Major Treatment Decisions for Patients with Acute Myeloid Leukemia or AML
Monday, October 17, 2022
Presenter: Fred Applebaum, MD, Executive Vice President and Deputy Director of the Fred Hutchinson Cancer Center
Presentation is 46 minutes long with 28 minutes of Q & A.
Many thanks to Syndax Pharmaceuticals whose support, in part, made this presentation possible.
Summary: Acute myeloid leukemia is a fast-moving cancer that can be fatal in weeks or months without treatment. This presentation reviews the causes, symptoms, and treatments for AML and recent progress in cure rates or prolonged remission for an increasing number of patients.
- Although some people have genetic predispositions to AML, more common causes include exposure to radiation, a history of heavy smoking, exposure to solvents like benzene and prior chemotherapy or myeloproliferative disorders that cause secondary AML.
- There are four major diagnostic tools for AML and all four should be utilized to get an accurate diagnosis in order to make appropriate treatment decisions.
- Favorable risk leukemias can often be cured without transplantation. Intermediate risk and adverse risk leukemias do much worse with standard chemotherapy alone and should be treated with transplantation if patients are fit and suitable donors are available.
(00:03:07): AML is more prevalent as patients get older.
(00:09:13): AML symptoms include fatigue, anemia, bleeding, and infections.
(00:14:21): Flow cytometry can produce a unique “fingerprint” of a patient’s AML and detect small amounts of residual disease.
(00:16:52): Cytogenetic testing can reveal chromosomal abnormalities.
(00:24:17): Treatment for AML at academic medical centers has a significantly higher success rate than treatment at community hospitals.
(00:27:13): Fit patients will be treated with induction chemotherapy while less fit patients may only receive supportive care.
(00:30:26): The ideal outcome of induction therapy is complete remission without measurable residual disease.
(00:36:34): In recent years there have been significant advances in transplantation including greater donor availability and more effective treatment of infections and other side effects.
(00:39:12): Less fit patients are also being treated more successfully with regimens that prolong remission although they do not provide a cure.
(00:42:16): In some cases, maintenance regimens may enhance patient fitness so that a transplant becomes a feasible option.
Transcript of Presentation:
(00:00:01) Susan Stewart : Speaker Introduction. Hello and welcome to the workshop, Major Treatment Decisions for Patients with Acute Myeloid Leukemia or AML. My name is Sue Stewart and I'm an AML and 33-year transplant survivor, and the founder and the executive director of BMT InfoNet, who's your host for this webinar.
I'd like to thank Syndax Pharmaceuticals whose support helped make this presentation possible.
Now it's my pleasure to introduce to you our distinguished speaker today, Dr. Fred Appelbaum. Dr. Appelbaum is the executive vice president and the deputy director of the Fred Hutchinson Cancer Center. He's the past chair of the Board of Scientific Advisors of the National Cancer Institute and is a member of the National Academy of Medicine. He has served as a board member on numerous scientific societies, including the American Society of Hematology, the American Society for Clinical Oncology, the American Association for Cancer Research, and the American Society for Transplantation and Cellular Therapy.
Dr. Appelbaum is head of the hematologic malignancies program at the Fred Hutchinson/ University of Washington Cancer Consortium and the principal investigator on several national Institutes of Health grants. He's the author of over 900 scientific articles and was the lead author on the first paper to describe the successful use of autologous marrow transplantation. In the early days of transplantation, Dr. Appelbaum worked closely with Nobel Laureate, Dr. E. Donnall Thomas, who pioneered the use of bone marrow transplantation to treat patients with blood cancers. Dr. Appelbaum's current areas of research center on the biology and treatment of hematologic malignancies, especially acute myeloid leukemia. Please join me in welcoming Dr. Fred Appelbaum.
(00:02:03) Dr. Fred Appelbaum : Thank you, Susan. It's a pleasure to be here to discuss acute myeloid leukemia which is, after all, a remarkably dramatic and difficult disease. It often comes out of the blue and therefore is a shock for the patients and their families.
(00:02:21): AML occurs in about 21,000 new cases in the United States every year. That's not as common, of course, as something like breast cancer or prostate cancer, but 21,000 is a lot of people. Unlike breast cancer or colon cancer, where people can live for months to years with the disease, if AML is not treated, it is fatal within weeks to months. Therefore, early appropriate diagnosis and treatment are incredibly important in managing acute myeloid leukemia.
