers continue to try to look for new therapies and new combinations of these drugs to better serve these patients. 

In today's show, we are very fortunate to have Dr. Gabriel Mannis with us from the Stanford Cancer Institute in California. We are so pleased to have you here with us on the show today, Dr. Mannis. Before we get started, let me provide an introduction for you. 

Dr. Gabriel Mannis completed his medical degree at the University of California Davis School of Medicine and did his internal medicine residency and hematology/oncology fellowship at the University of California San Francisco Medical Center. Dr. Mannis is now an attending physician for both the Outpatient Adult Hematology Clinic and the Inpatient Adult Hematology Unit at Stanford University Medical Center. He is also an Assistant Professor of Medicine for the Division of Hematology at Stanford. 

Dr. Mannis is board certified in hematology and oncology. His research efforts focus on three principal areas, including identifying novel molecular and genetic markers as predictors of outcome and of therapeutic targets in patients with acute leukemia, advancing new immunotherapeutic approaches for the treatment of acute leukemia, and evaluating the role of early advanced care and end-of-life planning in patients who undergo hematopoietic cell transplantation. He currently serves as principal investigator for several AML-focused clinical trials.

Thank you, Dr. Mannis, for joining us today.

Dr. Mannis: Thank you, Katie. It's my pleasure to be here. I think this is a great thing you guys are doing. 

Katie: Thank you. We're so happy to have you. Let's go ahead and jump into our discussion. So I'd like to start by having you describe the overall treatment landscape for older adults with AML. Can you talk about the changes that have happened over the years in treating these individuals? 

Dr. Mannis: Sure. I think to step back a little bit, just AML in general is one of the most common leukemias in adults, and it tends to be more common as people get older. So the average age of diagnosis is around 70. So while people of all ages can get AML, it tends to be more common in older adults with more than half of people being diagnosed when they're over the age of 60. And as you mentioned in the introduction, sort of the standard treatment for aggressive cancers and AML is definitely considered an aggressive cancer. Sort of the historic standard has been to use sort of high-dose chemotherapy, kind of fighting fire with fire approach. 

So for younger patients, those in their 20s, 30s, 40s, we use a combination of drugs called 7+3, which is seven days of a drug called cytarabine and three days of another type of drug, typically daunorubicin/idarubicin. That's sort of the nuclear approach where we give those two chemo therapies that wipes out all of the bone marrow, and we hope that when the bone marrow grows back that what grows back is all good stuff. That approach typically requires patients to stay in the hospital for a month. As you might imagine, there's the potential for a lot of different side effects. So that hasn't been really an option for the majority of patients who are newly diagnosed with acute myeloid leukemia. 

In the early 2000s, a class of drugs called the hypomethylating agents emerged. That really includes two different drugs, azacitidine and decitabine, which actually work in a very different way and have fewer side effects than this sort of standard 7+3 high-intensity approach. So up until, I would say, just a couple of years ago, the standard of care for older patients with AML had been treatment with one of the hypomethylating agents, either azacitidine or decitabine. 

Katie: So it sounds like focusing on the development of treatment options for older adults specifically is really important because of this very harsh sort of standard of treatment. Are there any other things you could elaborate on when it comes to why focusing on research for older adults with AML is a really important area that needs to be looked at more? 

Dr. Mannis: Yeah. It's in part because most AML patients are older, and so there's a huge need for treatments that are not as toxic as the high-dose chemotherapy approaches. As we age, our bodies accumulate damage, whether we like it or not. Most people, when they get to their 60s or 70s, they have other issues. They have heart problems, lung problems, diabetes, things that can make it even more challenging to tolerate various types of chemotherapy. 

When we look at these hypomethylating agents, these are lower intensity chemotherapy medicines. When I say lower intensity, what do I mean? The sort of high-dose traditional chemo drugs that we think of, that we see on TV that people get for breast cancer, lung cancer, that kind of thing that we associate with nausea, vomiting, hair loss, those drugs work by directly damaging DNA in the cancer cells. So it actually causes direct death of cancer cells, but it's not specific to the cancer cell. So there is some collateral damage, and that's why people lose their hair because it also affects hair cells. That's why people get sick to their stomach because it can affect the stomach and the intestines. 

