Transplant Outcomes in Older Adults with MDS and AML

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Transplant Outcomes in Older Adults with MDS and AML

Monday, April 19, 2021

Presenter: Gabrielle Meyers MD, Associate Professor, Center for Hematologic Malignancies, Oregon Health & Science University

Presentation is 37 minutes long with 20 minutes of Q & A.

Summary: Stem cell transplants can be a successful treatment option for older adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Patients with high-risk AML or MDS who undergo a transplant fare better than high-risk patients who do not have a transplant.

Highlights:

• All patients with high-risk MDS up to age 75 should be considered for transplant.
• 70% of patients with AML have high-risk disease and should be considered for transplant.
• The biological age of patients with MDS or AML is less important than their overall health, functional status, and comorbidities such as a history of stroke, long-term smoking or diabetes. 

Key Points:

(05:59) Most patients who have an allogeneic stem cell transplant (transplant using donor cells) have either AML or MDS.

(07:15) MDS is primarily a disease of older adults. It has been called “pre-leukemia” because it often evolves into leukemia.

(09:09) MDS is classified as high-risk or low-risk, depending on the likelihood that it will  become leukemia.

(09:44) Patients with low risk MDS may not need a transplant.

(14:58) Patient with high-risk MDS fare better after transplant than those who did not have a transplant.

(18:03) Transplant for patients with high-risk MDS can improve both survival rates and quality of life.

(19:26) Transplant is the only cure for patients with high-risk AML and should be done while the patient is in first remission.

(23:33) Survival rates for patients with AML who are over age 70 are better for those who undergo a transplant than for those who do not.

(29:00) Exercise to improve functional status before transplant, sometimes called pre-habilitation, and improving nutrition, can lead to better quality of life after transplant.

(34:04) Treatments are available to reduce the risk of relapse after transplant.

(35:13) The risk of graft-versus-host disease after transplant is a major concern. Ways to reduce the risk and improve treatments are currently being studied.

Transcript of Presentation:

(00:00) [Mark Spina]   Introduction. Hello, my name is Mark Spina, and I will be your moderator today. And welcome to the workshop Transplant Outcomes in Older Adults with MDS and AML. It's my pleasure to introduce to your speaker, Dr. Gabrielle Meyers. Dr. Meyers is an Associate Professor at the Center for Hematologic Malignancies at Oregon Health and Science University. Her research focuses on optimizing outcomes for stem cell recipients who have a bone marrow failure disease such as aplastic anemia or myelodysplastic syndrome, and for patients with acute myeloid leukemia. Dr. Meyers is particularly interested in treatment options for older adults, including prevention and management of disease, relapse after transplant, and improving outcomes for patients with graft-versus-host disease. Now please join me in welcoming Dr. Meyers.

(01:06) [ Gabrielle Meyers]  Overview of Talk. Thank you so much for that kind introduction. And I want to also express my appreciation in being allowed to talk with all of you today about transplant outcomes in older adults.

(01:26) So I wanted to first talk about some goals of this talk. And so I do want to present you information about transplant for both acute myeloid leukemia, or AML, and myelodysplastic syndrome, MDS. And in particular, I'm going to present data regarding the transplant outcome compared to patients that don't get a transplant. And then also talk about quality of life after transplant, which I think is a really important aspect to discuss. We'll talk about response rates, what to expect with transplant in these diseases, and then also talk about treatment before and after transplant. And in particular, treatment after transplant is a growing field.

(02:20) When we think about outcomes with transplant, there are some strategies to talk about that can be helpful for patients. So talking about exercise and nutrition, and highlighting that as an important aspect as getting ready for transplant and how patients do after transplant. And then also talking about treatments to help reduce relapse risk.

(02:46) Allogeneic transplant for older adults is becoming more common. And then here are some key points that I will talk through and support for this talk. And so first off, most AML and MDS can only be cured with a transplant. So I think that's a really important reason that we're talking about this today, and in particular thinking about older adults. I hear all the time, patients are concerned that they're too old to get a transplant. And I hope to dispel that myth today. Allogeneic transplant for older adults is becoming more common. And in particular, as I'll talk about, these are diseases of older adults, and we're now gaining a great amount of experience in transplanting older adults and how to do that well and effectively.

(03:34) Older, high risk adults benefit from transplant compared to those who do not get a transplant. There are numerous studies that show that age alone is not a barrier to a successful transplant. So again, this idea that age by itself is not a reason to avoid transplant. And several studies are now showing an advantage to transplant in higher risk MDS and AML in older adults compared to not getting a transplant.

