Kendra Sweet, MD
Moffitt Cancer Center
Interview Date: June 9, 2022

Immunotherapy continues to be an expanding and evolving area of research for AML with many drugs in development. In this show, Dr. Kendra Sweet, an AML expert from Moffitt Cancer Center, shared with us about an antibody drug conjugate called IMGN632 and the current trials using this drug.  IMGN632 targets CD123-positive AML cells and has shown promising results in relapsed/refractory patients in previous AML trials. 

Thanks to Our Episode Sponsor

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 the 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 June 23rd, at 3:00 p.m. Eastern, we will host a virtual event within our adult AML chapter titled "Finding Mental Strength Through Physical Activity." Linnley Sweening, HealthTree's Fitness Director and Cancer Exercise Specialist, will speak with us all about physical activity for AML. Movement is useful beyond keeping us strong physically. It can help you manage the stressful nature of an aggressive cancer resulting in significant benefits on your mental and emotional wellbeing. Come learn from Linnley about the benefits of physical activity and how you can incorporate movement into your daily routine as an AML patient. You can register for all 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. Sweet 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 are ready to ask your question. Now on to our show today.

Immunotherapy continues to be an expanding and evolving area of research for AML. More and more clinical trials and immunotherapy paved the way for this modality to become a viable therapeutic option in AML. As of today, the only immunotherapy options available are stem cell transplantation and the drug gemtuzumab ozogamicin.

Dr. Kendra Sweet from Moffitt Cancer Center in Tampa, Florida, is here with us today to help us learn more about the current landscape of immunotherapy in AML and tell us about an antibody drug conjugate in development called IMGN632. Dr. Sweet will explain what IMGN632 is, which AML patients may benefit from it, and discuss a trial she is working on using this drug.

We are so happy to have you here with us today, Dr. Sweet. Thank you so much for taking the time out of your busy schedule to join us and discuss immunotherapy for acute myeloid leukemia and specifically the clinical trials involving the use of IMGN632.

Before we get started, I'd love to provide an introduction for Dr. Sweet. Dr. Sweet is an associate member in the Department of Malignant Hematology at Moffitt Cancer Center and has an appointment as an Assistant Professor in the Department of Oncologic Sciences at the University of South Florida Morsani College of Medicine. Her clinical interests include myeloid malignancies with a particular focus on acute myeloid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Her work has been published in many prestigious journals.

Now let's jump into our discussion for today. Dr. Sweet, for anyone newly diagnosed, can you explain what immunotherapy is, and can you give us an overview of the current immunotherapy landscape in regards to AML?

Kendra: Absolutely. Thank you for having me here. I'm excited to be here. Immunotherapy, I think, if you want just kind of a very broad definition of what immunotherapy is, it’s treatment that would use a person's own immune cells to help kill a cancer cell. We can have immunotherapy that would either rev up the immune system, to use those immune cells to kill off a cancer cell or to suppress certain functions of the immune system to achieve an anti-cancer response. Either of those can be considered an immunotherapy.

Currently, there's a variety of different immunotherapies that are being studied in AML. There's a class of drugs called bispecific antibodies, or another very similar type of drug called a dual-affinity retargeting agent or antibody. It's easy if I could draw a picture of this, but I'll try to make this a visual if I can. Essentially, what these drugs are, they are two antibodies that are connected together by some kind of a linker. Then one of the antibodies is able to bind to a marker or a protein that's on the surface of a leukemia cell, so that antibody will attach to leukemia cell. Then the other antibody is able to bind to a marker or protein on the surface of the patient's T cells or immune cells. These T cells are your cells that are basically there to kill anything foreign in your body.

Essentially, you now have these two antibodies that are connected together by this linker. One is bound or attached to leukemia cell. One is attached to a T cell. Because those two antibodies are connected and brought those two cells very close together, so the T cell is aware of the leukemia cell and is now able to kill it. The drug itself isn't actually killing the leukemia cells. It's just working as a vehicle to bring the immune cells, the patient's own immune cells, into close proximity with the leukemia cells so that the immune cells can actually kill the leukemia.

