Transplant Options for Patients with Acute Myeloid Leukemia (AML)

Presenter: Olga Frankfurt MD, Robert H. Lurie Cancer Center at Northwestern Feinburg School of Medicine

This is a recording of a July 24, 2019 webinar titled: Transplant Options for Patients with Acute Myeloid Leukemia: Before, During and After Transplant

Presentation: 60 minutes, Q&A: 15 minutes

Summary:

In this webinar you will learn:

• which patients with acute myeloid leukemia (AML) should consider a stem cell transplant
• criteria used to select the best stem cell donor for a patient
• what's involved in undergoing a stem cell transplant
• side effects that can occur after transplant
• new therapies for patients who are not eligible for a stem cell transplant

Many thanks to Astellas and Jazz Pharmaceuticals whose support, in part, made this webcast possible.

Transcript of Presentation

00:00:01  Introduction: Good Evening. My name is Sue Stewart and I'm pleased to welcome you to tonight's webinar, "Transplant options for AML Patients." What you need to know before during and after treatment. I am very excited to night to hear what our speaker will be covering, and I am an AML survivor and a 30 year transplant survivor. So I'm anxious to hear about all of the new advances and what you need to know in order to prepare for transplant. I'd like to thank and acknowledge the support of Astellas Pharma and Jazz Pharmaceuticals whose donation has helped make this webinar possible this week in presentation. So now it's my pleasure to welcome our guest speaker tonight, Dr. Olga Frankfurt.

00:00:47  Background of Dr. Olga Frankfurt: Dr. Frankfurt is associate professor of medicine at the Northwestern University Feinberg School of Medicine, in Chicago. She's also an oncologist hematologist at Robert H Lurie Comprehensive Cancer Center, where she serves as co-director of the Leukemia program and the director of the umbilical cord blood program. Dr. Frankfort received her medical degree from the University of Chicago Pritzker School of Medicine and has over 20 years of experience conducting research and providing clinical care for patients with acute myeloid leukemia. Please join me in welcoming Dr. Frankfort.

00:01:28  Outline of points covered in presentation: Good evening everyone. Thank you for being here. I imagine majority of people here are not joining this conference as an intellectual curiosity. I presume that most you or people you care about are diagnosed with acute leukemia, and you are trying to make sense of this disease and trying to decide whether stem cell transplantation is an appropriate modality.

As you might imagine, leukemia and a stem cell transplant is a very large topic and one can talk for hours about each of them. So, what I've decided is to do is organize the presentation in the following manner.

I will talk a bit about acute myeloid leukemia, explain different subtypes of acute myeloid leukemia and highlights the ones that require, or at least in our opinion, requires stem cell transplantation.

We will talk about some basic functions of the stem cell transplant. Why we do it. How we do it. How do we choose the donors. How do we decide who is the right patient for stem cell transplant, and talk about factors that we think predict a favorable outcome.

I'd like to tell you a couple of things. First of all, this presentation by no mean is intended to be a substitute for a detailed discussion that you should have with your leukemia physician. However, I would like to provide some framework to help you understand how the doctor thinks, and how we make our decisions, and also to provide, hopefully, a list of questions that you can ask your doctors.

Because of the complexity of the subject, just assume that, for every general statement I make, there are likely to be exceptions.

00:03:30  Be careful how you interpret statistics: Another important point is statistics. Statistics can be a very dangerous tool and it's important to remember that when I quote you percentages I cannot tell you about you, but I can tell you about a hundred patients like you. And so the statistic applies not to an individual patient, but to a group. So when we talk about medians, you have to remember that 50% of patients do better and 50% of patients do worse. So we have to be very careful of how to interpret percentages.

00:04:07  Information about AML is evolving and two doctors may have different ideas about the best treatment: It is also important to remember that information is evolving, and what is relevant today might not be relevant, or would be less relevant, a year from now. Another point I'd like to make is that there's science and there's art of medicine. I mean one would imagine that the majority of the leukemia and transplant physicians read the same information, go to the same meetings and know exactly the same information, but, our practice is colored by our own experiences and probably some personal things. Don't be surprised if you go and ask for a different opinion at different centers; you may get a slightly different answer.

00:04:52  Acute myeloid leukemia is a bone marrow disorder in which abnormal cells accumulate in the bone marrow: With all those caveats, let's begin. So, what is acute myeloid leukemia? Acute myeloid leukemia is the bone marrow disorder characterized by accumulation of abnormal leukemia cells in the bone marrow. So basically, the leukemia cells are cells that stop the normal process of differentiation. They are unable to become a normal cell and they populate the bone marrow, preventing other normal cells from developing. So when patients die from leukemia, they usually die from the bone marrow failure consequences above normal bone marrow.

00:05:34  Acute myeloid leukemia is not a single disease, but many different disorders that behave in a completely different fashion: But, this pretty much is where the similarity in acute leukemias ends, because acute myeloid leukemia are many different disorders that behave in a completely different fashion, and this is probably the most important point of this conversation.

00:05:52  Treatment of acute myeloid leukemia depends of the subtype: When I get a phone call from a friend of mine asking me, "How do I treat my elderly aunt with acute myeloid leukemia?, I'm not able to answer this question, because I need to know which specific subtype of acute myeloid leukemia that patient has, and that determines what kind of treatment we can offer.

So as an example, here the 25-year-old patient with low white count and severe bruising throughout his body and abnormality of chromosome on 15 and 17 will likely have acute promyelocytic leukemia, which has over a ninety percent chance of being cured with minimal, if any, amount of chemotherapy. While the 25-year-old with very high white count , gum infiltration with leukemic cells and FLT3 molecular abnormalities will likely require a stem cell transplant in order to be cured of this disease. So completely different disorders. Both of them leukemia, but, based on the molecular characteristics completely different diseases.

00:07:01  How normal blood cells develop from a blood stem cell: This is a simplified version, not incorrect, but a simplified version of what is happening in leukemia development. If you may imagine, there is a stem cell and that blood stem cell has two major functions. It's able to self-renew, and it's able to differentiate into a different cell. And that the blood stem cell can become myeloid or lymphoid stem cells. The myeloid stem cell gives rise to all myeloid cells in the bone marrow. It gives rise to the red cells to the platelets, to the myeloblast, and to the finally differentiated wide variety of white cells. Let's concentrate on that since we're talking about acute myeloid leukemia. So somewhere in this process of development the differentiation stops, so cells do not develop any further, and as I already mentioned, they populate the bone marrow with those abnormal ugly-looking leukemic cells and no additional normal development of cells occur.

