Allogeneic stem cell transplantation is the only curative option for patients battling acute myeloid leukemia. However, a significant number of patients will relapse after transplant. Innovative research and therapies are needed in order to improve outcomes in AML patients.
The drug Jakafi (ruxolitinib), a kinase inhibitor, is being explored in a current phase 2 clinical trial, as it may help reduce the risk of relapse. Other therapies such as pre-emptive donor lymphocyte infusions, hypomethylating agents and FLT3 inhibitors combined with donor lymphocyte infusions, CAR T-cell and CAR-NK cells are some of the options being explored.
In this show, we were joined by Dr. Gabriela Hobbs with Massachusetts General Hospital who discussed the challenges that exist with stem cell transplants and some of the therapies that are being explored to reduce the risk of relapse. Dr Hobbs told us about her current clinical trial using Jakafi (ruxolitinib) after allogeneic stem cell transplant, which has also shown to be beneficial in reducing graft-versus-host disease (GVHD).
Thank you to our episode sponsor, Bristol Myers Squibb.
Kerith: Welcome to today's episode of HealthTree Podcast for AML, a podcast that connects patients with acute myeloid leukemia with researchers. I'm your host, Kerith Amen. We'd like to thank our episode sponsor Bristol Myers Squibb for their support of this HealthTree Podcast for AML episode.
Before we get started with today's show, I'd like to mention an upcoming event that we will be hosting. This Saturday, October 8th, from 11am to 1:30pm, Central time, we will be hosting a virtual HealthTree Roundtable for AML with MD Anderson. We have invited six top AML experts from MD Anderson to join us. They will cover the following topics, treatment in younger and older patients, maintenance therapy, evaluating MRD status, stem cell transplantation, new and emerging therapies and supportive care during treatment. We will hear from the experts on each topic, and there will be a Q&A session at the end. We hope you will join us for this informative discussion. If you can't attend live, we encourage you to still register as the recording will be sent out to everyone who registers after the event. You can register for all of our events by visiting our website healthtree.org/aml/community/events.
As a reminder for today's show, if you have joined us online and would like to be able to ask Dr. Hobbs a question during our Q&A period at the end, you will need to call in via telephone to 515-602-9728, and press “1” on your keypad when you are ready to ask your question. Now on to our show today. Allogeneic stem cell transplantation remains the curative option for patients with acute myeloid leukemia. However, relapse after transplant poses a significant challenge and is an area where continued research and clinical trials are needed. The challenge is a very difficult balancing act between promoting the graft-versus-leukemia effect or GVL, and reducing graft-versus-host disease or GVHD.
There are a number of different novel therapies being explored in trials in order to reduce the risk of relapse after stem cell transplantation. One of those trials we will hear about today is a trial using the drug Jakafi or ruxolitinib, and Dr. Gabriela Hobbs is here with us today to discuss this clinical trial. Dr. Hobbs will also share with us some other therapies that are currently being used and tested in this area.
We are so happy to have you here with us today, Dr. Hobbs. Thank you so much for taking the time out of your busy schedule to join us. Before we get started, I’d like to provide an introduction. Dr. Hobbs is the Clinical Director of Leukemia Service at Massachusetts General Hospital Cancer Center in Boston. She specializes in the care of patients with myeloproliferative neoplasms or MPN, chronic myeloid leukemia and leukemia. Dr. Hobbs is an active clinical researcher and leads the MPN research program at Massachusetts General. She is a principal investigator on a number of active clinical trials, and her work has been published in many prestigious journals. Welcome, Dr. Hobbs. We are honored to have you on the show with us today.
Dr. Hobbs: Thank you so much for the invitation.
Kerith: Of course. Thank you for being here with us today. Okay, let's jump into our discussion for today. I wanted to start with just some basic questions about stem cell transplant. Can you tell us what a stem cell transplant is, and if there is a difference between a bone marrow transplant and a stem cell transplant?
Dr. Hobbs: Great question and always good to start from the beginning. The terms stem cell transplant and bone marrow transplant are generally used interchangeably, although there are some subtle differences. A stem cell transplant is basically a form of treating a variety of cancers including leukemias and sometimes lymphomas, as well as myelomas, to treat the cancer in a different way. Basically, instead of just giving chemotherapy, a transplant is a form of immunotherapy where you're giving the patient somebody else's blood-forming capacities and immune system as a way of being able to recognize and, hopefully, attack through a patient, that leukemia.
In terms of the difference between bone marrow transplant and stem cell transplant, a bone marrow transplant is when the person that is donating bone marrow literally has a lot of their bone marrow taken out. Generally, the patients need to go to the operating room to have several bone marrow biopsies to get the liquid part of the bone marrow collected to be able to give to the patient. When we talk about stem cell transplant, we're talking about what's called a peripheral blood stem cell transplant. For that, the person that is donating is usually given a medication such as growth factor, to produce lots and lots of stem cells in the bone marrow, and those stem cells spill over into the blood and can then be collected from the peripheral blood. In general, when a patient is told, you will need a bone marrow transplant, or you will need a stem cell transplant, those terms generally are interchangeable.