(00:03:07): The disease is one that shows a dramatic increase as patients get older. On this slide, you can see that from the time from birth until about 50 years of age, the incidence of AML stays fairly constant at about three to four patients per 100,000. Once patients pass age 50, the incidence of the disease goes up dramatically.
Now that's in contradistinction to ALL, acute lymphocytic leukemia, which is much more commonly a disease of childhood with a peak incidence at between five to seven years of age. Thereafter, its incidence goes down and stays fairly constant over the rest of life.
In AML, on the other hand, there is this dramatic increase as one passes the age of 50, and that's thought to be due to the accumulation of mutations in the hematologic system with time. That isn't too different than the increase in many other cancers. This looks a lot like the incidence of colon cancer that goes up as you get older, lung cancer, and prostate cancer as well.
(00:04:25): Well, why do people develop AML? First off, there are increasingly a number of genetic predisposition syndromes that we've been able to identify. Some years ago, we used to think that AML was, by and large, a spontaneous disease, but more and more as the numbers of patients who are being followed with the disease increases, and we are doing more molecular testing, we're finding that it does, in some cases, run in families and have a genetic basis.
(00:04:55): Genetic predispositions linked to AML. There are three different kinds of genetic predispositions that we've identified. The first are what are called pure leukemia syndromes. That is multiple members of a family develop AML, and there are no other abnormalities detected. It just is a pure leukemia syndrome, and there are several of those, which are named after the gene that is mutated, for example, RUNX1 and GATA2. In these cases, a parent carries the mutated gene and the child inherits it; with time the inherited gene causes AML.
(00:05:24): Bone marrow syndromes linked to AML. There are also some syndromes where it's not just leukemia, but there's also marrow failure. These diseases are seen usually in childhood and include syndromes like Blackfan-Diamond syndrome, where patients who inherit the abnormal gene develop aplastic anemia or marrow failure and then go on to develop AML.
There are also some syndromes where there's multiple problems beyond leukemia that the patients can develop - other kinds of malignancies as well as leukemia. A classic example of that would be the Li-Fraumeni syndrome.
Then finally, there are some syndromes like Down Syndrome, chromosome 21 trisomy, where there's lots of developmental problems along with acute leukemia.
(00:06:07): Lifestyle and exposure risks that increase chances of developing AML.. Overall, if you look at the total incidence of AML, genetic predisposition probably still only accounts for maybe 10% of cases if that. Much more common are these other causes. We know that radiation can cause acute leukemia. If we look at survivors of the atomic bomb blasts in Hiroshima and Nagasaki, seven years later, there was a dramatic increase in the instance of AML.
(00:06:38): People that have a history of smoking, particularly heavy smoking, probably double or triple their incidence of AML. And exposure to certain solvents like benzene has been associated with AML. OSHA, the governmental agency responsible for making sure that workplaces remain toxin free, has really decreased the incidence of these sorts of leukemias by getting benzene exposure out of the workplace.
(00:07:12): Prior cancer treatment-related AML. Two other causes of AML are being increasingly experienced. The first is prior chemotherapy. As individuals are now surviving diseases such as lymphoma, where they are treated with an alkylating agent and an anthracycline, or adjuvant chemotherapy for breast cancer, or Hodgkin's disease, what we're seeing is that there is an increased incidence of them developing subsequent chemotherapy-induced AML. It usually comes on five to seven years after the exposure to these drugs, but there are a few cases where it can come on as early as 18 months in certain circumstances. The broad term we use for those AMLs is treatment-related AML or tAML. We'll talk a little bit more about that later.
(00:08:08): Secondary AML. There also are individuals who have myelodysplasia, which is a low-grade myeloid malignancy that can go on for quite a few years, or other myeloproliferative disorders like polycythemia vera or essential thrombocytosis. After a number of years, some of these more indolent myeloid malignancies can suddenly turn into acute myeloid leukemia. We call those secondary AMLs.
reatment related AMLs and secondary AMLs have a lot in common, and so sometimes they are lumped together when talking about AML etiology. Whatever the cause of AML, the clinical symptoms are pretty much the same.
(00:09:13): Symptoms of AML. Classically people will be fatigued, and that's because they are anemic and without enough red cells being produced by the disordered bone marrow, there's not enough oxygen being carried to the muscles and the brain, so people will be fatigued. They will be pale and not have the same exercise tolerance that they used to have. They will be needing naps. Generally, all the classic signs of anemia.