00:08:07  Pictures of leukemia cells: And this, just to give you a picture, this is what the leukemia cells look like. They're a large, tend to be large, they have a large nucleus with many nucleoli, and normally, if you look at the bone marrow, it has all kinds of cells in there, many different cells. But, if you look at the bone marrow core biopsy that I gave you here in the picture, it looks very monotonous. And the reason it looks monotonous is because all of those cells, all leukemia cells, the bone marrow is effectively replaced by the leukemia cells.

00:08:42  21,000-25,000 people are diagnosed with AML in the U.S. each year: So acute myeloid leukemia, I guess, is an uncommon disorder. Between 21,000 and 25,000 patients are diagnosed each year in the United States, and as you can see, unfortunately, ten to eleven thousand patients die each year from this disease. So it's a highly lethal disease.

00:09:03  Acute myeloid leukemia is primarily a disease of older adults: This graph, this next slide, demonstrates that acute myeloid leukemia is a disease of older adults. As you can see, the number of new cases are particularly prominent in patients in their 60s and 70s. And as you can also see on athe second graph, the survival is inversely related to age.

00:09:28  What doctors look for when evaluating an AML patient for treatment: So when a patient with acute leukemia comes to the hospital or clinic, a lot of things need to happen very rapidly. At the beginning we would like to do a history and physical exam to determine how healthy the patient is, and what other medical problems the patient has.

00:09:57  It's important to know if acute myeloid leukemia is a new disease or the result of a prior blood disorder: Several important things that we try to ascertain when we evaluate the patient are: Do we think they have a prior bone marrow disorder, or this is a new acute leukemia? So I usually like to look at the blood counts done, you know, a month ago, three months ago, a year ago, to see if I notice any abnormalities in the blood counts to suggest that maybe there is a prior bone marrow disorder. Because we know that acute myeloid leukemia. what we call de novo acute myeloid leukemia - it showed up from nowhere, has a different behavior than acute leukemia that arose from the prior bone marrow disorder like MDS, myeloproliferative disorder. We're looking to see if the patient has an enlarged spleen which also may suggest a prior bone marrow myeloproliferative disorder

00:10:46  Acute myeloid leukemia due to prior exposure to chemotherapy or radiation are treated differently than other types of AML: And we also want to know if a patient had other cancers and has been exposed to chemo or radiation because, again, secondary acute myeloid leukemia - acute myeloid leukemia arising due to the prior exposure to chemo radiation - has a different behavior and may be treated differently.

00:11:06  Need to know patient does not have any other serious problems before going to transplant: We obviously want to make sure the patient is stable because if the white count is very high, that by itself it can be a problem, as those large ugly blast cells can plug up the small blood vessels and people can have strokes and heart attacks and kidney dysfunction. So we need to make sure that patient is stable right away.

We also do an aggressive infectious workup first of all, to make sure that they don't have active infection and that once we start treatment, we need to make sure that if they do have an infection, that we have it covered with antibiotics. We begin evaluation of the patient by looking at the peripheral smear, because right now we're talking about acute leukemia, but when a patient comes into with a high white count, we don't know if it is acute myeloid leukemia, acute lymphoblastic leukemia or some other chronic disorder in the blast phase.

00:11:59  Bone marrow biopsy is needed to determine how best to treat the patient's acute myeloid leukemia (AML): So, we begin evaluation with a [blood] smear, which is usually followed by a bone marrow biopsy. We always, always, always want to do a bone marrow biopsy to look. So we do morphology, core flow cytometry, cytogenetics ,which is a chromosomal analysis, as well as molecular analysis. And while, in the old days, all of that information would come later, right now I would like to have all of this information right at the beginning, because that will determine or may determine how I will treat the patient. In our institution, risk assessment for stem cell transplantation literally begins at the time of the diagnosis, because it takes a long time to prepare for the stem cell transplant. So for any patient whom we would potentially consider as a stem cell recipient, we begin insurance approval and donor identification because that process, as I said, takes a long time.

00:12:57   Many patients with acute myeloid leukemia (AML) require psychosocial support: Psychosocial support is required for many patients, obviously, because suddenl,y you know, they probably came in with a little infection, a little not feeling well, and they are being told that they have this life-threatening illness. So all kinds of psychosocial support is required.

00:13:14  Fertility preservation can be done for some patients prior to treatment: For younger patients, we do fertility preservation.,We're, usually not able to do it for female patients because it takes some preparation and takes time and most of the leukemia patients cannot wait. However, male patients typically can wait a day or two, and we do fertility preservation for them.

Then you need to evaluate all of those things that I have just listed, and discuss with the patient standard of care therapy that we think is the best for them, and also consider a clinical trial if some novel and interesting therapy is available. So again, as I said the first couple days again very hectic.

00:13:56  Factors that predict the outcome for patients with acute myeloid leukemia: This slide demonstrates our approach to acute myeloid leukemia. So, prior to the 1980s, when the only thing we had was a microscope, the factors that were very important in determining the prognosis of patients with acute leukemia were age, performance status - how healthy they are - high white blood cell count, and presence of a prior bone marrow disorder. Now, although those factors are old they're, still they still fairly relevant, so age continues to be a very important prognostic indicator of outcome. Performance status as well. White count is less important at this time. Having a prior bone marrow disorder also continues to be very important.

In the 80s and 90s, we began to understand the recurrent chromosomal abnormalities that very strongly predict the outcome. And based on a specific set of genetic signatures, patients were divided in the favorable, intermediate, and unfavorable risk categories, and their treatment would be determined by that group. Now, the initial treatment was exactly the same for all this all three category, but patients with intermediate and unfavorable risk were recommended to have a stem cell transplant, while patients with a favorable risk had a reasonable chance of being cured with chemotherapy alone.

In the 90s and 2010, we began to understand that the presence of certain molecular abnormalities, even in patients who had normal chromosomes, also determined the outcome and behavior of the disease. At that time those molecular abnormalities were not targets, although now they are. So not only do those molecular abnormalities predict the outcome, they also become a target for the drugs that are currently FDA-approved, and many, many drugs that are currently in clinical trials.

Since 2010, use of next generation sequencing has become a standard practice and it's understanding of a presence of families of molecular abnormalities that determine the personality of the disease. So this slide, again, highlights the evolution of our understanding of acute myeloid leukemia.

And this is just an example how we viewed the risk of acute myeloid leukemia based on chromosomal abnormalities. So acute promyelocytic leukemia, characterized, by the abnormality of chromosome 15 and 17, again, nowadays, is being cured with ATRA arsenic and maybe small amounts of chemotherapy in the majority of cases.