So these drugs that are in the class of hypomethylating agents, they actually work in a very different way where they're their main mechanism of action is not directly to kill cancer cells, but they actually change the signals that the cancer cells send. By this mechanism of hypomethylation, it actually changes the methylation of the DNA and cells use methylation as a way of sort of flagging certain genes to either turn on or off. So these drugs actually just put different flags on the DNA so that the message that is transmitted changes. Because we're not directly killing cancer cells, these are much easier to tolerate. So that was one huge advance with this new class of drugs which now, of course, is not so new. 

The problem specific to older patients with AML who are getting these drugs is that when you look at the big studies where they looked at either azacitidine or decitabine as a single agent, meaning used by itself, only about 20%, 30% of patients went into remission. That means that 70% or 80% of patients didn't go into remission, which I would say is really not an adequate treatment if you know you're a patient and listening to your doctor tell you what your chance of response is. 

So as a single agent, it's been a pretty meager response rate. The responses also can take a while, so most responses don't occur until after three or four months. So it's a long time to wait before you know if something's going to work or not. Even when it does work, the survival for patients that are treated with these drugs as a single agent is still only in the eight to 10 months range. I would argue that this is totally inadequate in terms of the treatments for older patients with with AML. So that's why it's been exciting over the last couple years to see the landscape start to change. 

Katie: Absolutely. Yeah, you gave a great overview of what hypomethylating agents are and how they work. You mentioned decitabine and azacitidine. Are those our two hypomethylating agents, or do we have others? 

Dr. Mannis: Those are currently the two agents out there they are, you know, I would argue more or less interchangeable. They've never really been studied head to head. But in a lot of studies that have done sort of indirect comparisons, it seems like they're just about the same in terms of how effective they are. There are some slight differences. Azacitidine is typically given for seven days out of every month. So a cycle, we consider a 28-day or four-week cycle. So the Azacitidine has to be repeated for seven days out of every four weeks. It can be given either through an IV, or it can be given as a shot under the skin, whereas decitabine is given for five days out of every 28 day cycle and up until just a little while ago, there was only an IV formulation of it. 

Katie: So is it mostly up to the doctor and whichever one they're more comfortable working with, or do they really take into account the schedule that you were talking about when choosing between the two? 

Dr. Mannis: I think it's mostly a comfort issue. I think around the world, the use of azacitidine tends to be more common. Here at Stanford, we tend to use decitabine more commonly in part because of the schedule and in part because I think there's probably not much of a difference between the two drugs. So for patients, spending less time seeing me, I think, is always preferable. So we tend to do the the five-day instead of the seven days of decitabine. But I think it's really up to the preferences of the center. 

Katie: Okay. So when you have a newly diagnosed patient, how do you decide between going the route of intensive chemotherapy or using hypomethylating agents? 

Dr. Mannis: Gosh, that is a tough question. We could probably spend the whole hour talking about that. It's unfortunately often not based in a lot of science. So we talk about fit versus unfit. The factors that go into that age obviously is an important one. I think increasingly it's accepted that around 75 years old, anything above 75 or so, no matter how good a shape you're in, that's probably considered unfit for intensive chemotherapy. But certainly, there are a lot of people under the age of 75 who may also not be fit for intensive chemotherapy, and some of the things we look for are heart function and lung function, how the kidneys are working, how the liver is working. Some of these are things we can glean based on just basic lab tests. Sometimes we'll do lung function test, an ultrasound of the heart to see how the heart is squeezing. 

So looking at various markers of organ function is important. It's also important to assess just how active a patient is. Are they able to get around and do all their daily activities, or do they need assistance with mobility or other tasks? So there's a whole range of things that we will look at to sort of make this decision in terms of what is the safest and most effective treatment option for patient. 

Katie: It definitely sounds like that could be a full episode on its own, like you said. It sounds like there’s a lot that goes into it. 