(04:03) Pre-transplant health and fitness affects transplant outcomes. So last two key points, we do know that how strong and fit you are prior to transplant affects how well you do. And finally, overall transplant outcomes continue to improve even in those over the age of 60.

(04:22) Transplants for older adults are increasing in percentage and actual numbers. So let's dive into some details here. So this is from CIBMTR, which is The Center for International Bone Marrow Transplant Research. And they're a big database of transplants here in the United States and in other countries. They give slides that talk about trends in transplant and outcomes. And so I'll have a couple of these slides in this talk highlighting what we know at a grand scale. And the importance of this slide is really to show that the number of transplants for patients greater than age 65 is increasing. And you can see that lighter blue is the boxes representing patients over the age of 65 that get transplant.

(05:15) One thing that's easy to see is that that percentage of transplants in this older adult population is getting larger. And 2019 is the last data we have, and 26% of all transplants were performed in patients over the age of 65. And then I think the top shows the actual numbers, and you can see that again, the total number of transplants is increasing as well over time. So overall, both percentage wise and in actual numbers, we're doing more and more transplants for patients over the age of 65.

(05:59) AML and myelodysplastic syndrome are the two top reasons for allogeneic transplants. This slide also from the CIBMTR talks about what diseases people get transplants for. And AML and myelodysplastic syndrome are the two top reasons that we do transplant, allogeneic transplants specifically. And you can see the top line, the dark blue, is our AML transplant numbers, and it's a very large proportion of all transplants. And then myelodysplastic syndrome with a little bit of myeloproliferative neoplasms as well, is the second line down in the lighter blue. And you can see that number, in particular, seems to be growing as is the number for AML. So very important for us to be talking about transplants in these diseases.

(06:52) I want to separate out MDS and AML because there is a different approach to transplant in these diseases, specifically, although many times when people report their outcomes, they'll cluster MDS and AML together. I did want to start by separating them out and talking about them separately.

(07:15) MDS means damaged stem cells don’t produce adequate blood. So we're going to start by talking about MDS and transplant for MDS in particular. So MDS, myelodysplastic syndrome, is primarily a disease of older adults. And the average age at diagnosis is around 71 years old. MDS is a bone marrow stem cell problem and the stem cells that are supposed to do the work of making all the different kinds of blood cells. In MDS those stem cells are damaged, so they don't make blood like they're supposed to. And I talk about MDS stem cells is being workers that are permanently on lunch break, because they don't do the work that they're supposed to do. And so I sometimes will call them lazy as well.

(08:06) MDS has been called pre-leukemia. So MDS is associated with low blood counts and patients frequently require blood transfusions. Patients with MDS are also at increased risk of bleeding and infection, but also very importantly, in the old days we called MDS pre-leukemia, because there's a risk of developing into acute myeloid leukemia in particular, and so that name pre-leukemia really made sense. We do have treatments for MDS to make those bone marrow stem cells function better and produce blood cells better, but the damage remains. And the only way to get rid of those damaged stem cells, and to potentially cure MDS, is with a bone marrow transplant, where we put fresh new, healthy bone marrow cells in that make blood cells like they're supposed to.

(09:09) MDS can be high risk or low risk, depending on the likelihood that the MDS will become leukemia. Now MDS is really a lot of different kinds of bone marrow failure. And there are a lot of patients that have the diagnosis of MDS, but their diseases may act differently. So we think of MDS as being in two categories, lower risk MDS and higher risk MDS. And the risk means that that risk of turning into leukemia or the risk of having complications related to the MDS.

(09:44) Patients with low risk MDS may not need a transplant. And as you could appreciate, the short- term and long-term treatment options vary between these two groups. And while MDS can only be cured by transplant, in lower risk MDS, patients may not benefit from a transplant if it's done too early, so to speak, because with lower risk MDS, patients may live a long time with their MDS and not have any complications from their MDS. And so we wouldn't want to transplant them too early.

(10:17) And so let's talk more about how risk of MDS helps us decide about that timing of transplant. So how do we do this risk assessment in MDS? So there are numerous scoring systems that you'll see out there that can be really useful. And these scoring systems take into account features of the disease. So one is the need for blood transfusions, and people that their MDS is significant enough that they're needing blood transfusions all the time, have a more aggressive disease than those patients with MDS that don't need blood transfusions.