00:16:41  Cytogenetic risk groups for patients with acute myeloid leukemia (AML): Acute myeloid leukemia with inversion 16 and 8, 21 chromosomal abnormalities are considered to have a favorable disease, so called core binding factor acute myeloid leukemia. Patients who have abnormal chromosomal abnormalities are considered intermediate risk. And then the patients with unfavorable cytogenetics are patients who have at least three or more chromosomal abnormalities, as well as patient patients with other abnormalities involving chromosome 5, 7 inversion 3, 17p, etc.

And this to show you, this is not just empty words. The incidence of relapse and overall survival are directly related to the cytogenetic abnormalities. So, as you can see, patients with adverse risk disease pretty much are guaranteed to relapse. This is a risk of relapse and overall survival is very low. While patients with favorable risk disease, although not a guarantee of cure, have a pretty reasonable chance of being cured.

00:17:56  Not every high risk acute myeloid leukemia is equal: Further, we realize that not every high-risk disease is equally high-risk. So, for example, this graph shows the survival of the patient. So these are core binding factor leukemia patients, those who have favorable risk disease. This is patients with intermediate risk, or normal karyotype, and those two graphs are the patients with high-risk cytogenetics.

But you can see that if they have something, that's called monosomal karyoptype - I'll define it in one second, -they do really terrible. And patients who have other high-risk features do almost as well as patients with normal karyotype. Again, my point being is that you need to know what kind of disease you have, so you can decide whether stem cell transplant is important for you. So monosomal karyotype, for those who want to know , is defined as at least two autosomal monosomies, so dilution of chromosome, 7 and chromosome 5, so the whole chromosome is missing, or defined as one of those chromosomes is missing and there two other structural chromosomal abnormalities present. So that's the definition of monosomal karyotype.

This is just to highlight that our understanding of acute leukemia is evolving, and evolving very rapidly, and this just shows the family of the molecular abnormalities that are present in patients with normal chromosomes right. So chromosomes are normal, considered intermediate risk, but based on the presence of many molecular abnormalities, those diseases are going to behave in a very different manner and I will show you in the next slide.

So if you look only at the patients with intermediate risk disease, chromosomes are normal. And then us[ing] eight molecular abnormalities, we're able to break those patients into three categories, based on the molecular abnormalities that they have, and you could see the survival. Those patients do very well. Favorable risk, probably as good or better than patients with favorable chromosomes. And those patients are not doing well at all and they all have normal chromosomes.

So, for example, FLT3 -NPM1+ disease is considered to be a favorable high risk disease, while the FLT+ disease, with addition of some other molecular abnormalities, is considered to be a very high risk disease.

00:20:38  Molecular abnormalities in acute myeloid leukemia (AML) occur in  groups: This is just to show that we now understand that those molecular abnormalities do not occur independently. Many of them like to occur in specific families of mutations. So the width of this curvature shows how common the mutations are present in acute leukemia. So, for example, you could see FLT+ abnormality is quite common, that acute myeloid leukemia MPN1 is common in acute myeloid leukemia. CEBPA is common in acute myeloid leukemia. p53, for example, is five to ten percent of patients who would have an acute leukemia and the width of the band to show how much those two mutations like to occur together.

So, for example, FLT-3 mutation loves to occur together with MPN1 mutation. This is just to highlight the complexity of our world right now and it's only going to continue to become more complicated. This is based on the most recent NCCN guidelines, risk stratification of the patient, based on the cytogenetic and molecular abnormalities. And I certainly have this slide available for you if you'd like to look at it in detail ,and we can discuss it at the end of day at the end of the lecture, if you like.

00:21:58  Molecular abnormalities not only predict outcome, but are the target for new drugs: Again why is this relevant? So I just listed the most common molecular abnormalities that that we test for. Not only do those molecular abnormalities,predict the outcome, but they also become a target for novel drugs.

So, for example, FLT-3 mutation, although it has a negative prognosis, it has two FDA-approved drugs available today,. There are five or six currently in clinical trials. So, now we test for it because we have drugs available for it, and I need to know whether this mutation is present at the time of the diagnosis so, it can give the patient the best treatment available.

The same thing for IDH1 and IDH2 mutation. While they're not particularly strong predictors of the outcome - depending on the literature you look at, some consider it favorable and some consider it not favorable - however, there are several FDA-approved drugs available for treatment of IDH1 and IDH2 positive disease. TP53 mutation, although not common, is always associated with a very high-risk disease, and now there are drugs in clinical trials that hopefully will be able to fight against this mutation.

00:23:29  There were no new significant drugs developed to treat acute myeloid leukemia until 2017: So this is the trajectory and the timeline of the therapy that is available for acute myeloid leukemia. As you can see, for many years, giving this kind of presentation on the treatment of acute myeloid leukemia was very easy. Not much was changing.

As you can see, in the 70s, bone marrow transplantation became kind of the standard of care. In the earliest 70s intensive chemotherapy, so-called 7+3 - so many of you probably received this kind of chemotherapy. It's daunorubicin given for three days and cytarabine given for seven days, and that's why it is called 7+3. And there are many other similar induction chemotherapies, but, as you can see, over the years, nothing was proven to be better than 7+3. We worked with the optimal dosing, optimal weight of administration of the drug, but until 2017 there was really nothing new that was FDA-approved for treatment of acute myeloid leukemia.

In 2017, finally, this cumulative information about the nature of the disease and presence of molecular abnormalities finally translated into the development of new drugs. So in the last two years we have what - 1 2 3 4 5 6 7 8 9 drugs FDA-approved for treatment of acute myeloid leukemia, and this is just the tip of the iceberg because, as you might imagine, many clinical trials are going on trying to improve further on those treatments.

00:25:12  What is the therapy for acute myeloid leukemia? So in general, acute myeloid leukemia is not a disease that can get better by itself. Without treatment, patients will die from this disease, and the disease can behave differently.

Sometimes I meet a patient with a new diagnosis of acute leukemia and I will not let them go home because they need to begin therapy as soon as possible, sometimes even before I know everything about their disease, because the disease is so dangerous. And some people I can send home for a week or two until I figure out everything about their disease because their disease is very slow progressing and very stable.

00:25:52  The goal of therapy is to first obtain a remission. Remission is a state, when I look at the bone marrow, when I look at the blood, I have no evidence of acute myeloid leukemia. And then the second step, you want to convert this remission into cure. How do you do it? That's the big question, whether it is with additional therapy or with a stem cell transplant.