We also see thrombocytopenia., that is not enough platelets, in a lot of our patients. That leads to the problems of bleeding and bruising.
Oftentimes, because of AML, patients will not produce enough normal granulocytes. These are the cells in the peripheral blood that fight bacterial infections. And because of that, you can see fever, you can see non-healing infections of the skin, sometimes of the gums. Fatigue, bleeding, and infection are the common manifestations of acute myeloid leukemia.
Occasionally, the acute myeloid leukemia cells can form a mass, underneath the skin oftentimes. It's usually non-tender and soft, and those are called chloromas.
(00:10:33): How AML is diagnosed. To make the diagnosis of AML, one needs to show that there are sufficient numbers of leukemic blasts either in the peripheral blood or in the bone marrow.
(00:10:53): A “blast” is the word that we use to describe a cell that is obviously an AML cell, a leukemic cell. If there are more than 20% blasts in the peripheral blood, then a bone marrow exam is unnecessary. If there aren't enough blasts in the peripheral blood, then we need to do a bone marrow aspiration biopsy to make the diagnosis. Either in the peripheral blood or the bone marrow, we need to have 20% or more blasts to call it AML.
(00:11:21): There are four major ways that we look at leukemic cells. The first is morphology. That's looking through a microscope. A second is something called Immunophenotyping, which is also called flow cytometry. A third is cytogenetics and a fourth are molecular studies.
If someone is undergoing evaluation for acute myeloid leukemia, it's really important that all four of these categories of tests be done. Up until a few years ago, frequently there were patients diagnosed with AML at community hospitals where these tests were not routinely done. More recently, through educational programs including those developed by BMT InfoNet, the word has gotten out and so it's less common that patients don't have appropriate diagnostic studies done at diagnosis.
(00:12:27): This slide shows a picture of a leukemic blast. The cell in the corner has a dark blue central area, that's the cell nucleus and surrounding that is a gray area. That's called the cytoplasm. Then the other things you see in that picture are red blood cells.
An AML blast has a very large nucleus filling up most of the cell. The reason the nucleus is so large is that AML cells are dividing rapidly and the nucleus is the site of all the DNA. The DNA has to replicate before cells can divide and because there's so much DNA replicating, the nucleus gets very large and fills up most of the cell. That's what an AML blast looks like. That's the cell that's causing the disease.
Now, when you see it by itself, it's relatively easy to identify an AML blast. When you see it in a sea of cells, it's more difficult and quite frankly, often pathologists disagree about whether a cell is a blast or not, even if you have two or three different pathologists look at it. Morphology by itself is imprecise. It's also not very sensitive. Normal individuals can have a few percent blasts in the bone marrow that are not AML. You need some young cells after all, if your bone marrow's going to keep dividing and forming new cells, so 1 or 2% is normal. Anything above 5% is considered abnormal, but you need 20% to make the diagnosis of AML. Morphology by itself is how we used to make the diagnosis. Now we have other techniques that are more precise and more sensitive.
(00:14:21): The second way that we evaluate patients with suspected AML is something that's called flow cytometry. Now, I'm showing you this not because I expect you to become a flow cytometrist, but only to let you know what the doctors are looking at when they say they need to do flow cytometry. What they're doing is they're looking at 10 different markers on the surface of a cell. Each one is labeled with a different color or fluorochrome that lights up when a laser hits that cell. This is just a remarkable technology. The cells come through a capillary tube at 10,000 cells per second. A laser hits each one of those cells, that cell lights up and some combination of the 10 different colors light up on that cell and those are recorded.
Imagine if you wanted to describe a person. You might start by saying, "Well, let's look at their height versus their weight." After you determine those two dimensions, you could look at their skin color versus their hair color. Then look at their muscle mass versus their fat. By looking at all these different parameters, you eventually can get a fingerprint of that individual, which is unlike any other individual in the entire city. That's what this does. With flow cytometry, we're able to get a fingerprint of the leukemia, which is unlike any other cell in the body. Because of that, we are able to detect leukemia down to a range of one in a thousand or even one in 10,000 cells in the bone marrow.
Now, this is important for three reasons. Number one, it is reproducible, and is much more reliable in establishing a cell as a leukemic blast than morphology. Number two, the different fluorochromes that light up tell us something about prognosis. If you have a lot of, for example, CD33, that's a little better prognosis if you have very little CD33 on the cell surface.
Finally, after you are treated, you may look like your bone marrow has gone back into complete remission, but with flow cytometry, we can still detect some measurable residual disease, something called MRD, and that can be very useful in guiding further therapy.