(10:58) Percentage of blasts distinguish MDS from AML. Looking at the other blood counts, like the neutrophil count and platelet count are important. And then another strong feature is what we call the blast count on the bone marrow biopsy. So blasts, many of you probably know this term, but blasts are immature cells that are in the bone marrow, and they're not maturing like they're supposed to. And ultimately blasts are what become those leukemia cells. So if you have a blast count of 20% or higher, then you're automatically in the acute leukemia category.

(11:37) But with MDS, you can have a blast count of 1% all the way up to 19% and still be MDS. So as you can appreciate, if somebody has a blast count of 17%, your disease is much closer to leukemia compared to somebody with a blast count of 2%. So that blast count is a very important feature of assessing one's risk with their MDS.

(12:05) Other features of MDS and AML are things like chromosome changes that are present in the diseases. If there are mutations in genes, these are very important in assessing someone's risk.

(12:21) Lower risk MDS may respond to non-transplant treatments. And then finally, is the MDS responding to treatment? So we have non-transplant treatments we can use for MDS designed to make those bone marrow cells produce blood better, designed to reduce the risk of transforming into leukemia, and in MDS that responds to those treatments, that's a good thing. But if it's not responding to treatment, then that's a problem and a higher risk feature. So these factors are all very important for each individual patient to know because that really individualizes their MDS and the risk associated with their MDS.

 (13:04) Lower risk MDS often means a longer life span. So for many patients with truly lower risk MDS, their expected life span is many years. And on the flip side of that are patients with high risk MDS, where these patients have a high risk of turning into acute leukemia or having another life-threatening complication. And some high risk MDS may have an expected life span of less than a year without treatment.

(13:29) For lower risk MDS, the risk of transplant may be greater than that of the disease itself. So there are, like I said, very, very different risks associated with MDS that's important to know. And so before deciding to pursue transplant, you have to look at the MDS and the risks of that MDS and balance it with the risks of transplant. And I'll try to show this in a visual way in these next two slides.

(13:56) So in somebody that has lower risk MDS, we look at the risk of their MDS on the left side, and they might be responding to treatment or they have low risk disease. And on the right hand side is the risk of transplant, where we might see the risk graft-versus- host disease, infection, organ toxicity, and those risks of transplant are heavier or larger than the risk of the disease. So when we have a risk of transplant that's higher than the risk of the MDS, that's the time where we say we're not ready for transplant yet. This is a patient where I might say, let's look at your transplant options and let's look at donor options for you, but we're not going to pursue transplant right now, because the risk of the transplant is higher than the risk of your disease. And so that's a feature that we talk about with lower risk MDS.

(14:58) For higher risk MDS, the disease risk is greater than transplant risk and transplant is indicated.  For higher risk MDS, it's a different story, because now you have the risk of bleeding, the risk of infection, that risk of turning into leukemia. And those are heavy risks that are associated with the disease, and those risks are bigger than the risk of transplant. And so in higher risk MDS, that's a time where we say, gosh, the risk of your disease is bigger than the risk of transplant. And so that's a time where we want to seriously talk about transplant and seriously pursue transplant for patients. And in this situation, studies have shown us that transplant leads to improved survival versus no transplant. And that's really important to know as well.

(15:51) So there has been multiple studies that have compared transplant to no transplant in MDS. And the best study has just been reported out in the last few months. And that's where they actually did a randomized study where they took patients with higher risk MDS, and they looked at whether they had fully matched donors or not. In patients that had fully matched donors, they got a transplant. In patients that didn't have a fully matched donor, they didn't get a transplant. And they looked at overall outcomes between those two groups.

(16:31) A couple of features about this trial that are important is number one, there was this randomization to create two equal groups of patients. The second piece is that these were patients that were older for the most part. The average age in both arms was 66, and 60% of patients were over the age of 65. And the highest age in this trial was 75. So [it] very well-represented our population of patients with MDS.

(17:07) When they looked at three year survival, so how many people were alive at three years, 48% of patients in the transplant arm were alive versus 27% in the no transplant arm. And this difference was statistically significant. They did look at other features like quality of life. And there was no difference in quality of life between the two arms.

(17:30) All patients with higher risk MDS up to age 75 should be considered for transplant. So what we can conclude from this study is all patients with higher risk MDS up to age 75 should be considered for transplant, because there is a survival benefit. And this is just a picture showing that overall survival and that black [line] on top are people that had a donor and went to transplant versus patients that didn't have a donor in the yellow line and didn't go to transplant. And that's how their survival looked.

