Acute Myeloid Leukemia: Increasing Complexity and Increasing Treatment Opportunities

Learn about the different types of acute myeloid leukemia (AML), how it is treated, and when transplant is the best option.

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Acute Myeloid Leukemia: Increasing Complexity and Increasing Treatment Opportunities

Thursday, October 14, 2021

Presenter: Dr. Mark R. Litzow, MD, Professor of Medicine, Mayo Clinic

Presentation is 42 minutes with 23 minutes of Q & A

Ths presentation was made possible, in part, by a grant from Syndax Pharmaceuticals

Summary: Acute myeloid leukemia (AML) is a blood cancer that has been historically challenging to treat. It often requires a bone marrow or stem cell transplant that can be curative but brings significant risks and side effects. However, new drugs and clinical trials have expanded treatment options and moderated side effects for many patients.


  • AML has two phases of treatment: induction to achieve remission and consolidation to maintain it.
  • Different subtypes of AML have different prognoses which can be favorable, intermediate, or adverse. Favorable risk patients may only require induction and consolidation chemotherapy. Intermediate or adverse risk patients usually need a transplant following induction chemotherapy.
  • Several donor types are available to provide bone marrow or stem cells for transplant. The closer the match of donor to recipient, the less chance of graft-vs.-host-disease (GVHD) where donor cells attack the recipient’s body.

Key Points:

(00:02:54) Leukemia arises from a small number of malignant blood cells that grow uncontrollably. It can be acute or chronic and involve either myeloid or lymphoid cells.

(00:04:48) Acute myeloid leukemia (AML) is the dominant acute leukemia and mainly affects older people.

(00:05:56) AML can present with several symptoms, including a “blast crisis” of too many malignant white blood cells

(00:11:24) AML may also involve abnormal chromosomes or karyotype and multiple genetic abnormalities.

(00:13:20) Many mutations and abnormalities are being studied and some have targeted medications to control them. These mutations create many different subtypes of AML.

(00:22:16) New treatments for some genetic abnormalities have recently been approved.

(00:25:22) FLT3 is a common mutation for which there are now several targeted treatments.

(00:30:20) Some newer drugs are especially appropriate for older or less fit patients.

(00:36:33) Traditional transplants used chemotherapy and radiation to wipe out diseased bone marrow. These are called myeloablative transplants.

(00:38:47) Reduced intensity transplants are now more common for older adults and are more easily tolerated by older patients.

Transcription of Presentation:

(00:00:00) [Susan Stewart]          Introduction. I would like to begin and welcome you to the webinar, Acute Myeloid Leukemia, Increasing Complexity and Increasing Treatment Options. My name is Sue Stewart, and I'll be your host for today's session. I'd like to thank Syndax, whose support in part made this webinar possible.

(00:00:24) So it's now my pleasure to introduce to you today's speaker, Dr. Mark Litzow. Dr. Litzow is a Professor of Medicine at the Mayo Clinic. He served as the head of the Acute Leukemia and Myeloid Neoplasm Group at Mayo Clinic's campus in Rochester for 12 years and was the Director of the Blood and Marrow Transplant Program at Mayo Clinic for 17 years. He remains an active member of both programs.

(00:00:53) Dr. Litzow's research interests include clinical trials for acute and chronic leukemia, blood and marrow transplantation, and supportive care for transplant patients. His efforts have contributed to improvements in outcomes for patients with leukemia and to improved survival of patients after blood and marrow transplantation.

(00:01:16) Dr. Litzow is the chair of the Leukemia Committee of the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network. He is also the co-chair of the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplant Research. He just completed an eight-year term as chairman of the Committee on Education for the American Society for Transplantation and Cellular Therapy. So please join me in welcoming Dr. Litzow.

 (00:01:52) [Dr. Mark Litzow]           Overview of Talk. So thank you very much. It's a great honor for me to speak with you today. The BMT InfoNet is such a valuable resource for our patients and our families, and I'm honored to have this opportunity to speak.

(00:02:07) Acute myeloid leukemia has shown increasing complexity as we understand the pathogenesis, the development of the disease, and as we have developed some new treatment opportunities, which I will try to elaborate on. So my goals today are to review the current classification and the clinical manifestations, how this presents in patients with AML, talk about how we now classify AML and the different subtypes, discuss some of the new treatment options that I mentioned, and then I want to conclude the last part of my talk talking about some new approaches to the use of blood and marrow transplantation.

(00:02:54) Leukemia arises from a small number of malignant cells that grow uncontrollably. So leukemia is a cancer. It's a malignancy. And we use this term clonal, meaning that it arises from one or a very small number of cells, and then these grow uncontrollably, and there's a successive production of these immature, sometimes mature, white blood cells that build up in the bone marrow, go out in the blood, and sometimes can grow in some of the organs and tissues in our body.

(00:03:26) Leukemia can be either acute (fast-growing) or chronic (slower growing). So acute leukemia is when there's a lot of these immature cells, which we call blast cells, and they tend to proliferate at a higher rate. That means they grow faster. And then there's chronic leukemia. And there the cells are more mature. They're still abnormal, but they don't tend to grow as rapidly.

(00:03:45) Leukemia can also involve either myeloid or lymphoid cells, leading to four major types of leukemia. And then we divide white blood cells and cells in the bone marrow into what we call a myeloid group and a lymphoid group. So you can have acute myeloid leukemia, which we're talking about today. You can have acute lymphoid leukemia. You can have chronic myeloid leukemia. You can have chronic lymphoid leukemia.

(00:04:07) There are additional subtypes of leukemia. And this looks kind of how we classify these groups. You can see on the left in the yellow is a myeloid cancer. On the right is a lymphoid cancer. And then I talk about the chronic and the acute. And under the chronic myeloid disorders, there is a chronic myeloid leukemia. I don't list that here, but then there's other disorders called myelodysplastic syndrome and myeloproliferative disorders. And then on the lymphoid side, I won't go into all those subtypes because they're not our topic today, but you can see there are a number of different categories. Plasma cell disorders, the main one, is multiple myeloma.

(00:04:48) Acute myeloid leukemia (AML) is the most common form of acute leukemia and mainly affects older people. So acute myeloid leukemia is the dominant type of acute leukemia. 90% of acute leukemia cases are AML. It tends to be a disease of older individuals. The median age at diagnosis is 68 years. That means that half the patients are under 68, but half of the patients are over 68.

