John Reagan, MD
Lifespan Cancer Institute at Rhode Island Hospital
Interview Date: September 30th, 2021
Thanks to our episode sponsor
The use of the immune system to treat patients with AML is being heavily pursued as a strategy to more effectively fight AML and give patients with relapsed or refractory disease a better chance at achieving remission or a cure.
Immunotherapy in the form of allogeneic stem cell transplant has been a foundation of curative therapy in AML since the 1970s. While the effectiveness and tolerability of stem cell transplant has improved over the years, significant limitations still exist, warranting the development of new and improved immunotherapy options.
In this episode, Dr. John Reagan, an AML expert from Rhode Island Hospital talks about what steps you can take if you have relapsed or refractory AML. He discusses what immunotherapy is, its current use in AML and his open clinical trial looking at whether the FDA-approved drug gemtuzumab, followed by an infusion of blood cells called leukocytes from a donor, can stimulate the immune system to fight AML.
To learn more about the trial being discussed in today's episode
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, AbbVie, for their support of this HealthTree Radio for AML show.
Before we get started with today's show, I'd like to mention a few upcoming events. On October 25, at 2:00 p.m. Central, I'll be hosting a show with Dr. James Blachly of the James Comprehensive Cancer Center at Ohio State, who will be giving us an overview of the current landscape of AML clinical trials, so we can get a sense of what's being studied and what types of new treatments appear to be promising.
Also in October, we are excited to announce that we will be hosting our very first Adult AML Chapter event. Dr. Stein, an AML expert from Memorial Sloan Kettering Cancer Center, will be giving a presentation on the importance of personalized medicine for AML and discussing why it is crucial to be treated by an AML expert.
We will have more information about both of these upcoming events posted next week on our website, and you will be able to register for them at healthtree.org/AML/community/events.
As a reminder for today's show, if you've joined us online and like to be able to ask Dr. Reagan a question during our Q&A period at the end, you'll need to call in via telephone to 5156029728, and press “1” on your keypad when you're ready to ask your questions.
Now on to today's show. The use of the immune system to treat patients with AML is being heavily pursued as a strategy to more effectively fight AML and give patients with relapsed or refractory disease a better chance at achieving remission or a cure.
Immunotherapy in the form of allogeneic stem cell transplantation has been a foundation of curative therapy in AML since the 1970s. While the effectiveness and tolerability of stem cell transplant has improved over the years, significant limitations still exist, warranting the development of new and improved immunotherapy options.
In today's show, we are very fortunate to have Dr. John Reagan, an AML expert from Lifespan Cancer Institute at Rhode Island Hospital, here to talk with us about what steps you can take if you have relapsed or refractory AML. He'll be discussing what immunotherapy is, its current use in AML and his open clinical trial looking at whether the FDA-approved drug gemtuzumab, followed by an infusion of blood cells called leukocytes from a donor, can stimulate the immune system to potentially fight AML.
We are so pleased to have you here with us on the show today, Dr. Reagan. Before we get started, let me provide an introduction for you.
Dr. John Reagan completed his medical degree at Upstate Medical University in Syracuse, New York and did his internal medicine residency and hematology/oncology fellowship through Brown University. Dr. Reagan is now the Director of Hematology for Lifespan Cancer Institute at Rhode Island Hospital. He is also an Assistant Professor of Medicine at Brown University.
Dr. Reagan is board-certified in hematology and oncology. His current research focuses on awakening a patient's own immune system cells to recognize and target their blood cancer. This project is termed Nonengraftment Donor Leukocyte Infusions for Refractory Hematologic Malignancies. The central aspect of this project, which we'll be talking a lot about today, is a clinical trial in which white blood cells taken from a relative are transfused into patients with leukemia that have not responded to traditional therapies.
Thank you, Dr. Reagan for joining us today.
Dr. Reagan: Thank you, Katie, and thanks for putting this together. This is a great opportunity from HealthTree to talk directly to patients about different problems with AML.
Katie: Well, we're so happy to have you and have you share all of your knowledge with us today on such an important topic. Let's go ahead and get started and jump into our discussion. I want to start by discussing relapsed and refractory AML. Can you explain to us what these two terms mean?
Dr. Reagan: Sure, because sometimes they get sort of packaged together with relapsed refractory AML. An AML relapse means, at some point, you got into some form of remission. Remissions are a little bit funny with AML in terms of how they're graded, but for the most part, when we say someone's in remission, it means that they have restored their normal blood counts. They make white blood cells now effectively, and they make platelets effectively, and they've at least eliminated the leukemic cells which are called blasts. That's based on a bone marrow biopsy and achieving that means you've gotten into a complete remission.
You'll sometimes hear some other things out there, whether someone has measurable residual disease or MRD. Those are very, very low levels of cancer still being able to be detected within the bone marrow, and that's on an order of about one in 10,000 cells. If you're MRD-negative, it means that down to a level of one in 10,000 cells, we can't find any leukemia. If you're MRD-positive, it means we can still find that very, very small tip of the iceberg.
A relapsed AML is when you get into some form of remission, and then the AML comes back. That means that it probably was there, it probably was still lurking somewhere in the background, we just were unable to detect it. Refractory AML, on the other hand, means that your AML was never in remission to begin with. Those are patients that are initially diagnosed, they're treated, and unfortunately, we're not able to get them into some form of remission.