(18:03) Transplant may improve quality of life as well. Two key points about transplant for MDS. One is that in higher risk MDS, transplant increases survival compared to non-transplant therapy. Quality of life does not appear to be worse in those undergoing transplants, and over time there may actually be improvement in quality of life. And I'll talk more about quality of life after transplant later on. We do know that relapse can be a problem after transplant for MDS. It also can be a problem after transplant for AML. And so I'll talk some more about that as well.

(18:43) So here's a little break and this is a cartoon from one of my transplant patients, and he's actually in his 70s and he got transplanted a few years ago and he in his retirement. In his post-transplant joys in life, he has discovered cartooning. And so he has a website, Martin and Teresa, and they have a lot of cartoons about life. And I liked this one. "I'm feeling great but Theresa sent along this list of things she wants you to fix!". And sometimes I feel like as a doctor, I'm trying to fix things, or sometimes I say, "There are some things that I can't fix."

(19:26) For AML, transplants should be done after the first, full remission. So let's talk about transplant for AML. And some key points right from the get-go, first off is transplant for AML is best performed when patients are in an excellent remission. And remission can be defined as no blasts in that bone marrow biopsy or no abnormal number of blasts in that bone marrow biopsy. But when we look at specific markers for the AML cells, we want to see that we can't find any of those leukemia cells. And that's what we call minimal residual disease. And if that's negative, that's a good factor going into transplant.

(20:12) Oftentimes when people have AML, and they're in that first remission, they say, "Gosh, I'm feeling good. I'm in remission. Do I have to do this transplant? How about if we just wait for the leukemia to come back and then do a transplant?" And the challenge with AML is that it can be difficult to get people into a second remission, so that when people relapse after their first remission, those leukemia cells are smarter. They're harder to get back under control. And we may never be able to get a patient into a second remission and get them to transplant. So important factor to think about.

(20:57) Transplant leads to longer survival rate than non-transplant options for AML and it is the only chance for cure. And we do know that transplant for AML leads to longer survival rates compared to no transplant. And for many patients, transplant is the only chance of potentially curing their AML.

(21:13) AML is a disease of older adults and most are higher risk. So let's talk about AML in older adults. AML is a disease of older adults. The average age of diagnosis is 68, and like MDS, there are features of the disease that do impact the risk and how well we might expect that AML to respond to treatment. Unlike in MDS, over 70% of older AML patients have higher risk disease, so disease that is going to be harder to treat with chemotherapy alone and harder to maintain and remission without a transplant. So most of the AML we see is higher risk. So therefore, almost every patient over the age of 60 could be considered for transplant if we just focused on their disease. But we know there are many factors beyond disease that impact that decision to consider transplant. And I'm going to try to tease out some of those factors.

(22:18) But let's first start with talking about what are the outcomes for patients with AML who are undergoing a transplant. And so this is a slide from CIBMTR, and it represents over 13,000 transplants for AML. And again, this is in the age of 18 or more, and this is from 2008 to 2018.

(22:44) The features here, number one, we see that CR1, so complete remission 1, which is really that first time people get into remission, we know that transplant outcomes are best at that time point. And you can see that right below that is CR2. So if people are able to achieve a second remission, then they can do pretty darn well with the transplant. But like we talked about, that can be a challenge in leukemia. And then the fourth line represents people that never achieve a remission and you can see their outcomes are the lowest overall.

(23:33) Survival rates are better for AML transplant recipients compared to non-transplanted people even over age 70. We looked at our own experience in transplant in patients over the age of 70, and at our institution, we do have fair number of transplants in those over the age of 70, and this looked at patients that had achieved a complete remission. And then part of them went to transplant and part of them didn't go to transplant. And you can see those that went to transplant are in green. And they had a percent survival of around 50% to 60%. And compared to blue, those patients that didn't go to transplant that didn't have much of a survival even up to two years. So in our experience, we found a significant improvement in survival in those patients that went to transplant versus no transplant, even in those over the age of 70. And I think our oldest patient that we've transplanted was 78.

(24:38) Age is less important than functional status and comorbidities in transplant outcomes. So what influences outcomes of transplant in patients with AML or MDS? Because there are some common features that are important. So we've talked about number one, age alone is not a factor that influences outcome. And there've been multiple studies that show similar outcomes in those that are over the age of 60, compared to those that are less than 60.

(25:02) Second is functional status and co-morbidities are important factors in outcomes. And you can appreciate this, right, how strong somebody is, how fit they are. That's important. Also knowing that if somebody had a history of strokes or diabetes or smoking for a long time, that's also important as well. So these co-morbidities do impact outcome.