We don't do as well as we'd like with treatment of older individuals. And so you can see here that at five years with chemotherapy, not many patients can survive who are older. Transplant improves that some, and we hope that some of the newer therapies will help make that better as well. We do better in younger, middle-aged patients. And unfortunately, even in children, AML is not uniformly curable.

(00:05:46) The other type of acute leukemia, is ALL. Over 90% of children can be cured with that leukemia, but we don't have as much success in children with AML.

(00:05:56) AML can present with several symptoms. So what are the symptoms of AML? Well, people can have a high white blood count if there's a lot of the blast cells up in their blood. But then, their good white blood cells, like the neutrophils, and the hemoglobin, the red cells, and the platelets can be low. And that can contribute the bleeding, fatigue, and infection. Sometimes the cells can get into the liver and spleen and enlarge those.

(00:06:22) If a lot of blast cells get out in the blood and they get up to a real high level, we use this term blast crisis, meaning that that's an urgent situation that we need to deal with. And then sometimes the cells can grow in the soft tissues. The bones are hard tissue, but the bones, the skin, the lymph nodes, the breasts, the lungs, in the intestines, almost anywhere in the body, sometimes you can get, I'll say a tumor of leukemia cells. It doesn't happen real often, but we do see that.

(00:06:58) And then there's something called a tumor lysis syndrome, and that's when the cells lyse or break down, and they release a lot of proteins and other substances into the blood that can make a person sick. So we call that tumor lysis syndrome. And you can think of leukemia in a way as a tumor. So those cells are breaking down and causing problems.

(00:07:23) And then leukemia can also affect blood clotting, partly because the platelets are low, but also because of some of the proteins that help with clotting can be affected.

(00:07:34) This is an example of some leukemia out in the skin, that orange-ish nodule just above the lip, and then that smaller one below the lower lip. Those are collections of leukemia cells that are growing in the skin and causing this little bump. And we call that leukemia cutis. Cutis refers to the skin.

(00:07:59) Too many white blood cells can create a blast crisis. So I mentioned the very high white blood cell count that we call blast crisis. This tends to occur when the blasts in the blood get up to a hundred thousand or close to that, hundred times 10 to the ninth per liter. Remember the normal white count is between three and 10, roughly. So now the white count has gotten up to 100, and many of them are blast cells. Because these are big cells, it can cause, I'll say the blood to sludge and slow down its flow and kind of clog up the blood vessels. And so that can affect our vision. If it gets into the small blood vessels in the brain, it can affect our thinking, altered mentation. Sometimes it can cause bleeding in the brain. Sometimes it can cause arm or leg weakness. That's a focal neurologic deficit. Sometimes it could affect the speech and cause slurred speech. If it clogs up the lungs, it can be harder for oxygen to get into the blood vessels, and so people can get shortness of breath. And then, as I mentioned, it can cause difficulties with clotting of the blood, so people can have bleeding sometimes, or they can have excessive clotting of the blood.

(00:09:19) A process called leukapheresis can reduce a dangerously high white blood cell count. So how do we treat this? Well, there's a machine that can remove the white blood cells. It's a pheresis machine. And when we say leukapheresis, that's the leukocytes, or white blood cells. So we do that urgently to get the white count down as quickly as we can. We make sure the patient is well-hydrated so they lessen the risk of the blood sludging. And then we use an oral chemotherapy drug that we call hydroxyurea. And sometimes we need to use allopurinol because that's the medicine for gout, and these cells can release uric acid that causes gout. And allopurinol lowers that uric acid level so people won't get the uric acid causing gouty manifestations or, the big thing we worry about is that uric acid can get in the kidney and damage the kidney.

(00:10:15) Pathologists are usually needed to diagnose AML under the microscope. So what does AML look like under the microscope? Our pathologists are crucial to making the diagnosis of AML. And these are blast cells. You can see the red blood cells in the background here, and you can see what size they are. And there are some white blood cells that are about the same size. So you can see how big these blast cells are. They don't have a lot of granules in the cytoplasm. Those are little orange dots that we see. That means the cell is more mature. You can see that a little bit in some of the cells.

(00:10:52) And then you see those rod like structures. We call those auer rods, and that's when some of these granules crystallize. And if we look under the microscope and we see those, we know that we have AML, because otherwise looking at this slide, I wouldn't be able to say for sure whether this is AML or whether this is acute lymphoblastic leukemia, the other type of acute leukemia - ALL. So there are tests that the pathologists can do to tell us that. But if we see these auer rods, that suggest that this is AML.

(00:11:24) AML may also involve abnormal chromosomes or karyotype. Now, most of the cells in our body have a set of chromosomes, and chromosomes contain the genetic material, the genes, that make proteins and control a lot of our body functions. And you can see that we have 22 chromosomes. And everybody has two of those, so that's 44. And then we have our two sex chromosomes. Men have an X and a Y, and females have two Xs. It should actually be an X down there with the female. So we have a total of 46 chromosomes in most of our cells. And you can see in the cartoon on the left that within the chromosome, that's the DNA in that red kind of circular structure. That's the double helix that was discovered many years ago. And so it's frequent with AML that in the AML cells, the blast cells, we can see abnormal chromosomes. And we call the chromosome pattern, we call that the karyotype. You can see that word here.

(00:12:35) AML patients may have no, one, or multiple genetic abnormalities. Now, some patients, almost a half, can have a normal karyotype. We don't see any abnormalities. Some people can have a complex karyotype where there are multiple genetic abnormalities. And then there's some other ones that you see kind of in the lower left, where two genes can swap material. So you'll see that which says a t (8;21), or t(9;11). That means a chromosome number eight and a chromosome 21 have swapped material, or a nine and 11 have swapped material. And then sometimes a chromosome can flip. We call that an inversion. Part of it can flip. That's the inv(16).

(00:13:20) Many mutations and abnormalities are being studied and some have targeted medications to control them. The newest thing that we're discovering is that we can now determine a lot of gene abnormalities, mutations in particular genes. And that's what's written in red. So these are common genes that get mutated, and we can now determine many of the genes that are mutated in AML. And more importantly, we now have been able to start to target those with some medications to help treat the leukemia. So I won't go through all of these. I'm going to talk about a few of them later on, but there's these chromosome abnormalities. That's when the karyotype becomes abnormal. And then there's also these gene mutations, or gene abnormalities, that we can now study.

