James Blachly, MD
Ohio State University James Comprehensive Cancer Center
Interview Date: October 25th, 2021
Progress in understanding AML and developing therapies that treat this challenging blood cancer is occurring at an astounding pace. Up until recently, treatment options for AML remained largely unchanged for nearly the past 5 decades, with cytarabine and anthracyclines, or 7+3 therapy and the use of hypomethylating agents like azacitidine or decitabine for less intensive therapy. Implementation of large-scale genetic studies in the past decade have unraveled the genetic landscape and molecular understanding of AML leading to the approval of several new drugs for targeted therapy by the US Food and Drug Administration. These drug approvals have significantly widened the treatment options for patients with AML and opened the doors to many new clinical trials looking at their use in various combinations and settings.
In this radio show, Dr. James Blachly, an AML expert from the James Comprehensive Cancer Center at Ohio State University reviews the use of many of these newer treatments and discusses their use in clinics and hospitals today. He also shares an overview of the promising agents currently under development along with information on key clinical trials taking place that will further shape the future of AML treatment. Dr. Blachly simplifies the significant work being performed by researchers all over the world who have a common goal of curing all patients with AML.
Katie: Welcome to today's episode of HealthTree Radio for AML, a show that connects patients with acute myeloid leukemia researchers. I'm your host, Katie Braswell. We'd like to thank our episode sponsor, Amgen, for their support of this HealthTree for AML show.
Before we get started with today's show, I'd like to mention two upcoming events. Later this week, on October 28th, at 2:00 p.m. Central, we are excited to announce that we will be hosting our very first adult AML chapter that we will kick this event off with a brief introduction about the HealthTree for AML Foundation given by the foundation's president, Jenny Ahlstrom, which will be followed by a presentation from Dr. Stein, an AML expert from Memorial Sloan Kettering Cancer Center.
He'll be discussing the importance of personalized medicine for AML and why it is crucial to be treated by an AML expert. He'll be taking your questions during the Q&A session at the end. We encourage you all to join this adult AML chapter, which will be hosting both educational and support group-style meetings regularly. You can join by visiting healthtree.org/aml/community/chapters.
Also, on November 15th at 2:00 p.m. Central, we'll be hosting another event within our adult AML chapter. We will have the unique opportunity to hear from Nobel Prize winner and immunotherapy pioneer, Dr. Jim Allison, and his wife, Dr. Sharma.
By registering for this event, you will also receive free access to Dr. Allison's documentary, which we'll encourage you to watch prior to the event. By registering, you will also receive a link where you can submit your questions to Dr. Allison, and he will answer them live during the Q&A session on November 15th. You can register for both of these virtual events by visiting healthtree.org/aml/community/events.
The registration page for the Jim Allison event will be posted later this week. By signing up for our newsletter, which is on the homepage of our website healthtree.org/aml/community, you'll receive an email when the registration page is posted and stay up to date on all of our future events.
As a reminder for today's show, if you have joined us online and would like to be able to ask Dr. Blachly a question during our Q&A period at the end, you'll need to call in via telephone to 515-602-9728 and press 1 on your keypad when you're ready to ask your question. Now on to today's show.
Progress in understanding AML and developing therapies that treat this challenging blood cancer is occurring at an astounding pace. Up until recently, treatment options for AML remain largely unchanged for nearly the past five decades with cytarabine and anthracyclines or seven-in-three therapy and the use of hypomethylating agents like azacitidine or decitabine for less intensive therapy. Implementation of large-scale genetic studies in the past decade have unraveled the genetic landscape and molecular understanding of AML, leading to the approval of several new drugs for targeted therapy by the US Food and Drug Administration. These drug approvals have significantly widened the treatment options for patients with AML and opened the doors to many new clinical trials looking at their use and various combinations and settings.
In today's radio show, Dr. James Blachly, an AML expert from the James Comprehensive Cancer Center at Ohio State University will review the use of many of these new treatments and discuss their use in clinics and hospitals today. He will also share an overview of the promising agents currently under development along with information on key clinical trials taking place that will further shape the future of AML treatment. Dr. Blachly will simplify the significant work being performed by researchers all over the world who have a common goal of curing all patients with AML.
We are so pleased to have you here with us on the show today, Dr. Blachly. Before we get started, let me provide an introduction for you.
Dr. James Blachly completed his medical degree and internal medicine residency at the University of Arkansas for Medical Sciences in Little Rock, Arkansas. He completed his fellowship in hematology and medical oncology at the Ohio State University Comprehensive Cancer Center in Columbus, Ohio.
Dr. Blachly is now an assistant professor of Biomedical Informatics and Internal Medicine at Ohio State University. He primarily sees patients with AML and hairy cell leukemia within the hematology and transplantation clinic at The Ohio State University James Comprehensive Cancer Center.
His current research conducted within the Blachly Lab focuses on understanding the role genetics and genomics play in the development, progression, and treatment of acute myeloid leukemia and chronic lymphocytic leukemia and returning that information back to the clinic, informing the design of future clinical trials to improve patient care. He is currently an investigator on several AML-specific clinical trials.
Thank you, Dr. Blachly, for joining us today.
Dr. Blachly: Thank you for inviting me to visit, Katie.
Katie: We're so happy to have you. And I'd like to go ahead and get started and jump into our discussion.
Dr. Blachly: Great.
Katie: I'd like to start by having you more broadly discuss the evolution of AML treatment over the recent years. Can you tell us about the progress that is taking place in research and drug development that has gotten us to where we are today?
Dr. Blachly: Sure, that's one of my favorite things to talk about. Before I get started, I want to say briefly that I have done consulting for companies that are involved in AML drug development, and I will discuss the use of off-label medications today.