Katie: That's great that you broke those two apart because, yes, they do get lumped together a lot. Obviously, they're different, different terms. Relapse and refractory disease happen all too often in AML. Can you talk about some of the reasons or maybe even theories as to why AML treatment doesn't always work for people?
Dr. Reagan: Sure. The backbone for upfront therapy for AML is chemotherapy, and a lot of patients on here who have had AML will probably have gotten two drugs called 7+3, which the seven is seven days of a drug called cytarabine, and the three is three days of a drug called daunorubicin. 7+3 has really been born out of extensive studies over decades and multiple cancer centers, and sometimes the most cooperative groups, to find a better regimen for AML. Unfortunately, we haven't found anything better other than just increasing the daunorubicin dose for patients, if they're young enough and healthy enough to tolerate it.
As you can imagine though, chemotherapies, traditional chemotherapies are not very sophisticated. They're not nuanced. They kill off every cell that's there. Some cancer cells are efficient enough in, either pumping out the chemotherapy drugs and so they actually get them out of the system, or they're just, by nature of themselves, resistant to the chemotherapy. Sometimes, the reason behind that is chemotherapy relies on cells actively dividing and rapidly dividing. That means the cells turning over very quickly and going into something called cell cycle where it's duplicating itself.
If the cell though is this word we use called quiescent, which means it's kind of resting, it's kind of slumbering but still around, it's harder for chemotherapy cells to kill it off -- chemotherapy cells, chemotherapy drugs to kill it off. That seems to be one of the modus operandi of AML cells in a way that they persist is that they are resistant inherently to these chemotherapy drugs. Remember, all you really need is a few AML cells to lurk in the background.
What happens is you might kill off the AML you see, but also AML, by and large, is a heterogeneous type of cancer. By heterogeneous, I mean that there might be multiple clones of the AML lurking in the background so that while one clone might be dominant, initially, and that might be sensitive to the chemotherapy; one of those smaller clones that's there, once the dominant clone gets knocked off, one of those smaller clones rises up and results in the relapse. The traditional chemotherapeutic drugs don't always lead to curative intent with AML. That's a big thing that happens, especially in patients over 60 that, inherently, a lot of their cancer is resistant to AML.
The other thing you have to think about too is if we're mostly using chemotherapy for these patients, as we get older, it becomes inherently more difficult to tolerate chemotherapy. When it becomes inherently more difficult to tolerate chemotherapy, you can't get as high of doses of chemotherapy. A high-dose chemotherapy that might work for somebody, might be intolerable for somebody else, because of either age or other medical conditions that they might have.
Katie: How would a patient know if they've gone through treatment and have experienced a relapse, or maybe they didn't respond to it at all? What are some of the tests that would be run or maybe even symptoms they may have?
Dr. Reagan: The easiest symptom is always to remember what did you initially present with? If you feel like those symptoms are coming back, that should, at least, heighten the suspicion for some sort of relapse. The other thing that you can always look at, though, is the goal of treatment in AML is to restore normal blood counts. Chiefly, the way you can monitor that is by how many red cell transfusions and how many platelet transfusions you require.
For the most part, with treatments of AML, the first thing you'll see come back or the first thing you'll see normalized are your platelet counts. The first thing you’d notice is that you just need less platelet transfusions and then to the point where you need no platelet transfusions. Whereas, when you were diagnosed, your platelets might have been 6,000; now they've gone back to normal in the 180 or 220 or somewhere in that range. They've gone back over to normal ranges, 180,000, 220,000. Normal platelet is about generally 150,000 to 400,000. That's the first thing you'll see is those cells counts come back. The platelets come back first, and then your white blood cells will come back second. Red cells do come back last, for the most part.
The other thing that you'll notice is you generally feel better. When those blood counts do recover, the fatigue will go away, the shortness of breath will go away, the risk of infections generally goes away also. When our white blood cells are very low like they often are with an initial diagnosis of AML or with the treatment of AML, we are very prone to developing infections, and those spontaneous infections are a problem. By and large, those issues will all go away. If they don't go away, if you find that you're still needing transfusions, then that's a situation where the AML can be refractory to upfront treatment.
The other way that you know if the AML is still there is by doing a bone marrow biopsy. The thing you have to always be a little bit cautious about with the bone marrow biopsy, though, is you want to make sure that you're not doing it too early. For example, when people get high-dose chemotherapy for treatment of AML, they often get a bone marrow biopsy about two weeks after that treatment started. That's more to let us know, do we expect you to go into remission or not? That's not a guarantee of whether you're going to go in remission or not. Really, you want to wait until your blood counts recover and then do a bone marrow biopsy at that time.
Those are the key aspects of knowing if the AML is there or not. Now if you still see that you're needing transfusions, and there are still those leukemic cells or those blasts floating around in the blood, then those are patients that unfortunately haven't responded to treatment.
Katie: It's a great overview in terms of labs and bone marrow biopsy and symptoms to consider. How common is relapse after treatment, in AML? Is there a statistic you could share with us to give us a better sense of how common relapse is? Then maybe talk a little bit about what group of patients are most likely to experience relapse.
Dr. Reagan: Sure. The relapse depends on what the treatment regimen is that you're going to end up deciding on. We can stick with most patients if they're going to go onto a bone marrow transplant, first and foremost. Relapse can happen as frequently as -- remember, these are people going into remission initially, so this carries a little bit of difference also. It can happen as often as 40 to 70% of the time.