(00:14:06) These mutations and abnormalities create many different subtypes of AML. So the World Health Organization does a classification of diseases, and they've done a classification system of AML, and they update this every few years. The last time was in 2016, and next year we're going to get a new version. But you can see over on the right all the different categories. And I'm not going to go through all of these, but up toward the top there, you can see where it says AML with the small letter t(8;21). That's one of the ones that I just talked about. And we now see certain genes that are abnormal with that chromosome abnormality. That's the RUNX1. So you can see a number of those. So with a number of these gene abnormalities, that's now a subtype of AML. At the bottom, there's ones that we determine more by how the cells look and how they stain with certain procedures that we do. Or they don't necessarily always have a genetic abnormality. So this is still an evolution, and as we continue to learn more about how AML develops, it should refine the classification system. But you can see there's many subtypes of AML. AML is not just, I'll say, one disease.

(00:15:17) Different subtypes have different prognoses: favorable, intermediate, or adverse. So we know that these different groups that I just talked about have different prognoses. So it's never good to have AML, but with some types of AML, we have better success with treatment. And so we call those a favorable group. And you can see that on the right side at the top. There's a group of doctors from both Europe and the United States... They call it the European Leukemia Net... came up with this classification. Then you can see there are some that we put in an intermediate category. And then there's some that are in an adverse category. And the adverse ones are the more stubborn ones. Those are the ones that are harder for us to get into remission and keep in remission. And so we talk about the prognosis of patients, somebody got a good prognosis where we think that we have a higher chance of success, or they maybe have a poor prognosis where they may not be quite as successful with treatment, and we have to maybe consider transplant more often or consider other treatments.

(00:16:21) Several factors, including older age, contribute to an adverse prognosis. So we use some of these genetic abnormalities, or chromosome abnormalities, to help us determine that. I'd mentioned earlier that older individuals don't tend to do as well. They often have more of the stubborn subtypes. Extramedullary disease, that's when you have leukemia outside the bone marrow, like I showed with that lip lesion. If people have a prior hematologic disorder, like a myelodysplastic syndrome or a myeloproliferative disorder neoplasm, and then they get AML, that's often a more stubborn subtype. And then if they come in the hospital with a very high white count with a lot of blasts in their blood, that can be more significant. And then there's the genetic prognostic factors, and that's what I'm showing over on the right side with the different chromosome abnormalities. So again, these different subtypes can categorize them as to whether they're a more favorable subtype or a less favorable subtype.

(00:17:24) AML has two phases of treatment: induction to achieve remission and consolidation to maintain it. So how do we treat AML? So traditionally we've had two phases of therapy. The first we call induction, and that's where we're trying to induce or achieve a remission. And we want to get the leukemia cells down as low as possible and allow the normal cells in the bone marrow to grow and build the blood counts back up. And that's what we call remission. If we can get someone into remission, which we can most of the time, then we want to do consolidation to consolidate that remission that we've achieved and make sure it continues, because after induction, we haven't gotten rid of all the leukemia. We've just knocked it down to a low level. And actually, if you stop treatment after induction, almost everyone, the leukemia will start to grow again.

(00:18:15) The traditional therapy is “7 + 3” combining two chemotherapy drugs. Now, traditionally over the years, we've used two drugs, either a drug that's in the anthracycline family... and the typical ones are either daunorubicin or idarubicin. That one we give daily for three days. And then there's one called cytarabine that we drip in around the clock for seven days. And so we sometimes abbreviate this and say oh, this patient is going to be getting three plus seven, or they're going to get seven plus three. We as doctors know what someone's referring to when they say that. So that's kind of been the traditional therapy.

(00:18:50) 7 + 3 can have numerous side effects. And I'm going to talk about how some of that has changed at times. Now, these medicines have side effects, they all lower blood counts because that's how we want to get rid of leukemia, but cytarabine sometimes can cause some brain damage, cause loss of balance, and sometimes it can irritate the white part of your eye so that your eyes get red and burning. And we put in steroid eyedrops to help prevent that. We call that conjunctivitis. And the anthracyclines sometimes can damage the pumping function of the heart, so that isn't as good. Again, doesn't happen all the time. Does appear to be dose-related. If you give too much of daunorubicin or idarubicin, there's more chance of developing that problem.

(00:19:42) Some AML patients receive a stem cell transplant with donor cells. So there are some patients where we do a transplant when they're in first remission. And we typically use a donor, and so that's an allogeneic transplant. If we use someone's own cells, that's an autologous transplant. Sometimes that can be done in AML, but not very often. Now, I often tell patients that an allogeneic transplant is the best leukemia treatment we have. The downside is that it can have significant side effects. A big one is graft- versus-host disease. There's also infection. And then sometimes with all the treatment we give with a transplant, the kidneys or the liver or the lungs can be damaged. And that's what I mean by internal organ damage.

(00:20:25) Favorable risk patients may only require consolidation chemotherapy; intermediate and adverse risk patients usually need a transplant. Now, that favorable risk group that I talked about earlier, if they get into a good remission, we typically don't offer them transplant because we think that they can be cured with chemotherapy alone. Some of them do relapse, and then we need to consider a transplant. But most of the other group, the intermediate group, and then the high-risk group, we consider for transplant after they get into remission, because we're concerned that even though they're in remission, they've got a more stubborn leukemia, and there's more risk that the leukemia is going to come back. Kind of a way to think about that is that just like we have normal stem cells, the mother cells of our bone marrow, we can have a stem cell for the leukemia, and there can just be a few of them there that we may not be able to see, but they can grow again and cause the leukemia to come back.

(00:16:21) Several factors, including older age, contribute to an adverse prognosis. So what do we do if the leukemia comes back in a patient? Well, we try to get them into another remission. We call that second remission. If they relapse soon after they get into remission, under six months, then they don't tend to respond as well to standard chemotherapy like we gave at the beginning. They can, but not as often. If the remission lasts longer, more than a year, then up to 50% of them can respond to either using the cytarabine in a high dose or doing more of the seven plus three. We do try to consider enrolling these patients in a clinical trial if we think there's a suitable one for them. And then if we can get them back into remission, we think they need to have a transplant, because if you have relapsed once with chemotherapy and we give more chemotherapy, you're likely going to relapse again. And so a transplant is definitely indicated in that situation.