(00:16:52): The third diagnostic test for AML is cytogenetics. Each of us have, in all of our cells, 46 chromosomes: 23 that come from mom and 23 that come from dad. (sperm and eggs are exceptions with only 23 chromosomes) These 46 chromosomes come in pairs. You have two chromosome 1s, two chromosome 2s, two chromosome 3s, et cetera. Now if you stop a cell as it gets ready to divide, the chromosomes thicken and start to look like these little worms, which you can then stain and visualize under a microscope.
Notice that the chromosomes have black stripes across them. Those are very reproducible and distinct for each normal chromosome. Now here the cytogeneticist has done us the favor of lining up each of the chromosome 1s and each of the chromosome 2s. Once they are lined up, the cytogeneticist can determine if they are all present and look normal.
Sometimes in AML the cell may lose a chromosome, or may gain a chromosome, or may have a chromosome that is broken. Sometimes when they break, one piece of a chromosome goes from one chromosome to another. Here you can see that there is a change where part of chromosome 8 has gotten stuck onto part of chromosome 21. That's called a translocation between 8 and 21.
(00:18:11): Cytogenetics is important to determine prognosis for an AML patient. Cytogenetics is not very sensitive, not nearly as sensitive as flow cytometry. But it is important because, first of all, it is often abnormal supporting the diagnosis of AML. Second, it's important determining prognosis. Patients that have AML with the 8, 21 translocation, for example, have a good prognosis, whereas those that have many more cytogenetic abnormalities, something that's called complex cytogenetics have a very poor prognosis. Finally, , historically it's been really important because it has allowed scientists to identify genes involved in leukemia. For example, the recurrent translocation from 8 to 21, suggested that at that site, there's a gene that's important in the regulation of myeloid cells and maybe that explains how leukemia develops. That, in fact, has turned out to be the case.
(00:19:11): The genes are that are actually mutated in AML are shown on this slide; these are so-called recurrent mutations in AML. As we have gotten better at being able to sequence the entire DNA of individuals, we have been able to find those genes that are recurrently mutated in AML.
(00:20:01): In a single AML case, usually there's about 12 different genes that are mutated in the person's AML. Six of those are what we call passenger mutations and have nothing to do with the leukemia. They just are random things that have happened in that cell. Six of them are related to the development of AML, and it takes probably a sequence of them to develop before you get overt AML.
(00:20:34): You can have a mutation in one gene. Let's say DNMT3A is mutated, but the cell still functions quite normally. You don't even notice that it's abnormal or hardly noticed it at all. It might be like driving in a car and the shock absorbers aren't working quite well enough. The ride might be a little bumpy, but the car still works just fine. With time, that bumpy ride can cause a second problem. For example, it can cause the brakes to start to fail. Now, the ride might be a little more abnormal. Because of all that shaking, the throttle becomes abnormal and the gas pedal can get stuck. You can imagine that suddenly you have a real problem. You can't stop your car. It's going too fast as you careen down the road and suddenly you have acute leukemia.
(00:21:25): Today, we can determine which genes are mutated in AML. We do that by DNA sequencing. This is really important because it tells us both the characteristics of the leukemia, that is, is it a good or bad prognostic leukemia. More importantly, it can guide therapy because with certain of these mutations now we have therapies that are targeted specifically for those mutations. The classic here is FLT3, which is probably the most frequently single mutated gene in AML. We now have a drug that helps specifically with FLT3 mutated AML.
(00:22:08): AML is classified into three main categories: favorable risk, intermediate risk and adverse risk. When we put all these things together, that is the morphology, the cytogenetics, the flow cytometry and mutations, we classify AML into three large categories. There are those that are called favorable risk, and these include AML with the translocation 8, 21 or inversion 16; those that have a mutation in NPM1, but not FLT3; and those that have a mutation in this gene called CEBPA. Then there's the broad category of intermediate risk AML. Finally, there are the bad actors, the ones that are adverse that have complex cytogenetics or abnormalities in p53 and a few others.
When we say favorable, intermediate or adverse risk, really what we're talking about is what happens if you treat the patient with standard chemotherapy and the patient is under age 65 and can get full dose therapies. With those caveats, our favorable risk AMLs have a cure rate, without transplantation, which is well above 50%. Those with intermediate or adverse risk disease, if just treated with chemotherapy, do much more poorly. Adverse risk AML, without transplantation, if just given standard chemotherapy, are probably cured in no more than 15% of cases or so. Because what we expect with conventional chemotherapy differs, our subsequent management of those patients is influenced by whether they're favorable, intermediate, or adverse risk.