So with that, this has been a really exciting story. It has a fascinating history. In particular, because we have 30 or 40 years where it was like a desert with no water in sight, we had 7+3, which many of your listeners have heard of as the conventional chemotherapy regimen for AML developed in 1973, and then bone marrow transplant really became established as a consolidated and potentially curative mechanism at the Hutch in Seattle in about 1977. But then in the rest of the '70s, throughout the 1980s and all the 1990s, there was absolutely nothing developed for AML. It's not to say that there weren't really important clinical trials going on and a lot of fundamental and translational research was happening, but we just couldn't make it work. Nothing could really beat the standard of care.
In the year 2000, a drug called gemtuzumab was approved. And so we had that drug, which is an immunotoxin conjugate essentially, a drug bound to a monoclonal antibody, for 10 years. It was actually withdrawn from the market in 2010. So ignoring gemtuzumab, we had really no new AML drug approvals or standards of care established between the mid-'70s and the late 20-teens. And so, in 2017, something really, really exciting in our field happened, which was the approval of a number of drugs. Once it hit, they just sort of all started hitting.
We had midostaurin, which is a FLT3 inhibitor -- I'm sure we'll talk about that later -- was approved in April of that year. And then, in August, we see quickly right after that a drug called enasidenib, which has an IDH2 inhibitor. And also in August, two days later, we have a liposomal formulation of daunorubicin and cytarabine, which is called CPX-351, marketed as Vyxeos. Then in September, just a few weeks later, gemtuzumab, the drug I mentioned that was approved in 2000 and yanked from the market 10 years later, was reapproved on the basis of new data that shows how to better use it with less toxicity. And then an IDH1 inhibitor called ivosidenib was approved in July the following year, in 2018. And then in November of 2018, we see two different drugs approved, venetoclax and glasdegib, right next to each other. A week later, in 2018, gilteritinib, another FLT3 inhibitor was approved at the end of November. And then, finally, in 2019, ivosidenib got another indication in the frontline setting.
So in 2017 and 2018, there's just this flurry of activity, and I view that really as the payoff for all those decades of research. People really were working hard and it's like we started to hit the exponential part of the curve. So I think that's really a short summary of the landscape of AML treatment. We started with chemotherapy. We worked hard to find something else. We had a hard time establishing a better standard of care. I'm leaving out a lot of things. For example, in Europe, they may do double inductions. There are certain centers in the United States that have modified the basic 7+3. But we had decades and decades where all we have is intensive chemotherapy, and then all of a sudden now we have a plethora of choices for targeted therapy. We can talk about what targeted therapy means a little bit later.
Katie: Yeah, that's a great overview. I've seen timelines put together basically depicting what you explained. It's amazing to see the explosions since 2017. Very good. I think it's always great to talk about the progress and the excitement in that. But despite the progress, I think you and I and probably everyone listening can agree that there's still a lot more work that needs to be done. Can you talk about the major gaps in AML treatment and drug development that still needs to be filled, and maybe highlight the groups of people with AML who especially need more research and better treatment options?
Dr. Blachly: Sure, that's a really great question and to really understand that question and the answer, we need to take a step back and understand AML as a description of a collection of diseases. Now, we define AML as 20% or more myeloid blasts in the bone marrow or peripheral blood, and then there's a bunch of other footnotes to that. But really there is a variety of genetic causes, and they lead generally to similar we say phenotype, which means what your disease or condition looks like. But we could instead think of AML as a collection of a dozen or more genetically distinct diseases.
And so a lot of the drugs that I rattled off that had been approved in 2017 and 2018 are what we call targeted therapies, meaning, for example, if a patient has a mutation in a gene called IDH2, they may be able to take an IDH2 inhibitor. If a patient has a genetic alteration in a gene called FLT3, then they may be able to take a FLT3 inhibitor alone or in combination with other chemotherapy or other hypomethylating agent, for instance, and that's called targeted therapy, right? But what about those genetic groups of patients who don't have a targeted therapy available for them yet? Well, there are other drugs like venetoclax which targets a protein called Bcl-2, but it does not target a mutated Bcl-2. That's something that could be used broadly in somebody who does not have a specific inhibitor for their disease.
But in a genetic sense, there are many, many, many groups of patients who have one or a combination of mutations for which there's no specific or pathway relevant inhibitor, and that's something that's being actively worked on. As an example, patients with an MLL or KMT2A is what we call it now, but an MLL rearranged leukemia may benefit from a Menin inhibitor. And there's a number of companies with Menin inhibitors in clinical trials.
So in a way, one way we're approaching drug development for AML is to slice the pie into a whole bunch of different pieces and go after them individually, and that could potentially be really successful. We see high response rates to specific targeted therapies. In other cases, we don't. Maybe we need a combination of targeted therapies.
I guess that's a group or many groups of patients with AML that need more research and better treatment options. We can talk about specific groups maybe a little bit later. But then there's other factors like demographic or socioeconomic factors. Our group had a presentation at the American Society of Hematology meeting last year that showed that under the age of 60, Black Americans have worse outcomes compared to Caucasian Americans and that self-identification of race might be one of the single most important prognostic factors. Really importantly, this was even in so-called good risk or favorable risk AML. So there's a lot of ways to slice that question. We could talk about genetic groups. We could talk about socioeconomic or other factors. I think as it relates to your listeners today, we may want to discuss individual genetic groups now or when we get to questions later.
Katie: Yeah, sure. So we might as well go ahead and talk about targeted therapies, and you've listed some of the FDA-approved ones and who they may benefit. Can you talk about some of the additional ones that are being studied and in development now and which subsets of people those may be beneficial for?