(00:22:16) New treatments for some genetic abnormalities have recently been approved. So we finally have some new treatments for AML. For almost 40 years, the seven and three was the mainstay of our treatment. But now with some of these gene abnormalities that we've discovered, we have agents that are targeted to those gene abnormalities and are helping improve treatments. So midostaurin is one of the first ones that was approved. There's another one I'll talk about called the CPX-351, or Vyxeos. And then there's this medicine, I'm just going to say Mylotarg rather than the long name. This is based more on a marker on the cells. It got approved in 2000, and then the FDA didn't think it was as good as it could be, and so they took it off the market. But then some more studies were done showing it was beneficial, and it came back on the market a few years ago. And then another gene mutation is IDH2. This drug, enasidenib, was approved in 2017.

(00:23:18) And then between 2018 and 2020, there were five more drugs that were approved, and I've listed these here. There's IDH2. There's also IDH1, and we have this medicine for IDH1. We have these two... So I guess there's actually six here... glasdegib and then venetoclax. They work in a different way, not targeted to one gene mutation by itself.

(00:23:46) We now have a second drug that treats FLT3 mutation that's called gilteritinib. And all these names I give you, that's the generic name. And then the one in parentheses, that's the trade name. Every drug has two names.

(00:24:00) And then there's this other one with a funny name, tagraxofusp. That was approved for this rare subtype of AML called blastic plasmacytoid dendritic cell neoplasm.

(00:24:11) And then azacitidine is a drug we've had around for a long time to treat myelodysplastic syndrome, sometimes AML. That always had to be given by injection, but now we have an oral form of that, and that's been shown to have benefit for maintenance therapy.

(00:24:30) So CPX-351 is kind of an interesting medicine. It's based on nanotechnology, and nano means one billionth of a meter, so tiny, tiny, tiny. But these chemotherapy drugs that we've used for many years, cytarabine and daunorubicin, they put them inside this fat capsule. So it's got a fat membrane around it, and then the chemotherapy drug is inside. And that goes into the cells more easily, and it sticks around longer and tends to have fewer side effects than these chemo drugs alone. And there was a study done where they gave it to people that had a poor adverse risk AML, and they showed that the survival was better with the CPX compared to the old seven plus three, as I show here.

(00:25:22) FLT3 is a mutation for which there are now several targeted treatments. Now, I mentioned FLT3 and drugs that we have available for that. And I just wanted to show this just as a placeholder to show. This is a FLT3 molecule in the cell. You can see the cell membrane. And then the FLT3 can get altered in a couple of different ways. And that's what's in the boxes. And I won't go into all of that, but it gets mutated, and then it causes the cells to grow more than they should.

(00:25:47) So midostaurin is a drug that inhibits FLT3. And it was combined with chemotherapy and compared to the other half of the patients getting a placebo plus chemotherapy. And you can see that the black or dark blue line was the chemotherapy plus midostaurin, and the survival was better on the left side there with midostaurin versus giving a placebo. And when patients had a transplant, which we often do for FLT3 AML, they did the best, there up on the top, on the right side, the patients that were transplanted. And these were some patients who were transplanted when they were in first remission and some that were transmitted outside first remission or after first remission, and midostaurin didn't have as much impact there.

(00:26:37) Now, gilteritinib, XOSPATA, this is a second drug for FLT3. This was by itself in a clinical trial they called the ADMIRAL trial, and it showed that even by itself, it was better than chemotherapy. Now, the overall survival wasn't great. These are patients where the leukemia had come back. So unfortunately, they only lived about nine months, but it was better than the six months that we saw with chemotherapy, and more patients were alive at one and two years compared to chemotherapy.

(00:27:10) And we're now combining gilteritinib with chemotherapy and comparing it to midostraurin and chemotherapy to see if the gilteritinib does even better than the midostaurin. And one of my colleagues is leading this study for our ECOG group that I'm part of.

(00:27:32) There are also targeted therapies for IDH1 and IDH2 mutations. Then there's a molecule called isocitrate dehydrogenase. It's an important molecule in our cells, and this can get mutated in AML. And these mutations were first found in September of 2009, and then it was realized how they altered the cell the following year. And then drugs were found to inhibit these mutated cells. And the first patient was treated in September of 2013, and by 2017 and 2018, the two different... There's an IDH1 and an IDH2, as you see in the bottom there... those drugs got approved. So don't worry about the small letters. This is just saying that from 2009 to 2013, we already had a drug, and within a few years after that, we had these approved. And I will say that that's a record time for drug development. Many drugs, it can take 10 years or more from the time they're discovered until they're approved by the FDA. So this was exciting for us as well.

(00:29:37) Definition of a “fit” person for transplant. So who do we say is fit? Well, I just elaborated on that. Some of it is age. Performance status is kind of how well you function. Are you up and around and doing things? Or do you have to rest most of the day? Do you have other health issues? We don't have this well-defined, and so there are studies going on to try to help us better define who's a fit person and who's not to help us decide what the best treatment is for them. And sometimes the way the leukemia acts suggests that we should do a less intense treatment, even if somebody is fit. I just gave an example here of a chemo drug we use for patients that have this mutation called TP53.

(00:30:20) Some newer drugs are especially appropriate for older or less fit patients. So in treating patients that aren't as fit, this new drug came along a few years ago. It's called venetoclax, and it inhibits this gene and protein called BCL2. And BCL2 works in our cells kind of when our cells have lived off their lifespan. Excuse me a second. When they've lived out their lifespan, BCL2 actually helps them to die in a controlled way. So if BCL2 gets mutated in a cell, that cell can keep living a long time. And so we see that that can happen in AML cells, and it can contribute to the cells living a long time. The venetoclax inhibits the BCL2 and causes the leukemia cells to die.

(00:31:13) And so venetoclax, you can see up in the title here under the new England Journal of Medicine, it says azacitidine and venetoclax in previously untreated acute myeloid leukemia. So azacitidine has been around a long time, used to be used to treat myelodysplastic syndrome. Sometimes we used it by itself to treat acute leukemia, AML. So this study compared giving azacitidine plus venetoclax to giving azacitidine alone or with a placebo. And you can see that the survival of the patients that got azacitidine and venetoclax was much better than those who got the drug and the placebo. This has been a real advance for us in the treatment of AML. Again, not as good as we'd like, but it certainly has helped give better response rates.

