IDH mutations are found in approximately 20% of adults with AML. Both IDH1 and IDH2 mutations are typically found in older AML patients and have an intermediate risk profile, with IDH2 being the more common of the two. Targeted therapy drugs, called IDH inhibitors have been developed to address these mutations.

Ivosidenib (Tibsovo) and enasidinib (Idhifa) are IDH inhibitors and were approved for use in relapsed/refractory AML with IDH1 and IDH2 mutations, respectively. Clinical trials have been exploring the use of different combinations with other drugs such as azacitidine and venetoclax to improve their effectiveness. 

In this show, we were joined by Dr. Eytan Stein, an AML expert from Memorial Sloan Kettering Cancer Center, who summarized the IDH1 and IDH2 mutations and the current treatment options available. Dr. Stein covered the use of ivosidenib (Tibsovo) to treat IDH1 mutations and the use of enasidnib (Idhifa) to treat IDH2 mutations. He also addressed the recent FDA approval of the ivosidenib (Tibsovo) combination with azacitidine and how that will affect the treatment of IDH1-mutated AML.

Thank you to our episode sponsor, Bristol Myers Squibb.

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

Before we get started with today's show, I'd like to mention an upcoming event that we will be hosting. On Saturday, September 17, at 10am, Eastern, we will be hosting a virtual HealthTree Round Table for AML event titled, “Decision-Making in AML: What's Next if You Relapse?” We have invited four top AML experts: Doctors Eunice Wang and Amanda Przespolewski from Roswell Park Comprehensive Cancer Center, Dr. Lourdes Mendez from Yale Cancer Center and Dr. Jane Liesveld from the University of Rochester.

Our experts will discuss MRD status, relapse after transplant, clinical trials after relapse, and how to manage the fear of potential relapse. We will hear from the experts on each topic and there will be a Q&A session at the end. We hope you will join us for this informative discussion. If you can't attend live, we encourage you to still register as the recording will be sent out after the event to everyone who registers. You can register for all of our events by visiting our website healthtree.org/aml/community/events.

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

IDH mutations occur in approximately 20% of adult AML patients. There are two IDH mutations, IDH1 and IDH2, with IDH2 being the more common of the two. In recent years, small molecule inhibitors or IDH inhibitors have been developed and approved for the treatment of IDH-mutant AML. There are two IDH inhibitors that are currently approved for use. Ivosidenib or Tibsovo, and enasidenib or Idhifa are approved to treat IDH1 and IDH2 mutations respectively. In May 2022, ivosidenib received FDA approval for use in combination with azacitidine in newly diagnosed patients age 75 years or older.

Dr. Eytan Stein is here with us today to talk about the current treatment options for IDH mutations, and discuss the newly approved combination of ivosidenib plus azacitidine. We will also hear from Dr. Stein about what other drugs there are in development to target IDH mutations and how the treatment of IDH1- and IDH2-mutant AML could change, moving forward.

We are so happy to have you here with us today, Dr. Stein, and thank you so much for taking the time out of your busy schedule to join us. Before we get started --

Dr. Stein: Great. Thank you so much for having me.

Kerith: Thank you. I'd love to provide an introduction for you, Dr. Stein. Dr. Stein is an assistant attending physician, clinical investigator and director of the Program for Drug Development in Leukemia on the Leukemia Service at Memorial Sloan Kettering Cancer Center. Dr. Stein specializes in caring for patients with acute and chronic leukemias, myelodysplastic syndrome and myeloproliferative neoplasms. He is the principal investigator on a wide variety of clinical trials in AML and is working to develop new therapies such as small molecule inhibitors that can more effectively target AML.

 Dr. Stein led the clinical studies of the IDH1 inhibitor ivosidenib and the IDH2 inhibitor enasidenib in patients with relapsed and refractory AML that led to their FDA approvals in 2017 and 2018. Dr. Stein's work has been published in many prestigious journals, and we are honored to have him on the show with us today. Welcome, Dr. Stein. Thanks for being here with us today.

Dr. Stein: Great. Thanks so much for having me.

Kerith: Okay, let's go ahead and jump into our discussion for today. Can you just give us a summary of what the IDH1 and IDH2 mutations are and maybe how they're different? Does one carry a higher risk profile than the other?

Dr. Stein: Yeah, that's a really good question. As was mentioned in the introduction, when a patient develops acute myeloid leukemia, there is always, almost always going to be some mutation in the bone marrow that has developed as the patient has gotten older that is going to contribute or lead to the development of their disease. IDH1 and IDH2 mutations, they're two different mutations, but they are, together, probably the second most common abnormality or mutation that is seen in patients with AML.