That's one type of immunotherapy that's being worked on. There are drugs of that class. They're already FDA approved for acute lymphoblastic leukemia or ALL. They're being studied in AML but not yet approved in AML. Another type of immunotherapy that has gotten a lot of press recently. I'm sure lots of people have heard about this or read about this is CAR T cell therapy. Again, CAR T cell therapy is already FDA approved for treatment in ALL and in various types of lymphoma as well as multiple myeloma. As of yet, we haven't been as successful in finding effective CAR T cell therapy in AML, but we are certainly working on it.

But the way that CAR T cell therapy works is that we take out a patient's T cells. It's a process called apheresis where we take out the patient's -- we basically take out the blood, filter out the T cells, and put the rest of the blood back. Then these T cells are genetically modified so that we can get a specific target on those T cells, or we can modify them so that they can go after a specific target on the leukemia cell. Then once they've been modified, we put the cells back. We give them back to the person who has leukemia and then they can attack the leukemia cells. Those T cells have this specific antibody basically and can go after the specific marker on the leukemia cell. CAR T cell therapy does require chemotherapy to be given prior to getting the car T cells. But it, again, has been very effective treatment people with lymphoid malignancies and with myeloma and we are still working on finding an effective CAR T cell in acute myeloid leukemia.

Then what we're talking about today is a little bit different in that it's not necessarily using the patient's own immune cells, but it is antibody therapy. It is an antibody drug conjugate. It's slightly different, but it is still antibody therapy. It's just not the patient's own immune cells that we're using.

Kerith: I see. Well, thank you for giving us that background because that helps me understand the different aspects of it or different aspects of immunotherapy and how to break those down, so thank you for clarifying that.

Kendra: Absolutely.

Kerith: The trial you're going to talk about later in this episode involves IMGN632, which is, as you said, an antibody drug conjugate. Can you explain to us a little further about what an antibody drug conjugate is, what it does, and why antibody drug conjugates or ADCs are an important area of research for AML?

Kendra: Yes. Antibody drug conjugates, they are antibodies that target a specific marker protein on the surface of the leukemia cells similar to what I was describing with those bispecific antibodies or dual-affinity retargeting agents. It's an antibody that will go after a specific marker to find the cell and then attached to that antibody is chemotherapy. We call it a payload, but it's a chemotherapy agent that is attached to the antibody. When that antibody drug conjugate or ADC is given, it binds to the leukemia cell and then the cell draws in the chemotherapy into the leukemia cell and the chemotherapy essentially kills that leukemia cell. You can kind of think of it as like a targeted drug delivery system. If the antibody seeks out the specific cells with that marker, attaches to it, and then the chemotherapy gets brought into the cell and kills it.

Kerith: I think I remember reading a little analogy about it being like a little dump truck. Does that sound accurate? The payload being like a little -- it delivers the chemotherapy like a little dump truck and dumps off the chemotherapy to the cancer cell. I don’t know if that's a good visual or not.

Kendra: Yeah, I think you could say that. I guess, the dump truck would need to know exactly which cell it was going to, but as long as the dump truck, it only went to specific cells and then the dump truck dropped off the chemotherapy into that cell and then the chemotherapy did its job in that particular cell. The antibody is just a mechanism of getting the chemotherapy there. It's just a vehicle to get it there. Rather than giving chemotherapy that just goes throughout the whole body, this is targeting it to only cells that have that particular protein on the surface. If a leukemia cell has a protein on the surface that your normal cells do not have, then you can make an antibody that targets that protein that is only on leukemia cells and not on your normal cells so that these antibodies only bind to leukemia cells and not the normal cells. Then theoretically, that chemotherapy is only being delivered to leukemia cells and not to the normal cells.

Kerith: The key being finding and identifying the proteins on the cells that are present in AML cells only and not normal cells.

Kendra: Absolutely. That's the hard part. Yes, exactly.