(00:23:51): Summary of points made thus far. I'm going to pause at that point and just summarize what I've said so far. Acute leukemia is an explosive disease and in order to properly diagnose it, we need experienced pathologists to determine that there are more than 20% blasts in the peripheral blood or bone marrow. We also need to evaluate the leukemia using flow cytometry, cytogenetics and by mutational analysis.
(00:24:17): Where is the best place tot be treated for AML? Once all that's done, we're ready to start treatment. A question I’m frequently asked is “where should I be treated”? I will admit that this study may be viewed as self-serving. We looked at a large cohort of patients, over 60,000, and asked were they treated at an academic medical center (i.e.a cancer center) or were they treated in the community? By our analysis, which has been reviewed by others, your chance of living five years is almost doubled if you're treated at an academic cancer center, compared to treatment in a local hospital.. Your chance of dying within the first month is doubled if you're treated in the community versus at an academic center.
(00:24:59): Now, I will readily admit that there may be selection bias here, that is, those who are sicker and perhaps older didn't want to travel to an academic center and were treated in the community. We did try to do statistical corrections for those risk factors, but you never can be absolutely sure when it's not a prospective randomized study. Nonetheless, if it were me or a loved one of mine, there's certain diseases where you get great care out in the community. I think AML is one where it's such a difficult disease, it needs all the support that you get from infectious disease experts and everyone else. My advice is that if patients can be treated at a cancer center or an academic center, I would encourage them to do so. Having said that, I also understand that it can be quite an explosive disease and there may not always be time to arrange for that transfer. I think that most centers would be eager to try and help you make that happen.
(00:26:07): The first big therapeutic decision is whether the patient is viewed as being fit or unfit for aggressive therapy. In general, we view people as being unfit if they have advanced age, that means over age 70 or 75, and they also have significant comorbidities. Age by itself is not necessarily an overwhelming factor. Certainly, it contributes, but there are lots of 70-year-olds who are in good health, out jogging every day without comorbidities. On the other hand, there are some 60- or 50-year-olds who have significant comorbidities due to alcoholism or smoking, obesity, diabetes, or other medical problems.
(00:27:13): In general, if we view a patient as being fit, then they are treated with induction chemotherapy. That's an attempt to get the disease into a complete remission. We'll talk about what standard induction is in just a second. If patients are felt to be unsuitable for induction therapy, then there are a variety of approaches. Hospice may be a reasonable choice for very old patients with co-morbidities.
(00:27:52): For patients unfit for aggressive chemotherapy there are now less intense regimens that are being used with increasing success. In fact, this is probably one of the bigger recent advances in the treatment of AML (we’ll talk more about this in a bit).
(00:28:17): If we do treat with induction chemotherapy, then at the end of induction we reevaluate the patient and based on how that induction therapy went, we then decide what subsequent steps to take..
(00:28:33): The standard induction chemotherapy for quite a few years now has been a combination of two drugs: an anthracycline like daunomycin, idarubicin or mitoxantrone, along with cytosine arabinoside (also called Ara-C). There are other recipes that people use. Frequently physicians use higher dose cytosine arabinoside included in regimens such as FLAG-Ida, IA, or G-CLAM. Many centers are studying which induction regimen is best, and we always encourage enrollment on IRB-approved clinical trials.
(00:29:20): If patients have favorable or intermediate risk disease, then we would generally recommend adding gemtuzumab ozogamicin (Mylotarg) to the standard regimen. While standard regimens have included cytosine arabinoside and anthracycline, there have been three changes over the last few years. The first is that if patients have favorable or intermediate risk disease, then we would generally recommend adding gemtuzumab ozogamicin (Mylotarg) to the standard regimen. This is based on several prospective randomized studies which have shown an overall survival advantage with the addition of gemtuzumab ozogamicin to standard therapy, versus standard therapy alone in patients who have intermediate and good risk AML.
(00:30:02): If patients have FLT3 mutated AML, then we recommend adding midostaurin to the regimen (midostaurin is a specific inhibitor of FLT3). If patients have treatment-related or secondary AML, we would consider using CXP-351 instead of the standard daunomycin/ARA-C regimen, based on prospective randomized studies.