Kerith: Okay, and is it fair to say that the majority of those stem cell transplants are taken from the peripheral blood these days?
Dr. Hobbs: Correct. Yes, so you can imagine that it's harder to get participants to agree to be donors if they know they need to be taken into the operating room and have lots and lots of biopsies. Also, just even the providers that are collecting the biopsies, it's much harder. It's much easier for the donor to just do the peripheral blood stem cell transplant. Once that was kind of discovered, and we could do it that way, that's definitely become the preferred modality.
Kerith: Yeah, that makes sense. I think that there has been quite a push from organizations like Be The Match, to communicate that it isn't a very invasive process maybe like it used to be.
Dr. Hobbs: Correct.
Kerith: For people to donate their stem cells. Okay, can you talk briefly about the different factors that are weighed in determining if a patient is a candidate for a stem cell transplant? Are there other health conditions or what they would call comorbidities that would make having a stem cell transplant not possible for someone?
Dr. Hobbs: Yes, that's a great question, and one that I think has changed a lot over the last decade. Whereas, before, basically, a patient would be a candidate for a central transplant if they were very young, like in their 30s, and for a while, probably not even older than that. Now, we consider patients for transplantation that are in their 70s. Many times, we even try not to think about age as much. I think the factors that we take into account in determining if somebody is a candidate for transplant have really changed. Part of that is because we can use different amounts of chemotherapy before the transplant, and that really makes a big difference in making the transplant more tolerable. A roundabout way to answer your question, but although we certainly consider a lot of factors that determine if a patient is a candidate for a transplant, we can now be more permissive in allowing patients that maybe have more medical comorbidities or other health problems and get them to transplant.
Generally speaking, we’ll say a patient needs to be fit enough for transplant, and that's a difficult definition. I would say that a patient needs to be at least able to walk around independently for the most part. Even if they have some medical issues, they need to have some level of independence, which is why, when patients are admitted in the hospital getting their initial treatment, I always talk to my patients about how important it is for them to not get deconditioned and to stay active and walking around so that they don't become ineligible for transplant. Other things that we really look at is what is that patient’s organ function? Are their kidneys working well? Is their liver working well? Do they have issues with pulmonary functions? Before a patient is told whether or not they're a candidate for transplant, they do a lot of those types of tests to determine if all their organs are functioning okay, and those are some of the comorbid conditions that we take into account.
Kerith: Can you tell us about the different types of stem cell transplants? I know this could probably be a lengthy answer, but basically, what are the different types of stem cell transplants?
Dr. Hobbs: Sure. When talking about stem cell transplants, we need to talk about several different things. The first is, where are the stem cells coming from? We've alluded to this already, but one source of stem cells is bone marrow. The other is peripheral blood, and that just means blood in the vein. The other is what's called the cord blood stem cell transplant. Then we need to decide, who are you getting those stem cells from? Is it a relative or somebody that's not related? You already spoke about Be The Match which, of course, is an international registry where volunteers get a cheek swab, and they get their DNA checked to see if they can be matched with other people. We can have either matched related transplants or matched unrelated transplants. Those are the general characteristics or different subgroups of transplants that one can get.
Kerith: When my husband was going through treatment, I heard the term haploidentical. Can you define haploidentical for us?
Dr. Hobbs: Yes, of course. First, I'm sorry that your husband has to go through all of that type of treatment. Haploidentical gets into a little bit more detail in terms of the degree that a donor is matched to the patient. When you have a donor, whether that's a related match or an unrelated match, we always talk about, is it a perfect match? That would be called a match unrelated or not related transplant. Is it a match at all places except for one? We call that a mismatched transplant. More recently, there's been the advent of what's called haploidentical transplantation which really was quite revolutionary because it allowed a lot of patients that otherwise wouldn't have a donor, to be candidates for transplantation.
One of the things that I should have mentioned in terms of factors that are weighed in determining if a patient is a candidate for transplant, one obvious one is, do you have a donor? There are many patients that unfortunately don't have matches in the registry, but almost everybody has a haploidentical donor. What does that mean? Haplo, the term haplo means half. These are donors that are going to be half-matched to the patient. For example, every person will be a half match to their parents or to their child or to a sibling. Almost everybody will have a half match donor available, and that has really helped to increase the availability.
When this was first being developed, people thought that was very risky because all the time, we talked about having a perfect match and the perfect match. How is it possible that somebody that's only a half match, meaning the other half of the genes don't match, and they’re not the same, how is it possible for a transplant of that type to be successful without leading to a lot of complications? In particular, something that I'm sure we're going to talk about later in the podcast, graft-versus-host disease. Thankfully, we are able to give this type of transplant with some chemotherapy after to prevent this complication of transplant from occurring, and making this transplant modality really important to increase access to transplantation to a lot of patients.