The big factors that we look at for patients and the things that, traditionally, have helped guide how they're going to respond to therapy is what is their genetic risk? You say, well, how do I know what my genetic risk is? When you're first diagnosed with AML, they do a bone marrow biopsy, or they send off your blood if there's enough leukemic cells in the blood. They send it to the lab to be looked at for two things. One is, what's the cytogenetics? What do the chromosomes look like? What do the actual genes look like? For example, if you're female, your genes are XX; if you're male, your genes are XY; and there are 46 chromosomes, overall, for males and females.
In AML, what you find is that those cytogenetics, those chromosomes are disrupted often, and there are bad or poor risk features that go with that, we call unfavorable risk features that go with just the genes themselves. The other thing that we do increasingly now is look for mutations, and those mutations can be bad. A bad one, for example, would be FLT3-ITD or internal tandem duplication. That's FLT-3. Whereas, they can also be good which is, one that's good is called nucleophosmin one or NPM1.
What you want to know at the initial diagnosis is, what's my genetic risk? There's favorable genetic risk, and those favorable genetic risk patients are patients, we think, might do okay with chemotherapy alone. Meaning, they might be cured by chemotherapy alone. For the most part, their risk of relapse is still fairly high. It's still probably somewhere around 40% or so, maybe 50% risk of relapse. People who are intermediate risk, which falls in between favorable and unfavorable, have a risk of relapse that might be even as high as 60%, even with a transplant. The lowest is patients that fall into the unfavorable risk classifications, and those are patients that might have as high as 60 or 70% chance of relapse.
Those are things that you all want to take and to consider, initially, at diagnosis, whether you think that the chemotherapy alone will be enough, and whether someone has to go onto a bone marrow transplant.
Katie: With these statistics in mind, and being quite high for certain risk categories for people, is it important to talk about the potential of relapse, upfront, and maybe create a plan more proactively for if that were to occur? Does that generally happen in clinic discussions?
Dr. Reagan: Traditionally, it's not. It is starting to enter to the mainstream a little bit more, and that's because we can detect at lower levels when we expect relapse to happen. As I mentioned before, we talked briefly about measurable residual disease. That's a process by which you can do tests on the bone marrow, and look at that very, very low level, that one in 10,000 level. Because we know, if you still have that small level of positivity, you will relapse at some point. If you do not though, then there's a potential that you might be cured much earlier.
What we're starting to do now is talk to patients about, okay, we can still see a small level there. We need to give you this medication now. Or we don't see any small level there. We don't need to give you this medication, or we don't need to do this bone marrow transplant. That is a way that we're increasingly able to treat patients when we know that there's, either a very high or virtually definite risk of relapse, and prevent that relapse from happening, or hopefully prevent that relapse from happening. Because, once again, these treatments, they're designed to put you back into remission or designed to eradicate leukemia. Unfortunately, they don't always do that.
Katie: Is MRD testing being used a standard of care that should be happening with every patient with AML?
Dr. Reagan: I think so. I think we're really starting to get there now. A lot of centers don't do the MRD testing themselves, but there are national centers that do. It's easy to send out for --we actually send out our samples here, so it's not a problem. It takes a little bit of time to get those samples back, but usually you get the results back within about a week or so. It's very useful, to me, to know if it's there or if it's not there.
We're learning stuff still, though. We're learning more information on this. We know that it's bad if there is that very small level, that MRD-positive. We know that's generally bad. We're getting better, or we're starting to do studies to figure out, can we intervene on that and prevent that from happening? That's still hanging out there a little bit, but it's certainly, I would say, a standard of care in terms of knowing if people are in remission or not. We're starting to really design studies based on the presence or absence of MRD.
Katie: Okay. What are some suggestions or words of advice you have for patients who have relapsed and they're trying to determine their next steps?
Dr. Reagan: That's a great question. I mentioned before, a little bit about that genetic risk and different mutations that might be present. We do have some drugs that are available now, and these are FDA-approved drugs, for specific mutations that are out there. One thing I would say is, if you didn't have the mutations at baseline, it's possible that those… Remember I said before that you have the dominant clone and then you have subclones? It might be that the mutation was there was just a subclone of diagnosis, and now it's the dominant clone when you relapsed.
The first thing that you always want to do when somebody relapses, is always take full account of what is their leukemia doing right now. What is it? What is it? Is it the same leukemia that was there before? Is it a different leukemia? Does it have a different mutational profile? Is there a drug that maybe would help target it? Now just because there's a drug that targets it, doesn't mean you're going to respond to that drug, but it gives you another treatment option. So that's an important thing to know right off the bat.
You want to make sure, okay, I've relapsed now, do I know everything there is to know about the leukemia? Have I repeated a bone marrow biopsy? Have I reevaluated that genetic risk? You want to have all that information in, first, so that you know what options you have in terms of therapy, moving forward.
Katie: Can you talk a little bit about the different avenues of therapy that could happen after relapse? Does that mean more chemotherapy? Does that mean another transplant? What might that look like?
Dr. Reagan: It can take a lot of different pathways here. The first is always, how's the patient doing? How are they feeling? What's their age? What would they be able to tolerate, based on both age and medical comorbidities? Do they have heart failure also? Do they have breathing problems? Do they have kidney problems? Because, once again, you don't want the treatment to ever be worse than the disease itself.