IDH2 mutations occur in about 15 to 20% of patients with AML, and IDH1 mutations occur in about 10 to 15% of patients with AML. What's interesting is that the difference between IDH1 and IDH2 really has to do -- so, IDH1 and IDH2 are enzymes that when they're not mutated, work to help generate energy for cellular processes. The difference between IDH1 and IDH2 are simply where those enzymes are located within the cell. One of the mutations is located within the mitochondria which is a type of thing that is found within the cell, and then the other is found within the cytoplasm which is the major goop that's inside of a cell.

The last thing I'm going to say is that when you have these mutations, what ends up happening is that the cell, instead of maturing normally to become a healthy infection-fighting cell, it gets stuck as a blast. You may know that in a person without leukemia, the normal progression of events is that you have this immature blood cell that is born in the bone marrow. It goes through various levels of growing up. When it's all grown up, it becomes a neutrophil, and it goes out into the bloodstream to fight infections. When you have acute myeloid leukemia, that growing up process doesn't occur normally.

The way I tell my patients is that those cells get stuck as teenagers, and those teenagers are called blasts. You can imagine, if you've got too many teenagers in your house, it's gonna wreak havoc. That's what these blasts do. The idea is that by targeting IDH1 and IDH2, it sort of gets those teenagers, those teenage blasts to grow up and become responsible adults that can then go out and fight infections as neutrophils.

Kerith: I like that analogy. I hadn't heard the teenager analogy before. That is a good explanation in helping understand the blast. Is there a typical demographic for patients that develop IDH mutations? Also, do they do they typically occur with other mutations?

Dr. Stein: Yeah. There is not a typical demographic, but there are a couple of demographic comments that can be made. The most important one is that IDH mutations increase in frequency as patients age or as adults age. It is very uncommon to find IDH mutations in younger patients with acute myeloid leukemia, and it is more common to find them among 60, 70, 80-year-olds. Now, IDH mutations rarely occur alone. It's pretty unusual that if you're diagnosed with acute myeloid leukemia, your doctor is going to say to you, the only thing we found is this mutation in IDH1 or IDH2. These mutations tend to co-occur with other mutations, and the spectrum of which other mutations they co-occur with differs a little bit between IDH1 and IDH2. However, I think, in general, what you can say is that these mutations co-occur with mutations in a gene called NPM1 or nucleophosmin. They can co-occur with a gene called FLT3 which we have another targeted therapy that targets with FLT3 mutations, and they also tend to co-occur with a group of mutations called SRSF2 mutations for which we're also developing targeted therapies.

The point of telling you all that is that I think one of the things that's happening or going to happen in the next one to three years for patients with AML is we're not only going to be targeting one mutation, because we know that targeting one mutation probably isn't going to be enough to permanently cure a patient, but what we're gonna be doing is we're going to be targeting multiple mutations. We'll be taking multiple drugs that target different pathways and different mutations in patients with AML, and put those drugs together, hopefully, so that we can cure the disease with these small molecule inhibitors alone, and not have to resort to things like intensive chemotherapy.

Kerith: I guess one of the challenges with the multiple drugs, just avoiding the toxicities of more drugs?

Dr. Stein: Yeah, yeah, that's always a concern. Whenever you start taking more pills, you worry that you're going to get more side effects. The good thing about, at least the IDH inhibitors is that the side effect profile is very, very favorable. If you compare IDH inhibitors and other small molecule inhibitors like FLT3 inhibitors that are already approved, to chemotherapy, the side effects are worlds apart. When I prescribe an IDH inhibitor for my patients, everyone asks me, of course, what are the most common side effects? The truth is that the most common side effect is not to have a side effect. The vast majority of my patients have no side effects when they're taking these medications. Of course, all medications can have some side effects, but because it's most common that patients don't have any side effects, it really allows the possibility that you really can combine these agents with other agents fairly safely.

Kerith: Talk us through what the current treatment options are for patients with IDH1 and IDH2 mutations.

Dr. Stein: Yeah. Why don't we just talk about at the beginning for patients with relapsed and refractory acute myeloid leukemia because I think we'll probably get into newly diagnosed acute myeloid leukemia a little bit later in the conversation. So for patients with relapsed and refractory acute myeloid leukemia, there is a targeted inhibitor of IDH1 that is approved by the FDA called ivosidenib. There's a different targeted inhibitor of IDH2 that is approved by the FDA called enasidenib. These drugs are, as we talked about, potent targeted therapies against the mutant enzyme, the mutant protein. In the relapsed and refractory setting, they both really work exceptionally well, in the sense that the overall response rate is about 40%. About 40% of patients who get either the IDH1 inhibitor or the IDH2 inhibitor will go into some sort of remission. If you look at the rate of complete remission, that rate of complete remission is about 20 to 30%, depending on whether we're talking about enasidenib, the IDH2 inhibitor, or ivosidenib, the IDH1 inhibitor.