00:26:17  Oral drugs that have been approved by the FDA in the last two years for patient with acute myeloid leukemia have changed treatment strategies: Our novel therapy, our oral targeted drugs that have received FDA approval in the last two years, totally change our view of acute myeloid leukemia. Prior to this, with chemotherapy, you either get people in remission and they don't have the disease, and maybe then they have a chance at normal life. And if they do have the disease, they do not have any chance of anything normal because they will die from the disease progression.

Now, with those oral targeted therapies, there is a paradigm shift. Our patients are taking the pill, they still have a little bit of disease in their bone marrow, but many of them have good quality of life. They're transfusion-independent, and while the pill is working, they continue to live a reasonably normal life. So then, again, that is all changing.

00:27:12  Therapy for patients with acute myeloid leukemia who are otherwise healthy: So patients with acute myeloid leukemia - I specifically said fit patients and, I didn't say young patients right, because our approach to older patients who are fit and healthy is similar to young, fit patients. So for fit patients, we typically use induction therapy 7 + 3, or something similar to that, to get them into remission.

Now, another important point is the depth of their remission. Again, in the old days when we used to have a microscope, the only way we could define a remission is by looking into the microscope and seeing there's leukemia there or not. Then we realized that even in those patients where we visually do not see any leukemia in the bone marrow, when we do cytogenetic testing and molecular testing, we still find disease there. So, it's very important to achieve a remission that is very deep, [what] we call MRD negative measurable residual disease, MRD. So basically, based on all the tests available to us, we have no evidence of the disease, and that's ideally what you want to achieve.

And then the second step, as I said, we would like to convert the remission into cure. How do we, do that? Well, realistically, two options: we either do chemotherapy or we do a stem cell transplant. And again, patients with favorable risk disease, they have good chance of being cured with just chemo alone. Those people will get chemotherapy. Patients with intermediate and higher risk disease likely require a stem cell transplant. For patients with very high risk disease. I usually like to employ a low dose maintenance to prevent the disease from coming back.

This is the graph demonstrating the importance of what I just said: measurable residual disease. So these three curves show the incidence of relapse for three categories of patients. These are the patients who do not have any evidence of disease, by all the tests available to us today. In the red line you see patients with active, acute myeloid leukemia. And in this, I think, black line, we see patients who have no visible evidence of disease, but they have evidence of disease by other,more sophisticated methods. And you can see the patients with active disease and so-called MRD+, pretty much do the same, and only patients who have very deep remission have lower incidence of relapse.

00:29:54  Treatment options for acute myeloid patients who are not eligible for transplant: So what do we do for patients who are either old and frail or who have many medical problems that preclude intensive therapy? Well, we still would like to get them into remission, right, some more intense chemotherapy - not aggressive chemo - but some form of chemotherapy possibly can get them into remission. And if we do that, then they can enjoy a meaningful period of life with normal counts and normal quality of life. We 're unlikely to cure them, there's always exceptions, but we're unlikely to cure them with the treatment. But again for a period of time, life can be normal.

We typically utilize, as I said, low intensity chemotherapy, hypomethylating agents and drugs that are FDA -approved for the treatment of MDS, such as Vidaza and Dacogen, and now all those targeted therapies that just received an FDA approval, for example, combination of Venetoclax with either Vidaza or Dacogen or even low dose cytarabine, as well as targeted therapies like FLT 3 inhibitors, IDH1 inhibitors, and IDH2 inhibitors.

Clinical trials are important to consider for patients with acute myeloid leukemia: Although I refuse to wear this little sign saying "ask me about clinical trials", I do believe that clinical trials are very important. And the reason I personally stay in academic medicine is so I'm able to give my patients options that they don't have access to in a regular clinical practice.

Alright. So, in summary, some with acute myeloid leukemia have high likelihood of being cured without stem cell transplant. Some, we know for sure cannot be cured without a stem cell transplant and some can be cured without a stem cell transplant, but stem cell transplant increase the risk of cure and those are probably the most complicated patients to decide on the stem cell transplant. Because of the risks of transplantation itself, so you need to know what kind of acute leukemia you have so you can properly decide what the transplant is for you.

00:32:09  What is the difference between a bone marrow and stem cell transplant: All right, now talking about stem cell transplantation. So the first question that usually comes up is, "Am I doing a bone-marrow transplant, or am I doing peripheral stem cell transplant and what is the difference?"

So the principles are all the same. It doesn't matter. The bone marrow versus peripheral stem cell refers to where we get the stem cells from. So, in the old days the only way we knew how to get a bone marrow cells or stem cells would be to take the donor to the operating room, put them to sleep and then do enumerable effectively bone marrow, biopsy aspirating the aspirate, the stuff inside the bones and collecting it and administering it to the patient.

Later, we figured out if we give a donor growth factors, that will stimulate the bone marrow production of the stem cells and then we're able to collect on those stem cells from the peripheral blood. So typically for acute myeloid leukemia, for adults, we would usually do a peripheral stem cell transplant collection. For pediatric patients the bone marrow collection still is the standard and there are reasons for that. Slightly lower risk of graft-versus-host disease, but again for most adult patients with acute myeloid leukemia, the [cells are] going to be collected from peripheral blood.

00:33:33  What can a stem cell transplant do for patients with acute myeloid leukemia that standard chemotherapy cannot? So why transplant: what can the transplant do that the chemotherapy cannot do? Well, those donor cells, they're smart. They find their way into the patient's bone marrow and they replace it, repopulate it with normal cells. That's first thing.

Second thing, [and] it's probably the more important one, it is able to recognize whatever leukemia is lurking here and kill it. And that's called graft-versus-leukemia effect and that's effectively the main reason to do a stem cell transplant.

00:34:05  What is graft-versus-leukemia effect? Again, graft-versus-leukemia effect, right. So the donor cells make new blood, new bone marrow, a new immune system. And that new, healthy immune system does [what a] normal immune system is supposed to do, which is recognize cancer cells and kill them. And that's the reason for a stem cell transplant.

00:34:24  There are two types of stem cell transplants - autologous and allogeneic: So there is autologous stem cell transplant and allogeneic stem cell transplant. For the purposes of this discussion, we're only talking about allergenic stem cell transplant, meaning that the donor cells came from somebody else, not from the patient. This may change with a new immunotherapy. The autologous stem cell transplant may come back, but right at this moment allergenic transplant is the standard of care, and that's what we're talking about today.

00:35:00  Source of donors for transplant: Donors can be either related or unrelated. So they could be sibling. They could be a half-matched donor. Nowadays, we're doing pretty well with those haploidentical stem cell transplants. It could be a sibling, who's half-matched - a child or parent - or there could be an unrelated donor perfectly matched unrelated donor.