Dr. Mannis: Yeah, and I think it takes experience. There's, unfortunately, not sort of calculator you can just plug things into there. There have been various attempts to devise things like that, tools that doctors can use. But either they're cumbersome to implement, or they don't capture the full story. So part of it just takes experience knowing sort of who is best going to be able to tolerate what. 

Katie: It sounds like seeing a doctor who sees AML day in and day out has that type of clinical experience and clinical expertise to really be able to help make those decisions. 

Dr. Mannis: Yeah, and then I think that's sort of off-topic here, but I do think for any patient with AML, it is a rare enough type of cancer that it's helpful, you know, even if it's just as a one-time consultation just to make sure that you get the input from someone who really specializes in this kind of thing. 

Katie: Yes, absolutely. So I want to have you give us some background information on your clinical trial in regards to how it came to be and a brief overview of the medications that are used. 

Dr. Mannis: Sure. Before we get into that, one of the big advancements in the last five years is that there has been a new drug combination that was approved specifically for older adults with AML. I told you that the historic standard has been azacitidine or decitabine. Just a couple years ago, a study compared azacitidine by itself versus azacitidine plus an oral drug, a pill called venetoclax. Venetoclax is a drug that's taken once a day, and it targets a protein called Bcl-2. It turns out Bcl-2 is a very important protein in cancer cells. We think of cancer cells as the off switch being broken. So they're stuck in the on phase, and they keep dividing and dividing.  The Bcl-2 protein is part of what helps that on switch stay stuck. 

So this drug venetoclax, actually targets the Bcl-2 protein and allows the cancer cells to turn off essentially and go through its regular sort of cell death pathway. When venetoclax is combined with azacitidine, the response rates were actually doubled. So instead of 20% to 30% of patients going into remission, now with the combination, we're getting two thirds of patients into remission, and instead of taking three or four months to find out if it works, this combination only takes one to two months. So ever since around 2018, the new standard of care for treating older patients with AML has been the combination of this pill venetoclax with either IV or injected azacitidine or decitabine. 

So that has been the new standard of care for the last several years, but it doesn't get around the problem of patients having to come into an infusion center for five to seven days out of every month in order to get their infusions. So in the last couple years, one of the exciting developments has been that of oral hypomethylating agents. There are two FDA-approved oral hypomethylating agents. There's an oral decitabine as well as an oral azacitidine. 

It's important to note that neither are approved for the treatment of newly diagnosed AML. So the oral decitabine is approved for a different type of blood cancer. It's approved for something called myelodysplastic syndrome and a chronic leukemia, chronic myelomonocytic leukemia. The oral azacitidine is actually approved as a maintenance treatment for patients who get intensive induction like 7+3 but then do not go on to get bone marrow transplant. So there are now oral versions of these hypomethylating agents. 

And this study in particular is the first study to look at oral decitabine in combination with venetoclax as a treatment for newly diagnosed older AML patients, and it's the first trial to study those two drugs in combination. It is not FDA approved yet and that's why we are doing this this study to look at whether this combination is safe and effective for patients with newly diagnosed AML. 

Katie: That's really exciting to hear. Who would you say is the ideal candidate for this specific trial? 

Dr. Mannis: That's a good question. So this trial is specifically for older or unfit patients with newly diagnosed AML. And so the way that is defined, at least in this trial and then several other trials before it, it's for patients who are at least 75 years old. If they're not 75 years old, then they have to have specific issues that might make them unfit for intensive chemotherapy. Like I mentioned before, that could include problems with the heart, problems with the lungs, kidneys, liver, etc. But there are pretty strict criteria that you have to meet if you're under the age of 75. 

Katie: The trial is being run with you at Stanford. Are you aware of the other locations? 

Dr. Mannis: Yeah. So at the moment, there are seven centers throughout the country that have this trial open. That includes us here at Stanford, the University of Southern California, Vanderbilt, Roswell Park, University of Chicago, Cornell in New York, and MD Anderson in Houston. I should point out that this is, it's currently in the Phase 1 portion, but it's about to go into the Phase 2, at which point it will expand to a lot of different centers even outside of the United States. 