The good thing is that, as I mentioned a second ago, the other treatment options for patients with relapsed and refractory AML, up until the time we had IDH inhibitors, was basically giving people chemotherapy if they were young enough to handle it. That chemotherapy, the remission rates of chemotherapy were significantly lower than what I just described of the IDH inhibitors, and as everyone on the call likely knows, comes with major side effects that no one wants to have. It usually requires hospitalization. I mean, in terms of quality of life and the side effects that the people experience, getting these IDH inhibitors for relapsed and refractory disease is worlds better than getting chemotherapy, and the IDH inhibitors are oral therapies. You write a prescription, the patient can go home, and they can take the medication at home. It's given once a day.

I think the one thing that has been slightly disappointing is while the IDH inhibitors have these high remission rates and while we have some patients who can do really well for a long period of time, it's more common that the IDH inhibitor will work for a period of time, usually maybe six months to a year, and then maybe will stop working. Having said that, just a second ago I told you that they can work for a long period of time. I have one patient who I talk about all the time, who was on the original phase 1 study of the IDH1 inhibitor, ivosidenib. I just saw her Monday via telemedicine. She has been on the treatment for now eight years, eight or nine years, and is probably functionally cured of her leukemia just with the IDH1 inhibitor. So there are these patients who are super responders and do fantastically well. We don't really understand why some patients do so much better than other patients, but that's what leads to the excitement with the use of these targeted therapies.

Kerith: Can I ask how old that patient is?

Dr. Stein: Yeah, she is now 87. When I started treating her, she was 77, and now she's 87 or 88. Her leukemia is really, it's like the least of her issues. She's taking a blood pressure medication when she takes the ivosidenib.

Kerith: Can you talk about the trials for the initial approval of ivosidenib and how ivosidenib has impacted the outcomes for AML patients? You sort of got into that a little bit, but if you can talk about the trials a little bit.

Dr. Stein: Yeah, so we talked about the relapsed and refractory patients with both ivosidenib and enasidenib. Whenever you have a drug that works really well, patients who have relapsed leukemia, you don't want to wait to give your best drug to a patient who's relapsed, you want to keep them from relapsing. That's why there were a couple of different studies that were done, one of which I'll just touch upon very briefly, and then the other one, which is the more important one.

One study was, there was a small study that was done where, for patients with IDH1 mutations, ivosidenib as a monotherapy, as a single agent, was given to patients with newly diagnosed acute myeloid leukemia with an IDH1 mutation. As a single agent, ivosidenib leads to rates of complete remission in the range of 40 to -- or the overall response rate, not just complete remission, the overall response rate is in the range of 40 to 50%, higher than when you give it for patients with relapsed and refractory disease. So ivosidenib as a monotherapy, as a single agent was actually approved by the FDA for newly diagnosed AML with an IDH1 mutation in patients older than 75 years old.

However, the standard of care, up until recently, for patients with newly diagnosed AML who were 75 or older, was to give them a drug called azacitidine, a type of drug called a hypomethylating agent. There's a sister drug called decitabine that’s also used which is very, very similar. Giving either azacitidine or decitabine was the standard of care for newly diagnosed AML patients, regardless of what mutation they have, they had an IDH1 mutation, IDH2 mutation, whatever mutation they had, older than 75 years old, couldn't get intense chemotherapy, the standard of care was to give azacitidine. The use of azacitidine in patients with newly diagnosed AML led to a complete remission rate in the range of 20%.

Okay, so when you've got a therapy, that is the standard of care for newly diagnosed patients with AML, and you have a new therapy that seems to be good for patients with newly diagnosed AML, the question we ask is, well what happens if you put these two therapies together? That was what was done as part of a large randomized clinical trial called the AGILE trial. It was a large clinical trial where patients with IDH1 mutations exclusively, with newly diagnosed acute myeloid leukemia, were randomized. That is a computer flipped a coin and said 50% of the patients are going to get azacitidine with the IDH1 inhibitor, ivosidenib, and 50% of the patients are going to get azacitidine with a placebo. Patients aren't going to know whether they're on placebo or ivosidenib. We're going to follow these patients and see how they do.

The results of that trial were actually quite dramatic. They were dramatic in the sense that the rate of remission when giving patients ivosidenib with azacitidine was significantly higher than when patients got azacitidine with placebo. The rates of remission are in the range of 60 to 70% in patients who get ivosidenib with azacitidine, compared to only about 10 to 20% in patients who got azacitidine with the placebo. Maybe the more important data is that if you look at the overall survival, the median overall survival, median means that 50% of patients at the time point I'm going to tell you are still alive. The median overall survival in patients who got ivosidenib with azacitidine was just about two years, while the median overall survival of the patients who got azacitidine with placebo was only about nine to ten months.

