Joseph Jurcic, MD
Herbert Irving Comprehensive Cancer Center at Columbia University
Interview Date: May 26, 2022

Immunotherapy is one of the most promising areas of cancer research. Drugs like checkpoint inhibitors, monoclonal and bispecific anitbodies, antibody drug conjugates and CAR-T cell therapy are all extensively being studied in AML. In this show,  Dr. Joseph Jurcic, an AML expert from the Herbert Irving Comprehensive Cancer Center at Columbia University, shared with us about the progress being made in immunotherapy. He discussed an exciting new immunotherapy drug in development called magrolimab and several clinical trials using this monoclonal antibody and immune checkpoint inhibitor.

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 AbbVie 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. In two weeks, on June 9th at 1:00 p.m. Eastern, we will host another HealthTree Podcast for AML episode. We will be joined by Dr. Kendra Sweet, an AML expert from Moffitt Cancer Center in Tampa, Florida. Dr. Sweet will be discussing an important clinical trial using IMGN632, a CD123-targeted antibody drug conjugate in development. I hope you can join us for this interesting discussion.

The event registration page for this show will be posted by Monday. You can register for all of our events by visiting our website: healthtree.org/aml/community/events.

I'd also like to take a moment to let everyone know, if they are not familiar with HealthTree University, it is a free comprehensive online curriculum for AML patients and their caregivers. It has over 150 lessons from top AML experts around the country. The content ranges from AML basics to more complex topics like AML genetics and stem cell transplant. It's a great way to educate yourself prior to appointment so you can spend clinic time discussing your specific situation rather than asking basic questions. You can find HealthTree University at healthtree.org/aml/university.

As a reminder for today's show, if you have joined us online and would like to be able to ask Dr. Jurcic 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 has become a very important area of research in acute myeloid leukemia. I think it's really important to understand how much progress has been made in the last five years. In a previous podcast episode, Dr. James Blachley from the James Comprehensive Cancer Center at Ohio State University described the AML landscape like a desert with no water in sight. It wasn't that there were no trials and research being done. It was just that nothing was working. Nothing could beat the standard of care. There has been quite a bit of progress since 2017 with over nine new drugs introduced targeting specific genetic mutations. However, in the area of immunotherapy, the only options that are currently available are stem cell transplant and gemtuzumab. So, there's still a lot of work to be done.

In today's radio show, Dr. Joseph Jurcic, an AML expert from Columbia University will discuss immunotherapy and the important role it is playing in new and developing treatments for AML. Dr. Jurcic will focus on a drug in development called magrolimab that has shown promising results in AML clinical trials. Dr. Jurcic will explain why magrolimab is an exciting development for AML patients, which AML patients might benefit from it, and he will also discuss two upcoming trials using magrolimab.

We are so happy to have you here with us today, Dr. Jurcic. 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 magrolimab. Before we get started, I'd love to provide --

Dr. Jurcic: Thanks so much for the invitation. It's a pleasure to be here.

Kerith: Yes, we're so happy to have you. Before we get started, I'd love to provide an introduction for you.

Dr. Joseph Jurcic is Professor of Medicine at Columbia University Medical Center and Director of the Hematologic Malignancies Section of the Division of Hematology/Oncology. His main focus is the treatment of acute and chronic leukemias, myeloproliferative neoplasms and myelodysplastic syndromes. Research interests include acute myeloid leukemia, radioimmunotherapy with alpha and beta particle-emitting radio isotopes, monoclonal antibody therapy for leukemia, the development of novel small molecule inhibitors for leukemia and the molecular monitoring of minimal residual disease.

Dr. Jurcic has been the principal investigator on over 40 clinical trials. He has been in practice for over 30 years and has a very impressive list of awards and published papers and we are extremely honored to have him on the show today. Thank you.

Dr. Jurcic: Thank you so much for that kind introduction.

Kerith: Of course. Well, you have a very impressive 42-page CV. Let's jump into our discussion. What is immunotherapy? Why is this such an important area of research for AML?

Dr. Jurcic: Well, immunotherapy is a type of treatment that uses substances to stimulate or suppress the immune system to help the body fight cancer or other diseases as well, like infections. We know that immunotherapy is a very powerful tool because I often say that allogeneic stem cell transplant you can think of as the ultimate immunotherapy. We're replacing a person's immune system with a new immune system, and we know that this is capable of curing people with AML. That transplanted immune system can recognize and destroy leukemia cells, and that's a process that's known as graft versus leukemia. The fact that we can do an allogeneic transplant in people and cure AML really provides proof of principle that the immune system is a very powerful tool to fight AML and really does merit further study.