(25:38) When we look at these survival curves, the first question I think about is, why did somebody not survive after transplant? And one of the big risks after transplant is still disease relapse. And that's a huge risk to patients, especially in that first one year after transplant. So we've had a big focus on reducing the risk of relapse after transplant. And we now have a group of therapies that we can use after transplant to reduce the risk of relapse.

(26:21) And of course, we're also figuring out how to do transplant better. So how can we optimize the conditioning regimen? How can we reduce graft-versus-host disease risk? And then also expand our donor options for patients. These are all areas that we're focusing on.

 (26:44) Quality of life often returns to pre-transplant levels in six to twelve months posttransplant. So let's talk about quality of life, because I can tell you that that's the number one question I get from patients. So we might talk about their leukemia or their MDS. I really think that you need a transplant from a disease standpoint, you're fit and healthy otherwise. And they say, "Well, yeah, but how am I going to feel after transplant?" Because people want to have quality and be able to do the things that they enjoy doing after transplant. And so that's very important. And in general, when we look at quality of life after transplant, it's reported as good. If you study that first year in particular, there is a dip to be expected after transplant, that quality of life goes down, but then it heads back up to pre-transplant levels in six to 12 months. And I have a number of patients that say, gosh, at six months they might feel better than they did even before transplant.

 (27:44) Graft-versus-host disease can have a negative impact on quality of life. So we do know that people can have good quality of life after transplant. Does everyone? Unfortunately not, because they're are factors that we know impact quality of life. So number one is graft-versus-host disease. And in people that have significant graft-versus-host disease, they do have a poor quality of life. And that's why we're focusing on trying to improve graft-versus-host disease.

(28:13) The second piece is functional status, how strong you are, and that impacts quality of life. So as you can appreciate, if somebody is not very strong going into transplant, and then you lose some strength from the transplant, that's a big road of recovery that you have to struggle through. And of course that impacts quality of life. Impacts on ability to work and financial security decrease quality of life. And that's a factor that impacts younger patients as well as older adults and really important features that patients and I talk about all the time.

(29:00) Prehabilitation is exercise that improves functional status before transplant and can lead to better outcomes post-transplant. So what are the factors that we can control or potentially control? So one is functional status. And how can we improve functional status? Well, number one right on top is exercise. And so in the cancer world, there's a lot of research on what we call prehabilitation. So this idea of getting ready to fight the cancer, getting ready for your transplant, working to exercise and build up strength. So you're at a better fitness level before going into that transplant. And people can do that. Patients can improve their strength, and we know that higher strength and higher performance status leads to better quality of life. And it does lead to better outcomes with transplant.

(29:50) How do we do that? So combining activity, so walking, rowing exercise, biking, bicycling, whatever type of activity that's aerobic in some nature, as well as doing some strengthening, some resistance exercise to counteract muscle loss, because we all know that these diseases, as well as the treatments, can really make you waste muscle tone. So having that combination of activity. And again, our goal of having 150 minutes per week or more is a first place that we talk about. Breaking that exercise into small time points, so instead of doing 20 minutes all at once and being exhausted, breaking that into three or four sessions is useful and still leads to that benefit.

(30:48) Adequate nutrition and improved mood promote better outcomes as well. Nutrition, very important, making sure you get adequate calories and adequate protein intake. So if we're trying to counteract muscle loss, maybe trying to build up some more muscle, then we're going to need to give the body protein to fill that muscle back in. And it's a large amount of protein. So when we think of somebody who's around 155 pounds, they may need for over a hundred grams of protein a day to help really build that muscle back. And so that's important to know and then thinking about getting enough protein.

(31:28) And then also optimizing your mood. So research has shown that mood and functional status are very connected. And so when we think about depression, we want to, in particular, help people that have mood changes, whether that's depression, whether that's anxiety. We know that managing that along with exercise and nutrition program, patients that have depression benefited the most from a structured prehab program. So we also want to make sure that your mood is optimized and talk with your treatment team about how you're feeling, because that's just as important as exercise and nutrition in allowing you to gain strength as quickly as possible.

(32:18) The disease control before and after transplant. So we talked a little bit early on about this idea of minimal residual disease and before transplant, ideally that blast count in MDS would be less than 5%. And ideally in AML we'd have no minimal residual disease. We do know that if you don't get to that level, we can still do a transplant successfully, but we have to really watch closely for relapse and be on top of it.

(32:49) The amount of chemotherapy given to AML patients just before transplant can be adjusted, depending on the amount they can tolerate. Best treatment for AML includes intensive chemotherapy. And we do know that patients over the age of 60 can tolerate the same type of therapy that we give to 40-year-olds or 20-year-olds.