Kerith: Let's see. Are there currently any other antibody drug conjugates that are FDA approved for AML right now?

Kendra: Yes, there's a drug called gemtuzumab ozogamicin. The other name for it is Mylotarg. That's an antibody drug conjugate. It's FDA approved for treatment of AML. It's got a pretty broad indication actually. We can use it in someone who's newly diagnosed and never been treated. We can use it in someone who has relapsed leukemia. We can use it with chemotherapy. We can use it by itself. It really is kind of a broadly used drug, and it is an antibody drug conjugate.

Kerith: Okay, how effective has gemtuzumab been at treating AML?

Kendra: That's a good question. It depends on a lot. That's not quite as black and white of an answer as I think we'd like it to be. I’m going to take it back a little bit to just AML in general, and you may know some of this already, but essentially when somebody is diagnosed with AML, we look at the chromosomes or the genetic makeup of the cells, and we look at various mutations that may or may not be present in the cells. With that information, we'll classify someone as either favorable risk, intermediate risk, or adverse risk. That's called a risk stratification. Really, the best efficacy where gemtuzumab is most effective is in our favorable-risk patients.

When we use it in newly diagnosed people, so people who've never been treated before, when we use gemtuzumab in combination with high-intensity chemotherapy in someone who has a favorable-risk AML, that's where we see the best response to gemtuzumab. When we look at the data with it, we see an increase in survival by 20% at six years when we add gemtuzumab to chemotherapy compared to people who got chemotherapy without gemtuzumab. It's really significant. There's a really significant benefit by adding gemtuzumab in that group of people.

In people who are in adverse risk group, if we use it in the frontline setting, meaning people who've never been treated, if we add gemtuzumab to chemotherapy, as they fall into an adverse risk, there's no benefit. That's not a group of people we're adding gemtuzumab to their treatment. In the intermediate risk group, there's a moderate benefit. It's about a 6% benefit in survival. It's still meaningful, but it's not as good as what we see in the favorable-risk group. It really depends on which, where in that risk stratification someone is, and that's the most common group of people that we're using gemtuzumab in.

But in addition to that, it is an antibody drug conjugate that specifically binds to a marker called CD33. If the leukemia cells do not have CD33 on the surface, then we can't use it because it's not going to bind to anything. There's nothing there for it to attach to. We have to be testing for CD33 at the time that someone's diagnosed. Almost everybody is tested for CD33 when they're diagnosed, and the majority of people with AML are CD33 positive. But that test has to be done at diagnosis, and then we'll typically use it up front because that's with favorable risks because that's where we're seeing the highest benefits.

Kerith: So far as the CD33 protein, that's not present at all or on normal cells?

Kendra: It is present on normal cells and that is one of the downsides of gemtuzumab is that it is present on normal cells. It's not only going to bind to leukemia cells, but can also bind to your normal cells. We see it can lower blood counts for quite some time because of that, because they can also go after normal early blood cells as well.

Kerith: So it becomes a balancing act of the dosing and trying to not have the toxicity factor?

Kendra: Exactly. We have to find the right dose that we can still allow the blood count to recover, and we want to give enough that we can get rid of the leukemia cells, but also allow the blood counts to still recover after getting chemotherapy.

Kerith: If we eventually ended up having --

Kendra: It's a balancing act because there's toxicity with it, and we don't want to suppress the bone marrow too much to the point that it couldn't recover.

Kerith: Right. If we end up eventually having multiple ADCs that are FDA approved going forward, how do we choose which one a patient gets?

Kendra: That's a good question. I think there's a few different ways to do that. One, obviously, we base it on the data that we have on safety of the drugs, as well as efficacy. I mean, if one looks like it gets a significant number of patients, more patients into remission than another, that obviously is meaningful. But typically, we try not to make those type of comparisons unless they've been compared head to head in a clinical trial. But also, we need to look at the patient population that the drugs have been studied in.