Other unrelated donor could be umbilical cord blood transplants, which are also pretty much a standard of care at this time. So not every patient has a perfectly matched unrelated donor or sibling. And so the umbilical cord blood transplantation - there are donor registries where we can select umbilical cord blood for transplant - we typically do two at a time for adults, and the outcomes are improving and they're pretty close to the matched, perfectly matched unrelated donors.

00:36:07  The number of stem cell transplants for acute myeloid leukemia are increasing in the U.S.: Those graphs just show you the statistics of what has been happening in recent years in the United States. And, as you can see, the trend in transplantation for acute myeloid leukemia is growing. The number of patients being transplanted is growing.

The second graph demonstrates that, although there are a high number of transplants being done in the United States for all the patients and for younger patients marked in blue, the proportion of patients receiving a transplant who are 60 to 70 years old, and even patients who are over the age of 70, is also increasing. And there are many reasons for that.

We are better at taking care of complications. We are better at finding a perfect donor. Our ability to test for the donor is more sophisticated now, so the rate of complications is less. And we are able to get more and more patients into a complete remission. So that that is why we do more stem cell transplants in all patients and in older patients as well.

00:37:16  HLA type is important when selecting a donor for transplant: Alright, so what are we matching for? It's not the blood type that we care about all that much.

There are several genes on chromosome six that are called the HLA region - human leukocyte antigen. And those are genes are responsible for rejection and engraftment. And that's what we are testing for. So we are looking for the A, B, C and DR and DQ - those are the most important genes that we want to match the donor for.

For an unrelated donor we want to have a 10 out of 10 perfect match. For a sibling donor, we want to have six out of six. The point being, is if you're matched for six you're going to be matched for the other one. So it's effectively the same as a ten out of ten match.

Umbilical cord blood, because it's more immature, it allows [us] to do a successful transplant with less matching. So, we can do four out of six matches from umbilical cord blood and have a good outcome right now. There are many clinical protocols ongoing doing a combination of haplo and cord stem cell transplantation. There are many expansion protocols trying to make the umbilical cord unit bigger, so give more cells. There's a reason to do that and I'll be happy to discuss it once we're done with this presentation.

00:38:48  Factors other than HLA-type considered when choosing a donor: So how do we choose the donor? As a general principle, we would also always choose a younger versus older donor. Everything else being equal, I would prefer a male donor versus female donor without children. And the least favorite is a female donor with multiple pregnancies, the reason being is the higher risk of graft-host-disease if the donor is a female with multiple pregnancies.

Ideally, if I have options, I would like the donor and the recipient to have the same CMV status. Cytomegalovirus is a virus that many of us have been exposed to, and it causes no problem as long as we are not immunocompromised. Once we get immunocompromised, the CMV can get reactivated and cause significant toxicity.

Again, if I have a luxury, I would pick the donor with the same blood type, but it's not essential. And every stem cells program has their own list of criteria, and requirements may be slightly different from one another.

00:39:54  How stem cells are collected from the bloodstream: So this is how collection is done. People have been donors since the 60s and 70, so we know that there is really no long-term toxicity to the donor. The donor gets checked out to make sure that the donor doesn't have major medical problems, and then gets growth factors for a few days to stimulate the bone marrow to make stem cells. They get spilled into circulation and then get collected, and then they could be either be frozen or delivered fresh, and infused into a patient just like a blood transfusion.

00:40:29 Chemotherapy is given prior to transplant:  So, as I usually tell my patients, the process of transplantation itself is the most anticlimactic and boring thing you've ever done. You get some Benadryl, Tylenol, some steroids and then stem cells are going to be infused. So nothing exciting there. The excitement starts afterwards.

Stem cell transplantation always comes with chemotherapy, always. There's no such thing as doing the stem cell transplant without some kind of what we call conditioning regimen, something that comes right before the transplant.

So, in the old days, the only kind of transplant we knew how to do was myeloablative or high intensity conditioning regimen. So high intensity chemo-radiation. That does two things. It knocks out as much leukemia as possible from the bone marrow and also immunocompromises the patient so the patient be able to accept somebody else's immune cells, immune system. It obviously causes a very significant cytopenia and can cause a lot of toxicity.

So I usually tell my patients that all the early toxicity of the stem cell transplant, the toxicity of the chemotherapy, and those of you who had chemotherapy, know exactly what it feels like, you feel weak. You feel tired. You may have mouth sores, you have nausea vomiting. Obviously hair loss, diarrhea, neuropathy, organ dysfunction, etc. So again all the toxicity of chemotherapy. But for younger and fit patients we prefer this approach because, at least up to a point, the higher the intensity of the conditioning regimen, the lower the risk of relapse. Okay, so for patients who are able to tolerate it, we would give them intensive chemotherapy.

00:42:21  Reduced intensity chemotherapy before transplant is an option for some patients: For patients who are older -let's say patients 65 and older, in some centers it's patients 70 and older - you use a lighter conditioning regimen. Since we've learned that that graft-versus-leukemia is the main reason to do a stem cell transplant, we do a lighter chemotherapy, not to get rid of the leukemia, but to immunocompromise the patient, so that the patient will accept the [donor's] stem cells.

So for all the patients, it's very important to be in remission prior to undergoing stem cell transplant, because the outcome for patients transplanted in remission is significantly better. But it's particularly important for people who are older, who are receiving light chemotherapy, because again, we're not relying on that chemotherapy to get rid of the disease. So that's very important.

Again, at our institution, as I already mentioned, the evaluation for stem cell transplantation begins at the time of the of the diagnosis. And I do think it's important for patients to meet with the transplant physician, if it's a different physician than their leukemia doctor, to kind of begin the conversation about the stem cell transplant. To discuss the risks, to identify the donors, because all of that takes some time.

00:43:54  Patient-specific risks factors for patients undergoing a stem cell transplant: So what are the risk factors for stem cell transplantation? So I like to view them as a patient-specific factors and the disease-specific factors. So, for patients, age is important. So, there is a chronological versus physiological age, right? So, there are older people who are marathon runners in the spectacular shape and there are younger people who are morbidly obese and have 15 medical problems. So, it's not purely age, but age and performance status, so the healthier the person is the better shape they're in the higher the chance of success.

We use something called the comorbidity index to predict the outcome. So the comorbidity index is the presence of this list of disorders: arrhythmia, heart disease, gastrointestinal problem, pulmonary problem, psychiatric problems. And the reason it's important is because each patient has, depending on the number of comorbidities the patient has, this is their risk of mortality, so called non-relapse mortality. So patients die from the complications of the transplant, not from a disease relapse.