Kerith: Yes, and you're alluding to the different pros and cons, you might be a perfect match, but from what I understand, there may be more or less GVHD depending on the level of your match. It's, again, weighing your options, I guess.
Dr. Hobbs: Yes, lots of different factors need to be taken into account when deciding who is going to get a transplant and what transplant source you're going to accept. Sometimes we have the luxury of saying, well, you have five siblings. Two of them are perfect matches. They’re all young and healthy. Sometimes we may only have one mismatched donor from the registry, or someone may only have a haploidentical donor option. All of those different transplantations come with different pros and cons, exactly.
Kerith: You briefly touched on this, but does the treatment prior to stem cell transplant vary depending on the risk profile of your disease or your age? Does that prior treatment have anything to do with your propensity for relapse? Or has it been shown to have anything to do with the relapse?
Dr. Hobbs: Great question. I'm not somebody that does a bone marrow transplant, but I do treat the leukemia before then. I always joke with my colleagues, that they don't care how we treat patients, as long as we send them to them in good shape and in remission.
Your question is really, really important. Depending on the diseases being treated, let's say for this conversation, we're going to talk about AML, treatment really makes a big difference. It makes a difference in a few different ways. The treatment itself can have a lot of side effects and toxicities, and I alluded to that before. Oftentimes, patients that have a diagnosis of AML, acute myeloid leukemia will receive a lot of very intense chemotherapy that can ultimately be very debilitating for patients. That plays a really big role because in order to successfully undergo transplantation, a patient needs to be able to tolerate that initial chemotherapy, make it out of the hospital, and be able to live independently to some degree in order to be successful with the transplant. So, the type of chemotherapy that is given before transplant matters in that way.
The other thing that really matters as well is, what is the risk of leukemia itself? When we diagnose somebody with AML, not all AML is the same. We divide patients depending on the genetic changes in each individual patient's leukemia, to say, is this a person that has leukemia that is very responsive to treatment and can be treated with chemotherapy only, or is this a person that has a leukemia that's more high risk and won't respond that well to chemotherapy alone, and therefore they need a transplant? Those genetic changes are really important in determining whether a person needs a bone marrow transplant, doesn't need a bone marrow transplant, and also what type of treatments that person is given. All of those factors are played in, into determining how to talk to the patient about their diagnosis and their prognosis and then making decisions.
Depending on that risk factor, leukemia, it also plays into the risk of relapse after the transplant. Patients that have what is considered high risk AML have a higher risk of having the disease relapse after a transplant, compared to patients that have lower risk of disease. I guess one more factor that's really important to consider is prognostication and all those things only go so far. The most important thing, when getting a patient to transplant, is making sure that that person gets to transplant in the best shape possible and that their leukemia is treated as much as possible.
Sometimes patients ask me about that. They're like, well, if I'm going to transplant in remission, why am I going to transplant? You already put me in remission. You can think about the transplant almost as a vaccine to some degrees, where the leukemia has been taken down to the lowest level possible, we almost want to make sure that there's no leukemia detectable at all, and then the transplant is really successful in that if any leukemia starts to pop up, it'll eradicate that. It doesn't do well with very active disease. If somebody goes into transplant very active, the transplant is not going to work. That's really important, going into transplant, that the disease is very well controlled and in remission.
Kerith: Right. You brought up something about there being so many different kinds of AML. It's really about the personalized and very tailored treatment prior to even the stem cell transplant, and getting that person ready for stem cell transplant, depending on what kind of mutations they have and all of that. It's very complicated.
Dr. Hobbs: It's definitely very complicated. It has become much more complicated in the last five to ten years, which is really good actually. My grandmother had AML three decades ago. When she was diagnosed, AML was treated in one way. They had one way to treat. Nowadays, we really have a lot more to offer patients. We can say, if you're young and fit, we can give you this really intense chemotherapy. If you're a little bit older, and we're not sure that you can handle intense chemotherapy, we can give you a combination of treatments that actually aren't as aggressive as that intense chemo, but still have a really good chance of getting the person in remission. If we have certain genetic changes, we can offer you targeted treatments against those genetic changes to ensure two things that are really important; one is that we're going to get that disease in remission, and two, that we can get into a remission without having to cause so many side effects. The beauty of the targeted treatments is that they are much more effective and much less toxic.
Kerith: Yes, it really has come so far in the last five years even.
Dr. Hobbs: Absolutely.
Kerith: Okay, we started to touch on this a little bit before. Can you talk about GVHD or graft-versus-host disease? Both what it is and why it occurs?
Dr. Hobbs: Yeah, great question. What's so interesting about bone marrow transplants or stem cell transplants is that we are giving a person somebody else's blood, including somebody else's immune system. This is different than when we're giving somebody else a solid organ, like a heart or lungs, or liver. When somebody gets a solid tumor, I mean, a solid organ transplant, like heart, liver, etcetera, the immune system of the person that's receiving the organ can reject the organ. With a bone marrow transplant, it's kind of the opposite. The donor, the cells that go inside of the patient, they're the immune cells. When they're in the patient's body, they look around, and they say, wait a minute, the skin isn't mine, these intestines aren't mine, this liver isn't mine. It's basically rejection of the donor of the person, as opposed to the other way around where the patient rejects the transplant itself.