Because of that -- in these clinical trials, there are safety loops that the trial built in. There's a committee that looked at the trial, even though the trial wasn't over yet, and said, hey, this study looks like the patients who are getting azacitidine and ivosidenib are dramatically better than the patients who are getting azacitidine. It's not ethical to keep enrolling patients on a trial where half of them are just going to get azacitidine because that looks like it's inferior therapy. We're going to stop the trial early. We're going to unblind everyone, and we're going to say, for now, the standard of care has now become that IDH1-mutant patients, at least as part of this trial, should only get azacitidine and ivosidenib. They should not get azacitidine monotherapy.

Again, in summary, dramatic results where the combination of azacitidine and ivosidenib for IDH1-mutant patients is really dramatically better, both in terms of remission rate and in terms of overall survival, compared to azacitidine alone.

Kerith: Okay. Aren't you also looking at the regimen of azacitidine and venetoclax in this scenario, 75 years and older patients?

Dr. Stein: Right, so this is where it gets complicated. Okay.

Kerith: I don't want to over-complicate this, but.

Dr. Stein: No, it’s okay. It's good to complicate it. Okay, so let's back up to the beginning of the AGILE trial. The AGILE trial is azacitidine-ivosidenib versus azacitidine. That trial starts, and I forget what year, let's say 2017 and 2018. While that trial is running, there is a new treatment for acute myeloid leukemia that is approved by the FDA, which is the combination of azacitidine and a drug called venetoclax. Many of you may have been on this regimen or have heard about this regimen. That then becomes the new standard of care for patients who have newly diagnosed AML, whether they have an IDH1 mutation or have some other mutation, whatever mutation they have.

The question becomes, what do you do then with the AGILE trial? You've already started a trial where patients are enrolling, and they're getting either azacitidine and ivosidenib, or azacitidine and placebo. I think the way the people who wrote the AGILE trial thought about it was that most of the trial was being enrolled in countries where patients did not have access to venetoclax. Therefore, they felt like they could continue the trial going. Because in these countries, patients, they couldn't get venetoclax. There was no mechanism by which they could get it, and they kept the trial going.

Because azacitidine and venetoclax is now a standard of care for patients with newly diagnosed acute myeloid leukemia, and it leads to very good outcomes in patients with newly diagnosed acute myeloid leukemia, whether they have an IDH1 mutation or whether they don't have an IDH1 mutation, the question becomes, what is better for a patient? Is it better for newly diagnosed IDH1 mutation, a patient with a newly diagnosed AML with an IDH1 mutation to receive azacitidine and the IDH1 inhibitor, ivosidenib? Or is it better for them to receive azacitidine and this drug, venetoclax? We don't know the answer to that question yet. There is a clinical trial that is being started within the next year that is going to try to answer that question by randomizing patients to receive either azacitidine and ivosidenib, or to receive azacitidine and venetoclax.

The other thing we don't know and why medicine is sort of a humbling business is that well, maybe you can start a patient on azacitidine and ivosidenib and then if they relapse, maybe then you can switch to azacitidine and venetoclax. Or maybe you can start a patient on azacitidine and venetoclax and if they relapse, you can switch them to azacitidine and ivosidenib. Or maybe you should start them on all three at once. These are the kinds of questions that are going to be answered in clinical trials over the next one to three years.

Kerith: Yeah, I'm curious, just to give everyone an idea of the timeline for the clinical trial, for the approval of this use of ivosidenib, what was the timeframe from the start of the clinical trial to FDA approval, say for the AGILE trial?

Dr. Stein: That's a good question. I think it was probably about four years. It wasn't that long, three or four years. The trial probably started in 2018, 2019. I don't remember exactly, but I don't think it was longer than three or four years. It was relatively quick. I mean, it's not quick in real life, but in the context of clinical trials, that was actually relatively quick.

Kerith: In your day-to-day practice, how are you approaching these patients? What do you do? How do you decide?

Dr. Stein: Yeah, right. That's the problem. How do you decide when you have a new patient sitting in front of you, whether they should get azacitidine and venetoclax, or azacitidine and ivosidenib if they've got an IDH1 mutation? There's the theoretical, and then there's the practical. Theoretically, in a perfect world, I would start my patients on azacitidine and ivosidenib. The reason being that, that clinical trial, the AGILE trial, which we talked about, of azacitidine and ivosidenib, was done specifically in patients with IDH1 mutations. It’s a trial just for that genetic subset, so I feel relatively comfortable that the results that I told you about and that have been published, are true, that that those results are going to be reproducible in the patients that I treat. The patients who got azacitidine and venetoclax, although it's a fantastic treatment, that trial was done in a more general population which included IDH1 mutant patients. It wasn't a trial specifically for IDH1 mutant patients. That's the reason, because it wasn't specifically for IDH1 mutant patients, in my theoretical perfect world, I would probably start them on aza-ivosidenib first.