It can take the form of more chemotherapy. It can take some drugs that aren't quite chemotherapy. The FDA-approved ones now are drugs like venetoclax, drugs like gilteritinib, drugs like midostaurin, drugs like enasidenib and ivosidenib. Those are all different drugs that, like venetoclax is fairly agnostic for different targets, but both midostaurin and gilteritinib target FLT3. Whereas, the enasidenibs and ivosidenibs target IDH2 and IDH1, respectively. So, those drugs are out there that can have single agent activity that you can use.
Generally speaking, if you got something before, it's probably less of a chance that that specific regimen is going to work again. If you got intensive chemotherapy before, you might get a different form of intensive chemotherapy. You might get a drug like azacitidine or decitabine with venetoclax at that point. You might get something targeted at that point. If you got the azacitidine or decitabine and venetoclax upfront, which is increasingly popular option for our older patients, then you might be getting a drug that's more targeted later on, or even low-dose cytarabine and another drug called glasdegib, which is also FDA-approved.
A lot of it's going to take the specific characteristics of that patient and then characteristics of their leukemia. You're going to kind of meld those two things together to figure out what the best option is for them. Typically, you'll only go on to a second bone marrow transplant, if you had one before, if you get back into remission again. There are sometimes cases, and I have a patient right now where we attempted to cure them with chemotherapy alone, and then unfortunately, the cancer has come back. Now they're going for their first transplant evaluation. That's another thing too.
The other part to it is, can you go to transplant right away? Well, you probably can, especially if you're only in that MRD-positive state where we call it leukemia, again, meaning that the leukemia hasn't really fully manifested itself, but you could probably just go to that transplant again. Once again, that's talking to your physicians, both your leukemia physician and your transplant physician. Or, if they’re the same person, they need to talk to themselves.
Katie: Let's get a little bit more specific and talk about immunotherapy. Can you give us an overview of what immunotherapy is, and why it seems to be a promising area of research for AML?
Dr. Reagan: Immunotherapy is the whole idea that you're taking the immune system somehow and that you're using that immune system to kill off cancer. The longest-tenured immunotherapy that's out there is allogeneic stem cell transplants. Allogeneic is a transplant from somebody else, and the target transplant is your own blood. In allogeneic transplant, the major therapeutic effect of an allogeneic stem cell transplant, or allo transplant for short, is that graft versus leukemia effect. That's the idea that the cells that you get from somebody else, actually serve as surveillance, and they kill off any residual tumor cells. We found this out over the years of bone marrow transplants.
Interestingly, if you ever go to the Baseball Hall of Fame in Cooperstown, the first transplants were also done in Cooperstown, New York. They were done by E. Donnall Thomas who is considered the father of transplants and these were done in the 1950s. They didn't work out so well, so they went back to the drawing board to figure out how to do this.
What they initially thought or the way that transplant was initially developed, was to give high doses of chemotherapy or radiation because it was thought that the chemo or the radiation is going to cure all the cancer. Because we've killed off all the blood cells, though, the blood cells aren’t going to come back, we have to get them from somebody else. That's the idea that you'd have a donor for the transplant. They thought that, initially, even when they first started doing transplants.
Interestingly, in the 1980s, they found that patients who had a little bit of graft-versus-host disease. This wasn’t graft-versus-host disease that was life-threatening, but those patients that had a little bit, like a rash or maybe some dry eyes or something like that, those are the patients that did better, long-term. Their leukemia didn't come back. That's when they started to figure out, oh, this really seems to be that the donor cells are circulating around and killing off any of those residual leukemia cells. We've kind of been chasing that for all these years, ever since.
Immunotherapy has really become a hot topic in all of cancer biology because of the effects you've seen probably with lung cancers now and melanomas and kidney cancers and those sorts of things, but it's really always been there for acute myeloid leukemia. More recently, there was some nice data that came out at last year's American Society of Hematology meeting, for a drug called magrolimab, which is a drug that basically blocks these don't-eat-me signals. There’s all cells to prevent these macrophages which are these professional cells that go and gobble up different cells, from eating you. They have this molecule or this receptor that they put out. What the drug does is it blocks that and shuts it off, so then you can use your macrophages to gobble things up. That's a form of immunotherapy.
That's really where a lot of my interest came from, interest in this, is we've had this immunotherapy that's worked for so long for AML. Are there ways that we can actually pull the levers on the immune system to get the patient's own cancer to recognize, excuse me, their own blood cells to recognize and attack the cancer? Probably, more recently, you've seen a lot of the effects of these chimeric antigen receptor modified T-cells or CAR T-cells that have come out that have been so successful with acute lymphocytic leukemia and the lymphomas.
Katie: Immunotherapy is obviously not a new term or a new area of study. I'm curious, your thoughts on, do you feel like in other blood cancers, immunotherapy has been more effective than AML? Are we kind of a bit behind here? Or do you feel like we're making pretty good progress?
Dr. Reagan: I don't think it's been more effective in the long term just because of how effective bone marrow transplant, the allo stem cell transplant is, as a curative measure for AML. I do think AML is a little bit behind more so with the newer therapies. For that, I'm talking about things like CAR T-cells.