Graft-versus-host disease is something that has limited the success of transplants for a long time or since they started, but several things have thankfully improved, that we can talk about more, but the reason why graft-versus-host disease occurs is because you are receiving, as a patient, immune cells from somebody that's not yourself. That is also the main reason why for diseases like acute leukemia, we don't do transplants from the patients themselves, not only because the patient's bone marrow is not working well, but also because we would be giving the person the same cells that aren't able to recognize their leukemia. We need to give somebody else's cells to recognize the patient's leukemia and take care of it. Graft-versus-host disease occurs because you're getting somebody else's immune system.
The rates of GVHD vary depending on where that transplant is coming from. When we are doing what's called a match, where we do genetic testing on the potential donor, genetic testing on the patients, and then we say, oh, you have a ten out of ten, or eight out of eight match; we're just testing a limited number of immune genes that we know really make a difference. Of course, a person has many more genes than that. If you're getting a transplant from a sibling, for example, you and your sibling share many more genes that we're not testing for, and so then the likelihood of having graft-versus-host disease goes down. If you're getting a transplant from somebody that's not related to you, then of course, you share less genes in common with that person and that increases the likelihood of having graft-versus-host disease. If you're receiving a transplant from a donor that isn't perfectly matched, what we call a mismatched donor transplant, then the rates of graft-versus-host disease increase as well.
Kerith: Thank you for explaining all of that. I know that there's acute GVHD and chronic GVHD. Does your level or severity of GVHD predict relapse or have anything to do with relapse?
Dr. Hobbs: Yeah, that's a good question. Historically, everybody says, you want a little bit of GVHD. The truth is that's not necessarily the case. Many times, patients wish for that. The thing is, you can't really control how much GVHD you have. Honestly, what we want is no GVHD, but a lot of what's called GVL or graft-versus-leukemia, or graft-versus-tumor effects. Certainly, if a little bit of GVHD is an indication that the transplant is awake and working and whatever, like you said, that's a good thing, but it doesn't necessarily correlate. Because those T cells or those cells that are the immune cells that are attacking the patient, they can attack that patient and lead to very, very severe graft-versus-host disease. If they're not attacking the leukemia also, then it doesn't really matter. Those are different cells within the transplant, and so we prefer to see no graft-versus-host disease and a lot of graft-versus-leukemia.
Kerith: Is there anything that is currently approved for treatment that is being used to reduce the risk of relapse at this point in time?
Dr. Hobbs: There's a lot of things that are being studied. I would say the thing that's probably the most advanced is the use of medications against certain genetic mutations after transplant. The most established, probably for patients that receive transplants for chronic myeloid leukemia, they will probably receive at least, to some degree, treatment with the same medications that they received before transplant, called tyrosine kinase inhibitors. These include medicines like dasatinib or imatinib. For patients that have AML that have mutations in a gene called FLT3, I would say many, many centers use FLT3 for therapy afterwards. There are lots of different treatment approaches that are being studied after transplant to predict relapse, but there's not yet a true standard that every single place follows.
Kerith: Right. There are lots and lots of studies going on, it sounds like.
Dr. Hobbs: Yes, for sure. There are studies specifically looking at those genetic mutations that I was talking about before. There are definitely studies looking at blocking the genes called FLT3 after transplant because those are pills that are relatively easy to take, or blocking a mutation called IDH, with pills because they’re also relatively easy to take. There are others we can talk about.
Kerith: I was reading about donor lymphocyte infusions. Can you tell us a little bit about how donor lymphocyte infusions are being used and how those are being used to reduce relapse risk?
Dr. Hobbs: Yeah, sure. Donor lymphocyte infusion or DLI is sometimes described to patients as an immune boost. You will take more cells from the person that gave you the transplant in an effort to wake up the transplant to help it better fight leukemia. What a donor lymphocyte infusion is made of is basically a lot of a certain type of immune cell called a T cell. T cells are really important in producing that GVL effect we've been talking about, the graft-versus-leukemia. It is those T cells that are really the medication that's being given to the patient, and it's those T cells that literally recognize the leukemia cells as something that's foreign and that needs to be destroyed. In some cases where a patient is maybe showing early signs of relapsing, or even in cases where a patient has already relapsed, we will use donor lymphocyte infusions to help a patient get back into remission, but really, most importantly, staying in remission, oftentimes, after having received some chemotherapy.
Kerith: Okay. I know that measurable, well, I guess, called minimal or measurable residual disease or MRD, that’s talked about a lot as a tool being used in AML and other cancers, to measure the disease or what's left of the disease. Can you talk about how that's being used as a tool to predict chances of relapse, either before or after a transplant?