So if somebody has more than three abnormalities, the risk of death is quite significant. While if the patient has none of them, I mean their risk is not zero, because the risk is never zero, but it's significantly lower. So, obviously we like to take people to transplant who are in a really good shape.

00:45:31  Disease-specific risk factors for patients undergoing a stem cell transplant: So then the risk factor associated with the disease. So just the way things are, we are a lot better at taking care of the disease that is less aggressive. Also, it's very important for patients to be in a remission prior to undergoing stem cell transplant. Sometimes we will take a young patient whom we are not able to get into remission, but you know there's probably also 20% chance that we'll be able to cure such patient by giving him very high dose intensive chemotherapy. But again, as a general principle, we'd like people to be in a remission prior to the stem cell transplant.

It used to be that the type of donor significantly affected the toxicity and even was a major decision whether to do or not to do a stem cell transplant. And nowadays the outcome of double cord stem cell transplant, haploidentical stem cell transplant, matched sibling stem cell transplant, perfectly matched unrelated donor stem cell transplant are similar enough that it's not a major determinant of the risks. There's some, but it's not the major thing.

00:46:49  Other factors important for the success of stem cell transplantation: Another important factor, I think, that determines the outcome is patient compliance. Because things could go wrong in so many ways, so we really need to make sure that patients know their medications, understand why he or she is taking those medications and comply with instructions.

Social support. Patients who are alone versus patients who have a lot of family members able to help them and to bring them to the appointments and to make sure that they eat. Those, unfortunately, are very important factors .

And the experience of the transplant centers. The number of transplants done by centers per year is an important determinant of how well the patients will do, and that's self-explanatory.

00:47:39  Pre-transplant testing: So prior to transplantation, once a decision is made, we do extensive work up evaluating the kidney function and liver function and the heart and lungs. There's a social work consultation to make sure they're in a safe environment. There is a financial consultation to make sure that insurance covers all the important medications. So a lot of a lot of work that needs to be done before.

00:48:06  Possible acute complications from a stem cell transplant: So what are we worried so much about, the complications of the stem cell transplant? As I already said, all the early toxicity of the transplant is related to the chemotherapy. There's something called veno-occlusive disease of the liver that we don't see all that much anymore, but this is a specific liver failure problem that we worry about, but now have medications that are FDA-approved for treatment of this condition. And of course, the biggest issue is a graft-versus-host disease right, acute graft-versus-host disease.

So a moment ago, I told you that the reason for stem cell transplantation is that we want those donor cells to attack the leukemia - the graft-versus-leukemia effect. But sometimes what we get is graft-versus-host disease, when those donor cells recognize you as foreign and attack you, and that's called acute graft-versus-host disease.

00:49:01  Causes of death in the first 100 days after transplant: Just on this slide, I summarized all the causes of death in 2000, whatever 14 or 15, from the matched sibling donor transplant. So what were the causes? So 27% were due to underlying disease, 20% infection, organ dysfunction, the gray is graft-versus-host disease, and variety of other reasons. So this is early after transplant, 100 days after transplant. Again, primary disease continues to be a major cause of death, so disease relapse and then we have also graft-versus-host disease about 7 percent, bleeding complications, infectious etc.

00:49:49  What is acute graft-versus-host disease? So acute graft versus host disease most commonly involves skin, the liver, and gut. So basically, you have those activated donor cells, t-cells, attacking the patient. The incidence has been reported, depending on the protocol, between 10 and 40 percent. Symptoms can present at any point after the engraftment. So after the donor cells recover at any point, the graft -versus- host disease can show up.

So we obviously have treatment for graft-versus-host disease, but the best thing to do is to try to prevent it from happening, which means you have to take the medication, the immunosuppressant medications that you will be on, just as the doctor prescribed. And at any inkling that something is beginning to change - you start to have rash, you start to have diarrhea - you are not to wait for your next appointment with a doctor, but you call the special pager numbers that you'll likely be given after the discharge and make sure that they know that something is changing. So again, that's what I usually tell my patients. The best thing is to prevent it from happening. The second best thing to intervene right away.

Just because you have a rash or diarrhea, there could be many reasons why this is happening. So we need to figure out what it is, and if it is graft-versus-host disease, we can treat it very aggressively which gives us the highest chance that we'll be able to get this under control.

00:51:21  Common chronic complications of a stem cell transplant: So common, chronic complications of stem cell transplant. Obviously, disease relapse,. Although transplant may be the best therapeutic option available, unfortunately, it's not a guarantee. There is a meaningful risk of relapse, depending on the nature of the disease, and type of the transplant. And, as I already mentioned, I will frequently utilize low dose maintenance therapy, targeted therapy post-transplant, especially while patients are on the immunosuppressants, to prevent the disease from coming back.

Infections also could be a problem, especially if the patient has graft-versus-host disease and is on immunosuppressant medications for a long period of time. As the immune system is not normal and patients do tend to have infectious complications, we do have medications to decrease the chance of that happening. We frequently employ something called intravenous immunoglobulin, kind of a nonspecific way to boost the immune system to try to fight that. But again, infections are real problems.

00:52:29  Chronic graft-versus-host disease: Then chronic graft versus host disease. If you've ever seen a patient with scleroderma, that looks like the patient that has chronic graft-versus-host disease. You get fibrosis and scarring of the skin. You can have dryness of the eyes and mouth, and in females, in vaginal areas. So you can have a chronic lung graft-versus-host disease. Again, we're able to deal with those things, but not everybody responds to treatment and patients may suffer long term consequences of chronic graft-versus-host disease.

00:53:06  There's increased risk of certain cancers. Usually, I make sure that all my patients see dermatology on a regular basis because the risk of skin cancers is increasing. And also, depending on the kind of conditioning regimen patients receive, there could be a risk of other cancers. And, of course, a risk of psychological disorders and depression, because patients go through so much.

00:53:34 So, this just a summary of the chronic graft versus host disease when you have immune dysregulation, which include the fibrosis and impaired organ function. Depending on the conditioning chemotherapy, depending on the type of the transplant, the incidence could be between 20 and 70 percent.

00:53:58  Is a little bit of graft-versus-host disease good? Although patients frequently ask, "Isn't a little bit of graft-versus-host disease is good?", and in a way it is true. So if it's a minor graft-versus-host disease, it frequently is associated with very good graft-versus-leukemia effect. So, patients who have some degree of chronic graft- versus-host disease will have a low likelihood of relapse. However, if this graft-versus-host disease is severe, then patients have a lot of toxicity because we're trying to treat their severe graft-versus-host disease. I don't know if I'm making sense, it's hard to do this in a way, but I'm sure you guys will ask me questions afterwards.