(00:32:03) Some drugs are also now available in oral form. Now, azacitidine, as I mentioned, is also now available as a pill. So we call it an oral hypomethylating agent. And we can give this now to patients after they get into remission to see if we can keep them there as a maintenance treatment. And this study was done comparing giving the oral azacitidine to a placebo. And you can see the blue curve was better than the gray curve. So patients did better and lived longer if they got the azacitidine.

(00:32:42) Immunotherapy is a major advance in solid tumor cancers but not yet for AML. Now, we've been hearing a lot about immunotherapy of cancer that's made some major advances, particularly in solid tumors, like colon cancer, lung cancer. It's shown benefit in the other acute leukemia, ALL, but we've had more trouble in AML. And so these are some of the agents that we're using here on the left. These are still in clinical trials, and they're showing some benefit, but not as good as we'd like. And none of them have gotten FDA approved yet. So I'm not going to go into that a lot more.

(00:33:12) Several donor types are available to provide bone marrow or stem cells for transplant. So I want to finish up and talk a little bit about blood and marrow transplant. So on the left, you can kind of see how patients go through a transplant. You've got the patient on the left. They get chemotherapy or radiation therapy in high doses or moderate doses. They have their transplant, either with their own cells or with the cells from a donor on the top. And then they recover and are reconstituted. And we can get stem cells from the bone marrow. We can collect them from the peripheral blood. A baby's cord blood has a lot of stem cells in it, so there are cord blood banks available, and mothers are now approached to see if they would donate their baby's cord blood to a cord blood bank.

(00:33:54) The closer the match of donor to recipient, the less chance of graft-vs.-host-disease (GVHD) where donor cells attack the recipient’s body. So allogeneic, as we mentioned, means coming from another individual, and that could be a matched related donor. Donor could be a matched unrelated donor. Could be a mismatched related donor, a half matched. There's some at more risk of graft-versus-host disease in that setting. Sometimes we can even use a mismatched unrelated donor, or sometimes we can use cord blood. Occasionally, people have an identical twin, and we could use their cells. They're all the same. And then I mentioned autologous, where you use a person's own cells or marrow. And we don't tend to do that so much in AML.

(00:34:28) The chance of a fully matched sibling donor is 1 in 4. So what are the chances that a sibling would be a match with you? Well, it's about one in four, maybe a little better than that, one in three, because you get one set of proteins from your mom and one set from your dad. And you can see that makes four different combinations, and so you could have some siblings be a match and some not. I've sometimes seeing somebody with 10 siblings, and none of them matched. So that can happen too. It's kind of genetic roulette in a way.

 (00:34:57) So what are the chances of finding a donor? Well, again, about a third, we can find a sibling. We at one time said that some patients we couldn't find a match. That's less and less likely now. And then I mentioned unrelated donors and mismatched family members.

(00:35:16) Family members are most often half matched or haploidentical, and there are medications to minimize of control any associated GVHD. So now using half matched family members, that's called haploidentical transplant. So this could be your kids. Or if you have a child, it could be their parent. Sometimes a brother or sister could be a half matched. We might consider that. That used to be associated with a lot of graft-versus-host disease. So when we'd give the stem cells from the donor, they also got a lot of these T-cells. Those are thymocytes or lymphocytes, and those could react against the patient. That's what it means when it says alloreactive. And they react against the patient, and they proliferate and grow, and they can cause graft-versus-host disease. And now we give them a chemotherapy drug called cyclophosphamide, that's CY, at day three and day four after transplant. And we can get rid of these cells that are proliferating and causing graft-versus-host disease, or going to cause graft-versus-host disease. And then the ones that are not reactive, non-alloreactive, those persist and can help reconstitute or rebuild up the immune system. So that's allowed us to do half-matched family members.

(00:36:19) One trial found half matched donors to be better than cord blood. And then we did a study comparing half-matched family members, or haploidentical, to cord blood, where we gave two cord blood units, double cord blood. And haploidentical, or half-matched, was better.

(00:36:33) Traditional transplants used chemotherapy and radiation to wipe out diseased bone marrow. Now, when we do a transplant, we typically in the old days gave very high doses of chemo, or sometimes chemo plus radiation. These are some of the chemo drugs that we would use. And sometimes we'd give total body irradiation. And so this was called myeloablative. Myelo means bone marrow, and ablate means to wipe out. So that used to be how we always did transplants.

(00:36:55) T-cells from donor cells can have a graft-versus-leukemia effect that helps eliminates any remaining disease. We still do them sometimes this way, but then we subsequently learned that these T-cells that I talked about, they can cause graft-versus-host disease, but they can also attack the leukemia. They can recognize them as foreign, just like they recognize the liver or the lungs or whatever is foreign, and they can help get rid of the leukemia. And that's why transplant can be helpful in patients, because of this graft-versus-leukemia effect. That's the good part that we like.

(00:37:27) Donor cells can thus have both an undesirable GVHD effect but also a beneficial graft-versus-leukemia effect. This is a study done now 30 years ago, which showed that if people got graft-versus-host disease, these lower lines, they had a lower risk of relapsing. So the higher the curve goes up, the more the chance a relapse. So identical twin is great because they're all matched, but they don't get any graft-versus-leukemia. So their risk of relapse is higher. If you remove the T-cells, that's T depletion, you can get more relapse or recurrence of the leukemia after the transplant. So this just shows that the graft-versus-host disease, while it can make a person ill, it can also help fight the leukemia with this graft-versus-leukemia effect.

(00:38:07) If leukemia returns after transplant, “booster” cells from the donor, also called donor leukocyte infusions, can be helpful. So when we learned about this, we said well, let's give patients, if their leukemia comes back after transplant, let's give them a boost of these lymphocytes from the donor.... We call that a donor lymphocyte infusion... to try to get them to attack the leukemia and help get rid of it. Now, that can cause more graft-versus-host disease, but sometimes, not always, it can be helpful in fighting the leukemia. And it works best in a leukemia we don't transplant anymore, called CML, chronic myeloid leukemia, up at the top there. Doesn't work quite as well, obviously, as you can see, in AML and all, although it still has some benefit there.