(33:02) With transplant, we do have a mixture of different intensities of treatment that we can use. And so oftentimes in our older adults, we'll think about using reduced intensity chemotherapy to reduce toxicity and complications. But on the flip side, we do see a higher risk of relapse when we reduce the chemotherapy before transplant. Each patient I see, I take into account the features of their disease, how strong they are, what their pre-transplant testing looks like, and I want to give them as much chemotherapy as possible to help control their disease, but balance that with enough that I'm not overdoing it and causing excess toxicity. So it can get down for each patient and trying to optimize that condition regimen becomes very important.

(34:04) Relapse risk can be managed with post-transplant targeted medications. After transplant we have to stay watchful for relapse. We do have treatment options to help control disease without harming the graft. Because remember, we want that graft-versus-leukemia activity with transplant. And the use of agents in particular, azacytidine, decitabine or targeted agents after transplant for both MDS and AML has been shown to be well tolerated, although the doses are reduced compared to what we use before transplant. And these treatments also have been shown to reduce relapse.

(34:40) And so this slide, in no way is this a definitive list of treatment options, but just to highlight that, depending on disease features, we may have targeted therapies. We have agents like azacytidine and decitabine that we can use that won't harm the transplanted immune system, but can keep the disease in check and allow time for that new immune system to take hold and get strong enough to help control relapse.

(35:13) GVHD is receiving more research into how it can be prevented or effectively managed. We talked about graft-versus-host disease be important and of course it's the biggest fear that patients have when considering a transplant. So we're focusing a lot of energy on trying to prevent graft-versus-host disease, manage GVHD if it comes. We do know the benefit of graft-versus-host is that it does reduce the risk of relapse. And there are a lot of clinical trials that are being used, we have some in our institution, looking at agents to try to prevent graft-versus-host disease and also modifying the types of transplanted cells to try to regulate graft-versus-host disease. So it's an area of active research and worth investigating.

(35:59) And so in summary, we can successfully transplant patients with MDS and AML over the age of 60. And we're getting more and more experience with this population. The number of patients getting transplant in their 70s continues to rise. So again, age by itself is not a factor.

(36:20) Several factors optimize transplant outcomes and are more important than age alone. What optimizes outcome? Good control of disease, good performance status prior to transplant, those are critical in making that transplant go as best as possible.

(36:32) The importance of exercise and good nutrition, very important before transplant, very important after transplant. And keeping an eye on disease and talking about treatments after transplant to prevent disease from coming back. It's really important and an active area of research. I think for patients, it's really hard to think about getting back on a treatment program. Like, gosh, I just finished chemotherapy. I want a break, but we try to be respectful of that, but also balance that with trying to prevent relapse.

(37:07) And just as a final word, age alone is not a factor, but the health status, functional status are key markers of success. So I think with that, we have some time for questions and I really want to thank you for your attention.

Question & Answer Session

(37:29) [Mark Spina]   Thank you, Dr. Meyers, that was an excellent presentation. We will now take questions. And as a reminder, if you have a question, please type it into the chat box in the lower left hand corner of the screen. We do have a number of questions. We'll try to get as many as possible.

So our first question. Are transplant survivors still considered immunocompromised even once off immune suppression meds like steroids.

(38:03) [Gabrielle Meyers]   I think that's an excellent question, especially in this day and age. There are a number of features that do impact the quality of the immune system after transplant. And one of them is not only the drugs that you were exposed to, but also for how long. So I have some patients that may have had a short course of steroids, and if we look at their immune system after they're off the steroids, their immune system may recover to near full. And I do have patients that were on steroids for a long time and their immune system has not recovered even years after being off steroids. So there are a number of features that do impact an individual's quality of their immune system. And there are tests that we can do to try to understand that.

(38:56) [Mark Spina]  Great. Next question. What is considered a cured AML patient and when considered cured, is there still a risk of relapse?

(39:09) [Gabrielle Meyers]      So that's an excellent question. The first year to year-and-a-half after transplant is the highest risk period for relapse to occur. And so as we hit that one-year point, we're very excited. As we hit the one-and-a-half-year point, we're even more excited. Two years, great. But we do know that even after that point, it's under 5% of patients, but we unfortunately can see later relapses that occur after transplant. So that first year to year-and-a-half is a key time period where most of our relapses will occur if they're going to occur, but unfortunately leukemia can be sneaky and it can come back even after two, three, five plus years post-transplant, but it's very uncommon to occur that late.

(40:19) [Mark Spina]      Next question. What's the difference between MDS and MPN?