For example, gemtuzumab, most of the clinical trials with gemtuzumab is used with high-intensity chemotherapy. Again, kind of that upfront setting when we use a regimen called 7+3, which is again high-intensity chemotherapy or what we call induction chemotherapy. A regimen like that, 7+3 or something very similar to it, that's a lot of where gemtuzumab has been studied. That's a lot of where we're using it now. But then some of these other ADCs that have been studied or being studied now are being combined with lower intensity treatment options, not necessarily high-intensity chemotherapy.

That doesn't mean they won't be studied in that situation later. But right now, they're being looked at oftentimes this lower intensity treatment. The patient population is different. They're not always the young newly diagnosed patients, but sometimes they're older adults with relapsed disease, or maybe older adults with newly diagnosed AML. But really that's part of what makes the difference is where was the drug studied? Who was the drug studied in? In addition to that, what we call a molecular subset will also make a difference. Different mutations that may or may not be present, if we see that certain mutations impact the response to one of these drugs, that will make a difference. Or like I said before, the favorable-risk patients are the ones that really seem to benefit from gemtuzumab, so that's where we have been using gemtuzumab. If we see with IMGN632 or another ADC that comes along that perhaps a different subset of patients really benefits from that drug, then that's the group of patients we use IMGN632 in. But we have to do these clinical trials and kind of drill down to the group that really benefits from the drug to make sure we're getting the right group of patients. Obviously, we have to make sure the patient has the right target. If you don't have CD33, you're not going to use gemtuzumab. But if you don't have CD123, you're not going to use IMGN632. You have to have the target, the drug target to be able to use it too.

Kerith: That makes sense. What important lessons have been learned from gemtuzumab, do you think, that can be applied to antibody drug conjugate development moving forward?

Kendra: I think there's a few things. One is that I think to be most effective, they should be combined with other agents. When given by themselves, they're not as effective. But when we combine them with other drugs, we see better efficacy, which I think is the case with almost everything in AML, to be honest with you. Then with gemtuzumab, there's a lot of -- I'm sure you've probably read the history of it, maybe not. But it was approved back in, I want to say 2000 or 2001 and then it was voluntarily withdrawn from the market in 2010 and then put back on the market in 2017. I mean, that could be a whole discussion in and of itself, but there's been a number of clinical trials looking at safety, looking at the efficacy, looking at who should get the drugs, who shouldn't. But at the end of the day, we found that the safety is better and the efficacy is quite good when we give gemtuzumab in what we call fractionated dosing, so smaller doses given repeatedly rather than one big dose at one time.

I think that's something we need to pay attention to as well is that the dosing maybe needs to be fractionated or lower than we think and paying attention to the toxicity as well. There's the potential for liver toxicity with these drugs, and we need to watch that closely. But that chemotherapy payload is different on some of these drugs and that can also change the toxicity. I think those are some of the lessons that we've learned from using gemtuzumab, but we really need to drill down to the specific patients that derive benefit.

Kerith: Yes. Okay. That makes sense. Let's transition into talking more about the IMGN632 drug and what it is and how it differs from gemtuzumab.

Kendra: Yeah, IMGN632 is, again, it's an antibody drug conjugate, but instead of targeting CD33 like gemtuzumab does, IMGN632 targets a different marker called CD123. It's an antibody. Again, CD123 and then, again, it's conjugated or connected to chemotherapy or something we call DNA alkylating agent. That's the type of payload. It basically alters or breaks the DNA in the leukemia cell.

The main differences between IMGN632 and gemtuzumab are the antibody target is different, and then the payload, the chemotherapy payload is different. For this reason, the toxicity of the drug is a little bit different and very likely the efficacy of the drug will probably be different. The similarities are in the concept. That whole antibody drug conjugate concept is the same. But, otherwise, we can't really say that we expect the same side effects or the same outcomes with it because the rest of it is quite different.

Kerith: I see. I don't know if this is going to get too involved here, but I wanted to ask a question about and see if you can explain the difference between a drug targeting a mutation such as FLT3 or IDH1 mutation versus drugs that target the specific markers on the cell surfaces like CD33 or CD123. Can you explain that briefly?