Kerith: Okay, thank you for answering that. That made it very clear on what immunotherapy is. Can you tell us how immunotherapy is currently being used in AML? Why might it be important in specific treatment resistant mutations of AML?

Dr. Jurcic: We know that immunotherapy has really gained a major place in the armamentarium for various hematologic malignancies, but as you pointed out in the introduction, really its role in AML has been rather limited to date. We know, for instance, there are CD20 monoclonal antibodies that are useful in treating lymphomas and chronic lymphocytic leukemia, acute lymphoblastic leukemia. We have engineered T cells known as CAR T-cells that are useful in lymphomas and ALL. We have blinatumomab which is a molecule that targets ALL cells as well as T cells known as a bispecific T-cell engager that's useful in ALL.

We have all of these agents and other diseases, but really AML does seem to be lagging behind a bit. As you also mentioned earlier, that the only approved antibody-based therapy for AML right now is drug called gemtuzumab ozogamicin. This is a drug that targets a molecule on AML cells called CD33, and it delivers a chemotherapy drug directly to the cancer cells called calicheamicin. In general, most antibodies by themselves haven't been potent enough to kill large numbers of AML cells. Perhaps this is because the immune system tends to be damaged so severely in AML. But we know that there are other bispecific antibodies and antibody drug conjugates and also radioimmunotherapy where antibodies can be used to deliver radiation to the leukemia cells that are being studied and show promise.

I think these therapies are important since they represent therapeutic options for patients regardless of their genetic mutations. As you know, there are multiple drugs now that are approved for people with a specific gene signature FLT3 mutations, IDH1, IDH2 mutations. But the fact of the matter is the majority of patients with AML don't have these specific mutations and even when they do, these drugs don't always work. We need new therapies that can kill the disease across the entire spectrum of chromosomal and genetic mutations.

Kerith: Okay, great. Well, you mentioned this briefly when you were just speaking, but do you feel the use of immunotherapy has lagged behind in AML? Do you feel that we've made progress in catching up compared to other cancers?

Dr. Jurcic: I think progress is certainly on the horizon. As I mentioned, one of the problems with most monoclonal antibodies is that they're just not potent enough to kill large volumes of leukemia. The idea has been, one idea at least, has been to take these antibodies and arm them with something to deliver to the cancer cells and this is the notion of an antibody drug conjugate. In your introduction you had mentioned, you'll have a show dedicated to some promising agents in this particular field. Another is to take an antibody and label it with a radioactive element, delivering that directly to the cancer cells.

These are promising. There are also bispecific molecules that are under development. Many times, when we think of immunotherapy, you see advertisements on television for these drugs all the time that target certain checkpoint inhibitors like PD-1, PDL-1, CTLA-4, right? These drugs have been very successful in certain solid tumors like lung cancer and kidney cancer and melanoma, but they really haven't panned out so well in AML. One reason might be that AML has relatively low numbers of genetic mutations compared to the solid tumors. When you have a large number of these gene mutations, you can create so-called neoantigens that can be recognized by T cells. That is simply just not happening in AML.

Kerith: That makes sense. Why don't we start from just simple -- why don't you tell us what magrolimab is?

Dr. Jurcic: Sure. I can break this down for you. Magrolimab is a monoclonal antibody that targets a molecule on the surface of a cell called the CD47. An antibody, monoclonal antibody in particular, is a type of protein that's made in the lab that can bind to certain targets in the body such as the antigens that sit on the surface of cancer cells. There are many different types of monoclonal antibodies. Each antibody is made so that binds to only one antigen on the surface of a cell.

Monoclonal antibodies can be designed to function in different ways. A particular drug may actually function by more than one means. Antibodies can trigger the destruction of a cell by basically poking a hole in the cell membrane. Sometimes they can block cell growth. They can inhibit the immune system. They can sometimes directly bind to a cancer cell causing a series of events that leads to the self-destruction of that cancer cell. We have all of these methods that a native antibody can work by. But we also can use antibodies to deliver radiation or chemotherapy, other toxins to cells. We can combine two antibodies, one that attaches to the cancer cell and one that attaches to a specific immune cell, to promote the immune system to attack the cancer cell. Those are called bispecific antibody. We have all of these different ways that we can use an antibody.