Now, there's the theoretical, and then there's the reality. The reality is that the issue with the AGILE trial is that you need to wait for the results of IDH1 mutational testing before you can start a patient on azacitidine and ivosidenib, because you need to know whether they've got an IDH1 mutation. With venetoclax, you don't need to wait. Or you can give anyone venetoclax, whatever mutations they have. Sometimes it can take a week or 10 days for that IDH1 mutational testing to come back. And then, for those of you who've taken any small molecule inhibitors, it's not as easy as writing a prescription to Walgreens or Duane Reade. You have to write a prescription to a specialty pharmacy. The specialty pharmacy then sends you a piece of paper that says you need to fill out a prior authorization. You send it back to the specialty pharmacy who then approves that, but then they say to you, okay, the drug is approved, but your patient’s co-payment is going to be $5,000. Most people in the world can't afford that, so then you have to scramble around and try to figure out how to get a patient co-payment assistance.

That whole process can take longer than patients are usually comfortable waiting.  I might be comfortable waiting as the doctor, but as a patient, you've just been diagnosed with cancer, and your doctor is saying to you, okay, you’ve got cancer, but I want you to wait three weeks to get these results. Most people are like, no. Even though you're telling me it's going to be okay, I don't want to have cancer in my body. I want to get started as soon as possible. So for practical reasons, we often end up starting azacitidine and venetoclax, even though in a perfect world, that's not what I would do. If I could get the results of my mutational testing back within, like 48 hours and know whether the patient had an IDH1 mutation or not, and/or if I could then write a prescription and get that prescription filled within another 48 hours with the co-payment assistance, I’d advise my patients strongly to wait for the ivosidenib to come through. In the absence of that, I've been starting a lot of patients on azacitidine and venetoclax.

Kerith: I think I read somewhere that perhaps the azacitidine-venetoclax is a slightly more intense regimen, so it might have more side effects. Is that the case?

Dr. Stein: Yeah, so it's a good question. Certainly, the combination of azacitidine and venetoclax will lower the blood counts more than the combination of azacitidine and ivosidenib. All else being equal, that is something that you would look at. You'll probably need more transfusions if you're getting azacitidine and venetoclax. Where I practice at Memorial Sloan Kettering, and I think at other large hospitals and medical centers, we have the ability to monitor patients pretty closely and give them transfusions very frequently, so it's less of an issue. I think, in places that might not have easy access or reliable access or quick access to a blood bank, or for patients who live very far away from the hospital, where it's a real burden to get back and forth to a hospital, giving a combination like azacitidine and ivosidenib which might require fewer transfusions and hospital visits might be the preferred thing to do.

When I gave you my little spiel a second ago, that was specifically talking about the patients that I see in New York City where they've got relatively easy access to getting into the city and to being treated. That might be different for different locations within the world or within this country, and different practices.

Kerith: That's good information to have. One thing I wanted to ask about was, because I don't want to ignore IDH2, do you think that there's going to be an approval of an enasidenib combination with azacitidine coming as well? Is the data as encouraging for IDH2 mutations with enasidenib?

Dr. Stein: I don't think there's going to be approval. I'll tell you why. There was a phase two trial that was similar to the AGILE trial where patients were randomized to enasidenib and azacitidine or azacitidine alone. This was not a placebo-controlled trial. It was a small trial, only 100 patients. There were some methodological, not methodological, maybe it was a little bit under-powered from a statistical point of view. In that trial, there was no difference in overall survival between the patients who got azacitidine-enasidenib or azacitidine-placebo. Now, it could be, if you did a large randomized phase three trial, placebo controlled, that you would get a similar outcome, as you did with the AGILE trial. The problem is that with the data that's available, which is that phase two trial, it does not look like enasidenib and azacitidine is better than azacitidine monotherapy.

While I think one should do a large randomized phase three trial, because I think the results might be different in a large randomized phase three trial, the issue is that it requires essentially an investment of a lot of money for a result that you might not see a benefit. I suspect that that we're not going to see that randomized phase three trial. I mean, I hope we do, but I suspect we're not. Therefore, I don't think the combination of enasidenib and azacitidine is going to get an FDA approval.

Kerith: We briefly touched on the side effects of enasidenib, and it sounds like they're minimal side effects, which is good, but I've read about differentiation syndrome. Can you talk about that, and is there anything that can be prophylactically given to avoid it? Also, if someone is taking it and they're at home, besides taking it as a patient who is taking it, is there anything they can look out for if they're taking it at home, signs and symptoms?