There are also different drugs that we give quite a bit in the clinic called bi-specific antibodies. What those are is those are antibodies that both bind to a tumor cell and then get your own T-cells, which are immune system cells. It binds to those cells as well, and it actually brings your immune system cell, that T-cell, close to the cancer cell, and it stimulates it to kill off the cancer cell. Those bi-specific antibodies are being used increasingly in acute lymphocytic leukemia and in lymphomas. They're actually FDA-approved with acute lymphocytic leukemia, and probably will become approved pretty soon with lymphomas. That's using your own immune system to recognize and attack the cancer.
You might have also seen the immune checkpoint inhibitors that are used for Hodgkin lymphoma. Hodgkin lymphoma is a type of lymphoma that really suppresses the immune system quite a bit, and those drugs work in Hodgkin lymphoma. I think we've fallen behind a little bit. It's not through lack of effort, though, because they've tried some of these other drugs, and they just haven't quite worked out all that well yet. The other problem is that AML by itself, we think about AML, most of the targets on AML cells also are targets on normal cells. That's just something we have to be a little bit careful about.
Katie: Can you give us some background information on your specific trial? I'd like for you to take us through the evolution of the project. I think it's been something you've been working on for many years, so I'm excited to hear about that.
Dr. Reagan: Yeah. I owe a lot of this to my mentor. His name's Peter Quesenberry, and he's been in practice since, really the 1970s. He started two transplant centers, one at University of Virginia, one at UMass. While he was at UMass, they were very, very interested in giving donor cells but not giving high doses of chemotherapy.
Traditionally, the thought was that you always had to give high doses of chemotherapy or you had to give high doses of radiation therapy to allow for those donor cells to come in and do something called engraft. What engraftment means is that those cells can go in, and they can start taking over the blood cell production system of your body. His thought was, well, this is all about competition. You can actually give some cells and from those small number of cells will engraft. Then you can actually use those donor cells to target the leukemia or blood cancer effectively.
They tried actually just giving people transplants with less chemotherapy or radiation beforehand. When they did that, they found that the patients, the donor cells didn't stick around, but patients had responses. That was kind of funny. It's like, why did the patients respond if the donor cells didn't stick around? They extended that out to people who were half matched, meaning that they were an incomplete match. They were half match for the patient. They gave those stem cells and found that patients, once again, those donor cells didn't stick around. Some patients had some responses, and some of those responses were actually pretty good.
In that process, when you give a competent immune system, donor cells, you actually overexcite that patient's own immune system. One of the most potent stimulators of your own immune system is actually see white blood cells from somebody else. In that process, you generate very, very high fevers. A lot of these patients had rashes. We call that the cytokine release syndrome that happens. We think that when they generate those high fevers and that giant rejection response that you get from the donor cells, in some way, that reawakened your own immune system to recognize and attack the cancer.
Some other people picked up on this also. In China, they did two studies, and they actually were pretty well-received. One was in one of our big publications called Blood Journal, and the other was in Journal of Clinical Oncology. They gave patients these donor cells without the high doses chemotherapy beforehand, and they had some really, really good outcomes also. These are things where they're increasing the remission rates from 40% to 80%, and increasing overall survival up into the 60 or 70% range, which is really important and really important aspect to look at.
What we did is, a few years ago, this is about six years ago or so, we thought, well, what happens if you give someone with leukemia, just the donor cells? Does that generate enough an immune response to actually get them to recognize and attack their cancer? What we found is that it doesn't seem to do that. It seems like you need something else in there to help at least get rid of some of the cancer cells, to begin with, to allow that immune system to work. That's why we've gone to our current study, which is to give that drug gemtuzumab, which is a sort of specialized, directed chemotherapy to leukemia cells, and then we give donor cells afterwards. They get the doses of the gemtuzumab over three different days, so, on days one, four and seven; then they get those donor cells.
The idea is that those donor cells, when your body sees that, it's going to reject those donor cells. It's going to generate this big immunological phenomenon, and then it's going to actually have your own blood cells recognize and attack your leukemia cells. We're really excited about this program and are still working on getting patients treated on.
Katie: Yeah, it’s super interesting to think about. Who would you say is the ideal candidate for this trial?
Dr. Reagan: These patients that we're treating right now are not frontline patients. They’re patients that have relapsed or refractory acute myeloid leukemia. They have AML that has either gone into remission and then came back, or they have AML that has never gone into remission. Really, it’s any of those patients who then have a donor.
Whenever you do a study like this, you have to talk to the FDA and things they let you do and things they won't let you do. The FDA has required that they have to have a first or second degree donor who's willing to give or donate their white blood cells for this treatment. First or second degree donor is a son or a daughter or a parent or a nephew or niece or even aunt or uncle, are all the different donors we can take for these patients to give them these treatments. That's really all you have to have. Then you have to have adequate heart and kidney function and that type of stuff. Those are some things also, but generally speaking, if you can walk into the doctor's office, and you have a family member who's willing to donate white blood cells, and you have relapsed or refractory AML; then you can go on this study.
Katie: Interesting. The trial, is it only being done with you at Rhode Island, or are there other sites?
Dr. Reagan: Yeah, it's just available for us here in Providence, Rhode Island at Rhode Island Hospital, Lifespan Cancer Institute.
Katie: Okay. Let's talk a little bit more about donor leukocyte infusion. Can you walk us through the process of what receiving that entails? I want to clarify for people who are listening who might maybe start Googling, are donor leukocyte infusions and donor lymphocyte infusions referring to the same thing?