For those who aren't familiar with sort of how clinical trials work, there are typically three main phases of a clinical trial. Phase 1 is typically a small study where drugs are being given for the first time to people, or they're being combined for the first time in people. So this is the Phase 1 where oral decitabine, which again is only approved for MDS and CMML, is being combined for the first time with this drug venetoclax. So we are looking mostly at this point to see is this combination safe and do drug levels in the blood seems similar to what you might expect when you give the IV form of the decitabine? 

Assuming it looks safe and and relatively equivalent, the Phase 2 portion will then enroll a much larger group of patients, and we'll look not only to see whether it's safe and whether the drug level seems similar but if the efficacy, what you would expect relative to the IV formulation in combination with venetoclax. As soon as the Phase 1 portion is over, we will then hopefully look to see whether we get the same sort of two thirds response rate in newly diagnosed older AML patients. 

Katie: You read my mind about explaining the trial differences. I think that's really helpful for everyone to know, where we are and where it's moving to. So that was great.

Dr. Mannis: Yeah. So just to be thorough, so Phase 3 typically is a very large study where half the people get a placebo and half the people get the actual drug. So in both Phase 1 and Phase 2, everyone gets the drug. And then Phase 3 typically is the kind of study where it's randomized and half the people don't get the same treatment. 

Katie: So while we're on this subject, to move a drug from where it is currently in Phase 1 to FDA approval, can you give us a time estimate of how long that may take? 

Dr. Mannis: The short answer is no. It can be very hard to predict how long it will take to get a drug approved. Sometimes drugs, especially if they're being studied for the first time, if it's a brand new drug, it can take years and years to go from studying in the lab, putting it into people for the first time, and then getting it into a big randomized study. Especially in a disease like AML where it's relatively rare, you can imagine that it's hard to find hundreds and hundreds of patients to enroll in these clinical trials. So unlike things like breast cancer where you can put 1,000 people on a trial within a pretty short time, in AML, it can take a while. 

That being said, it has been a very exciting time for patients with AML in that since 2017, we've actually had nine new drugs approved. And so I think there has been some progress in figuring out ways to get drugs approved in a more expeditious manner. I think that if everything goes well with these studies, there's a possibility that we could see an approval for this combination potentially within the next couple of years. It probably wouldn't be in the next six months or the next 12 months, but I think it's not too far in the future. 

Katie: The advancement in drug development and analysis has been so explosive and exciting to see. But I could see how, if you're dealing with a newly diagnosed population, how enrollment may be difficult. Do you see that in practice with patients maybe not necessarily wanting a clinical trial up front, or does that not matter? 

Dr. Mannis: I think it does matter. You know, there are a lot of challenges to clinical trial enrollment, not just in AML, but I think in AML, it's actually particularly difficult because this is a relatively fast-moving type of cancer. People are generally feeling pretty sick when they're diagnosed. There's often not a lot of time to sort of explore options and kind of travel around to see what's out there. There are challenges.

I think as exciting as the advancements in AML have been over the last several years, I would argue that we still have a long ways to go until we can sit back and say we're really doing a great job. We haven't really talked about the fact that these treatments for older AML aren't really thought to be curative treatments. So sort of the way that these drugs work by kind of changing the signal in the cancer cells, we think only probably works as long as you keep doing these cycle after cycle after cycle. I have patients now who have been on this treatment for three plus years, which is great, but still on average people with older AML are still only living in the one to two-year range average. I think we have a long ways to go before we can pat ourselves on the back. And that's why I think participating in clinical trials, whether it be in the newly diagnosed setting or once the leukemia comes back, I think it's very, very important. 

Katie: Yeah, I'm glad that you said that. I think that's super important too. So as you mentioned, this is already an FDA-approved therapy for MDS, which can be a precursor condition to AML. The medication is called INQOVI. Is it going to have the same name when it's hopefully approved for AML? 