Dr. Stein: Yeah, let me define differentiation syndrome first. We have to go back to the analogy I used with the blasting teenager that still won’t grow up. Let's say you've got these blasts, they're the teenagers in the analogy, and now you're giving these blasts with IDH mutations or IDH1 mutation, a drug that's going to cause them to start growing up. That process of going from a blast to a mature neutrophil or going from a teenager to an adult is called differentiation. As those blasts are maturing and turning into adult because they're being prodded along by the IDH inhibitor, they -- I guess the analogy is sometimes your kids don't want to grow up. They want to remain teenagers for a long time because then they don't have any responsibilities. I say this having my own teenagers. They kick and scream. They don't want to grow up. They don't want to do this. They don't want to take this responsibility.

The blasts do a similar thing. The blasts start kicking and screaming as they're starting to grow up into mature neutrophils. What they do when they kick and scream is that they release certain substances as they're maturing, that can cause fluid accumulation in the body. That doesn't sound too bad, but the problem is that when you get fluid accumulation in places like your lungs, it can make it difficult to breathe. That is what differentiation syndrome is. Differentiation syndrome is these blasts not behaving nicely and kicking and screaming, they don't want to become adults, adult neutrophils, and releasing substances that cause fluid buildup in the body, specifically in the lungs, which in its most severe form, can cause profound shortness of breath and on oxygen or in an intensive care unit.

The good thing is that there's an easy way to calm down these blasts as they're differentiating, if they develop differentiation syndrome, and that is by giving the patient steroids. When you give the patient steroids, it calms down the blast. They stop releasing these substances, and the differentiation syndrome goes away. There is no prophylactic treatment that we give to prevent differentiation syndrome when we give IDH inhibitors. However, if you're a patient who’s taking an IDH inhibitor and you're at home, and you start noticing that, it used to be the either you could walk up your front steps to get into your house without getting short of breath. Now all of a sudden, you're walking up your front steps. It's the third step. You’ve got to stop, and you’ve got to catch your breath. Or you're becoming increasingly short of breath, or you develop a new cough, or you develop swelling in your legs that wasn't there previously. That would be the kind of thing that I would say you should call your doctor immediately. It doesn't mean that you have differentiation syndrome, but it means you could.

The one thing you don't want to do is you don't want to let differentiation syndrome wait around. It's so easy to treat with steroids, but if it's not treated, it can get really bad really quickly. So the message for a patient would be, if you're on an IDH inhibitor, and you develop shortness of breath, you develop symptoms of fluid accumulation, don't wait till the next doctor visit. Call your doctor right away and say, hey, I'm having these symptoms, is it possible I have differentiation syndrome. The doctor will think that you're very, very well-educated because you know what differentiation syndrome is, and then let them guide you, let them tell you what to do.

Kerith: Okay. You started to touch on this a little bit. I wanted to just go back to it. We talked about that, at some point, there may be, and there's I think a trial being done right now on azacitidine plus venetoclax plus a targeted agent like ivosidenib, which they call triplets. Is there any preliminary data from this trial as of yet?

Dr. Stein: There is. That's a trial being done out of the MD Anderson Cancer Center in Texas, in Houston. There's data that shows that the combination, the triplet combination works really well. You get very, very high rates of remission. I think the issue with those trials is that they're not randomized. It's very hard to tell whether it's better than giving just the doublet of aza-ivo or of aza-venetoclax. The reason that's important is because, and the reason I would say that to a doctor, not to just combine all three drugs together outside of a clinical trial is because we really don't know whether that's better than just the two-drug combination, and the three-drug combination leads to an immense increase in cost. The cost of a drug like ivosidenib and the cost of a drug like venetoclax are quite high, not only on a personal level, to the patient, but especially if they've got high co-pay, but also on a societal level, where insurance companies are paying for all these very expensive drugs. That affects all of us because then all of our insurance rates go up.

I think, in the absence of a really clear data that it's better than the doublet, I would not do it off trial. Having said that, I think that trial is important, and I'm hoping there's going to be a randomized trial that’s going to answer the question of whether the triplet or the doublet is a better approach.

Kerith: Right. Okay, and you mentioned the blood counts and weighing the options of ivosidenib plus azacitidine versus azacitidine plus venetoclax. I was listening to a talk that Dr. Harry Erba from Duke was moderating, and I guess it was Courtney DiNardo was speaking from an ASH conference. She's from MD Anderson, as you know, and she was talking about how the blood counts immediately went up, instead of down, which distinguishes it from the azacitidine plus venetoclax regimen. The azacitidine-ivosidenib distinguishes it from the aza-ven regimen, that is. I'm curious, how that is that the blood counts go up? Because that seems to be counter-intuitive to me. I was just wondering how that works. That seems like that would be a big, strong case for using the ivosidenib plus azacitidine.