Dr. Blachly: Sure. Well, first of all, I think it's important to note that even though we already have FDA-approved drugs for certain mutational statuses or categories doesn't mean that we can't further develop better drugs. I'll give the example, FLT3 inhibitors, the very first targeted therapy approved for AML, and the first drug in a very, very long time in 2017 was midostaurin. That's a FLT3 inhibitor that was approved in the frontline setting in combination with chemotherapy.
Midostaurin is a great drug and I think is important standard of care in terms of FDA-approved therapies for frontline AML. But meanwhile, there's been a lot of development in second generation FLT3 inhibitors. All that work has paid off because the next year, in 2018, another drug called gilteritinib was approved, and it was approved in the relapsed refractory setting, but there's a number of centers and clinical trials that use gilteritinib in the frontline setting instead of in the relapsed refractory setting because it's a more potent and selective inhibitor.
There are yet other FLT3 inhibitors in trials currently. Likewise, there are FDA-approved IDH1 and IDH2 inhibitors, ivosidenib and enasidenib, respectively. But that doesn't mean that there's not more room for improvement. In fact, there are IDH1 and IDH2 inhibitors and combination of IDH1 and IDH2 inhibitors under development.
So other groups of patients that have sort of active drug development or that were looking to improve the status of things are NPM1 mutated patients. NPM1 mutated patients may benefit from inhibition of the SYK pathway. They may also benefit from Menin inhibition. I mentioned the Menin inhibitors as an important potential strategy in patients with MLL-rearranged AML. It's really interesting because NPM1 mutated patients are traditionally and there's a couple of footnotes here, again considered favorable risk. NPM1 mutated patients may not be transplanted in their first complete remission because there's a likelihood that some of these patients could be cured with chemotherapy alone. So that's a good risk patient.
MLL, on the other hand, is typically considered a poor risk marker. So if you have a rearrangement of the MLL or KMT2A gene, that's a very, very poor risk. And not only if you achieve the CR, would you be recommended to get a transplant? The probability of obtaining a CR is generally lower among these patients. And yet because these two groups can converge on the same pathway, if you will, or some of the same genetic programs are activated might be a better way to think about it, they might both benefit from Menin inhibitors. And in fact, Menin inhibitors are being studied in both of these patient populations.
There's a number of other populations where it could be very difficult to drug. For example, RUNX1 as a transcription factor that is frequently mutated in AML, and transcription factors were historically thought to be undruggable. There's a lot of newer strategies looking at drugging transcription factors using, for example, degrading compounds and other techniques in other diseases, but there's an example of a patient with poor risk disease that really needs some further development.
TP53 is another example of a mutation that confers a really poor prognosis that needs really active development. I think some of the most promising things for TP53 mutated AML include CD47 monoclonal antibodies, one of those, it's called magrolimab.
Katie: Yeah, I definitely want to talk more about that when we get into our immunotherapy discussion in maybe a few more questions.
Dr. Blachly: Sure.
Katie: I think we could talk about targeted therapy for an entire hour. It sounds like there's so much going on there, so many new developments, so many different things being looked at. But I'd like to take maybe a step backward and talk a little bit about 7+3 chemotherapy as it's been the mainstay of treatment for a very long time, as you've mentioned, for newly diagnosed patients who are deemed appropriate. I'm wondering if you see the use of 7+3 in this setting changing anytime soon, or are there any new chemotherapy regimens being studied or in development to replace 7+3 or give patients another option at diagnosis?
Dr. Blachly: Yeah, that's a really great question. I should state that 7+3 is the standard of care in the United States, but the practices vary worldwide. I think I've already alluded to the fact that in some places in Europe, particularly in Germany, it's standard to do a double induction, you know, something like 7+3, but given twice. So intensity may vary. So we'll talk about conventional 7+3 as practiced in the United States as a standard of care.
As a reminder to the listeners, 7+3, you'd think that 7+3 equals 10, but 7+3 equals 7 because of the way that these overlap. What it refers to is that you get seven days of one drug, which is cytarabine or Ara-C. The first three days of which overlapping, you're also receiving an anthracycline, something like idarubicin or daunorubicin, and that is the standard of care. I do see that remaining the standard of care at least for a while, but there are some interesting new data that's coming out. Some data that has already come out and that I think has made a big impact on practices is the addition of gemtuzumab, which the trade name is Mylotarg. You may also hear it called that, with the addition of gemtuzumab to 7+3 chemotherapy in specific subsets of patients, for example, good risk patients.
So a number of studies have shown that the addition of gemtuzumab or Mylotarg to 7+3 in the upfront setting provides even better outcomes for patients with good risk disease like core binding factor AML. I haven't said what core binding factor AML is, but it's a group of chromosomal translocations that predict that patients are more likely to be cured with chemotherapy alone. So these patients already had a high likelihood of being cured, but we can boost that further by adding gemtuzumab to 7+3.
There's other data in some very nice studies, for example, from MD Anderson, showing that the addition of drugs of the class purine nucleoside analog like cladribine to intensive induction with 7+3 or 7+3-like regimen can further improve outcomes. There have been additional studies with other purine nucleoside analogs, but I think cladribine has some of the best data. This has been done both in the frontline setting and the relapsed refractory setting, but what we'll probably see is a modification to the 7+3 backbone. As I mentioned, the addition of gemtuzumab in good risk patients or favorable risk patients or the incorporation of other agents like cladribine into the backbone can further improve outcomes for, say, intermediate risk patients.
Katie: So 7+3 seems to be here to stay but adding additional things to that therapy to further increase its effectiveness is the way the thought is going.