Magrolimab binds to an immune checkpoint inhibitor. Immune checkpoints are actually part of the normal immune system. Their role is to prevent an immune response from being so strong that it destroys healthy cells in the body. Immune checkpoints can engage where proteins on the surface of immune cells recognize and bind to partner proteins on other cells like tumor cells. These proteins are called immune checkpoint proteins. When the checkpoint and its partner protein has bound, it can send an off signal to immune cells. That prevents the immune system from destroying the cancer.

Immunotherapy with drugs called immune checkpoint inhibitors work by blocking the checkpoint proteins from binding to their partner and that prevents the off signal from being sent, so then immune cells are able to kill the cancer cells. Again, drugs like PD-1, PDL-1 and anti-CTLA-4 antibodies can prevent the destruction of cells using an arm of the immune system known as T cells. As mentioned earlier, there's really been limited success using those checkpoint inhibitors. CD47 actually represents a novel immune checkpoint inhibitor and in this case, it functions as a macrophage immune checkpoint.

Macrophages are part of the immune system, and it's their normal function to basically eat other cells. This is a process that's called phagocytosis. CD47 sends a "do not eat me" signal to these macrophages and says "leave me alone" basically. That is how certain cancer cells can evade the immune surveillance by macrophages. When we inhibit CD47, basically what happens is you stop CD7 from binding to its partner protein, which is seen on the macrophage called SIRPα. By binding to CD47, magrolimab prevents the interaction with this molecule and then allows the cells to be destroyed by macrophages. 

Kerith: Just so I can make sure I'm clear on this. Magrolimab, it's a monoclonal antibody, and it's also an immune checkpoint inhibitor?

Dr. Jurcic: That's correct. We use the antibody to block CD47 which prevents CD47 from binding to its partner to send this "do not eat me" signal. 

Kerith: When you refer to tumor cells interchangeable with cancer cells, correct?

Dr. Jurcic: Correct. Correct.

Kerith: Because I was curious to know about this "don't eat me" signal and how it interferes exactly with that signal. Can you just walk me through that again just in a simple way as possible? Because the signal is being overexpressed on cells?

Dr. Jurcic: Yes. It's important to note that while CD47 is seen on the cancer cell, it's also seen on normal cells in the body including healthy stem cells in the bone marrow. This widespread expression of CD47 on normal cells could actually cause a concern for toxicity when you're basically allowing macrophages to recognize the cell by blocking the signal from CD47 with magrolimab. But we know that targeting with magrolimab, CD47 with magrolimab, for most cells is not enough to cause the immune system to destroy the cells. There are also other signals that the cells give, basically what are called pro-phagocytic signals or eat-me signals, other signals that allow the cell to be recognized and destroyed.

Cancer cells express both CD47 the "don't eat me" signal as well as other "eat me" signals. While the normal cells lack CD47 or do express CD47, sorry, but can lack the eat-me signals. By using magrolimab to block this interaction, the "do not eat me" signal, it exposes the "eat me" signal on the cancer cells and allows them to be killed or eaten up basically by the macrophages in that process that I referred to as phagocytosis. In contrast, when we blockade CD47 on normal cells and there's no "eat me" signal, the cells actually are fine. That's essentially how CD47 functions in the immune system. It sends a "do not eat me" signal to the macrophage by blocking it. You're then stimulating the immune system to kill the cancer cells. 

Kerith: Thank you for walking me through that.

Dr. Jurcic: Makes sense?

Kerith: Yes, that makes sense. Thank you. Can you walk us through some of the trials that have been done so far using magrolimab and share what has been learned so far from these trials?

Dr. Jurcic: Yes. I think there are some exciting results that we've seen already. Magrolimab in combination with azacitidine, again another commonly used drug for myelodysplastic syndromes and AML has shown some promising activity. Initially, in the development of this drug, we treated [0:19:40] [Audio Glitch] and they received magrolimab at that point as a single agent. Now, the drug only produced a response in one of these ten patients who had relapsed AML. But, again, it showed that the magrolimab could be given safely to patients with acceptable side effects. In fact, it did have some activity. The really exciting part happened when, in fact, magrolimab was combined with azacitidine.

So far to date, there have been 95 patients with high-risk MDS who've been treated with the combination of magrolimab and azacitidine, and 75% of these patients responded to treatment. That's significantly higher than you would expect with azacitidine alone which is the current standard of care for these patients. Based on that data, there's now a randomized phase 3 trial for higher risk MDS patients who are receiving either azacitidine with placebo or azacitidine with magrolimab. That study is currently underway. We're participating in that trial here at Columbia.