Dr. Hobbs: Yeah, that's a great question. I'm actually going to take one second to just explain what we really mean by minimal residual disease or MRD. When we try to tell a patient or determine if a patient is in remission, what historically we do for leukemia has been to do a bone marrow biopsy, look at that bone marrow biopsy under the microscope, and based on the fact that the pathologist sees or doesn't see leukemia, we say the person is or is not in remission. You can also get a sense of if a person is in remission if their complete blood count levels are normal. Obviously, if bone marrow is working properly, the patient is going to have normal levels of white blood cells, red blood cells and platelets.
Now, what we understand with diseases like AML is that all it takes for disease to come back is one cell. You can imagine a pathologist's eyes aren't good enough, not that there's anything wrong with pathologists, but to find one cell in a million. That's where the concept of MRD or minimal residual disease comes in, and they’re really important. Basically, there's some techniques that can detect one cell in a million to help to say, are there any leukemia cells that we can find at all in this person's body? The use of MRD has been really important in helping to determine, when a patient goes to transplant, for diseases like acute lymphoblastic leukemia or ALL. Really, the standard of care for that disease is to get a patient to be what's called MRD negative, where not only are their blood counts normal and not only is their bone marrow biopsy normal, but when we do these sophisticated tests for MRD detection, that's negative too.
For AML, it's still an evolving field of research, but it's certainly starting to be used more commonly. One example of how it's being used is, remember before, we were talking about dividing patients with AML, into groups, depending on those genetic changes that they have. Not that long ago, literally just a few years ago, patients that were considered good risks and had mutations in certain genes, the one that comes to mind as being used most often is one, for example, called NPM1. Those patients generally were told, you have a good risk of leukemia. All we need to do is give you chemotherapy, and you don't need to go have a transplant. Of course, we were frustrated because some of those patients would relapse, and we wouldn't necessarily know what brought that on. Now, we'll use MRD specifically to follow those patients and to help determine if those patients have a higher risk of relapse and if those patients should then be taken to transplant.
In the case of, for example, NPM1, we’ll say, okay, you probably don't need a transplant, but let's measure that NPM1 gene by these really sophisticated, highly sensitive tools. If that NPM1 mutation does not go away completely with chemotherapy, then we recommend a transplant to prevent that leukemia really from coming back. It's made our decision-making, like we were saying before, definitely much more nuanced and complicated, but I think ultimately, it'll help patients do better. In general, how is MRD being utilized in AML? It is still an evolving field, but definitely something that I think will become more and more important to help us better predict who is going to relapse, both before and after transplant.
Kerith: Yeah, you mentioned MRD is a standard of care in ALL, and you're trying to achieve MRD negativity. Is that just getting it below a certain threshold? Or is that presence of no leukemic cells?
Dr. Hobbs: That's a great question. Depending on what study you see and what disease you're treating, it'll be different. For ALL, it's not that it's fully negative, it's a certain threshold. For AML, again, it's still being defined. Depending on the paper that you read and the study that was published, they use different thresholds and different tests for measuring whether it's from the blood or the bone marrow, etcetera. Definitely something to keep your eye out for additional research to really clarify how MRD should be used and if it can be utilized for every single patient.
Kerith: Okay, yeah. Do you see MRD in AML becoming standard of care in the next few years, or do you think that has a longer time frame, in your opinion?
Dr. Hobbs: I think that, for sure, we’ll be using MRD. I think that we'll be using MRD much, much more in AML. There are two things that I think really need to happen to make it more standard of care. One is that we need to have a more reliable form of testing for MRD in all AML subtypes, not just those that have those specific mutations. Those tests can still take a long time. Utilizing it in your everyday practice is so challenging because it takes a long time for a lot of these assays to come back. The other thing is that we really need to be able to really utilize this to its full potential in AML, to make sure that we have therapies that can get rid of MRD. For example, there are some patients that have very high-risk mutations in AML. For those patients, let's say we don't even have targeted therapies for them. We just have standard old-fashioned chemotherapy, and all we have is to say, well, we gave the best chemotherapy that we have. This is the best remission that we can achieve today. Knowing whether that person is MRD positive or not, actually wouldn't even help us because there's nothing that we could do further to get that MRD from going from positive to negative before transplant. We also need to really improve in our treatment options to be able to really say, okay, the best thing is to do or to give medication to get the patient to MRD negative state, but for many leukemia patients, just don't have that option.
Kerith: Thank you for clarifying that. Okay, let's shift gears a little bit and talk about your clinical trial that you're working on. You currently have a phase two clinical trial that’s studying the use of Jakafi or Ruxolitinib to see if it's helpful in reducing the risk of relapse after transplant. Can you tell us about the drug Jakafi, how it works and what it targets?
Dr. Hobbs: Yeah, sure. Jakafi is another one of these drugs that are called tyrosine kinase inhibitors. Basically, it's a medicine that blocks an enzyme or a pathway inside of cells that are overactive. Jakafi is a medication, a ruxolitinib that blocks a molecule or enzyme inside of the cells called JAK2 and also JAK1. It was initially approved for a disease called myelofibrosis which is a type of chronic leukemia that belongs to the group of leukemias called myeloproliferative neoplasm. It's really good at improving patient's symptoms because patients with this disease have a lot of symptoms, like itching and fevers and night sweats and also reducing the size of their spleens.