Kendra: Yeah, I think really what we're talking about is the difference between a gene which has some importance in the development or a role in the development of the cell and how the cell kind of matures or grows or changes over time. Those are the genes like FLT3 or IDH. Then the cell surface markers, which are just, again, like proteins that are on the outside of the cell that kind of identify that cell.

FLT3 is a gene that -- the purpose of FLT3 is it plays a role in the development of early white blood cells, basically. When it gets mutated, you get this uncontrolled division of very immature cells that we call blasts or leukemia cells. We can give a drug as a FLT3 inhibitor to block those cells that have the mutated FLT3, and it basically shuts off that mutated gene to restore the normal function -- to kill off those cells and then restore the normal function of the cells in the bone marrow. IDH, when the gene IDH gets mutated, it basically stops the cells, the blasts in the bone marrow. It stops them from maturing. It prevents them from maturing. We can give a drug called an IDH inhibitor, and that forces them to mature. It forces him to grow up. It's basically adjusting or altering the genes to restore its function more or less, to force the cells to mature.

It's kind of altering these mutated genes to restore function or kill the cells with the mutated gene. But when we're targeting a marker on the surface of the cell, we're essentially using that as a way to identify a leukemia cell to say the leukemia cells have CD33 or CD123, so we're going to go after those. Kind of like if you had a roomful of people and you wanted to just identify, it'd be like saying, we want to pick all the blonde people out of the room. You just look for everyone who's blonde and you pull them out of the room. This is basically the drugs are saying we're going to pick all the CD33 positive cells out and it attaches to them and gets rid of them. It's just looking for a marker and attaching to those rather than altering the function of a gene in the cell. Was that clear, maybe?

Kerith: Yes. That's very helpful. Thank you. Thank you for explaining that. I appreciate that. Can you tell us more about CD123? How do patients know if they have the marker? Does it tell us anything about how aggressive a patient's AML is, etc.?

Kendra: Yeah. CD123 is, I mean, it's expressed on basically early bone marrow stem cells, but there's not a lot of expression on those early bone marrow stem cells. But AML cells, AML stem cells, it's usually overexpressed, so we typically will see a lot of CD123 expression on AML cells,  on blasts. That is what makes it a nice target for drugs in AML is that we usually, in most cases, see a lot of it on the leukemia cells and not very much of it on the normal early bone marrow cells.

There are some preclinical studies that suggest that higher levels of CD123 expression will correlate with worse overall outcomes. But that's all -- it's kind of, I think we can find some of that data, but we could probably find other data that doesn't support that. But there definitely is data that suggests that. The way to test for this is with a test called flow cytometry. It's usually done in the bone marrow. The pathologist would do this test in the bone marrow and look for the presence of specific markers on the leukemia cells or on the blasts to determine if CD123 is present. There are blasts in the person's blood. We can do it from the blood, but usually it's done in the bone marrow.

Kerith: Okay. Why don't we talk about the trials that have been done so far for using IMGN632 and the current trials and what we've learned so far from the trials that have been done?

Kendra: There have been two primary trials that have been done right now or so far with IMGN632, and they're still ongoing, one in AML and one in a disease called -- this is going to sound like a lot of words but blastic plasmacytoid dendritic cell neoplasm or BPDCN. They're both still ongoing. The AML study has certainly enrolled far more patients because BPDCN is quite rare. In AML, we started out with just IMGN632 by itself just to determine the safety of the drug, to learn the common side effects of the drug to figure out the right dose of the drug, and then we started combining it with other agents. Because that, of course, is what we're planning on doing moving forward. Because as I mentioned, we know that that these drugs, they'll be more effective in combination with other agents than just given by themself.

The most recent data that's been presented, we have enrolled more patients in this now, but the most publicly available data, most recent publicly available data, we've put 51 patients on the study with a combination of three drugs. IMGN632 in combination with a drug called Vidaza and another drug called venetoclax. Those two are already FDA-approved drugs that we use quite commonly to treat AML.