Dr. Reagan: That's a good question. They pretty much are. We've changed it to leukocytes infusions because we know we're giving them white blood cells, and we based it on the lymphocyte number. We just don't know what the putative cell is. All we know is we're just labeling all we’re giving them, but that's also what they'll generally be doing when you're getting a donor lymphocyte infusion also.
Remember, like I said before, we can go back a little bit. One of the main curative measures of AML is to get that bone marrow transplant, that allogeneic stem cell or bone marrow. Stem cell and bone marrow, they’re slightly different, but for for simplicity, let's just keep them as the same. That transplant is the curative measure for AML. The problem with transplant is that not everybody who gets AML can have a transplant. Often, patients that are over 75 years of age, are not candidates for transplant. To get that transplant, initially, you have to be fit enough and young enough to be able to get it.
Now, if your leukemia comes back, those are the patients that, in general, are the candidates for a donor lymphocyte infusion. Donor lymphocyte infusion is what your doctor’s going to call it because that's what it, historically, has been designated as. That's really based on their CD3 numbers that they collect from your donor. In those instances, if you have AML, you got a transplant and they find that your blood counts are off, or they're just doing monitoring that, they have standard monitoring for your leukemia, and they find that your cancer has come back; they will probably talk to you about doing a donor lymphocyte infusion. The idea of that donor lymphocyte infusion is it will help your graft, it will help those donor cells recognize and attack your cancer.
The other thing they're going to do though is, remember you're getting someone else's immune system, you're getting someone else's blood cells; you're going to be on drugs that suppress that immune system from recognizing and attacking the rest of your body and causing graft-versus-host disease. If they do see the leukemia coming back, the first thing they do is they start dropping down those immunosuppressive drugs, and one of the most common ones is tacrolimus. They may also be using drugs like Mycophenolate mofetil. They are these drugs they have you on, to suppress that donor immune system from recognizing and attacking your cancer. Generally, that immunosuppression is tapered over time. It's tapered, hopefully, over the first six months after your transplant.
The donor lymphocytes are given because the idea is that that's going to generate this -- it's going to attack the cancer cells. That's when you're going to be thinking about getting a donor lymphocyte infusion. What do they do? They take out more white blood cells from that donor, and that should help that graft reawaken and attack the leukemia cells. So that's going to be the process of the donor lymphocyte infusion and why they're going to want to give it, because the AML has come back after a bone marrow transplant. To have that be effective, you already had to have a transplant once.
Our study’s a little bit different because it's this donor leukocyte infusion, we're not trying to get those cells engraft or those cells to attack the leukemia, we expressly want to use those cells to kind of goose up or stimulate your own immune system. We're using them for a slightly different process.
Katie: With the infusion given in your trial, is there risk for graft-versus-host disease?
Dr. Reagan: There isn't because the cells don't stick around. The one thing we do know is that by 48 hours, all those donor cells, for the most part, are out of the patient's body. They might stay at some very, very low level. Before, I talked about cells being present at one to 10,000. They might stay at that one to 10,000 level or that very micro level. They might still stick around at extremely low levels, but nothing that would lead to graft-versus-host. It is something though that we watch for. We have to watch for, we have to catalog for that. It's something we look out for, but we've not seen it in any patient so far.
Katie: Okay. You briefly mentioned gemtuzumab. Let's talk about that drug a little bit more. Can you explain to us what it is and how it works?
Dr. Reagan: Yeah. Gemtuzumab is, it's a drug that was developed in the 2000s. It was actually FDA-approved. They got pulled from the market, and then it got re-approved again. What it is it's this neat class of drugs that's called an antibody-drug conjugate. So, on the surface of every cell that you have, you have these little, it's like these little tags that are on the surface, and different cells have different tags. Leukemia for the most part, AML for the most part has a tag called CD33, which just stands for cluster differentiation 33. It's this little tag that's on the surface.
What gemtuzumab does is it has an antibody, and then it has a drug that’s stuck on to the antibody. The antibody binds to CD33. The drug is this class of drug called a microtubule inhibitor, which is a classic chemotherapy type of drug. What happens is that the drug attaches to the leukemia cell and binds to that cell and gets brought in, and so it delivers the chemotherapy directly to that cell. They thought, initially, this would be a boon. This was a new kind of way to figure out how to deliver the chemotherapy to leukemia patients, and that it would fix all leukemias. It didn't quite do that. It initially got pulled from the market because it didn't seem to confer any benefit for patients.
They looked back and found that there are subsets of patients that it does seem to confer a benefit and seem to confer a very good benefit. The other thing was dosing. They seemed to be giving too high of a dosing, initially, early on. If you lower that dosing down, for example, in the trial, we lowered that dosing down to what's the FDA-approved dosing now, and that seems to at least confer benefits to where if it's relapsed or refractory AML, it seems to put about a third of patients back into some form of a remission.
Katie: Interesting. The way I interpreted it was that gemtuzumab is most effective in lower risk AML. To me, these relapse refractory patients are more higher risk AML, so I was glad that you talked a little bit about that. That was interesting to me.
Dr. Reagan: Yeah, it seems to work best in the patients that have favorable risk AML. It does. That was based on -- and remember, those are the patients whose AML responds to chemotherapy. Those are the chemotherapy-sensitive, is a way you can think about it. Those are the chemotherapy-sensitive group of AML patients.
Katie: How would a patient know if they have CD33-positive AML? Is that all patients?