Now, Jakafi is also interesting because it's really a very powerful anti-inflammatory. That molecule called JAK2 that lives inside of cells plays an important role in the production of these molecules called cytokines that lead to inflammation. Patients that have GVHD have elevated levels of inflammation and an activated inflammatory response in their body, and so Jakafi is a medicine that has been studied and now approved for graft-versus-host disease. It can be used both for certain conditions before transplant, but also to treat graft-versus-host disease after transplant.
Kerith: That's great, just like a dual target.
Dr. Hobbs: Correct.
Kerith: Do you have any preliminary results you can share about the trial?
Dr. Hobbs: Yeah. We did the clinical trial, utilizing Jakafi after transplant in patients that were over the age of 16, initially just with AML, but then we opened the study as well to patients with a condition called myelodysplastic syndrome for which many participants also get transplants, with two goals. One was to see if this medication could also help prevent relapse by turning off many pathways that are sometimes overactive inside of cancer cells. Our other hope was that the use of this medication would also help to prevent graft-versus-host disease since we already knew that this medication was helpful in treating graft-versus-host disease in participants that had been previously treated with several other medications.
We have enrolled almost all of our patients in this study, and hopefully, it'll be done in the next couple of months. Hopefully next time we talk, we have more data, but from the preliminary information we have from the study and talking to all the doctors that have put patients on this study, I think the most notable thing is that the rates of graft-versus-host disease has really been very low. More importantly is that the degree of graft-versus-host disease has also been very minimal. Graft-versus-host disease is rated on a scale of not so severe to severe, grade one through grade four, and most patients that have gotten graft-versus-host disease have gotten just mild graft-versus-host disease.
That's really important because when we're thinking about how tolerable transplants are, and when we think about the things that really impact quality of life for patients after transplant, and when we're talking to our patients, especially our older patients about whether or not they're good candidates for transplants; one of the things that we really worry about is graft-versus-host disease. Because although GVHD can be mild in many patients, it really can be very serious. It can be life threatening, and it can really alter a patient's quality of life in a permanent way.
I'm really excited to see the preliminary results that were presented by my colleague, Dr. DeFilipp, in this past year’s Tandem Meeting, which was a big meeting for bone marrow transplant study. I can't wait to see what the final results show in terms of survival for our patients, and on rates of graft-versus-host disease.
Kerith: That sounds very exciting. I know graft-versus-host disease is very challenging for everyone. It's such an incredibly big part and challenge of the stem cell transplant process, so that's really exciting. Hopefully, we can have you back on to hear about the update.
Dr. Hobbs: Absolutely.
Kerith: I know you're in phase two. When you get to phase two in a clinical trial, what does that mean, and what needs to happen in order to move to the next phase?
Dr. Hobbs: That is such a good question. When you're a student learning about clinical trials, you learn about phase one, phase two and phase three, and it all seems pretty straightforward. Phase one is when you test the safety of the drug. Phase two, you start to get some efficacy signals. Phase three is bigger studies. Oftentimes, we think about randomized studies to really decide, is this drug better than whatever is available now to get it FDA approved? Now, it's difficult, honestly, in the space of blood cancers where they're more rare, and it's harder to do these bigger studies. Sometimes, after a phase two study, that's sufficient to change the standard of care, but not always.
For this study in particular, my colleague, Dr. DeFilipp who's a bone marrow transplant specialist at Mass General, is going to do a study with a collaborative group. Basically, a bigger network of sites to open across the country and test if we can use Jakafi or ruxolitinib, after transplant, really, as a strategy to prevent graft-versus-host disease from happening. Once you have preliminary results from one study, then we decide, is this worth pursuing? If so, let's do a bigger study to really confirm our findings. Because oftentimes, in small studies, you'll get a result, and then if you do it in a bigger study, you see, oh, maybe when we include many more patients, actually, that effect wasn't as big as we thought that it was. It's really important to get confirmation from bigger studies.
Kerith: Right. Let's cross our fingers that that happens, for that to happen in [0:43:50] [Indiscernible].
Dr. Hobbs: Absolutely.
Kerith: Okay, I have a question about CAR-T cell therapy and the use of CAR-T cell therapy. It's definitely a hot topic of discussion, and I know everyone is hoping to see positive results come out of that modality and research in AML. Can CAR-T cells possibly be used as another immunotherapy option to potentially reduce the risk of relapse?
Dr. Hobbs: Yeah, absolutely. Great question. I think that one of the goals of bone marrow transplant doctors forever has been to make transplantation a more precise science. Right now, if you think about it, similarly to old-fashioned chemotherapy, a bone marrow transplant basically replaces the entire bone marrow of a patient and gives them a brand new transplant. What if, instead of doing that, we can just give the cells themselves that are going to attack the leukemia without having to put patients through this whole process? CAR-T cells, for that reason, have been really exciting, especially for diseases like lymphomas and in the leukemia world, for diseases like ALL or acute lymphoblastic leukemia, where CAR-T cells have really helped both to get people into remission after transplant and also just to get them into remission and then avoid transplant altogether.