(00:38:47) Reduced intensity transplants are now more common to encourage the graft-versus-leukemia effect. So when we knew there was this graft-versus-leukemia effect, we said well, let's not give such high doses of chemotherapy. We call that the conditioning regimen. Let's reduce the intensity of the conditioning regimen. That's what we call the transplant, a reduced intensity conditioning transplant, or a RIC. We thought we had to make space in the bone marrow, but we don't. We just have to suppress the recipients so they'll accept the cells from the donor. So we call this reduced intensity, or non-myeloablative. We're not ablating the bone marrow. And you can see, you got a patient on the left there, and the A cells are their cells. The AL cells are the leukemia. You do the transplant, some of their good cells and some of their leukemia cells can persist. You can give them a donor lymphocyte infusion and convert them over to all donor. And that's what we want. That lessens the risk of the leukemia.

(00:39:42) Reduced intensity transplants are more easily tolerated by older patients. So these are RIC transplants, and this has allowed us to offer transplants to older individuals. And you can see here that over the years on the bottom here, these are the different ages of donors. So the blue are patients under the age of 18, kids. Green is 18 to 39. Orange is 40 to 64, and blue is above 65. So we're doing more transplants for patients over the age of 65 now, because we can do the reduced intensity. And survival has improved over time with using these different approaches. And also we have better antibiotics, better supportive care. So you can see the top curve is 2016 to 2018. These are for adults with AML. The solid blue curve is back 2001 to 2005. But transplant is still a big undertaking. It's still risky, but the outcomes are improving.

(00:40:41) AML is a category of several disease with several new medications to improve treatment. So I'm going to conclude there. I've covered a lot of ground. I've tried to show you that AML is not one disease, but it's a heterogeneous disease with multiple subtypes, based somewhat on the cell that it originates from, but also on those chromosome or cytogenetic and those molecular abnormalities.

(00:41:02) We have some new medicines now that are improving things. They're not, I'll say home runs, but they definitely have improved things and made things better than they were. And some of them target specific gene abnormalities, like FLT3 or IDH, in the leukemia cells.

(00:41:18) There are now better ways to identify and treat even low levels of leukemia, and donors can be found for almost all eligible patients. Now, one thing I didn't talk about so much, but we can now pick up low levels of leukemia. And we call it minimal residual disease, or sometimes we say measurable residual disease, where it seems like there's a normal number of blasts in a bone marrow, but some of them be leukemic, and we can detect those now. And we know if we find that, if someone is MRD positive, minimal residual disease positive, [inaudible 00:41:42] after treatment, that we still have something more to do to try to get that under better control.

(00:41:48) And now with these new advances in BMT, we can identify a donor for almost everyone, and we can offer BMT transplant to older individuals in the attempt to improve outcomes and cure more patients of their leukemia.

(00:42:05) I think that's my last slide. And I'm happy to answer questions. And again, thanks very much for giving me this opportunity.

(00:42:17) [Susan Stewart]          Q & A. Well, thank you very much, Dr. Litzow. That was an incredibly comprehensive, complicated, and informative presentation about AML. And we have a lot of questions. The first question that came up was, "If someone has been cured of AML as a younger person, what's the likelihood that that person will relapse at an older age?"

(00:42:45) [Dr. Mark Litzow]      That's pretty unlikely. If someone's going to relapse, they typically relapse within the first few years after their transplant. I mean, I have to tell my patients that I can never say never. Unfortunately, and it's been rare, but I've seen patients relapse eight, 10 years after their treatment or after a transplant. But that's unusual. So if someone is in remission at a young age and they stay that way for a long time, it's very unlikely that the leukemia is going to come back.

(00:43:20) [Susan Stewart]          All right. The next question is, "Do you think all stem cell transplant physicians should routinely order advanced genetic testing panels in conjunction with bone marrow biopsies? Is it true that one panel is inconclusive, that some genes drop off and new ones are added with sequential testing in conjunction with bone marrow biopsies?"

(00:43:48) [Dr. Mark Litzow]      Well, that depends a little bit on when they were tested. I mean, we try to test all patients at diagnosis to see what gene abnormalities they have. If they should relapse, then we want to test them again at that time. If they're going to transplant and they're in remission and a bone marrow is done right before the transplant just to make sure they're staying in remission, it doesn't necessarily need to be done at that time. Now, remember I talked about leukemia being a clonal disease, rising from one or a few cells. Well, what we're learning is that in many AML patients, they could have multiple clones. So they could have two or three clones or more. And there's one that dominates a diagnosis, and that's the one that we see the most. And then they get rid of that with treatment, but then they relapse. It could be one of these other clones coming up. And so that other clone could have different genetic abnormalities. But sometimes the genes that were seen at diagnosis that were abnormal, they disappear, and new ones are seen when the leukemia comes back.

(00:45:07) [Susan Stewart]          All right. The next question is, "If you have the DDX41 mutation, is there anything you can do to help prevent AML from occurring? Or is it just a waiting game?"

(00:45:22) [Dr. Mark Litzow ]      Well, unfortunately, I have to say it's kind of a waiting game. We don't have a known method right now to alter that. We're working actively on that with, I won't say just with DDX41, but with some of the other gene abnormalities. I actually have a family here that I have taken care of with a DDX41 mutation and some individuals in the family who have it, and they're, I'll say getting more mature... Let me put it that way... getting older, and we haven't seen it. So it doesn't inevitably happen in every family member, but it is challenging to know that other family members had that, and now you have it and not necessarily something we can say that we can do to prevent that right now.

(00:46:19) [Susan Stewart]       All right. The next question is, "If AML almost always comes back after induction, what does a favorable risk category mean? Does it mean the likelihood of recurrence or likelihood of successful consolidation? Is higher or lower? What does it mean?"

(00:46:40) [Dr. Mark Litzow]        Well, what I meant by that is that if you stopped treatment after induction and didn't do any more treatment, the leukemia's almost always going to come back in every patient. So with a favorable risk, you still need to give the consolidation chemotherapy. And we take the cytarabine and give it in a higher dose by itself, and that seems to be particularly effective in the favorable risk patients in keeping them in remission. So the favorable risk, you need induction and consolidation, but in many of those patients, you don't need a transplant, particularly in first remission. So I just want to clarify that you do need the induction and the consolidation to keep them in remission.

(00:47:26) Now, some of those patients can be MRD positive, even though they're in remission, and that's, again, a different situation. And that's when we would worry more about those patients and we might think about transplanting them. [crosstalk 00:47:37]. That's the minimal residual disease.