Dr. Reagan: That's almost all patients. Rarely, rarely, rarely, you might not have it, but it's something that simply they'll do when you have your initial pathology done. They'll have something called flow cytometry which will look for that marker on the cell surface.
Katie: Okay. How far away, in your opinion, are we from seeing immunotherapy as part of standard of care for AML treatment?
Dr. Reagan: I don't think we're very far away at all. There are newer drugs that are coming out. There are drug combinations that are coming out. There are increasingly different ways to turn off and turn on the immune system. I think, as we get that figured out, one of the big barriers to doing transplants for everyone, like I talked about before, are the side effects of the treatment, the high doses of chemotherapy you have to give to somebody to get the bone marrow transplant to engraft or to work.
The other part is that risk of graft-versus-host disease. With these different immunotherapy treatments, you're not having risk of graft-versus-host. Now, certainly you can have other autoimmune conditions crop up, which can be managed, but you also aren't having to give the high doses of chemotherapy anymore. Something that we know works is putting in that new immune system, that new immune system that doesn't get blocked by the cancer are now, I think you'll see the drugs develop. It might not be all of these drugs, but I think it will be some of them.
I think, like we talked about before, that drug, magrolimab, the anti-CD47, is, I think, something you're going to see really soon come out to show to be effective for patients with AML. I hope it does. It's got certainly all the initial earlier phase clinical trials that are pointing towards that. I do think you'll probably see more on the horizon as well. I think you'll see that in the next one or two years.
Katie: You said one or two years?
Dr. Reagan: For some of them to come out, yes.
Katie: Wow, that's exciting. Were there any other major immunotherapy classes that maybe you didn't mention? You said CAR T, bi-specifics. Are there any others that are being looked at that are exciting to you?
Dr. Reagan: Yes, the regular monoclonal antibodies. Monoclonal antibodies are drugs that bind to a specific target and then those get your own immune system to recognize and attack the cancer. They get these different arms in your immune system to kill off the cell. That's a class that's out there, those antibody drug conjugates, bi-specific antibodies. CAR T’s, they're still looking at for AML. I think you'll see the potential for all of these to show up.
Some of those monoclonal antibodies target these different immune things. There's a couple of drugs out there that target these molecules called PD-1 or PD-L1. There are some other ones out there that target one called TIGIT. There are some that target another one called Tim-3. There's a lot of them that are in the pipeline right now that are being looked at, and that might be over-expressed in some AMLs. The other interesting thing is, could you use these in combination together, and could you use them to track the AML to kill it off, or to express more of something and kill it off? Those are things that we're trying to figure out.
Katie: I want to make sure you have time for questions, so I want to wrap up my questions. I think this is a pretty important one to end on. I just want to see if you have any final thoughts or anything extra thing to mention for patients who have relapsed and they're considering a trial like yours or other immunotherapy options in a clinical trial setting. What other words of wisdom might you have for them?
Dr. Reagan: I think one of the big things is always, you want to go in, realistic. Clinical trials are great, but you also want to know, well, what's the potential benefit? What are the side effects, are things you always want to know. You also want to know what your options would be, off of study. The only real path forward in the treatment of AML, though, is to have more clinical trials. I saw, I think, on your website, Katie, or we mentioned this before, that only a fraction of patients with AML actually end up going on clinical trial. One of the ways that childhood ALL, childhood acute lymphocytic leukemia, has gotten so much better being treated is that most of those patients do go on study, so they do learn better ways of treatment.
I think we have to do better ways of getting people on studies and making it easier for them to get on the studies. It's not that it's the patient's fault, it's just that we don't have the studies open appropriately for them to get on studies, effectively and easily and safely too, because that's a big thing that we want to know as well. Those are things that we're working on throughout the US with these different cooperative groups working together to try to get more targeted studies out that keep people on pathways and allow them to get treatments.
Katie: That's great to hear that there's an initiative on increasing accessibility to these trials. We've noticed that too, as a foundation, and we have done somewhat of our first iteration of a clinical trial finder tool for AML patients. We want to work to help patients simplify the trial finding process because there are so many trials out there. It's overwhelming to know which may be appropriate for you personally, so we have this clinical trial finder tool on our website.
The second iteration of it coming very soon is that, by entering some of your health information, it will be able to narrow down trials even further for you in that it'll show you the trials that you meet the inclusion criteria for and exclude the ones that you would not be able to participate in. You're right in that it takes both sides. It takes the patients being connected to the trial, and the researchers and organizations really working to increase the accessibility of these trials. It’s really great insight. Thank you for that.
Dr. Reagan: Yeah, definitely. I think that’s one of the keys.
Katie: Yes, absolutely. I'd like to open it up now for caller questions. If you have any questions about Dr. Reagan's research or anything we discussed today, you can call in to 5156029728. Once you're on and ready to ask your question, press “1” on your keypad. I see a few popping up here. Let me unmute caller that ends in 1034. I'm unmuting you.
Caller: Hi, Dr. Reagan. Thank you so much for sharing your insight and for this trial. I think, just as a cancer patient, I just think that's the way that these new discoveries are going to happen and things are going to be cured, is if we participate in clinical trials. So, I'm all for it.