There are definitely many studies now trying to look at good targets for CAR-T cell therapy for AML. Hopefully, in the next couple of years, we'll get some exciting results from those studies, and we can start to use CAR-T cells for AML, but there are no CAR-T cells for AML at the moment.
Kerith: Right, and I know that that's an active area and changing rapidly. Hopefully, there will be more research to come on that horizon.
Dr. Hobbs: Absolutely.
Kerith: Are there any other current trials that are showing promising results in the area of relapse or preventing relapse?
Dr. Hobbs: Yes, I think all of us are looking.
Kerith: After transplant.
Dr. Hobbs: What did you say? Sorry.
Kerith: Sorry, I just said after transplant.
Dr. Hobbs: Yes, I think that studies that start treatment based on changes like, for example, the detection of MRD are important. There are studies looking at different FLT3 inhibitors or IDH inhibitors after transplant, to see if we can prevent relapse in those patients. Those are therapies that are given preemptively to prevent relapse. Other things that I think are exciting, of course, are CAR-T cells and giving different types of transplants that use different combinations of stem cells.
We talked about this a little bit, but if instead of giving just a blanket, let's take away your bone marrow transplant completely and give you a brand-new bone marrow, if we could be a little bit more precise and giving more of the cells that are important for preventing relapse and more of the cells that help a patient defend themselves against infections, and less of the cells that cause graft-versus-host disease, then we can give transplants to patients in a more precise kind of way.
There have been some studies looking at those kinds of different combinations of cells to help make the transplant more tolerable with less graft-versus-host disease. Some of those things are called Orca-T cells, for example, where there are several different cells that are given like that to make the transplant more precise.
Kerith: Great. Okay, this is kind of an opinion question. What's your opinion on pre-transplant treatment and the current best options to set a patient up for success before transplant?
Dr. Hobbs: What's the best thing to set up a patient for success? Is that what you said?
Kerith: Yeah, before transplant.
Dr. Hobbs: I think really sitting down with the patient and going over the explanation of the patient's own disease, explaining what the options are with and without a transplant, what is involved in the actual transplant itself, the side effects of the transplant, life before and after transplant, all of that education. I really think that it's critical to get the patient and their family members to be really prepared to handle the transplant. Because although transplant is a really important modality of treatment, and it really is the reason why we can cure so many patients with AML, it is not easy, no matter what type of transplant a patient receives. I think that education and preparation really sets somebody up for success after transplant.
In the months leading up to transplant, of course, in addition to taking the medications that are prescribed, and being informed and asking questions about, why am I getting this medicine or this other medicine, or how are you monitoring me, kind of alluded to this a little bit at the beginning of our conversation, but making sure the patient is able to remain as active and as healthy as they are able to, is really, really important.
One of the things I always tell my patients when they leave the hospital after they’re first diagnosed with AML, is that they're going to be in the hospital for a few weeks with us. Go outside, fill your batteries, get emotionally and physically ready for that transplant. It's not just something that I'm saying for no reason. I think it makes a really big difference for the patients to be both emotionally and physically at their best before they go to transplant because that is going to be a long hospitalization, and I think that really helps patients to get prepared.
Kerith: Right. I know there have been discussions about that. I was listening to Dr. Rutgers and Dr. Kedia discuss this the other day. Do you think eventually there's a possibility that transplant may go away, that there will be other curative options available? Or that we'll really just still be trying to get patients successfully to transplant? Again, that's more of an opinion question.
Dr. Hobbs: This is a general answer. Yeah, sure. Just anecdotally, I'll tell you, when I first started my training, I thought that I was going to be a bone marrow transplant doctor. When I went through my sub-specialty training, I was like, no, the excitement is all before transplant. There are all these new drugs that are being studied and different immunotherapies that are being studied and whatnot. Truly, my hope is that we won't depend on transplant to cure our patients. Hopefully, in ten years we'll be using transplants less. I think, along with that, because I know some of my transplant colleagues will be upset with me if I just say, hopefully, we never have to give a transplant again; hopefully, transplant can become much more precise.
I know that for the transplant community, it's been really important to try to make their treatment much more tolerable. I think these different technologies that either use specialized cells like the CAR-T cells, or the idea of being able to pick and choose the cells that are going to help prevent relapse but not cause things like graft-versus-host disease, have really great potential to make transplant more precise and much easier to tolerate so that we really want to use it for everybody. I think there's a lot of progress to be made, but hopefully, we'll be using less transplant and more targeted therapies.
Kerith: Yeah, I think that's a great point. I think that's a hopeful viewpoint because I think there's so much research happening, so many drugs being explored, and so many that have been FDA-approved in the last five years.
Dr. Hobbs: Absolutely.