(00:47:43) Now, typically the definition of remission was that there's less than 5% blasts in the bone marrow. That's what's normal, but we now know that some of those blasts could be leukemic, and some are not, because when the pathologist looks under the microscope at a blast cell, any individual one, they can't say this one's a normal one, and this one's a leukemia one. Sometimes they can, but most of the time they can't. So we use this machine now, or we use some gene tests. That way we can pick up small numbers of leukemia cells. And that's the minimal residual disease. It's minimal, but it's residual, still there. It's part of the disease.

(00:48:21) [Susan Stewart]          All right. The next questioner wants to know, "How should the standard treatment be modified because of the presence of FLT3-ITD? And do you recommend post-transplant maintenance with a FLT3 inhibitor? And if so, which inhibitor would you recommend?"

(00:48:43) [Dr. Mark Litzow]      Wow. Those are knowledgeable and great questions. So the ITD is one of the gene abnormalities in the FLT3 gene. And that's the one we worry about the most. Now, that's the one where midostaurin as a FLT3 inhibitor was approved by the FDA to give with the seven and three chemotherapy. And that showed a better survival. So we modify the treatment. Now, if a patient has as a FLT3-ITD, then we add midostaurin to their chemotherapy, both for the induction and the consolidation, but we still think that that's a poorer-risk leukemia. And for those patients, we do think that if we can get them to transplant, we should.

(00:49:31) Now, the question about the post-transplant maintenance, could you bring that question back up, Sue, just so I can make sure that I-

(00:49:39) [Susan Stewart]          Let me see if I can-

(00:49:40) [Dr. Mark Litzow]        [crosstalk 00:49:40] if you're not able to. I think I can. So you asked about should we give something after transplant to help-

(00:49:47) [Susan Stewart]          Right.

(00:49:47) [Dr. Mark Litzow]        Lessen the risk of the leukemia coming back? And you mentioned gilteritinib, midostaurin, or sorafenib. So I'm going to say that's a controversial area, and there's not a clearcut answer. There were studies done, particularly with sorafenib that suggested when that was compared to other patients that didn't get it, not in a randomized study, but just looking back at groups of patients, that the patients did better if they got sorafenib. So that would suggest that that might be a good idea to do. Now, there was just a big clinical trial where patients got randomized after transplant, either gilteritinib or a placebo, and that study finished last year. And now we're waiting to see the results. And that should be definitive to tell us whether adding gilteritinib after transplant is beneficial or not. I will say that in most of my patients, I do discuss this with them and consider trying typically either gilteritinib or sorafenib. Midostaurin might have some benefit as well, but we think it might be, in this setting after transplant, maybe not quite as good.

(00:51:06) [Susan Stewart]          All right. The next question, "I don't see the DNMT3A mutation listed in your slides. Does that mean it hasn't been risk stratified at this time?"

(00:51:20) [Dr. Mark Litzow]        No, no, that's not the case. I mean, there's just so many genes that I could mention. I mean, that's an important gene that we take into account. Its significance depends a little bit on the other genes that might be mutated at the time. There was one study that suggested if you have a high level of the mutation, there's, say more of the cells that have it, but that could be a poorer prognosis factor. So it's one we definitely take into account, either in the context of the other genes, or if we see it at a high level, we worry a little bit more about that being associated with a poorer prognosis. It's that there's a whole other aspect of that too that I won't get into a lot, but there's some people, like my age, if you tested my bone marrow, I could have like a DNMT3A mutation in my bone marrow and it won't necessarily mean I'm going to get leukemia or MDS, but it's something that just happens as we get older.

(00:52:37) [Susan Stewart]          All right. So next question, "Does a successful treatment for AML eliminate both the cancer as well as the genetic and chromosomal abnormalities? Or do they remain even if the patient is cured?"

(00:52:54) [Dr. Mark Litzow]        Well, in most instances, we think we need to get rid of that as well. And then if those are still around after the transplant, even if someone's in remission, we worry that there's more risk of relapse. That's kind of a short answer. There's not sort of one answer to that to say that that's always the case, but I would say in general, if a person's in remission, the blasts are at a low level, but we still see the genetic abnormalities, we worry that there could be more risk of a leukemia coming back.

(00:53:32) [Susan Stewart]          Okay, next question, "I have a germline GATA2-P161A mutation. I was told it is now considered a benign polymorphism. Can I have CMML? You listed GATA2 as an adverse prognosis for BMT. Is that true for the P161A variant?"

(00:53:58) [Dr. Mark Litzow]        Oh boy. I'm going to have to beg a little bit of ignorance on that one. I mean, I would have to look that up. And I don't know every nuance of these gene abnormalities. I mean, I think if you were told that it was a benign variant, I mean, the different subtypes of these genes are important, but if you were told it was a benign variant, that's likely true. We call that GATA2. If somebody will say somebody has GATA2, well, you can't just stop there. You do have to look at these different subtypes before you can and make a definitive opinion about that.

(00:54:47) [Susan Stewart]          All right. The next questioner said, "Did you say everyone can have a transplant donor these days due to advancements? And if so, can you please clarify that and expand?"

(00:55:01) [Dr. Mark Litzow]        Sure. Well, what I meant by that was that the options for donors include a matched sibling. That's about, as I said, maybe 25% to 30% chance, 35%. So if you don't have a matched sibling, then we would look for a matched unrelated donor. And we can find that often. If we don't have that, then particularly in our older adults, we like to have a young donor. We think a young donor is associated with less graft-versus-host disease.

(00:55:41) So people that have children, their children are going to be a half matched with them. And so they now can serve as a donor.

(00:55:52) We now more recently, with some of the advances we made with these half matched family members, have found that mismatched unrelated donors... So an unrelated donor is not perfectly matched with you. If we use that post-transplant cyclophosphamide, that looks encouraging for good results. So that's a fourth donor option.

(00:56:12) And then a fifth donor option is cord blood. And a baby's cord blood, remember I said, has these stem cells in it, and because their immune system, I'm going to say is more naïve, it hasn't been exposed to as many bugs over time for the immune system to get activated, so you don't have to have a fully matched cord blood unit to be able to use a cord blood. So oftentimes we can find a cord blood.

(00:56:40) So between all these different combinations, we can almost always find a donor for someone. I can't say that absolutely every instance 100% that's the case, because sometimes there's other factors that weigh into that, but typically, again, for almost everybody, we can find a donor.