Dr. Blachly: For the majority of patients or at least for a lot of patients. I mentioned earlier that AML is a genetically defined disease. And as we learn how to divide things up, it may not be just the p53 patients who we would potentially exclude from upfront 7+3 chemotherapy. Maybe we'll learn which other patients have a propensity to DNA mismatch problems, and we would try them on some targeted therapy or some less intensive therapy up front.
Katie: Interesting. So for patients that have achieved remission, what are your thoughts on maintenance therapy in order to reduce risk of relapse? Is this an approach that's currently being used? And if so, what drugs may be considered?
Dr. Blachly: Great question. It is an approach that's being used, and it's been used for quite some time. So first of all, we have to consider whether somebody is appropriate for an allogeneic stem cell transplant or not. That's not necessarily considered a maintenance therapy. That's considered a consolidative therapy. We draw the distinction for the listeners is that consolidative therapy sort of improves the probability of a cure, and a maintenance therapy is designed to prolong a remission, which may or may not involve a cure.
So if somebody is appropriate for an allogeneic stem cell transplant, I think that would be the first thing to consider. If somebody is not eligible for an allogeneic stem cell transplant because they have really favorable risk disease, in general, outside of the context of a clinical trial, we're not recommending maintenance therapy. But for patients who may not qualify for transplant for one reason or another but who have unfavorable risk or intermediate risk disease, I think it is reasonable to consider maintenance therapy.
We have for some years been doing azacitidine, which I don't think we've mentioned yet on this call, but azacitidine is a so-called hypomethylator or hypomethylating agent, HMA. And that has been shown a number of studies, especially from Europe, as an effective maintenance therapy in AML. Now we actually have a drug called Onureg is the trade name, and it's oral azacitidine tablets, which are available for AML. But whether or not that improves outcomes for patients with favorable risk disease, I think, is not well established. And in general, we recommend these in patients with less favorable risk disease who are not moving on to transplant. Is that kind of what you're looking for?
Katie: Yeah, that was helpful. So I guess I'm wondering if hypomethylating agents or azacitidine, if that's kind of the mainstay when it comes to thinking about maintenance therapy, or if there are other drugs being considered.
Dr. Blachly: It is. Now in terms of other drugs being considered, absolutely. So I'll give you an example. Let's suppose that a patient had AML and they had MDS before they had AML. It may be an MDS that progressed quickly and was not treated. It may be an MDS they had for a really long time and it developed to AML, or maybe an MDS that was unrecognized, we would call that, an unrecognized antecedent MDS. And you can sort of work out after the fact that this AML probably came from an MDS on the basis of the genetic profile.
In any event, let's suppose that a patient had AML with an IDH mutation, and they get into a complete remission. And then you do a genetic study, DNA sequencing, on their remission bone marrow. There's no evidence of residual AML, but there's a fair number of the cells that still have, let's say, an IDH2 mutation. In that case, it's certainly not on label, but it would be reasonable and many experts would consider giving an IDH inhibitor as maintenance. This is also done in the context of a number of clinical trials. We're also investigating drugs like IDH inhibitors and other targeted therapies after allogeneic transplant as a mechanism of maintenance therapy.
So maintenance therapy conventionally and as FDA approved would be with a hypomethylating agent azacitidine. But depending on the patient's clinical context and their genetic context, you may consider specific target inhibitors as a maintenance therapy.
Katie: Yeah, that's very helpful. That example is great. Are you able to speak to any advances that are being made in allogeneic stem cell transplant and maybe talking about improvements to the transplant itself or any advances in managing side effects or toxicities that come along with the transplant?
Dr. Blachly: Well, let me just say that I am not a transplanter, and so I think what would be really nice is to have a future visit with an AML-specific transplanter. So bone marrow transplant physicians will often specialize in a specific type of malignancy. So there's bone marrow transplanters who specialize in lymphoma. Some specialize in AML. Some specialize in myelofibrosis, etc. And so I'm speaking from the perspective of an AML physician who sends my patients to my partners in the transplant department to be transplanted.
But, yes, there are a number of advances being made, and some of the most exciting advances are in, I think, supportive care and alternative graft sources. And so when I say supportive care, I mean everything from antibiotics to graft versus host disease treatment. And when I say graft sources, I mean the graft being the stem cells and where they come from, how they're manipulated, how can we select the stem cell source and how can we potentially manipulate the stem cell source potentially in conjunction with a medication given to the recipient to help reduce the chances of graft versus host disease and increase the chances of graft versus leukemia disease. But other than I can mention briefly some drugs that have recently been approved for GvHD, I would leave specific graft manipulations and the data regarding graft source to my transplant colleagues.
Katie: That was really, really helpful what you led with about trying to find a transplant specialist who specializes in AML specifically. I think that's great for our listeners to hear. What about for our transplant-ineligible patients, what's generally being offered to them now? What's being done to better serve this group of patients?
Dr. Blachly: Well, I'll say that, unfortunately, AML is often a disease of older adults, and many of these patients by virtue of age alone, although a transplanter who's listening is probably cringing, because we should not qualify for somebody on the basis of age alone. But usually what goes with age or what often goes with age is medical comorbidities or other conditions that you have, other health conditions, whether that is lung problems, heart problems, diabetes, etc. Anyway, unfortunately, a lot of patients with AML, being older adults may have conditions that preclude them from being transplanted.
Because of advances in donor selection and alternative graft sources, there are more and more AML patients who are able to be transplanted, but we're still left with a lot of patients who can't or won't or choose not to get a transplant. And for those patients, we've already talked about maintenance therapy. So for a subset of patients, maintenance therapy with something like oral azacitidine could be appropriate. Alternatively, you could ask your AML physician if there's anything about their disease or their mutational profile that suggests that they should have some alternative off label or clinical trial based maintenance therapy.