Dr. Stein: Yes. I think the blood counts go up because the ivosidenib is a differentiation agent. As a differentiation agent, it doesn't kill those cells, as, like we talked about, it causes them to mature and increase. I think that's why the blood counts might go up initially. I think in terms of the case of what to use, I think at the end of the day, the most important thing is the length of overall survival.

Let's say I told you that azacitidine and venetoclax -- this is not true. I'm going to make this up. Let's say azacitidine and venetoclax led to an overall survival of 15 years, and ivosidenib and azacitidine led to an overall survival of two years. Even if the blood counts went up with ivosidenib and azacitidin, you still use azacitidin and venetoclax because -- and vice versa, if it was 15 years for ivo-aza, and two years for aza-venetoclax, doesn’t really matter what the side effects were because at the end of the day, people are going to live longer with the azacitidine and whatever, either ven or ivo, depending on what it is.

I would say that I think what we really need is we need a trial that's going to tell us which one leads to an increased overall survival, and then that's it. Now, if they're equivalent, let's say the overall survival between ivo-aza and ven-aza are equivalent, well, if that's the case, then I completely agree, then you would pick the drug or you would pick the combination that has fewer side effects. I would only do that or I would only recommend my patients doing that, if it's not going to affect how long they're going to live.

Kerith: Right. That makes sense. Okay. Are there other IDH inhibitors currently in development, and would that be similar to what's happening with the three inhibitors, like first generation versus second generation, where they might be more potent?

Dr. Stein: I wouldn't say they're more potent. There is another IDH1 inhibitor that is being developed by a company called Forma Therapeutics. They may have actually filed to get it approved. It's very similar to ivosidenib. I wouldn't say that it's a second-generation drug. I think it falls into the first-generation category. Now there's a different IDH1 inhibitor being developed by a company called Loxo Oncology which is a subsidiary of Eli Lilly. That is a second-generation drug because as opposed to ivosidenib, it has activity against various IDH1 mutations that can develop while a patient is taking ivosidenib.

Again, just to back up for a second, imagine you're a patient. You're taking ivosidenib, and you do well. You go into remission, and then you relapse. The question always becomes, well, why did the patient relapse? What we've learned is that one of the reasons the patients can relapse is that the cell can actually develop mutations at the spot where the ivosidenib is supposed to bind, and those mutations keep the ivosidenib from binding into that spot. The new drug from Loxo Oncology is said, is said to overcome those resistance mutations. It's not that it's a more potent drug necessarily, although it might be. I'm not sure that it's so important, the potency of the drug, but it has activity against the resistance mutations. That's a drug that's in clinical trial now for relapsed and refractory IDH1-mutant AML.

Kerith: I also have a question about the targeted drugs. We've had a few shows now on different mutations, such as FLT3, TP53, and now, IDH. There seems to be quite a few targeted drugs to address these mutations, and they're being combined with other drugs for what you refer to as doublet or triplet regimens. It seems a lot of progress is being made in this disease with the targeted drugs, but I'm curious, in your opinion, is that translating to improved outcomes by achieving longer remissions or getting more patients to transplant?

Dr. Stein: Yeah, I think it is. I think it's definitely leading to improved outcomes. Certainly, it's improving outcomes because it's just making people live longer, even without a transplant, but then the other thing is that if you -- like we talked about at the beginning, with these small molecule drugs, I told you the exception, which is my patient is 87 years old, but with most patients that these drugs are not curative. If you can then take a patient who's gotten into remission with one of these drugs, and then get them to a stem cell transplant, the stem cell transplant potentially really, really is curative. I think that's a huge benefit for a patient and certainly leading to improved outcomes.

Kerith: I was curious, is there any trial looking at the standard inductions, 7+3 induction therapy, and adding ivosidenib or enasidenib?

Dr. Stein: Yes, yes there is.

Kerith: I mean, obviously, these are younger patients.

Dr. Stein: Yeah, so we did a trial, a small trial, adding ivosidenib and enasidenib to 7+3, which showed good results. It was a very small trial, so the results, whether they're reproducible or not, isn't the question. I think what's exciting is that now in Europe, there is a large randomized phase 3 study that is taking patients with IDH1 or IDH2 mutations, younger patients, and giving them induction chemotherapy, either with ivosidenib or enasidenib or induction chemotherapy with placebo. We're going to see, hopefully, in the next two to three years, whether adding on the targeted therapies to 7+3 is the way to go. So, yes, those trials are being done.