(40:27) [Gabrielle Meyers]      So MPN is myeloproliferative neoplasm. So that's typically where the bone marrow cells are focused on making too many cells. And oftentimes it's too many of one type of cell at the expense of other cells. So a disease like polycythemia vera or myelofibrosis, where we may see excess cells in the bone marrow and excess cells circulating, but these patients might have low blood counts in some of the other cell lines. So they are different diseases than myelodysplastic syndrome for the most part. And they are rarer than myelodysplastic syndrome overall.

(41:22) [Mark Spina]      Thank you. I am 59 years old and had a stem cell transplant two years ago for MDS AML, an allogeneic donor. In case of relapse before 70 years old, would you consider a second attempt at a transplant?

(41:45) [Gabrielle Meyers]      So if somebody has relapsed after transplant, there usually are a couple of treatments that we pursue. One is that we first want to get that disease back into remission. The second piece is that we know we need to get some more immune system activity to keep that disease in remission. And sometimes that involves a boost where we'll actually give more cells from the original donor, and sometimes it involves having a whole second transplant. So there are a number of features that help us decide which would be best for an individual patient, but it doesn't always have to be a second transplant. Sometimes we can boost the first transplant successfully.

(42:46) [Mark Spina]      I am a 71-year-old non-Hodgkin's lymphoma survivor, four year and three months post-transplant. Do I have a higher risk of the disease coming back as I get older?

(43:04) [Gabrielle Meyers]      Well, because you're so far out from transplant, I would say that your risk of the disease coming back gets lower over time. And I'm happy for you being at this time point after transplant.

(43:31) [Mark Spina]      Okay. Can a healthy 75-year-old woman with myelofibrosis have a transplant?

(43:41) [Gabrielle Meyers]      So that's a very good question. And like the MDS and AML, when I talked about risk features, with myelofibrosis, which is one of those myeloproliferative neoplasms I talked about earlier, there are risks features with myelofibrosis that help us to decide whether transplant is beneficial now or not. And so this would be a discussion to have with your physician and talk about your disease in particular, because you may be someone that could benefit from a transplant. And again, age alone wouldn't be a reason to not pursue that.

(44:31) [Mark Spina]      Okay. What is the data to support the use of maintenance therapy in MDS after transplant?

(44:41) [Gabrielle Meyers]      That's a very good question. And this is an evolving field, because we're just starting to learn the right doses of these agents. And there are agents that we're expanding our knowledge of understanding how they can help reduce relapse. For patients that haven't had drugs like azacytidine or decitabine before transplant, we know that there are some studies that are coming out, looking at those that get those drugs after transplant. [They] have evidence of reduced relapse, but it's a growing field because we're just gaining more and more experience. So some of the literature that's out there is smaller trials right now.

(45:42) [Mark Spina]      Can you speak about patients with MDS or AML due to prior treatment for non-Hodgkin's lymphoma?

(45:53) [Gabrielle Meyers]      Yeah. So this is what we call treatment related MDS or treatment related AML, and that is a high risk type of MDS or AML, because it came out of being exposed to chemotherapy, so it's harder to kill with chemotherapy. These are patients that, when we're faced with them, we universally want to pursue transplant if they're otherwise candidates for it, because these are high risk diseases that otherwise don't respond well to therapy for the long-term.

(46:44) [Mark Spina]      Do older patients get more graft-versus-host disease than younger patients?

(46:49) [Gabrielle Meyers]      So that's a really good question. And in short, the answer is no, but we do know that the way that we do the transplant, as far as the chemotherapy, which we sometimes combine with low dose radiation therapy, that chemotherapy we give as part of conditioning for the transplant, that does impact the development of graft-versus-host and the timing of developing graft-versus-host. So age of the patient doesn't impact graft-versus-host risk. But we do know the conditioning can impact the timing of graft-versus-host disease.

(47:50) [Mark Spina]      How often do AML survivors need bone marrow biopsies?

(47:58) [Gabrielle Meyers ]     And that's a good question. And that's going to depend a little bit on your institution. Our practice is that first year, which has that highest relapse risk time, we do a bone marrow biopsy four times in that first year, at day 30, day a hundred, around six months, and then at one year. Typically if things look good after one year, we won't repeat bone marrow biopsy. If there are concerns, we might repeat it on three to six month intervals until things are looking better. So that first year is our most frequent time for doing bone marrow biopsy. But typically after that year to year-and-a-half, then we won't do them routinely, only if needed.

(48:52) [Mark Spina]      Do you use hypomethylating agents prophylactically after transplant or only after you see evidence of MRD?