And then, finally, of course, some of these patients who are not cured with an allogeneic stem cell transplant may relapse. And so these patients may need treatment for relapsed refractory AML.
Katie: So let's move on to immunotherapy and other than stem cell transplant, can you tell us what immunotherapy options we currently have for AML? And what are some of the big ones right now in development?
Dr. Blachly: Well, I guess, first, we have to say what do we mean by immunotherapy, and you did say other than allogeneic stem cell transplant, which is great. So in terms of immunotherapy, I would think about this in terms of stem cell transplant, engineered cell therapy, something like a CAR T and monoclonal antibodies and antibody drug conjugates. So in terms of immunotherapies that fall under the engineered cell therapy, there's been a number of targets that have been investigated with CAR T. And just for listeners who aren't familiar with CAR T, CAR T stands for chimeric antigen receptor T cell, and engineered means that we're actually taking T cells, which are another important part of the immune system and a cell that's generally unaffected in AML because it is of a different lineage in the bone marrow, we take the T cells and we perform a genetic manipulation on them to cause them to express a gene that they never expressed before and they express a surface receptor that will target the AML cells. Or in the case of ALL or diffuse large B-cell lymphoma, we actually already have FDA-approved CAR T cells.
But this is a really exciting area of investigation in both solid tumor and hematologic oncology where we're taking cells from the patients themselves. Sometimes they're manipulated in some other ways ahead of time, but we take these T cells and then T cell is an important part of the immune system that can recognize pathogens or diseases and attack them, and we reprogram them to home in on the cancer cells. So in AML, there's a number of targets that are being explored and these include things like CD123, which is a protein on the surface of the AML cells. CLL-1 is another protein on the surface of some AML cells. CD33 is a target on some AML cells.
So again, just like we have to sort of subdivide all the genetic types of AML, we're going to have to choose immune therapy based on the we say immunophenotype, which means which proteins are expressed on the surface of the AML. There are also monoclonal antibodies, and I've mentioned already one is magrolimab, which is a drug targeting a protein on the surface of AML cells called CD47. If I back up a second and define what is a monoclonal antibody, in the same way that our body's immune system produces antibodies targeting bacteria and viruses and so forth, we can take the very same genes and express them in an artificial system and manufacture large quantities of antibodies targeting a specific protein. So this is different than the engineered T cell because there's no living cell involved. It's simply a protein. That's been an incredibly successful strategy in cancer generally. So those are all really exciting areas. I think CAR T cells for AML are going to be difficult but not impossible. Magrolimab as in monoclonal antibody is exceptionally promising.
Katie: I listened to very brief talk by Dr. Roboz, a specialist in New York, last week, and she was talking about CAR T in AML. She was saying that the difficulty here is that we haven't found good targets in AML because they're not necessarily always specific to AML cells. Did I gather that correctly? Is that why it's been difficult?
Dr. Blachly: Yeah, absolutely. One of the difficult things about this strategy in AML is that the AML blasts may express many of the same proteins which are expressed on a healthy blood stem cell or hematopoietic stem cell or healthy mature blood cells like neutrophils or monocytes. So the cells that we want to preserve, whether that's the healthy stem cell which may be few in number and fighting hard to recover and fight back against the malignant clone, or their byproducts which is the healthy normal, neutrophils, monocytes, etc. They have the same proteins on their surface as the AML blasts do. And so how do we find a target that's specific to the malignant blast or ideally the malignant AML stem cell and target that without depleting everything else?
One strategy is to be a little bit less sophisticated and just have a bone marrow transplant ready to go after targeting AML stem cells. But really, the Holy Grail would be to find a protein or a combination of proteins perhaps that uniquely identifies the AML stem cell or the AML blast or both.
Katie: I'm glad you talked about magrolimab. I wanted you to talk specifically about this one because the past few shows I've done with Dr. Mannis and Dr. Reagan, they both brought up their excitement about this therapy. I'm wondering if you could tell us where along the timeline are we with this. Is this something that could be available soon, or is it more early on in development?
Dr. Blachly: I would put it in between those two. I'll also say that I don't have any specific insight or information regarding magrolimab's specific path to regulatory approval. But I am very optimistic that we will see additional drug approvals in 2022 and 2023. Magrolimab has already demonstrated in early phase studies like phase 1b studies remarkable efficacy in patients, including with TP53 mutated disease. So that's a disease subtype I alluded to earlier that may not be suitable for upfront chemotherapy.
Many AML specialists may choose not to treat TP53 mutated AML patients with 7+3 with intensive chemotherapy. The reason being that TP53 being a master regulator of cell death, it's sort of response to signals that DNA has been damaged and if DNA has been damaged can cause the cell to commit suicide. If that's dysfunctional, then the cells can accumulate more and more genetic damage without dying and potentially become more and more aggressive.
So we're looking for non-chemotherapy strategies in TP53 mutated AML. Magrolimab has been fascinating because in some of the early studies, patients with TP53 mutation AML, which are traditionally considered difficult to treat, over 70% of them might achieve any response and about half of them could get a complete response. That's really remarkable. This is a drug that across the board we're very excited about because it doesn't have utilities only in TP53 mutated AML but in many settings, and in addition, it has utility in this setting that we consider very high risk and hard to treat.
Katie: Wow. No wonder I have each doctor speaking on it. It's very, very interesting and exciting.