00:54:39  Stem cell transplant is a marathon, not a sprint: So I also tell my patients that the stem cell transplant is not a sprint. It's a marathon. And I believe that the post-transplant care, so once patient goes home, is almost more important than the transplant itself, the months in the hospital that you'll spend. So I usually see my patients once a week and I'm sure the protocols might be slightly different [at different hospitals], but it's pretty intense follow-up after stem cell transplant., And my patients know that if any new symptoms occur during that week my team will need to know that immediately.

00:55:21  Post-transplant follow-up: And then we monitor patients for all kinds of things. So we monitor them for disease relapse. We'll monitor them for infectious complications.

We'll monitor them for development of graft-versus-host disease, and at the beginning, it's very important to make sure that the level of the immunosuppressant drug is just perfect in the system. So we measure that level at each visit. And after a few months, depending on the kind of transplant that could be slightly different, but after a period of time you begin to taper the immunosuppression. You reduce the dose of immunosuppression. You observe the patient little bit for a few and weeks to make sure there's no evidence of graft-versus-host disease and you continue tapering until you, hopefully, get the patients off of all of the immunosuppression, all of the antibiotics, and all those drugs you put people on during the transplant, with the hope that they can go back to completely normal life.

After stem cell transplantation, I probably already mentioned that we make sure that patient has an adequate dental evaluation because, if people have graft-versus-host disease of the oral mucosa, that increases your risk of cavities and gum disease.

We'll make sure we do pulmonary function tests to make sure that lungs are not affected. Bone density test, especially in patients who've been on steroids for a prolonged period of time. And examination by dermatology. I send all my female patients to the sexual health clinic because in our younger woman, we cause menopause in them, and there's vaginal dryness from graft versus host disease. So I think it's very important to address those issues. We'll make sure that heart is functional and then we proceed with the vaccinations.

00:57:09  Medications that have recently been approved by FDA for patients with acute myeloid leukemia: So the next number of slides I will go through pretty quickly, and we can concentrate on whatever drugs you guys are particularly interested in. But those are eight medications that received an FDA approval in the last two years, I think I put them in pretty much a chronological order.

00:57:28  Vyxeos: So Vyxeos is specifically FDA-approved for patients with acute myeloid leukemias that arise on the background of a prior bone marrow disorder, or acute myeloid leukemia with MDS-related changes. Notoriously this is a very high risk category of patients. They tend not to respond well to chemotherapy. So Vyxeos is actually a combination of standard 7+3 chemotherapy, but they are packaged in a specific liposomal formulation that gives a specific ratio between daunorubicin and cytarabine. And there was a phase 3 clinical trial in patients ages 60 to 75, who have this specific acute myeloid leukemia with MDS related changes, or acute myeloid leukemia rising on the background of a prior bone marrow disorder, and there was improved overall survival for patients who received Vyxeos versus standard 7 and 3 chemotherapy.

Another relevant point to this discussion is that it appears that those patients who did achieve remission with Vyxeos and underwent a stem cell transplant did a lot better than a patient who received 7 + 3 chemotherapy and underwent a stem cell transplant, which suggests that the depth of the remission is better with Vyxeos. Again, that's why it's so important for me to know what kind of acute myeloid leukemia it is at the beginning, so I can decide whether I give a standard chemotherapy or Vyxeos. Okay, so that's one.

00:59:15  Enasidenib: Two, enasidenib is an IBH2 inhibitor. So, there was a phase one-two clinical trial, a relatively early phase trial for those patient with relapsed and a refractory acute myeloid leukemia that happened to have an IDH2 mutation. So, patients received between 1 and 6 lines of prior therapy, and more than 50 % of those patients, I think, had at least two or more lines of therapy. And the single agent oral medication led to the rate of complete remission, CR and CRH - CRH, stands for complete remission with incomplete account recovery - in 23% of the patients. I mean, is that a home run? Well, maybe not, but for 23% of those patients that certainly was a game-changer. The median survival is not very long with 8.2 months, however, those are 8.2 months of normal life. As you might imagine, there are multiple clinical trials ongoing, combining IDH2 inhibitors with various other drugs to see how we can improve on those numbers.

01:00:24  Midostaurin: The next drug was a drug called midostaurin and that's FDA approved to be given in combination with the chemotherapy in patients with FLT3+ acute myeloid leukemia. As you can see, the overall survival was significantly longer in patients who received midostaurin. And again, I would like to know whether my patient have a FLT3 mutation right at the beginning, because that would be the patient who would get chemotherapy with midostaurin or another clinical trial which included the FLT3 mutation.

01:01:02  Mylotarg: This is, this is a drug called Mylotarg. Mylotarg has an interesting history. Twenty years ago, it received FDA approval for treatment of older adults with acute myeloid leukemia. So Mylotarg is effectively anti anti-CD33. And CD33 is a marker that is present on the myeloid cells. It's present in the leukemia cells. It's also present on some of the normal cells. And it has like this toxic antibiotic attached to it. So the idea is it binds to the 33 marker and this antibiotic, that the toxic substance, will kill the cells.

So, 20 years ago, it received an approval and then a company withdraw the drug from the market because it wasn't really clear who the drug was helping. And there were several studies - they did not show benefit of this drug. However, since that time, there have been several clinical trials that demonstrate single agent activity of the Mylotarg, as well as activity of this drug when it's combined with the chemotherapy. So again for specific patient subsets, this might be a reasonable option of combining Mylotarg with the chemotherapy. And for some elderly patients we might sometimes use it as a single agent to try to get patients into remission.

01:02:26  Ivosidenib: Ivosidenib. So a year ago, FDA granted an approval for patients with relapsed and refractory IDH1+, acute myeloid leukemia, and so again, it's an oral medication. The rate of CR and CRH was 33%. Again, it's important to remember those other patients with relapsed and refractory disease, many of whom fail other therapy about, you know, 23 percent of those patient had a prior bone marrow transplants are pretty tough group to treat , and again in that patient population there was 33 percent of rate of CR and CRH. It's also important to remember that some of the patients who did not achieve remission, they became transfusion independent. Again, I know it's a small kind of small prize, but for those people, they get at least a normal period of life when they didn't have to run to the hospital every 15 minutes to get a blood transfusion. In general. those drugs are reasonably well tolerated, they have some toxicities, and there is a risk of differentiation syndrome. Again, if anybody's interested I'll be happy to discuss that.