Also, as part of this initial study though, there were patients with AML that were studied. There were 29 patients where we have data available. It was a very high-risk group. Two thirds of these patients had poor risk chromosome abnormalities, two thirds had prior myelodysplastic syndrome, and almost half of these patients had a p53 mutation. This is a gene that we're going to talk about, probably come back to in a little bit, but it's an important tumor suppressor gene. When this gene is mutated, it confers resistance to traditional chemotherapy.

Among the AML patients, we had responses in about two thirds of these patients and 40% had a complete remission with normalization of their blood counts and elimination of the marrow blasts. Among those 29 patients, 12 of them had this poor-risk TP53 mutation. In that group, 75% of the patients responded and 42 achieved complete remission. That's considerably higher than you might expect to see with either intensive induction chemotherapy like the seven and three chemotherapy that probably many of you have heard of or other treatments with standard of care treatments like azacitidine and venetoclax. Those are the trials that have been completed so far that we've participated in at Columbia.

Kerith: The one trial, the one trial you mentioned at Columbia, was it using magrolimab by itself, the first one?

Dr. Jurcic: There was a safety run-in portion in this trial where we treated 10 patients. Again, we just wanted to prove that the drug was mainly safe to give. Among those ten patients with relapsed or refractory AML or MDS, only one responded. We know by itself and probably magrolimab is not going to be so useful. That's why it's been only developed in combinations primarily with azacitidine but also other possible combinations too. 

Kerith: Is there a reason why or an idea as to why it might not be so effective on its own, do you think?

Dr. Jurcic: Yeah. I think the issue with magrolimab is that one of the things that can happen is in order for the drug really to work well, you also need these "eat me" signals on the cells that I talked about earlier. One of the potential advantages of azacitidine is that it actually induces the expression of these "eat me" signals on the cancer cell. In particular, there's one called calreticulum that's increased up to 10 times with treatment with azacitidine. That's why I think the combination of magrolimab and azacitidine is particularly interesting to study for AML because you're not only blocking the don't "eat me" signal, but you're actually then increasing the number of these "eat me" signals on the cancer cell.

Again, there are other ways that you can potentially enhance the activity of magrolimab. You could use it in conjunction with another monoclonal antibody that targets a tumor associated antigen on the cell. This has actually been done in lymphoma already. There are studies looking at magrolimab with rituximab which is an anti-CD20 antibody. CD20 is seen very commonly on lymphoma cells. That trial actually yielded some very interesting results. You could also form a bispecific antibody, one that targets an antigen on a tumor cell and one that targets CD47 would be another interesting approach to use to try to overcome the resistance of cells. There are even growth factors that we can use that increase the number of macrophages. There's one called GM-CSF. You can expand the numbers of macrophages and then potentially enhance the activity of magrolimab. But I do think that as a single agent, it's not going to be completely effective.

Kerith: Interesting. I did read that the FDA had put a partial clinical hold on magrolimab studies in January 2022, but the hold was lifted in April 22 and the trials are resuming. Can you talk briefly about why there was a pause?

Dr. Jurcic: Yeah. The FDA did place this partial clinical hold. It was primarily related to issues in the enhanced study, which is being conducted in MDS patients, where the combination of azacitidine and magrolimab is being compared to azacitidine and placebo. This imbalance in side effects in these two arms was largely due to anemia that was seen after the first few doses of magrolimab. We know that anemia is an expected side effect of this drug. That's because younger red blood cells express CD47. As the red blood cells age, they lose CD47 and they gain "eat me" signals. This is how the body actually rids itself of old red blood cells. This is actually a natural process and part of the way the immune system in the body works.

We know though that these anti-CD47 antibodies like magrolimab can enhance the clearance of these red blood cells causing anemia. This poses a challenge in patients with MDS and AML because most people are starting already with some degree of anemia that's related to their disease. What's been found is that you can mitigate this anemia by using small doses, low priming doses of magrolimab initially and then increase the dose and follow the treatment with these higher maintenance doses.

That's always been part of the protocol. That's actually how the drug has been developed. But since lifting the clinical hold, there have been additional safety measures put in place. Patients now beginning treatment must have a hemoglobin level of nine or greater within 24 hours of starting a therapy. We can give transfusions to meet these criteria. In fact, we typically will transfuse the patient to that level before their first dose. Also, careful monitoring after those first two doses, which is really where we see the side effect happen, most commonly is necessary. Within three to six hours of receiving those first doses of magrolimab, you've got to check the CBC again looking for this rapid clearance of red blood cells. We've got to be ready to give additional transfusions before serious consequences can take place.