Dr. Blachly: I should also add there are other drugs targeting the same protein CD47 in development. So I think that as a field generally, CD47 targeting therapy is really promising. Just like I mentioned, development of FLT3 inhibitors continued along. Magrolimab is the first one out of the gate, but there may be side effects with magrolimab that we can improve with second generation CD47 inhibitors.
Katie: Yeah, very interesting. So more broadly, can you talk about what work is being done specifically in relapsed refractory disease?
Dr. Blachly: Yeah. That's a really tough area because relapsed refractory AML is often a disease that has an accumulation of genetic damage, and I talked about TP53. But the chemotherapy that we give for AML up front, in general, is typically much more intense than chemotherapy given in another diseases. Most of the listeners know that because they or a loved one might have even been told that you're going to be hospitalized from four to six weeks to get chemotherapy and recover from it. That's just such a high treatment intensity compared to chemotherapy that we give for other diseases like colon cancer or breast cancer that there's really a high potential for ancillary genetic damage. When you've had enough chemotherapy, it's my belief that this is just a very, very challenging area to develop new drugs in.
So one of the things that I think is important to explore in relapsed refractory AML is new drugs limiting the number of prior lines of chemotherapy that somebody has had. And without meaning to exclude patients who may have had a lot of chemotherapy, I'm worried that in a big picture sense we could miss out on signals from potentially active drugs if they are tried only in a clinical trial context where patients who have had many, many rounds and types of traditional cytotoxic chemotherapy are being enrolled. Otherwise, I think there's too many promising agents to mention specifically, but if there's, I think, specific questions that you or the listeners have, I'd be delighted to go over them.
Katie: Sure, yeah. So I want to switch gears just a little bit and maybe talk about studies or work being done outside of just drug development, maybe looking at AML survivors and managing long-term side effects or even things to improve health such as nutrition, physical activity, quality of life, are you aware of any initiatives being done in this area?
Dr. Blachly: I am. This, I will say again, is not my area of expertise, but there are doctors who specialize specifically in AML-related quality of life. Tom LeBlanc is a physician at Duke University who's an AML specialist but also a palliative care specialist, and I think would be somebody great to visit with about this topic. But there's a lot of data and development of new data regarding patient-reported quality of life metrics. So most large clinical trials at this time, not just in AML but in cancer generally, are starting to incorporate patient-reported quality of life indicators within the studies themselves. So this is a really rich area that is only going to get better.
I mentioned that some patients or their loved ones, some listeners or their loved ones may have been told you're going to be hospitalized for four to six weeks. A lot of times that comes out of the blue and some recent research has shown that survivors of AML carry a diagnosis or should be given a diagnosis really of post-traumatic stress disorder. When we really look at it through an objective lens, that's terribly traumatic, stressful, disruptive. You're living your life and AML is a disease where you might feel perfectly fine one week and the next week you're being told that you need to be hospitalized for a month or longer and that if you don't take treatment, that you could die. So there's investigation looking into survivors and post-traumatic stress they may have and also ways to reduce that stress at the time that the diagnosis is made. So it's not my area and I can't tell you about specific studies, but I am excited that there are people working on that for our patients.
Katie: Yeah, I agree. I think it's super important to look at the things outside of medication that can make a patient's life better. I think that's really important. I'd love to explore that further on future shows. For the sake of time, let's move on. I want to get in just a few more questions before we open it up for caller questions. But can you talk about some of the top clinical trials that are on your radar right now that you feel are going to be the most impactful for the future of AML treatment? Maybe talk about what we might see in 2022?
Dr. Blachly: Sure. One of the things we haven't talked about on this show just because it didn't come up was that -- or maybe I should have said it back when we were talking about 7+3 and the standard of care. I missed the opportunity to point out that for older adults and I'm going to say 60 or 65 is when you start to think of somebody who's older and that seems younger and younger to me every year. But for older adults, 7+3 or intensive chemotherapy generally may not be the best approach and instead the standard of care now, although it's FDA approved in an older age group, I would say that anybody who's 65 and up should really strongly be considered for a combination of venetoclax, which is a targeted therapy I mentioned earlier, and azacitidine, which I mentioned earlier, but I didn't mentioned them together.
So some of the most promising stuff that is being looked at right now is using venetoclax and azacitidine as a backbone. So instead of 7+3 as a backbone, looking at venetoclax and azacitidine or Ven + AZA as a backbone with a number of other different experimental agents. In this way, you could think of it as a chemotherapy-free AML treatment regimen. Azacitidine is, I guess, in theory, a chemotherapy, but we don't think of it in the same way.
So combinations that don't include 7+3, so non-chemotherapy combinations are really exciting in things we're looking for. We're also looking at whether venetoclax could be used in a maintenance setting. I'm excited about magrolimab, which we've already discussed. I'm excited about there are two different Menin inhibitors and these are for patients with MLL or KMT2A-rearranged AML or NPM1 mutated AML. There are activators of mutant or inactivated TP53 being studied. There are other protein inhibitors like BCL-XL being studied and MCL-1 inhibitors. There's just a whole bunch of things. I think I've already told you the things I'm most excited about.
I do think in 2022, we'll start to see some additional drug approvals, maybe later in the year. I expect to see that continue on through 2023. But there's so much exciting stuff going on. I hate to call out things specifically and leave somebody out, but there's a lot of upfront and relapsed refractory studies going on in AML, both for younger patients who might tolerate intensive chemo and older patients who would require a less intensive regimen like venetoclax and azacitidine.
Katie: Yeah, that's great to hear. We've talked about so many exciting, cutting-edge trials today that really provide a lot of hope for AML patients. I want to give our listeners some practical information about what it could be like for them if they do decide to join a clinical trial. Can you take us through what joining a trial looks like at your facility?