Dr. Mannis: Yeah. The drugs, previous name, and it's still referred to as ASTX727, that's sort of what it was called as it was being studied. Now that it's approved and MDS and CMML, it does have this brand name INQOVI, which I assume would be the same name, whether it's being used for MDS or if and when it gets approved for AML, it will still keep the same name. I should say that I'm not being sponsored by any of these companies, so all of this is my own personal opinion. But, yeah, I think if and when it does get approved for AML, it would keep the same brand name. 

Katie: So you mentioned IV decitabine as a current treatment for AML. Now we have this new oral decitabine. Do we know if there's any differences between the two? 

Dr. Mannis: Well, so the way that the oral decitabine got approved for MDS and CMML is really sort of interesting the way that they did this study is. They gave some people oral decitabine for the first cycle, then they gave them IV decitabine for the second cycle. And then another group of people they gave IV decitabine for the first cycle and then oral decitabine for the second cycle. In all those patients, they measured the blood levels of the decitabine and showed that they were essentially the same. Whether you got the IV, or you got the oral, whether you got one before the other or the other or vice versa, drug levels were the same. And so that's how it got approved in MDS. 

The whole purpose of this trial is to make sure that the same thing holds true in AML, that when you combine this oral decitabine with another drug, that there's no interaction between the two drugs such that levels of one are increased or decreased. That's what we're looking at in the Phase 1 study to make sure that the levels are sort of in the ballpark of what we would expect. 

I think the expectation is, because we know that at least by itself in MDS or CMML, that the drugs behave very similarly. I think it would be surprising if we saw a big difference in how this drug worked when you combine it in AML with venetoclax. That's why we're doing this study, and that's why even though each of these drugs are FDA approved outside of this context, people shouldn't be inclined to start doing this outside of the context of a trial until we understand that it is safe and effective. The hope is that we get this answer pretty soon. 

Katie: Yeah, absolutely. So now that we have an oral form, I want to talk about the benefits of an oral medication over an IV medication. What are some of the benefits to the patient? 

Dr. Mannis: I think there are two main benefits that I can see. The first one is the most important and that's that, unfortunately, like I said at this present day and age, we are not curing the majority of older AML patients. So the goal of treatment really is to maximize both the quantity of life, so extend people's lives, but also extend lives that are worth living, that are fulfilling, and don't involve spending a third of your life in the infusion center. 

So it ends up that with the IV formulations, patients are coming at least five or seven days out of every month to the infusion center and for all the patients out there who have undergone treatment, they know it's not as simple as just walking in, getting your infusion, and then heading home. There's a check in. There's a wait. In my clinic, I'm always running late and I apologize to any of my patients out there who would have to wait to see me. But there's blood draw. They're waiting for the results. They're waiting for the pharmacy to make the drug. All these things add up such that when you go in for your infusion, this could be a half-day or an all-day thing. 

I see as one of the principal advantages of this as a quality of life that you're spending less time at a cancer center and more time with your family or doing things that you want to do. I think, until we find a cure for this, which we are working on and hopefully we'll find soon, until that day comes, I think we as healthcare providers need to pay more attention to patient's day-to-day quality of life. So I think this would be a huge stride towards the sort of quality of life piece. 

The other part of not having an intravenous drug is that all of our patients have special IVs that either are permanent or semi-permanent that they walk around with. So to be able to have a pill form and not have to have any kind of port or PICC line. A PICC line is a special IV that gets inserted into the arm and can stay there for several weeks or months. To eliminate the need for those, I think would also be both an improvement in quality of life for patients, also decrease the risk of those things getting infected. So at least to start out, it's a quality of life issue. 

Katie: On the other side of the coin, are there ever times when an oral therapy might not be appropriate for someone? 

Dr. Mannis: Well, first, we have to make sure that these are just as effective as the IV formulation. So this is all contingent on us getting the results of this study. So until we can show that the oral version is just as effective, then I think it's hard to say. There are patients for whom oral treatments might not be ideal. There are certainly patients that may have trouble sort of remembering to take their pills. So for that kind of patient, maybe coming in on a routine basis to get their IV treatment. But keeping in mind that the venetoclax pills are sort of part of the standard treatment now. I'm not sure that would be a big issue. 