We started out in treating people who have relapsed or refractory -- or actually, I'm sorry, just relapsed AML. Again, it was a number of different groups of people with various doses of all three drugs to figure out the safety and efficacy. Then now, we have, after a couple of years of various drugs, I mean, I'm sorry, doses, we've settled on the right dose for all three drugs. Now we have moved to this triplet combination into the frontline setting, so we're now treating people who are newly diagnosed with all three drugs to try to get more information on how effective it is as a frontline treatment option.

Kerith: Yes, it seems like there's a lot of trials using triplets that I'm reading about, the triplet combinations. Kendra: Absolutely. Before Vidaza was the standard of care for lower-intensity treatment. Everything that came along was used in combination with Vidaza. And then venetoclax came along and was studied with Vidaza, and the combination of Vidaza plus venetoclax was found to be far superior to Vidaza by itself. That combination of Vidaza-venetoclax has now become the standard of care for someone who's not getting higher intensity chemotherapy. For that reason, now, the newer regimens are basically looking at these triplets of Vidaza-venetoclax plus drug X to see if we can improve upon Vidaza plus venetoclax. That's what we're doing here is seeing if we can improve upon the efficacy without significantly worsening toxicity. That's really our goal.

Kerith: Yes, that makes sense. What are the next steps in the development of IMGN632? What comes next?

Kendra: At this point, we're almost done enrolling people on the part of this study that involves people with relapsed disease. We are just finishing up that cohort of this study. We have plans to enroll about 20 more people with newly diagnosed AML on the triplet. Again, the idea here is to just get a preliminary idea of how effective this triplet is in the frontline setting and then to better understand how quickly the blood counts recover and things like that in the front line setting because that's going to be different than what we've seen in the relapsed setting. We want to get a good idea of that, a good understanding of that.

As long as what we see in that setting looks encouraging, then we'll design a phase 3 trial that, of course, this is up to the company, but I know that they would want to move it forward and look at a larger study, likely comparing the triplet to, I'm assuming this is what they're going to want to do. They have not said this for sure, but likely comparing it to Vidaza-venetoclax to see if we get better responses and better overall survival with the triplet than we do with just Vidaza-venetoclax. If we can keep people in remission, get more people in remission, keep them in remission longer and keep people alive significantly longer without worsening toxicity. That's, of course, our goal. But we need to compare it to the current standard of care to make sure that it's actually better.

Kerith: Okay. I have a question about -- so can you have CD33 and CD123 markers?

Kendra: At the same time?

Kerith: Yes.

Kendra: Yes, you can. Most people probably do.

Kerith: Most people, okay. Would it ever make sense to combine drugs to target two different CD markers like CD123 and CD33? Would that look like combining gemtuzumab and IMGN632, or would that be developing a new drug that targets both? I mean, this might be hypothetical.

Kerith: Certainly, you could. I'm trying to think of -- I mean, you certainly could. I don't know. Usually, we kind of combine drugs with different mechanisms of action. Because just so that we're not kind of overlapping against that overlap mechanisms, but potentially overlapping toxicities. But theoretically, you could because most people will have CD33 and CD123 expressed. But usually, we're going to pick things that kind of work differently and put those together. We have kind of different ways for the drugs to work.

Kerith: If you have both, then how are you choosing which drug to use then? If there's CD123 and CD33, is there an obvious choice in that case?

Kendra: Again, it'll kind of go back to if this is a young patient with favorable-risk AML, that someone could probably give induction chemotherapy with gemtuzumab. But if IMGN632 is approved in combination with Vidaza and venetoclax, very likely, that would be in a group of patients who are older and not considered eligible for intensive chemotherapy. For whatever reason, whether it's comorbidities or age. There's a variety of reasons that they would fall into that category. It would basically be whatever population that this triplet combination is studied in is where that would be used. But now, if we do a later clinical trial with IMGN632 in combination with intensive chemotherapy and find that this drug improves survival significantly in our favorable-risk AML patients, then it really is going to come down to the toxicity of the two drugs, which one results in higher response rates and improved survival? And then if all else is equal, it would come down to cost.