The other imbalance, I guess, in the two arms was related to infusion reactions with this antibody. This is something that's seen with pretty much every monoclonal antibody that's out there. You can get fevers, chills, back pain, nausea, sometimes low blood pressure or shortness of breath. Typically, we premedicate patients with Tylenol and an antihistamine like Benadryl. We can sometimes even give a corticosteroid like dexamethasone or methylprednisolone to mitigate this. Those were the reasons for the imbalance in the arms. I think the reasons are clearly understood and there are now plans in place to make the treatment even safer for patients.

Kerith: I think it's important to note here that clinical trials are so rigorously monitored. An example is this, where if there was any question about the safety or efficacy, the trials were immediately held so that additional research can be done to ensure that patients are safe before continuing on. Often, I think there's a lot of misinformation out there around clinical trials. Do you find that there are common misconceptions, or do you speak to your patients about common misconceptions around clinical trials?

Dr. Jurcic: Well, absolutely. I do think that, again, entering a clinical trial, obviously, it is a new drug and sometimes new side effects can be uncovered. Here, I think it's simply a matter of very close monitoring. The one thing that I will say about participating in a clinical trial is that the scrutiny that's done in the care which we take in monitoring people after this looking for side effects is potentially an advantage. If we're giving a tried-and-true treatment, you may not be watched as carefully. I think that's actually potentially an advantage of participating in a clinical trial is the careful scrutiny that goes on during the conduct of a study like this. Again, there were safety measures in place initially because the anemia that was seen is a known, expected side effect. But as we got further into the study and saw how people were reacting, we even put additional new measures in place to make it even safer. I think this is important going forward. There are similar things that happen with other drugs in development. Venetoclax is a great example.  In addition to being a really important drug in the treatment of AML, it was initially developed to treat chronic lymphocytic leukemia and it almost worked too well in those patients. There was massive destruction of CLL cells after these doses so much so that people would have what is known as tumor lysis syndrome and resulting in kidney failure. People would say, oh, my god, this drug is so dangerous. It'll never go anywhere. Let's just stop now. But thankfully, that's not what happened, right? Instead, new processes were put in place making the treatment safer. Of course, now it's a mainstay for treatment in patients with CLL and an incredibly important drug in treating AML. That's just another example of something that happened in the course of development of another really important drug in AML.

Kerith: That's good to know. Thank you for giving us that background. Can you tell us about the two current trials that you are working on with magrolimab?

Dr. Jurcic: Yeah. At Columbia, we currently have a study open. That initial phase one study that I described, it's nearing completion. Currently, there's only one group of patients that we're treating on this study, and those are patients with lower risk myelodysplastic syndrome. They're getting a shortened course of azacitidine and magrolimab. Then we're taking part in the large international phase 3 study that I already mentioned, the ENHANCE study for higher risk MDS. In that study, patients are going to get magrolimab and azacitidine versus azacitidine alone or azacitidine with placebo to be more precise. That study is ongoing.

We're looking forward actually to opening several other studies with magrolimab here at Columbia. The first is one that will look at various combinations, various combination therapies with magrolimab. We're going to be looking at magrolimab in combination with azacitidine and venetoclax in untreated AML for patients who are not eligible to receive intensive therapy. As probably many of you know in the audience, azacitidine and venetoclax has really become a standard of care for patients. We think that because of the non-overlapping toxicity of azacitidine and magrolimab that this will be a very useful combination. In fact, the MD Anderson Cancer Center has already begun looking at this combination of the three agents together, azacitidine, venetoclax, and magrolimab, in newly diagnosed patients and they have a very impressive 85% response rate. I'm very excited about that trial.

But other combinations that we're going to be looking at are magrolimab with salvage chemotherapy, so-called MEC chemotherapy which is mitoxantrone, etoposide, and cytarabine. That's one of the standard regimens that's used for patients with relapsed and refractory AML. Then also for patients who receive intensive therapy, but still have residual disease afterwards, minimal residual disease after, we're going to be looking at the role of magrolimab combined with oral azacitidine as maintenance therapy for these patients. I think that's going to be a very important study that looks at novel combinations with a standard of care adding magrolimab to them to see if there'll be any signs of improvement.

Another study that will be opening shortly, hopefully within the next few months, is a study dedicated to patients with this p53 mutation that I spoke about earlier. Remember, the TP53 gene is a tumor suppressor gene and when it's mutated, it loses its function. These patients tend to not respond as well to traditional chemotherapies. Even with azacitidine and venetoclax in TP53-mutated patients, the response rates are really only around 40% to 50% and the duration of responses are around six months. That's a population that we need to do better at.