There's the rare patient that may have some sort of issue absorbing drugs, whether they have some sort of gastrointestinal issue, maybe they have trouble swallowing pills, and for those patients, it's still may be more appropriate to use an IV formulation. 

Katie: So I want to talk a little bit more about venetoclax now, and you did a really good job of explaining what it is and how it works as a BCL-2 inhibitor. I want to know what the thought process is in combining it with oral decitabine. Are researchers thinking of testing it with any drug as a combination, or is there a certain reason why it may be added to drugs as combination?

Dr. Mannis: Yeah, as it turns out, venetoclax is useful in a wide range of different blood cancers. So we use it in chronic leukemias. We are using it now in multiple myeloma. Really, it has proven to be very effective against a wide range of blood cancers. And that's because this Bcl-2 protein really is sort of a master regulator of cancer cell life and death. Whether it's AML or CLL or MDS, as it turns out, all of these blood cancer cells tend to rely on this Bcl-2 expression to make decisions whether those cells live or die. 

By itself, in AML, it's not all that effective. Maybe about a 20% response rate as a single agent. So both the hypomethylating agents and venetoclax by themselves relatively modest response rates, but the combination seems to synergize in a way that makes it much more effective. I think one of the next steps and what a lot of people are looking at now is what if, instead of just the combination of these two drugs, what if you add a third drug to it, would that help make it even more effective and keep patients in remission longer? 

The main problem with that is that anytime you add another drug, you're adding side effects. We haven't really talked about sort of the side effects on this treatment, but sort of the main thing that all patients should expect if they're getting this combination is that their blood counts will go down. Both of these drugs independently cause lower blood counts. But when you put them together, they can cause especially low blood counts, and especially in the first cycle or two, before the leukemia goes into remission, we monitor patients very closely, typically twice a week, checking their labs to make sure that they don't need transfusions. 

I think we sort of joke about adding venetoclax to everything, but there's always sort of a downstream consequence. I think we're still working on figuring out what is the optimal dosing? What's the best combination? Should we add a third drug? All of these are ongoing questions. Certainly, there are trials here and elsewhere that are looking to answer some of those questions. 

Katie: I'm really glad you brought up the side effect conversation, and it's really important for people to know. But I'm curious now that you bring up adding a third drug. Is there a specific class of drugs that are being considered or looked at more in trials as being that third addition?

Dr. Mannis: Well, there are a couple big ones that come to mind. So one of the nice things about venetoclax and the hypomethylating agents is that it seems like it works across a relatively broad range of types of AML. When I say types of AML, everybody's AML is a little bit different, and they're made different typically by the specific mutations that are in the leukemia cells. But regardless of the type of mutation in the cells, it's a pretty effective combination. There are a couple types of mutations that make it a little less effective. One in particular is AML with a mutation in FLT3. There are drugs that we now have that can specifically target that FLT3 gene. One of the, I think, sort of popular thoughts is, well, what if you added one of these other targeted inhibitors to this combination, or perhaps even substituted one of the two drugs for a more targeted inhibitor? 

We are also about to open a trial that uses this combination of a hypomethylating agent and venetoclax in combination with an immunotherapy drug, a drug called magrolimab, which actually was developed here at Stanford, to see if by adding an immunotherapy to the combination, if that improves the outcomes for patients. But I think in general, adding a third drug that's a targeted inhibitor of various mutations, there are several out there that are approved versus either an immunotherapy drug or a more traditional chemotherapy drug. Those are all things that are being looked at. 

Katie: That's so interesting. I have so many more questions, but I want to make sure that we have time at the end for everyone else to ask their questions. So I'm going to try to wrap it up with my questions here, but I want to ask you one more thing, which I feel is important. This is one of our very first radio shows, so I think it would be great if you could provide our listeners any advice you may have for patients who are looking to get enrolled in a clinical trial. What are some important things they should know or consider when they're going this route? 