Kerith: Yeah, that makes sense. Obviously, cost becomes a huge factor.

Kendra: Yeah, I mean, if one leads to a cure and the other leads to 50% of people being cured, obviously, we're going to use the one that, sort of everybody, but as of right now, that's not what we have. If they're both equal on all accounts but one cost twice as much, we're going to use the one that's not as expensive.

Kerith: Okay. If we continue to see the positive outcomes in the trials, do you have any idea when this drug might become FDA approved?

Kendra: We're seeing very positive outcome in the trial that's being done for BPDCN. Again, that's a much smaller trial because it's a very rare disease. This drug has already been given a breakthrough designation status by the FDA for BPDCN. I imagine, I don't know, but I imagine if it's going to get FDA approval, it will probably get FDA approval in BPDCN before AML just because it's farther along in that setting. But as far as AML is concerned, I think it will still be a few years because we'll have to design a phase 3 trial that will take a few years to design and complete and then get the data to the FDA. I would say probably another three to four years before it would be FDA approved at least for AML.

Kerith: Okay, three to four years. I guess as just kind of a more general question, what do you think is the future of immunotherapy in AML over the next five to 10 years? I know you sort of gave us a great sort of overview of the different types of immunotherapy, but in general, if you could just speak to where we're headed there in AML.

Kendra:  I think we have, you know, the issue that we've been having is honestly finding a good target because a lot of the targets on AML blasts are also found on early bone marrow stem cells, and that makes things complicated because we don't want to kill off the early stem cells in the bone marrow that are normal early cells because we don't want to ablate the bone marrow. So we struggle there, whereas other diseases, we don't have that same complication.

I think that that's a big reason that we are a little bit farther behind. But we've definitely made some headway, and we're continuing to find newer targets that look promising and look encouraging. We had a DART, which is the dual-affinity returning agent, retargeting drugs. We had one that was targeting CD123 that looked encouraging, but then [0:46:39] [Indiscernible] but they're developing a new one kind of improving upon what they had.

I think there's some hope in that, moving in the right direction. There are a large number of CAR T cell trials done in AML. I'm hopeful that will start to make ground in that area over the next five to 10 years. We certainly have made huge strides in lymphoma and multiple myeloma in that area in the last five years. Then these antibody drug conjugates are definitely exciting, yet I don't think that using them as a single agent by themself, I don't think that's where we're going to see huge progress. But when we use them in combination with other drugs, that's where they make significant impact. If we find a good target and can use them in combination with other drugs, I think we can start to see some impactful changes.

Kerith: Well, that sounds promising. I know it's just exciting because there's been so many drugs that have been introduced in the last, I guess, since 2017, there have been nine drugs introduced.  I think it's pretty exciting and gives me a lot of hope for the future.

Kendra: Yes, absolutely. We're making headway. There's no question about that. We're making headway.

Kerith: Yes. I think that's just wonderful. Okay, I'd like to open it up now for caller questions. If you have questions about anything Dr. Sweet 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'm just going to give a second to see if any calls come in. Okay, I have a caller that ends in 7401. I'm going to unmute 7401. Okay, go ahead, caller 7401.

Caller: Oh, yes, thanks. Yeah, thanks for this. This has been interesting. I do have a question about side effects with IMGN632. Have there been any identified? If so, how did those side effects compare with gemtuzumab?

Kendra: The most common side effects that we're seeing are what we call infusion-related reactions, which are not uncommon when we give antibody therapy. Those would be like fevers during the infusion or what we call rigors. It is kind of like shaking, like if you were to have a fever, you get the shakes, or some shortness of breath, things that we can typically treat with Benadryl or steroids. We see that in about a third of people. But they're usually low grade and we actually just recently made a change to our premedication. What we're giving people before giving the drugs and that has significantly decreased the rate of infusion-related reactions. It was about a third of people, and it's dropped it once the closer to like 10%. Now that we've made many changes to the premedication, that's gotten much better.