This study is going to randomize patients to azacitidine with magrolimab versus basically the treating physician's choice. You could either get standard induction therapy with 7 + 3 style chemotherapy or azacitidine and venetoclax. I think that'll be really important trial to test the early signals that we've seen in the clinical studies looking at the activity of magrolimab in TP53-mutated patients.

Another study that's on the horizon is the so-called enhanced three study that's going to look at patients randomized through azacitidine and venetoclax alone or azacitidine, venetoclax, and magrolimab. I think that will be an important study to really establish that the three-agent combination could be better than the two agents in this larger randomized trial which will give us definitive proof.

Kerith: You mentioned the TP53 mutation group of patients. Is there another group of patients that has shown to benefit from the use of magrolimab in general?

Dr. Jurcic: The one aspect of this drug that I actually touched on a little bit earlier and I guess I'll amplify this now is the fact that it is really agnostic to all the other mutations. It can work in patients who have p53 mutations, FLT3 mutations, IDH mutations, DNMT3A mutations, you name it, there's a long list of genes that can be mutated in AML and myelodysplastic syndrome. It's not preferential to any of these. I think that's important again because it's really the minority of patients with AML that can benefit from these targeted agents. We need drugs that can have activity across the entire spectrum of mutations that are seen in these diseases.

What has been unique about the TP53 abnormality is that responses do seem to be as good for those patients as everyone else in the initial studies with magrolimab, and that has not been the case with all of the other combinations that have been tried to date. That's why that's of particular interest. But the trials that I mentioned, in fact, are open except for the dedicated TP53 trial is open to getting the entire spectrum of mutations.

Kerith: Thank you for clarifying that. Can you tell us about, in regards to the TP53 mutation, about how many patients typically have it? Can you tell us what makes this mutation so difficult to treat?

Dr. Jurcic: It's actually not a particularly common mutation. It's seen in probably about 10% to 15% of AML patients. Maybe up to about 30% in patients whose AML has evolved from a myelodysplastic syndrome. It can often be seen in conjunction with poor-risk chromosome abnormalities as well. TP53 is one of the most important tumor suppressor genes in the body. It does exactly what the name implies. It suppresses the growth of tumors. When it's mutated, it loses this function. That's the reason that AML that's associated with that particular mutation tends to have a poor response to chemotherapy and overall worse outcomes.

As I mentioned before, azacitidine and venetoclax, even that combination that typically produces responses in two thirds of patients, only works 40% to 50% of the time in TP53-mutated patients and the responses tend to be of shorter duration. There have been other drugs to try to target TP53, there was one APR-246 that actually did not show improvement in MDS patients with TP53 mutation when it was combined with azacitidine. I think this is really a major unmet need. Again, I think magrolimab can work across the spectrum, but it really does seem to have some interesting properties in regards to p53. Perhaps it's related to the genetic complexity of TP53-mutated AML. There may be also changes in the immune microenvironment caused by that mutation that might explain this. It's really not well understood at this point why the magrolimab seems to work particularly well in those patients, but it's something that's obviously being rigorously studied right now.

Kerith: The last thing, a couple few more questions left for today. I wanted to ask you, in your opinion, if we keep getting positive results from the magrolimab trials, how long do you think it might be until it becomes FDA approved?

Dr. Jurcic: That's always a tough question. The registration trial that they're going to put forward to the FDA to get magrolimab as an approved agent is that study that I mentioned in MDS patients. There are going to be over 500 patients with MDS in the ENHANCE study, again, looking at azacitidine and magrolimab versus azacitidine and placebo. The endpoints there will be the remission rate and the overall survival. The study is still accruing patients and then has to be completed. We need the readout from this trial. I will say though that, so I think we're still several years away from this definitive answer. But once the drug is approved, then the pace of investigation, which is still pretty, pretty rapid will even accelerate further because then you can use the drug with other novel combinations and find newer and perhaps better ways to use the drug than we already know about. I think we're still a few years away from the drug being approved. But the definitive trial, a randomized trial that will lead to its approval, is already in progress. 

Kerith: Other than magrolimab, are there any other immunotherapy drugs and trials now that you feel could be promising and have the potential to become FDA approved soon or in the next few years?