I have a question for you about running an immune system panel. As all these immunotherapies, the bi-specifics and the antibody drug conjugates and the CAR-Ts and all those are being developed, it would be so nice to know ahead of time, if a patient would or wouldn't respond to the therapy. Is there any type of immune system panel that's being developed or looked at to predetermine who might do best with some of these therapies?
Dr. Reagan: Yeah, that's a really interesting question, overall, and something that they don't really know right now. It is sort of depends on what therapy you're giving. It's funny because in the cancer center that we have some thoracic oncologists, they're asking the same questions about their immune checkpoint inhibitors. Can they find patients who are going to respond to it and patients who are going to have side effects from it also? That's another piece to it.
The good news, so just, if you took one of the bi-specific antibodies though, and that’s a drug called blinatumomab or Blincyto, and that's used for acute lymphocytic leukemia. The response rate for that in people who have MRD-positive B-ALL is 80%. Most patients are actually responding, meaning that 80% of people go from the MRD-positive to MRD-negative, which is crazy numbers, right? It seems like most patients respond to those sorts of treatments, but you're absolutely right, measuring to see if the immune system will respond, is truly important.
The other thing you always want to consider too, is the more treatments you go through, the more beat up the immune system is going to be. One of the other questions, and this is happening more in myeloma right now, they're trying to push those treatments to early in the treatment course so that they don't have as an exposed immune system or as a rundown immune system as they would have had earlier in the treatment course.
Caller: That’s so interesting. One more follow-up question, as you look at the immunotherapies and you're weighing the pros and cons of each one, do you really look at it by just genetic factor? If you have a CD33 protein, you should do X; or this, if you have something else. Or do you look at it and weigh, well, the antibody drug conjugates might be more potent because they're using the immune system to deliver this toxic payload, versus maybe the bi-specifics that are just using the immune system as a whole? I don't know. How do you lay that?
Dr. Reagan: Some studies will do it based on targets and what targets those are. If you do have an inhibitor, you're going to be shuttled into one of those that has a target for it. That's a big buzzword that's really entering acute myeloid leukemia clinical trial development is targetable versus non-targetable. Targetable means those drugs that you have an inhibitor for a very specific mutation like FLT3 or IDH1 or 2. Whereas, non-targetable are drugs that are more like the BCL-2 inhibitor like venetoclax or things like the magrolimab which is the anti-CD47 monoclonal. They still have a target because you still have CD47 that you have to express, although that's more expressed in your immune system cells.
There are some that come into play. Some of it also is still based on, is the patient going to tolerate the therapy or not? Is there traditional chemo backbone to it, along with some novel agents, or is it just novel agents? Is it a combination of novel agents? The thing you always have to keep in the back of your mind is, even what's perceived as a less toxic therapy because it's not traditional chemo can still be pretty toxic because of the different pathways that it can inhibit.
Caller: Okay, great. Thank you so much for answering my questions.
Dr. Reagan: Thank you.
Katie: Okay, I think we have time for maybe one more. Caller ending in 3268, I’ll unmute you now.
Caller: Hi. Thank you, Dr. Reagan, and to the moderator. We appreciate you answering all of our questions. I was calling to find out if your study would be beneficial for a healthy but relapsed 82-year-old woman.
Dr. Reagan: Oh, yeah. That's one of the benefits -- our exclusion criteria is pretty wide-ranging, but the big one that we don't include any exclusion criteria is age. It really takes in any age. You can't have a bone marrow transplant before. That's an allogeneic stem cell transplant. That's one of the big outliers. As long as someone has adequate kidney and liver and heart function and basically could walk into the office, like I said before, that they would be a candidate for the trial. That's one thing that we really wanted to do with the study too, is make it so that most patients would be able to go on it. Because the patients we have treated, it has been pretty well-tolerated, overall.
Caller: Okay. Because she's had the Dacogen and the venetoclax combo, and worked for a year and a half, and then she relapsed. She's on Idhifa right now. She's on Idhifa for a couple of months, and we're not sure if it's working. If we’re interested, how would we follow up?
Dr. Reagan: Yeah, actually, you can just run clinicaltrials.gov. It's right there, and it has all of our contact information right there.
Caller: Okay. Thank you.
Dr. Reagan: Yeah, sure, no problem. That's a great source for everybody, just while I'm out here. Katie's got this other website that sounds terrific. I haven't been on it yet, but the way you can find clinical trials local to your places, is this clinicaltrials.gov which will have all the clinical trials that have been registered on there.
Katie: I can help as well. If you want to contact me directly, my email is firstname.lastname@example.org.
Caller: Thank you.
Katie: Okay. I think we might have time for one more quick one. He has been lit for quite a while, so I wonder. Let's see. Ending in 3273, do you have a question for Dr. Reagan?
Katie: Okay. That's all the time we have for caller questions. Thank you so much, Dr. Reagan, for joining us today and letting us know that there's so much progress being made on the treatment of AML, especially for those with relapsed or refractory disease. We wish you all the best in your continued great work.
Dr. Reagan: Oh, thanks a lot Katie. Thanks, everyone, for being on, especially if you're a caregiver or a patient afflicted with AML. We are working to try to make treatments better and to try to make the whole experience. Thank you for all your patience so far.
Katie: You've given us such great insight. I've learned a ton, and I know everybody else has too, so we really appreciate your time.
Dr. Reagan: No problem. Take care.
Katie: Thanks for listening to HealthThree Radio for AML. Join us next time to learn more about what's happening in AML research and what it means for you
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