Dr. Blachly: Sure. I think I would say that this is the same at any tertiary care facility. There are even large private practices that have really robust clinical trial portfolios. So typically, you would meet with your AML physician or your oncologist to learn more. Make sure that you really understand your diagnosis and where you are in your journey. It may be this is your very first interaction. You're previously untreated. You may be very experienced and you've had a number of prior lines of therapy and you're talking about next steps, but you have to sort of clearly you and your physician talk about where you are. That will influence the clinical trials that are available to you because the trials that are available for patients who have previously never had anything for AML, so previously untreated, is typically totally different than the menu of clinical trials available for somebody who has what we call relapsed refractory disease, or I'll pitch a third setting, maintenance studies, which is an active area of inquiry.
So you and your doctor will understand where you are, and you'll talk about one or more clinical trial options. You may, knowing some more information about your own genetics, you may ask some questions about, is there any information known about how this agent might interact with my XYZ mutation, or the fact that I've already had this, that and the other chemotherapy, any data that you know about or that we should know about?
And then when you and your physician sort of decide on a best approach, you will meet with a clinical trial coordinator. The clinical trial coordinator will provide some additional information, the nitty-gritty kind of stuff like whether there'll be travel involved. How often will you have to travel? Will there be any overnights in the hospital? Some treatments are given initially in the first cycle in the hospital, some immune therapies. Patients might be prone to an immune reaction or an allergic reaction, and we will monitor them in the hospital.
Once everything is working really well, you can get treatments in the clinic. The clinical trial coordinator will go over all sorts of stuff like that. Is there reimbursement for hotel? How many times do I have to come in the first month compared to subsequent months? that sort of thing. You'll get an informed consent document. It's really important to read this really carefully. And if you have any questions at all, ask them or ask them more than once and don't feel bad about it. The clinical trial coordinator's job and your physician's job is to make sure that you really understand the study and that it's something that you want to participate in.
So after you read and understand and sign the informed consent document, then there will typically be some screening procedures. So to screen somebody for a clinical trial is to be super sure that you're eligible because trials, of course, have a list of eligibility and ineligibility criteria, so bullet points as to who can participate and who definitely can't participate. That may be something as routine as a pregnancy test to make somebody ineligible if they're currently pregnant, or it may be something as complicated as a sophisticated genetic study that has to be done on the bone marrow.
So the informed consent document will go over and tell you what all the screening procedures are. You'll, depending on your center, get all that screening done on the same day that you meet with the trial coordinator. Most AML studies will involve a bone marrow biopsy. You'll have some additional blood work done. There's almost no imaging done in AML. Once the results of all those screening studies are back, you're confirmed eligible. Depending on the tempo of your disease, you could then begin participating in the clinical trial within a few days to a couple of weeks.
Katie: That's a great overview and very, very helpful. How would a patient navigate a trial that's not necessarily at their AML doctor's facility? How would they know or find these trials? What steps could they take to get enrolled?
Dr. Blachly: Yeah, first thing to do is ask your physician because they may have a network of people that they could reach out to at various other centers to see what trials are available. So suppose that somebody is treated at a community oncologist here in Ohio two hours west of here, they might call me and they might call Indianapolis and they might call Cincinnati to see what trials we have at our centers that would work for their specific patient. If the patient themselves needs to go looking for things, clinicaltrials.gov is the most comprehensive resource. It can be a little bit difficult to navigate. It's gotten a lot better lately, but you'll type in AML and then you'll look for other things you know about your disease and yourself to see what you could be eligible for. There's a list of sites in the US and internationally that any particular study is offered at on clinicaltrials.gov.
HealthTree, of course, is working on a clinical trials matcher for patients. And then there's other AML focused sites like AML Hub that may or may not have a clinical trial matcher, but you could learn more about what trials are out there. You can then go search them on clinicaltrials.gov to see where they are.
Katie: Yeah, and just to mention our clinical trial finder really briefly, you can find that on our website at healthtree.org/aml/community/clinicaltrials. This is the first iteration of our clinical trial finder to help you filter yourself for trials that might be relevant to you. Our next iteration coming hopefully very soon is that it will do the matching for you based on some health information that you'll enter. So stay tuned for that, but it's definitely on our website right now for you to check out and utilize with our advanced filters feature.
So I'd like to open it up now for caller questions. If you have any questions about anything Dr. Blachly discussed today, you can call in to 515-602-9728. And once you're on the call and ready to ask your question, press 1 on your keypad.
I see here caller ending in 1034. I'll unmute you and let you ask your question now.
Caller: Hi, Dr. Blachly. Thanks so much for taking time today and to be on the program. I just had a question about clinical trials since we've talked so much about it. Is there any time point where I can't join a clinical trial where it's like I've waited too long?
Dr. Blachly: Great question. The only time that I could think of, practically speaking, that a patient could not join a clinical trial is when they're currently being treated with something else. That's not to say that you couldn't discontinue treatment and then join the clinical trial. But patients who are currently being treated for AML or any other cancer are excluded from therapeutic clinical trials. There are other types of clinical trials that maybe dietary or lifestyle or whatever that would not exclude you. But in terms of number of lines of therapy, no.
I talked about the importance of the strategy of drug development sort of limiting the number of lines of therapy, but certainly most relapsed refractory studies we have open don't limit the number of lines of prior therapy in that way. So on active treatment is the only thing I could think of to answer.
Caller: Are there other health issues that I might have that might prevent me from joining a trial?