Dr. Jurcic: Yes. I do think that there are other immunotherapeutic approaches that could lead to FDA-approved drugs. One particularly promising one is a drug called iomab. This is a drug that's composed of an antibody to target CD45 which is seen on all white blood cells. It's labeled with a radioactive element called Iodine-131. This drug is being used to deliver radiation selectively to the bone marrow and other leukemic sites of involvement before an allogeneic stem cell transplantation in patients with relapsed or refractory AML. Historically, the standard of care has been to try to give patients with relapsed or refractory AML, some kind of chemotherapy to get the disease under control and then go to an allogeneic stem cell transplant which is potentially curative.

This approach tries to intensify the treatment given before the transplant with what's known as the conditioning regimen with this radioimmunotherapy drug and then follow that with the transplant. That is currently being studied in a randomized trial. Hopefully, we'll have a readout on that in a relatively short period of time. But this sort of therapy could represent a potentially curative therapy for patients with relapse disease without having to undergo additional salvage therapy.

There are other radioimmunotherapy drugs being developed as well, one with Actinium-225, so-called actimab, that has shown some promising activity in earlier studies. A group in Seattle is looking at another isotope called Astatine-211, giving that before stem cell transplants as well. I also think that there are some promising drug antibody conjugates that are out there. Again, you're going to have to show dedicated to the one of those very soon. There are also bispecific antibodies that are in development. I think one that's probably furthest along there is a drug called flotetuzumab. That one targets CD123 that's seen on AML cells and CD3 that's seen on T cells, again, activating these T cells to kill cells with the CD123 target on them. I do think that there are certainly some other very promising drugs that are relatively far along in development.

Kerith: You mentioned radioimmunotherapy. Can you just give a brief description of what radioimmunotherapy is?

Dr. Jurcic: Yeah. Basically, the idea here is that you have a targeting vehicle. In many cases, it's a monoclonal antibody that binds to the surface of a cancer cell, in this case, a leukemia cell. Attached to the antibody is a radioactive isotope, basically a substance that emits radiation. You can think of that treatment as an injectable form of radiation that's going to seek out the leukemic cell and deliver the radiation directly to that cell.

There are mainly two types of radiation, two types of isotopes that have been looked at. One are the beta emitters, these are longer-ranged particles like Iodine-131 that are particularly useful in the setting of a transplant where you want to basically kill the entire bone marrow to replace it with a new one. Then there are alpha particles, I mentioned an isotope Actinium-225 and also Astatine-211, these isotopes emit alpha particles which travel a much shorter distance. If you're interested in killing specific leukemia cells or small clusters of leukemia cells, these short-ranged high energy alpha particles may be more efficient. These are two general approaches that are being actively investigated in the treatment of AML.

Kerith: Last question I have for you today is where do you see the future of immunotherapy for AML headed over the next five to ten years? That's kind of a bigger picture question.

Dr. Jurcic: We've talked about some of the drugs that are fairly far along in development, but I do think that the next step will be after these novel agents are approved is how can we use them best? Perhaps the five-year goal is really to develop novel combinations in specific clinical settings and find the best ways to use these new drugs that are being added to our arsenal to fight AML. But there are also other approaches, I think, that really need to be developed. That's maybe more like a ten-year plan. We know that engineered cellular therapy, so-called CAR T-cells have been extremely useful in treating ALL as well as lymphoma. But to date, CAR T-cell therapy has been more challenging in AML. This is primarily because the expression of the targets that are used for these cells can be seen on normal early myeloid cells, cells that give rise to normal blood cells. CAR T-cells can result in significant suppression of normal blood counts.

There are methods that are being studied to overcome this damage to normal cells for the CAR T-cell therapy of AML. There also other cells that could be useful, immune cells such as natural killer cells that could be useful in treating AML. I think cellular therapy is going to be some of the next big thing on the horizon for AML over the next five to 10 years.

Kerith: Thank you for summing that up for us. I'd like to open it up now for caller questions. If you have questions about anything Dr. Jurcic discussed today, you can call in to 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 here and see if I get any caller questions. It looks like we have a question from the caller ends with 1034. I will unmute you and you can ask your question. Go ahead, caller.

Caller: Hi, Dr. Jurcic. Thank you so much for taking the time today to explain all this. When it comes to finding appropriate targets, I know you've talked about -- I can't even say the name right -- targeting CD47. What other targets are people studying that look promising in AML?

Dr. Jurcic: I think some of the major targets have been CD33. This is an antigen that sits on the surface of the majority of AML cells. It happens to be the target for a drug called actimab which is the antibody labeled with Actinium-225. It's also the target that is used for gemtuzumab ozogamicin, an already licensed drug in AML. That has proven to be a useful target. One of the drawbacks from it is that CD33 is seen on some normal myeloid progenitor cells so this can result in suppression of normal blood counts. Many times, the time to recover from these agents can be prolonged.