Kerith: Okay, one last question I have, before we open it up for caller questions. I know that this is sort of a general question for you. AML is such a difficult and challenging disease. I was curious if you could just tell us what sort of excites you most about the work that you do every day, and what keeps you coming back every day and keeping at it.

Dr. Stein: I think what really excites me is taking care of patients. Fundamentally, that's what I like to do. It's helping people get better from a disease that's really serious. It's certainly helped me that, over the course of my career, I've seen these major advances in the treatment of acute myeloid leukemia and that there are many other drugs on the horizon that are, I think, going to continue to improve the outcome of patients with AML. Being part of these patients’ lives and helping them out and really making a difference in their life is why I became a doctor in the first place, and that's what brings me back to work. The research is important. I love the research, but it's really in the service of just helping people out.

Kerith: Yes, I would agree in that I -- my husband was diagnosed with CML, and it morphed into AML in 2017. He passed in early 2018. I know just since 2017, there have been, I think, nine drugs introduced, which is pretty amazing. While it can be a very challenging prognosis, I see there's just a lot of hope on the horizon. I hope that gives people a feeling of hope, as well.

Okay, let's see. I'm going to open up the line for caller questions at this point. Let's see. If you have questions about anything Dr. Stein discussed today, you can call into 515-602-9728. Once you're on the call and ready to ask your question, press “1” on your keypad. I'll just give it a minute to see any questions that come through. Okay, it looks like we have call, a question that’s coming in from 1704, ends in 1704. I'm going to unmute you, and you can go ahead and ask your question. Go ahead, caller that ends in 1704.

Caller: Hi, Doctor. Just a quick question. I was wondering, for your one patient that's been on ivosidenib for many years, is that patient on monotherapy or combo therapy? Or has there been changes over time?

Dr. Stein: That’s the patient who is on monotherapy. She has been on monotherapy with relapsed and refractory disease for all those years.

Caller: Okay, great. Thank you.

Kerith: Okay, thanks for your question. Let’s see if there are any other questions. Okay, there's a call coming in from 1159, that ends in 1159. I'm going to unmute you. Okay, go ahead.

Caller: Hi, Doctor. Can you talk more about the length of time people are on ivosidenib? You mentioned your patient was on it for ten years. Do the patients typically stay on a drug for as long as they're responding?

Dr. Stein: Yeah, that's a good question. For patients who would typically stay on ivo -- well, it depends what the goal is. If I had a patient, let's say, who's eligible for a stem cell transplant, and if I put them ivosidenib and they got into remission; I would, all else being equal, there are a lot of variables here, but all else being equal, I'd probably recommend they have a stem cell transplant once they got into remission. For older patients who might not, relapsed and refractory patients, that is, who might not be a candidate for a stem cell transplant just because of their age or because they've got other medical conditions that make it difficult, those patients, yeah, you would keep them on ivosidenib basically until it stops working. Hopefully it never stops working. I wouldn't play around with switching things. My general philosophy is that if it's not broken, don't fix it. So if something's working then I just keep it going until it stops working.

Caller: Thank you.

Kerith: Okay, looks like we have one more call from, it ends in 1113. I will unmute you. Go ahead, caller.

Caller: Hi. My question, is ivosidenib being used at all as maintenance therapy after transplant?

Dr. Stein: Yeah, is it being used as maintenance therapy after transplant? Maintenance therapies, for those of you who don't know, maintenance therapies, let's say you've had a transplant, and you don't have any evidence of leukemia. Is it an effective strategy to just give someone ivosidenib with the hope that that will keep any leukemia from coming back? It's not FDA approved for that indication. I think there are people who do give ivosidenib as maintenance therapy. There was a clinical trial that was looking at the benefit of ivosidenib as a maintenance therapy.

It really gets down to the issue I brought up before, which is, who needs ivosidenib as maintenance therapy, and who are you just giving a medication to that maybe they were never going to relapse anyway? That's the important question that needs to be answered. Having said that, yes, there are people who are getting ivosidenib as maintenance therapy. If anyone is considering that approach, I would talk to their doctor about whether it might be right for them.

Caller: Okay, thank you.

Kerith: I think that's all the questions we have coming through, so I think we'll wrap it up for today. Dr. Stein, thank you so much for joining us. We're incredibly grateful for your generosity with your time and your willingness to share your expertise with us. We'd love to have you on the show again in the future to share updates on IDH inhibitors and your other clinical trials. We wish you all the best in your clinical practice and your research endeavors. Thank you very much.

Dr. Stein: Okay. Thanks so much. Thank you. Bye-bye.

Kerith: I hope everyone has a great day, and thanks, everyone, for joining us.

Dr. Stein: Okay, bye-bye.

Kerith: Bye-bye. Thanks for listening to HealthTree Podcast for AML. Join us next time to learn more about what's happening in AML research and what it means for you.

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