(00:57:02) [Susan Stewart]          Okay. The next question is, "I have 15% blasts after relapse. Can I be treated to get into remission? And if so, how?"

(00:57:18) [Dr. Mark Litzow]        Well, you definitely can be treated. Exactly what to be treated with, I can't say because it's going to depend on what you got before, when the relapse happened. I hope that that gene mutation panel was done on your blast cells in the relapse, because let's say you now had a FLT3 mutation. That gilteritinib drug could be an option. Or if you had an IDH2 mutation or an IDH1 mutation, we now have drugs targeted at those. And those could be used. So I mean, a clinical trial might be an option. So there's a number of different possibilities there, but exactly which is the right one for you would just depend on knowing your history and when the relapse happened and what treatment you got before and so on.

(00:58:22) [Susan Stewart]          All right. Thank you for that. Next question, "I've had two failed stem cell transplants. I'm currently on gilteritinib..." I'm probably mispronouncing that-

(00:58:31) [Dr. Mark Litzow]        Gilteritinib.

(00:58:32) [Susan Stewart]          "For six months..." Thank you... "for six months, but still with 18% blasts as of the last biopsy. Any thoughts on treatment. I'm fit. Thank you."

(00:58:45) [Dr. Mark Litzow]        Well, there are other FLT3 inhibitors that are in clinical trials. So if you still have that FLT3 mutation, and it sounds like you may since you're on gilteritinib, it could be that a clinical trial with one of the newer FLT3 inhibitors that are not FDA approved yet, that that could be a possibility. Venetoclax, that drug that I mentioned, combined with azacitidine, that has some activity against FLT3.

(00:59:16) If you've already gotten treatment with that, that may not be an option. I mean, standard chemotherapy could be done, but that could be challenging to do if you've been through two transplants already. So I think that looking to see if there's one of the newer FLT3 inhibitors that's in clinical trials could be an option for you would be something to talk with your doctors about. If it's not available at your center, see if you could go to another center and get one of those drugs.

(00:59:53) [Susan Stewart]          All right. Thank you. Next question, "What would cause hemoglobin to keep dropping at 100 days after transplant? I was initially told it was the donor's blood type fighting with my blood type. Any other explanations? I've needed blood transfusions weekly."

(1:00:14) [Dr. Mark Litzow ]         Well, if it was what we call a major ABO mismatch, that's probably the main reason. There are some treatments that can be done to help get rid of that. With time, it may get better on its own. That often can occur, but I know it's challenging to keep getting blood transfusions.

(01:00:38) Sometimes the immune system... It sounds like you have your donor's immune system, but sometimes that can get out of whack a bit, I'll say, and cause what we call hemolytic anemia, where it can cause the red blood cells to break down faster and require more transfusions. Some of the medications you're on may be contributing to that. I assume you've probably had a bone marrow biopsy done recently, so I mean, I would hope that whatever you had the transplant for wasn't coming back. That's something we always worry about in the back of our minds. I think those would be the main things. I mean, sometimes people can bleed in their intestines and not really be aware of it so much. Typically, the doctors could pick that up. And that's not so likely, so I wouldn't be too worried about that, but something else that would cross my mind.

(01:01:36) [Susan Stewart]          All right. Next question. "I have a patient with MDS that evolved into AML, who had the SRSF2 mutation and now has progressed to-

(01:01:49) [Dr. Mark Litzow]        [crosstalk 01:01:49] venetoclax?

(01:01:54) [Susan Stewart]          There you go. "Is there a role for off-label use of a MEK inhibitor for this patient?"

(01:02:02): [Dr. Mark Litzow]      Yeah, I think there could be. I haven't reviewed that literature real recently. There is a MEK inhibitor called trametinib. So that might be a consideration. Yeah, I guess I don't want to give you definitive advice about that, but I think something you could discuss with your doctors and might be a consideration.

(01:02:28) [Susan Stewart]          Okay. Next question, "Is it normal to be losing weight after a transplant? And if so, what do you suggest to manage this?"

(01:02:40) [Dr. Mark Litzow]        Well, I'd want to try to look into the causes. Certainly, with graft-versus-host disease, people can lose weight if the graft-versus-host disease is affecting the intestines. So, I mean, I'd want to try to do testing to try to figure out why that is. I'd want to know how your appetite is. Sometimes after transplant, recovery of one's appetite can be challenging. So sometimes you just have to give it more time, and that will improve. And most people's tastes can be off for quite a while after transplant, and that can impact their ability to eat.

(01:03:24) [Susan Stewart]          All right. I think this will have to be our last question. First of all, he said, "Great presentation," and thanks you for that. But his question is, "Have there been any new findings in recent years about what causes AML? Is there an environmental factor or something else that's causing this disease?"

(01:03:45) [Dr. Mark Litzow]        Well, we're learning a little bit more about that. I mean, there are certain environmental exposures, but most people have not been exposed to those kinds of things. I mean, we know that exposure to benzene, people that work in petroleum plants, things like that. We know that cigarette smoking increases the risk of AML. I mean, some of these genetic abnormalities that we're hearing about, the question earlier about DDX41, there's certain other genetic conditions that can predispose the development of AML. In the vast majority of cases, what triggers that cell in the bone marrow to mutate and cause AML, we still don't understand sort of that initial step completely.

(01:04:40) [Susan Stewart]          Closing. All right. Well with that, we do have a few more questions. I'm sorry we can't get to them all, but I do want to thank you for a very wonderful presentation. That was very informative, very helpful to me for sure. And on behalf of BMT InfoNet, I want to thank you as well as Syndax, who did sponsor this webinar, as well as all of the people who participated and asked questions. Your questions were really wonderful, and it really helped us understand the topic more. This session was recorded and will be available on the BMT InfoNet website sometime next week. We'll send you an email and let you know when it's up. There will be a transcript of the presentation, as well as a copy of Dr. Litzow's slides. And as I said, we'll notify you when all of this is up and available to you. So please don't hesitate to contact BMT InfoNet at help, H-E-L-P, or by phoning 888-597-7674 if you have any questions or we can be of service to you. Thank you, everyone. Have a wonderful day. Hope you enjoyed the webinar.

(01:06:00): [Dr. Mark Litzow]      Thank you, Sue. Bye-bye.


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