One of the drawbacks, in general, is that there's no such thing as a truly tumor-specific targets in AML as far as these proteins that sit on the surface of the cells. They're all expressed to some degree or another on normal cells in the body. One of the things that can be used to an advantage is that there's overexpression of these targets on leukemia cells compared to the normal cells in the body, but it's not a completely clean target. There's still some collateral damage that occurs. So CD33 is one.

I mentioned iomab which targets CD45. This is not a specific leukemia targeted -- again seen on leukemia cells, but it's also seen on every white blood cell. Now in the setting the iomab is being used for in transplant, you actually want to target all of the cells because you want to clear out the bone marrow, and you want to target immune cells to suppress the immune system so that you can then accept the transplanted cells and they can grow and not be rejected. It's a good target for that particular use but not to kill leukemia cells alone because there will be lots of collateral damage.

Another really promising target is CD123. This is expressed on AML cells as well as the leukemic stem cell, the cell that gives rise to all of these, all of the leukemia cells. That's a potential advantage of that particular target. Again, it's being used in the bispecific antibody setting. It's being used as a target for drug antibody conjugates. I think that one is also very useful.

Caller: Can I ask a follow-up question?

Dr. Jurcic: Yes.

Caller: You talked about bispecifics being involved in AML which is fabulous. When you think about this potential off target that you don't want, will the trispecifics help with that? Because, let's say, you're saying, okay, I want this molecule to go find CD33 and one or the other CD45 you just mentioned or something and just find those two plus your immune --

Dr. Jurcic: I think it may actually enhance specificity. Again, there's absolutely no clinical trials yet to date, but it's certainly an idea that needs to be explored.

Caller: Well, thank you so much for answering my questions.

Dr. Jurcic: Sure.

Kerith: We have another question here coming in. That looks like it is from caller 7386. Caller 7386, I'll unmute you. Okay, caller?

Caller: Hi. Can you hear me?

Kerith: Yes.

Caller: I have a question for you on maybe one of the studies that you'd possibly recommend. My husband just turned 40. He was diagnosed with AML in December. He has TP53 and also deletion of 5q and 7q. He was able to get into remission prior to stem cell transplant in March. But day 38, he already relapsed again and did a round of decitabine and venetoclax. He's actually in the hospital now with sepsis but probable refractory disease. We just actually are waiting on results today. I was just curious if you have any suggestions as far as what study to maybe pursue with the magrolimab, or what you would have to say about it.

Dr. Jurcic: At this point, the relapse actually happened fairly quickly after transplant, but most of the studies that are currently ongoing are actually in the earlier settings. However, it may be open at some centers already looking at magrolimab in combination with salvage chemotherapy. I would actually have to check the details of the study because again giving a really intensive chemotherapy this quickly after transplant can be tough.

One thing that I would suggest talking about is again further manipulations of the new immune system. Even if the decitabine and venetoclax hasn't completely eliminated the disease, it may bring it under enough control that you can think about their giving donor lymphocytes, basically cells collected from the donor that can cause a graft versus leukemia effect and  that may be one thing that would be useful in somebody with your husband's situation where the relapse has occurred relatively quickly after the transplant.

Caller: Do you think all these studies that you have been discussing with the magrolimab combined with venetoclax and azacitidine, those aren't something that he would qualify for? He would need something -- I do recall them saying something about salvage therapy with magrolimab but…

Dr. Jurcic: Again, early on we actually did give it to some people with relapse disease as a single agent. Again, it did not work so well. The group at MD Anderson has an ongoing trial. They presented preliminary data at this past ASH meeting, the American Society of Hematology, back in December 2021. What they showed was that, in fact, the triplet combination does have activity for patients with relapsed disease, but not so much in patients who have received prior azacitidine and venetoclax. It never received it. It actually did have some promising effects. We've learned that already from some preliminary data out there.  

Caller: Thank you. Thank you.

Kerith: That's all the time we have for caller questions. Dr. Jurcic, thank you so much for joining us today. We're just 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 in the future to share more updates on immunotherapy and the magrolimab trials. We wish you all the best in your clinical practice and your research endeavors.

Dr. Jurcic: Well, thanks so much. It's been a real pleasure to be with you today.

Kerith: Yes, thank you again.

Dr. Jurcic: Have a good day, everybody.

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

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