(49:05) [Gabrielle Meyers]      So in patients that have disease that's very high risk for relapse, we are using hypomethylating agents, even if they don't have any MRD after transplant. So in some of our patients that have high risk features, that even with them being negative on those post-transplant bone marrow biopsies, we'll still talk and consider hypomethylating agents to do what we can to reduce relapse because their relapse risk is so high otherwise.

(49:40) [Mark Spina]      If you have been diagnosed with AML and had a successful transplant, can you then develop MDS?

(49:54) [Gabrielle Meyers]      So that's a very good question. And typically the answer is no. There is a very rare type of MDS that people can get after transplant, where it's actually an MDS from the donor. And the donor cells develop MDS because of the stress of being a donor. But that is something I would not worry about. It's very uncommon. But otherwise, if somebody has a transplant for AML, then they don't get a new MDS after transplant. I have had patients, and this is just a couple of patients in my hundreds of patients experience, where they had an AML was how they presented. And we didn't discover that they had an underlying MDS until we saw it start to come back after transplant. So that can be the time where a hidden MDS may present itself after transplant. But again, that's very rare overall.

(51:09) [Mark Spina]      What is the role of CAR T for relapse of AML following transplant?

(51:16) [Gabrielle Meyers]      So that's a great question. And the CAR T world is starting to move into diseases like AML. And so right now I don't have an answer because the CAR T world and treatment world is kind of in its infancy for AML and post-transplant management, but very exciting. And I'm very hopeful that we will have a lot of different uses for CAR T for AML before and after transplant.

(51:57) [Mark Spina]      Have there been any studies or anecdotal evidence on the role of primarily plant-based diet to help with outcomes and preventing relapse?

(52:10) [Gabrielle Meyers]      So that's an excellent question. And I had not seen any data about this specific to relapse, but this is something that really is being studied and looked at in a variety of places. And we do know that there are health benefits to a primarily plant-based diet. And so I think that we also know that diet impacts our bacteria in our intestinal track. That's going to impact that new immune system in the setting of transplant. So this is an area that's ripe for research, and I hope that we'll start to see some studies about this, but we don't have any yet that I know of.

(53:02) [Mark Spina]      We're coming towards the end of our session here, but we'll try to get one or two more in quickly. Can you comment on clinical trials? When should I look into one?

(53:15) [Gabrielle Meyers]      I am a big fan of clinical trials, because many clinical trials are designed to either give you what we know work or give you something that might be better. So I think that clinical trials can be a real benefit to patients, and we try to have a clinical trial available for every patient that's going through this process, whether it's at their diagnosis, at the time that they need treatment, at the time of transplant... So I'm a big fan of clinical trials, and it's an area that we're really trying to focus on getting patients that are older on clinical trials, because that's a population that's not well-represented in clinical trials currently.

(54:15) [Mark Spina]      And we'll take one last question. What about reduced intensity transplants? Can you explain what they are and should I do that instead of a regular transplant?

(54:27) [Gabrielle Meyers]      So again, a very good question. The idea behind reduced intensity transplant is that the chemotherapy that we use as conditioning, getting your body ready for transplant is not at that hundred percent level, but less than a hundred percent. And we can go everything down from 90% to 10%. It's fascinating that it actually takes very little chemotherapy and radiation to make a transplant work, but in the setting of using very low intensity chemotherapy and radiation for transplant, your problem is disease coming back. So you have to balance getting enough chemotherapy to make the transplant work, enough chemotherapy to control the disease, but trying to not give too much to cause toxicity to the body. And so reduced intensity transplants, the ability to use those effectively has opened up the world of transplant to patients over the age of 60, because that maximal dose of chemotherapy, that hundred percent chemotherapy can be too hard for many patients over the age of 60. So there's a real advantage to reduce intensity transplant.

(56:06) But for every individual patient, we know that we want to give as much as we can, because there was a clinical trial that involved people under the age of 60 with AML and MDS. And they were randomized to get a full, that hundred percent or a reduced intensity regimen. And those that got the reduced intensity regimen did have an increase in relapse risk. So we do know that the amount of chemotherapy with a transplant is important in controlling the disease, but we also know that there are increased toxicity associated with it. So every patient, we factor in those features to decide the best regimen for that individual. So that's a discussion that you would want to have with your transplant physician.

(57:03) [Mark Spina]     Closing. On behalf of BMT Infonet and our partners, thank you, Dr. Meyers for your very helpful remarks. And thank you, the audience, for your excellent questions.