Dr. Mannis: That's a great question. I think patients often struggle with sort of how do I find clinical trials, and how do I know if a clinical trial is right for me? There is a sort of master site for all of the clinical trials in the country, which is clinicaltrials.gov. But it can be hard for patients to navigate that. It's just a directory of all the clinical trials available. I would say, for most patients, it's hard for them to travel outside of their regional area to enroll on a clinical trial, and most clinical trials require that certain procedures be done at the main center. So if you're looking at a trial in New York but you live in Texas, then that might be hard for you to do. 

If you live in California, in Northern California, for example, my advice would be to check out Stanford, check out UCSF, check out UC Davis, centers that are close enough by that you might be able to travel back and forth should you need to a couple times a month. Some trials may only require once a month or even less frequent, but some like this trial of oral decitabine and venetoclax, at least in the first two cycles, we're seeing patients at least once a week if not twice a week. Part of it is distance to the center. I think it's also helpful if you do meet with an AML specialist. Typically, they will have a sense of what trials are out there. Even if a trial is not available at that particular center, if there is something that's really worth traveling for, they may be able to point you in the right direction. 

Katie: Yeah, that's really good insight to have. While we're talking about finding clinical trials, I'd like to mention that HealthTree for AML has actually created an AML-specific clinical trial finder tool which is designed to simplify and personalize your trial search. We recognize that, as you mentioned, this is a very tedious, overwhelming, and difficult process. So this tool is really helpful in in making it less overwhelming. 

So currently, you can use this tool to filter AML trials by age group, phase, treatment type, genetic target, location. And something really exciting is that soon the search will be even more personalized by taking into account your specific health information so that only the trials where you meet the inclusion criteria will show up. This tool will help patients sift through hundreds of trials and narrow the search down to a more manageable handful to look through. So you can find this clinical trial finder tool on our website. 

So now I'd like to open it up for caller questions. If you have a question about Dr. Mannis's research or anything we 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. It looks like I already have a question here. So I'm going to unmute the caller whose number ends in 1034 to ask your question now. 

Caller: Hi, Dr. Mannis. Thank you so much for taking the time. This is going to be an amazing series of shows for patients to learn more about AML, so I'm super excited about it. So thank you so much for taking the time to do it. I just had a question. You walked us through the clinical trial process. Phase 1 is mainly safety. Phase 2 is you're testing for how well it works. And then Phase 3, you're comparing it to something else. I think in some of the other diseases, blood cancer specifically, sometimes the FDA has been getting better and better and sometimes even approving after Phase 2. Do you see that happening in AML, or do you hope that that will end up happening in AML, especially when there's this big unmet need? 

Dr. Mannis: Yeah, that's a great question. I think we have already seen drugs get approved based on not just Phase 2 data but actually big Phase 1 data, the drug ivosidenib, which is a targeted inhibitor of the IDH1 gene is only present in about 10% of all AML. So it's a rare subset of a rare disease. I participated in the Phase 1 study where we enrolled well over 100 patients onto this trial from around the world. Based on those data, the FDA realized that it was going to be hard to get a much bigger study than this without waiting 10 more years. 

I think as long as we are conducting the studies in a way that is ethical and consistent, that certainly the FDA seems more open to approving drugs that seem particularly promising and safe. So I think, for example, it's possible that this combination of oral decitabine and venetoclax, if it shows in Phase 2, that it looks just as effective as the IV formulation without any other safety concerns. I think it's very possible that it could get approved as a combination off of Phase 2 data. So I am encouraged by the slew of new approvals over the last several years and the sort of more creative thinking that is happening at the FDA now. 

Caller: Yeah, I think it's fantastic. One more question. For clinical trials, how do you get -- I don't know how many AML patients end up being seen in general oncology, in the general oncology setting, but how do you get the word out to these trials to the general oncologists? We are trying to make this, like you said, you're trying to make this really fast treatment decision for newly diagnosed patients, and it might be better than standard of care. But how do you let the general oncologists know that you have this trial running that might be an option for their patients? 