A couple months ago, Ivosidenib, so the same drug, I just mentioned,- received an FDA approval for older adults - so patients, 75 and older, who are unfit for chemotherapy as the front line therapy - because, based on a small number of patients in that same study, the rate of CR and CRH was 43%, and 41% of patients achieved transfusion independence. So again, as you might imagine, there are multiple combination therapies on clinical trials, with combination therapies ongoing to utilize this drug in IDH1 positive acute myeloid leukemia.

01:04:19 Venetoclax: So, Venetoclax is a drug, that's already been FDA approved years ago for treatment of chronic lymphocytic leukemia. It targets the bcl-2 pathway. That is important for chronic lymphocytic leukemia. That pathway is also important in acute myeloid leukemia. And although, as a single agent, this drug was not very active, when it combines with either Vidaza , Dacogen or low dose cytarabine, as you can see, it gives a pretty reasonable response of CR and CRH's , in the range of 60% with the hypomethylating agents Vidaza and Dacogen, and 42% with low dose cytarabine. We have to remember that most of those patients probably received Vidaza or Dacogen for prior bone marrow disorder. Again, median duration of their response is not very long. Although, again, you can see their range - some of the patients go for several years, but again, median duration is short. So, clearly we need to do better, but again this is more than we had a year ago. The biggest issue with Venetoclax, it's very mild suppressive. Although it's an oral pill and, in general, pretty well tolerated in terms of you gastrointestinal problems, etcetera, it does drop the blood counts very significantly and people are prone to neutropenic fever and infections.

01:05:52  Gliteritinib: So, Gliteritinib is a targeted FLT3 inhibitor. It just received an FDA approval in November of 2018. In patients who is heavily pretreated FLT3+ AML, he rate of CRH was 21 %. This drug is really well-tolerated. Patients feel well on that medication and again there are innumerable studies combining it with everything you can think of - chemotherapy on the targeted therapy for patients with fully FLT3+ positive acute myeloid leukemia.

01:06:29  Glasdegib: Glasdegib is a hedgehog inhibitor that received FDA approval when given in combination with low dose cytarabine, specifically approved for older adults who are unfit for chemotherapy. The approval was given based on the results of the randomized studies that showed that the combination prolonged survival by about four months compared to chemotherapy alone.

01:06:53  Tagraxofusp-erzs: And this drug, I refuse to pronounce its name, because I simply cannot, I know the drug as SL401. There is a subset of acute myeloid leukemias called blastic dendritic cell neoplasm, a particular nasty disease, and it's not very common. But it's great to have the drug, you know, for that patient population. So for untreated patients - there was a small cohort of 13 patients - the rate of complete remission was 54% for patients who received multiple prior lines of therapy. There was only one complete remission lasting 111 days, and a complete remission with incomplete count recovery lasting for 424 days. It's sometimes not easy to tolerate the drug. It can be complicated by capillary leak syndrome, but again we can deal with that.

So, and I think this is it for the drugs. Yep, alright, so I'll be happy to take any questions.

Question and Answer Session

Thank you very much, Dr. Frankfort, for a very detailed and enlightening presentation. We appreciate that. We do have a few minutes left for questions and again, if you have a question, you can type it into the chat box in the lower left corner of your screen, and a couple did come in while you were speaking. Gordon wants to know what determines whether you take cells from the donor's bone marrow or peripheral blood?

01:08:31  What determines whether you collect bone marrow or stem cells from the bloodstream? So, again for adult patients with acute myeloid leukemia, we typically take the cells from the peripheral blood. It's for the donor convenience typically. Now for pediatric populations, I mentioned the donor cells are collected usually from the donor bone marrow. And rationale for that, is is thre is a slightly lower risk of the chronic graft versus host disease. Because it's children, you know the pediatricians - that's their decision. That's what they do.

The problem with the bone marrow collected stem cells, is that the risk of graft failure and delayed engraftment is higher. So again, that's why the standard practice in the United States is for the donor cells to be collected from the peripheral bloodstream.

So there are recommendations when you have a refractory aggressive disease to use an umbilical cord blood transplant. The issue with cord blood is this: it's kind of a one-time deal, right? Because you don't have extra cells. While with a matched sibling, donor or unrelated donor, you can get more cells and you maybe need additional treatment and another cell infusion potentially down the line. But with the cord you are done. Again, I'm partial to cord. I like umbilical cord blood, see really good results with that, and very few patients of mine who elapse after their umbilical cord blood transplant. So I do share that with you, but I do not think it's universally accepted.

01:10:13  Jason wants to know, "What are the side effects of a reduced intensity transplant? Can you get graft-versus-host disease after one of those?"

01:10:23  Can you get graft-versus-host disease after a reduced intensity transplant: Yup, you can. So the major advantage of the reduced intensity transplant is that chemo is not horrible., In fact most patients in the hospital look like visitors, right? Frequently the hair doesn't come out, they feel very well. You know, their counts don't crash. They kind of go down a bit, but they don't quite crash. So usually, people tolerate their reduce intensity conditioning. And there, of course, various degree of reduced intensities. There is a very light transplant. There is a little bit more, you know, just a slightly more aggressive ones and again the decision is being made [based on] what kind of disease you have, how old you are, what performance status you have, and how well controlled your disease is. But you can get graft-versus-host disease after the reduced intensity transplant as well.

01:11:18  Sylvia wants to know why a younger donor is preferred over older donors.

01:11:23  Why is a younger donor preferred over an older one: That's a very good question. So, oh that's a long answer. So, as we get older, we tend to accumulate various abnormalities in our stem cells that that might not be good for the patient. So, younger patients are better because they have a lower chance of having those abnormal mutations.

01:11:57  Alright and the last question, unless anyone has some. Dana wants to know, does a patient blood type change after transplant and does that cause any problems?

01:12:08  Does a patient's blood type change after transplant: God-willing, right? Because what I want is the patient to become their donor in terms of the blood and the bone marrow, right? So, yes, the blood type will change, and no, it should not cause any problem to to the patient.

01:12:27  Contact information for BMT InfoNet:  Okay. Well, with that it looks like we've answered all the questions, and we are a little bit over time, not a problem, though. So, thank you to Dr. Frankfurt for an excellent presentation and thank you everyone who's participated and asked questions this evening. That has enriched the discussion about AML and the transplant option. We do encourage you, if you have follow-up questions, you can email us at help@bmtinfonet.org, or you can call us at 888-597-7674 and we'd be happy to help you. Or if you want to reach Dr. Frankfurt we can put you in touch. Again, many thanks to Astellas Pharma and Jazz Pharmaceuticals, for sponsoring this event.