Dr. Blachly: There are really a lot of standard laboratory criteria that have to be met to participate in a clinical trial. And typically, these are things like adequate organ function, whether you're talking about kidneys or liver. And then depending on the specific drug or agent that's being studied, there may be additional hurdles to clear. This is really tough because many patients with AML already have organ problems maybe from their disease or maybe from treatment for their disease. It's really difficult to tell somebody that you can't participate because you don't meet this criteria. What I would say is keep looking. Continue searching because there's a broad variety in trial contexts and trial criteria.
Caller: Okay, great. Thank you so much.
Dr. Blachly: Thank you.
Katie: Okay, I have another question here from caller ending in 0579. I'll unmute you now.
Caller: Hi, yes. I also have a question about clinical trials. So there is one that I was very interested in for my mom who is now in a relapsed refractory state of her AML. It's called the SIERRA trial. It uses Iomab-B. So it seems like it just closed a few weeks ago. But because of the timing, we didn't know that she wasn't responding to traditional chemotherapy until after it had closed. I've emailed the doctors at all of the centers across the country, gotten in contact with the pharmaceutical company Actinium, and there's no possible way to get her in. So my frustration is, you know, we're talking about the future of care and how to help people survive and if this is a tangible investigational drug that is working for people, it works in people who have up to 30% blast and they still got into transplant on this. So if she qualifies for it, it's really mind boggling to me that because I was three weeks late on something that that could be a really life-changing time.
Dr. Blachly: That is so frustrating. The period between the closure of what we know as an active drug and the time that it gets FDA approved is one of the most frustrating for patients and their doctors because the data that shows that some agent or drug is active is already out there, but it has to undergo all of these regulatory checks before it can be approved. So I have to say, I sympathize with you and your mother because it's a really tough position to be in.
The only thing and potential way around this requires the cooperation of the pharmaceutical company, which you've already reached out to, and a physician who's experienced in either using the agent or agents like it. And that's something called a single-patient IND application. Those are really pretty uncommonly done, especially after data has been gathered in a phase 3 study like SIERRA. I didn't mention SIERRA. I think of that more of a transplant study, but I think that I'm really happy brought it up because it's really important to our AML patients. A single-patient IND is essentially regulatory paperwork that conducts a clinical trial of one. The problem is you have to have the pharmaceutical company agree to supply the agent and you have to have a physician.
In the case of Iomab-B, that involves also radiation control officers, and it becomes incredibly complex. But a single-patient IND is sometimes the only way to get access to agents that have already gone through a phase 3 study that appears successful or if, say, phase 2 is successful and they did phase 3 but is not yet FDA approved. This is one of the things that I'm looking forward to very much being approved, although I don't think that the final data will be available till the middle of next year, unfortunately.
Katie: Okay, I see one more question, which we're really short on time, but I'm going to unmute 5272.
Caller: Yes. You mentioned earlier about PTSD studies because it is extremely traumatic going into the hospital. Me, personally, I thought I was having blood pressure issues and the VI rushed me to the ER because they thought I had a stroke. And then I found out now I had some kind of blood cancer. A week later was officially diagnosed with AML, the same day that the country shut down for the pandemic. Are those PTSD studies already happening? And if so, how can I get signed up?
Dr. Blachly: I don't know the answer to that, but what I'll do is I will find out and get in touch with Katie, and we'll see what information we can get on the website. I just want to say that I'm so sorry for that. I think, as physicians, we didn't really understand until more recently just how traumatic that could be. I really appreciate you sharing your story.
Caller: The day I was officially diagnosed was also the day that -- my nurses actually had to fight for me to be able to keep a caregiver at the hospital with me because they were kicking everybody that wasn't patients out of the hospital. I went into remission a month later. I'm actually -- May 28th I got a stem cell transplant, so I'm 144 days post-transplant. I'm doing great other than a little emotional from time to time. I'm a mechanic, and I'm actually going back to work this week.
Dr. Blachly: That's great. That is great.
Katie: I've jotted your number down, and I'll talk with Dr. Blachly. The HealthTree Foundation will give you a call. We'll be in touch with you soon, okay?
Caller: Okay, thank you.
Katie: You're welcome. Okay, so that's all the time we have for caller questions. Thank you so much, Dr. Blachly, for joining us today. We're just so grateful for your generosity with your time and you sharing your incredible expertise with us. It's just unbelievable. We still have more progress that needs to be made when it comes to improving treatment outcomes for AML. But today, you've given us so much hope that there are just so many amazing doctors and researchers out there like yourself who really do have the AML patients' best interests in mind and are taking big steps towards improving the lives of every person with AML. We really do wish you all the best in your clinical practice and your research endeavors.
Dr. Blachly: Thank you, Katie, for inviting me. One of my favorite things is to visit with patients, and I really appreciate the opportunity to chat today. We will continue working because there's so much progress still that needs to be made in this terrible disease.
Katie: Absolutely. Thank you so much.
Dr. Blachly: Thank you.
Katie: Thanks for listening to HealthTree Radio for AML. Join us next time to learn more about what's happening in AML research and what it means for you.
As mentioned in the show, connecting patients to clinical trials is a top priority for the HealthTree Foundation. Increased clinical trial participation will lead to more life-saving treatments and ultimately a cure for every AML patient. To find an AML clinical trial that you qualify for,
If you need help finding a clinical trial or getting enrolled in one, contact our Patient Experience Team at 800-930-5159 or email them at email@example.com.
about the author
Katie joined the HealthTree Foundation as the Community Director for AML in 2021. She is a registered dietitian who previously worked at the VA hospital in Dallas, Texas where she coached veterans with blood cancer on how to use nutrition to improve their treatment outcomes and minimize cancer-related side effects. Katie is passionate about health education and patient empowerment. In her spare time, she loves to experiment with new recipes in the kitchen, spend time running outdoors and travel to new places.