Kerith: Even if it just means that it's a combination of transplants and those drugs working together, that would be great, just to reduce the toxicity and the challenge of the transplant itself.
Dr. Hobbs: Yeah, I hope so.
Kerith: One thing I just wanted to ask you, then we'll take a couple of questions from callers, what's the difference between the AML doctor and the transplant doctor? How are their different roles defined? I guess, at what point does the transplant doctor step in and take over with the patient?
Dr. Hobbs: I'm so glad you asked that. That can be confusing. I will say one thing, different hospitals and centers have different practices. It's not exactly the same for every place a patient goes. In many centers, especially those that are much more specialized, there is a clear separation between this is the leukemia team, and this is the transplant team. For example, at our institution, the leukemia doctor is responsible for everything that happens to that patient before transplant, giving the chemotherapy, getting a person into remission, all of that. Of course, we talk and work very closely with the transplant doctors, how things are going and to help them in the planning process of the transplant. Once the person goes to transplant, and this is actually a sad part of my job, but it's a good part of my job, then the patients are no longer my patients. They just transfer their care fully over to the transplant doctors, and the transplant team will take care of the patient through transplant and then after transplant. They really only come back to the leukemia doc if, unfortunately, they have a relapse.
In other centers, it's a little bit different where the leukemia doctors take care of the patients before the transplant and then the transplant doctors take care of the patients for maybe the first three months or 100 days after transplant, and maybe they are then sent back to the leukemia doctors to follow them after that. There are going to be some differences in the centers. There may be some places where there is no difference actually, and the Leukemia doctor also does bone marrow transplants. I think it's important, when establishing care at a facility, to really ask those questions. Who's going to be responsible for my care when I'm getting a transplant? Who's going to be responsible for my leukemia care? Because it really varies by center.
Kerith: Great. Thank you for clarifying that for us. Okay, we're going to take a couple of caller questions. If you have questions about anything Dr. Hobbs discussed today, you can call in to 515-602-9728. Once you're on the call and ready to ask your question, press “1” on your keypad. It looks like we do have a question coming in. I'm going to unmute that caller. Caller ending in 1159, go ahead.
Caller: Hi. Thank you. My question is, in your experience in treating patients leading up to transplant, are there any specific things you've seen patients practically do during this phase that are successful to them and helps them prepare for transplant and possibly reduce the risk of complications?
Dr. Hobbs: Great question, and it doesn't have a simple answer. I think some of it I talked about a little bit before. The first thing that I really think is so important is for the patient and their family to get as much information from their care team as possible. It sounds trivial, but it really isn't. Treatment for leukemia can be so complex that really sitting down with your physician and going over every step on the way. What treatment am I getting, how are we going to know it's working, when are we going to make a decision to go to transplant, what are the side effects, what can I do and not do, all of those things are really, really important.
The other thing that I talked about that I think is also super important, is that leukemia treatment can be really difficult. I don't mean to make it sound like this recommendation is an easy recommendation. It’s not. The healthier and more active a patient can remain, leading up to transplant, honestly, the better the outcomes are going to be for that patient, during transplant after transplant. This is difficult. Of course, there are going to be some days where all the patient wants to do is be in bed, and they're totally allowed that, but take advantage of those days where the patient is feeling well and trying to get up. Walk around, stay active. Functional status makes such a big difference in how patients are able to tolerate treatment as well. Also, not to mention, being physically active, going outside, getting fresh air whenever the patient can, also really helps to relieve some of the anxiety and depression that come with such a severe diagnosis.
Caller: Thank you.
Dr. Hobbs: My pleasure.
Kerith: Thank you for your question. Okay, we have another call coming in that ends in 7401. Go ahead, Caller.
Caller: Yeah. Hi. Thank you. I am just wondering, you talked about Jakafi. What side effects might be associated with that?
Dr. Hobbs: Great question. Jakafi, in general, is a relatively easy to take medication. Before transplantation, one of the common things that we see is weight gain actually. Some patients are going to have a little bit of GI symptoms and a little bit diarrhea, but it's pretty mild. Post-transplant, one of the biggest issues and limitations of using Jakafi in patients is that it can lower blood counts. In the immediate post-transplant days, patients already have low blood counts, and so having patients be able to start Jakafi and stay on Jakafi is sometimes challenging.
Dr. Hobbs: Thanks for your question.
Caller: Thank you.
Kerith: Okay, thanks for your question. In order to wrap it up on time today, that's all the time we have for caller questions. Dr. Hobbs, thank you so much for joining us today. We're incredibly grateful for your generosity with your time and your willingness to share your expertise with us. We would love to have you on the show again, especially to hear updates about this trial and, hopefully, to hear how it's progressed. We wish you all the best in your practice.
Dr. Hobbs: Thank you so much for inviting me.
Kerith: Yeah, we wish you all the best in your practice and your research endeavors.
Dr. Hobbs: Thank you so much.
Kerith: Thank you again for coming on the show, and we hope everyone has a great day. Thank you all for attending.
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