Another side effect that is not uncommon with IMGN632 is edema, which is fluid building up typically in the lower extremities, in the lower legs. In most cases, it's low grade. We grade things like one through four, one being kind of mild, not very severe, four being really significant, and most of it is grade one or grade two. It's more of an annoyance than a major problem, but it is still not uncommon. We've seen that in about 20% of people. We can give diuretics, water pills to get that fluid off, and usually that's good enough. But those have been kind of the more common things and then other side effects are things that we've seen kind of across the board with most AML therapy, as far as lowering of the blood counts and that kind of thing.

What we see with gemtuzumab oftentimes is -- not oftentimes but probably the biggest concern, I should say, with gemtuzumab is toxicity to the liver at something called veno-occlusive disease or VOD and that's a big concern, especially in someone who is potentially going to move forward with a bone marrow transplant or stem cell transplant. We have not been seeing VOD in people being treated with IMGN632, so that has been encouraging. We've been very pleased that we are not seeing VOD in these patients so far. It's really primarily the infusion related reactions, which I think we're getting our hands on as far as how to manage that and then the lower extremity edema, which is manageable. But I mean, it'd be great if it was less, but I think we're managing it okay.

Caller: Awesome. Thank you.

Kerith: Okay, let's see if we have another question here. We have a question from 0653. I'm going to unmute you right now. Okay.

Caller: Yeah. If I'm interested in a trial, how can I find out my eligibility? I'm kind of curious as to outside of your hospital, are there trials going on in other hospitals?

Kendra: Yeah, absolutely. Probably the best way to do it, short of asking your doctor to guide you, which may or may not be an effective route depending on where you are. There's a website called clinicaltrials.gov. If you go to clinicaltrials.gov and you can type in acute myeloid leukemia, if you just type in acute myeloid leukemia, you're going to get a whole wealth of stuff that may or may not be applicable to you, but you can start that way and you can kind of narrow it down, but every clinical trial that is open in the United States is listed on that website. You can look through the criteria for eligibility, and it will have the name and the contact information for the clinical trial coordinator and the principal investigator at all of the sites that the trial is open at. You can look through all of that and then you can reach out to the coordinator and see if it's something that might be applicable for you.

Caller: Awesome. Just kind of out of curiosity, the clinical trials that you mentioned, are those specifically running your hospital, or do they have arms in other locations as well?Kendra: The one that I mentioned was IMGN632 are open here and they're open at other sites as well. The IMGN632 AML study is open at probably 15 sites, I think, around the United States at least. Yeah. I can't remember all of them off the top of my head. I know it's Northwestern in Chicago, MD Anderson and Houston, City of Hope in Los Angeles, Cornell in New York, Roswell Park in Buffalo. I can't remember all of them, but -- it’s open at Duke, I think. It's quite a few places. But if you look on clinicaltrials.gov, you can see where that open, but then, again, there's going to be a lot more trials too if you look on that website.

Caller: Awesome. Thank you so much.

Kendra: Of course.

Kerith: I'll just mention too that on our website, healthcare.org, we have a clinical trial finder tool, which can also be helpful, and sometimes it is a little bit easier than clinicaltrials.gov and you can enter the search criteria. That can often help as well.

Kendra: Perfect. That’s awesome. That's perfect.

Kerith: Okay. I think we need to wrap up. That's all the time we have for questions today. Dr. Sweet, I'd like to thank you so much for joining us today. We're so grateful for your generosity with your time and your willingness to share your incredible expertise with us. We'd love to have you on the show again sometime in the future to share updates on immunotherapy and the different trials you're working on.

Kendra: Absolutely.

Kerith: We wish you all the best in your clinical practice and your research endeavors. Thank you for all that you're doing to help further a cure for AML.

Kendra: Thank you, I really appreciate it. This was fun and I’m happy to join anytime.

Kerith: Thank you so much.

Kendra: Take care.

Kerith: 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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