Dr. Mannis: Yeah, it's hard. I think everyone in health care at the moment is stretched thin and overworked and probably burnt out to some degree after everything that's gone on over the last 18 months. So trying to reach people and take an extra second to sort of think about something, I think, can get harder and harder. But we certainly do a lot of outreach. I'm certainly constantly handing out my phone number and my email so that if anybody has any AML questions, they can reach me directly. 

So I think part of it is just us on the academic side doing our best to reach out to oncologists in the community. I think they're honestly grateful to have us as a resource. I think they're seeing mostly breast cancer, colon cancer, lung cancer. So when they get an AML, they're often probably quite eager to talk to someone who has some more expertise in it. So part of it is just us being accessible and reaching out to the community. I think this kind of platform is also very helpful, informing patients what's out there, making sure that they're advocates for themselves and knowing that whenever they have a serious diagnosis, especially of a rare type of cancer, that it's always good to try and seek out a second opinion.

I think there's a misconception out there among patients that they're going to hurt their doctors' feelings if they request a second opinion. We encourage our patients to get different opinions. The most important thing is that a patient feels like they have the proper guidance, and they're comfortable with the decisions that they're making. 

Caller: Yeah, that's fantastic advice. Well, thank you so much for everything you're doing for AML patients because we really appreciate you. 

Dr. Mannis: Thank you. I appreciate the call. 

Katie: Okay, let me look down the list, see if I have any more. If you'd like to ask a question, press 1 on your keypad. Okay, I have a question from caller whose number ends in 7401. I'll unmute you now. 

Caller: Hi, thanks for this information. It's been great. I'm wondering if you could go into some detail about what some of these drug combinations we've talked about, what you can expect with your blood counts.

Dr. Mannis: The combination of a hypomethylating agent and venetoclax, like I said, the most common downstream effect is that the blood counts will get lower. It's very common especially in older patients with AML that even before treatment the blood counts are low. We look at sort of three main blood counts: the white cells, the red cells, and the platelets. The white cells are responsible for preventing infections. The red cells, which we typically measure via either hemoglobin or the hematocrit, those cells are responsible for carrying oxygen, and the platelets are responsible for preventing bleeding. Any or all of those may already be low when a person is newly diagnosed with AML. But all three of those will go down once treatment starts and typically will not improve until the third or fourth week or maybe even later when the drugs start to start to kick in and the bone marrow starts to recover in remission. But typically, the platelets and red cells will get low enough to the point where patients will need transfusions if they're not already requiring them at the time of diagnosis. So we will typically check twice a week with the expectation that at least once a week patients will need a transfusion of red blood cells or platelets typically in the second or third week of treatment. 

Caller: Okay, great. That's helpful information. One last quick question. I suspect we may have talked about this a little bit, but just, in your opinion, what is the most practical thing a patient can do to help get closer to a cure for everyone? 

Dr. Mannis: What can a patient do to help get closer to a cure? That's a great question. I think participating in clinical trials is probably the most important thing. All of the advancements that have been made over the last few years really have been made because of patients who are willing to enroll on these trials. Often being in a clinical trial requires more frequent visits, more frequent tests than you might otherwise need if you were to just get sort of the standard treatment. But really we are not going to make any more progress towards a cure unless we are able to study new and better treatments. We can't study new and better treatments without the altruism of patients who are willing to participate in clinical trials. 

Caller: Awesome. Thank you. 

Katie: Well, I don't see any more questions being asked, and it looks like we're getting really close to time. So thank you so much, Dr. Mannis, for joining us today and letting us know that there's so much progress being made on the treatment of AML, especially for older individuals. We wish you all the best in your continued great work. 

Dr. Mannis: Thank you so much, Katie. This was a lot of fun. I really appreciate the invitation to come talk to you guys. 

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

As mentioned by Dr. Mannis in the show, clinical trials are a major part of AML treatment and key to the development of more effective therapies. To find an AML clinical trial that you qualify for,

Visit the AML Clinical Trial Finder