(00:30:26): After induction is completed and blood counts recover, patients are re-evaluated. The best outcome of induction, the one we hope for, is a complete remission without MRD (CR MRD-). Remember, MRD stands for measurable residual disease that we can detect using flow cytometry or more recently by PCR. The desired outcome with induction chemotherapy is that the patient recovers blood counts, and we cannot find any residual disease using these sensitive techniques.
If testing for MRD is either positive or unknown, then we refer to this outcome as CR (complete response MRD+ or unknown).
There's something called CRi, which means that we don't see blasts, but the patient's blood counts haven't returned to normal. Unfortunately, CRi predicts for a poorer outcome than seen with CR or a CR without measurable residual disease.
If patients do not achieve a CR or CRi, this means that induction therapy has failed.
(00:31:50): Well, what do we do after induction chemotherapy is done? The choice of next therapy depends on the response to induction and the disease categorization of the patient. For favorable risk AML, we do not generally recommend transplantation in first remission. These patients can be effectively treated with multiple cycles of high dose Ara-C containing consolidation chemotherapy, and we generally reserve transplantation until first relapse. However, if patients have measurable residual disease after induction, or if the disease went away and we see recurrence of measurable residual disease, then we recommend proceeding to transplantation in first remission, even though the patient has favorable risk AML.
(00:32:46): For intermediate risk AML, in general, we recommend an allogeneic transplant in first remission if a suitable donor is available.
(00:32:56): The definition of a “suitable donor” has widened dramatically over the last few years. Many years ago, it meant a matched sibling. With the development of unrelated donor transplantation and the creation of donor registries with over 40 million people typed around the world, matched unrelated donors became possible for many individuals. More recently, cord blood and the use of haploidentical transplants has broadened what we would define as a suitable donor donor. Today, we can find a donor for almost everyone in need.
(00:33:27): For most people with intermediate risk AML, we recommend transplantation in first remission, unless, they have comorbidities that make transplantation more dangerous, i.e.a comorbidity index of greater than 2. If a patient gets into complete remission and is MRD negative and has significant comorbidities, then in some patients we might hold off doing the transplant. However, for most patients with intermediate risk AML and a suitable donor, if patients get into CR, and whether or not they have MRD, as long as they're relatively healthy and have a suitable donor, we recommend transplantation in first remission.
(00:34:13): Finally, for patients with unfavorable risk AML, we recommend transplantation, if at all possible.
(00:34:27): If patients do not achieve a complete remission, we recommend re-induction attempts, optimally delivered as part of investigational studies.
(00:34:43): If patients achieve a complete remission and elect not to have a transplant, then there are some maintenance options. For patients who are FLT3 positive, we recommend continuing treatment with midostaurin for 12 months, as done in the initial Ratify study. If they do undergo an allogeneic transplant, there are now studies suggesting that maintenance with an FLT3 inhibitor is probably effective in this setting as well.
(00:35:19): If patients are not going to transplant and do not have FLT3 mutated AML, then there are some data that suggests that maintenance with azacitidine may be effective. The most compelling data about maintenance with azacitidine comes from the QUAZAR trial that evaluated Onureg, an oral form of azacitidine. .
(00:35:49): Onureg was approved for maintenance based on a prospective randomized study in patients over age 55 who had intermediate or unfavorable risk disease and were in CR1. Whether it works in younger or good risk patients is uncertain.
(00:36:34): Transplantation is much safer and more tolerable than it was 20 years ago. We see much less in the way of transplant-related complications. We are better at preventing and treating infections with better antiviral and antifungal agents. We are better at avoiding direct organ toxicities by our selection of preparative regimens that fit the health of the patient. We have better ways of reducing or preventing graft-versus-host disease. Finally, we're better able to eradicate the leukemia with a transplant.
(00:37:28): The following information comes from three decades of work at the Fred Hutch. We studied over 1,400 transplants that we performed in Seattle between 1993 and 1997, including all patients that received a first allogeneic transplant for a hematologic malignancy. As you can see, there was about a 50% survival at three years.
(00:37:56): We then looked at patients we transplanted a decade later from 2003 to 2007, with the same criteria for entry into the study. As you can see, overall survival improved dramatically over that decade. This was largely because we were better able to avoid direct organ toxicities, prevent infections and prevent GVHD. In fact, between 2003 and 2007, the patients that were transplanted were older, had more co-morbidities, and more advanced disease than the earlier cohort. The curves are not adjusted to reflect these differences, and so the improvement is even more marked than it appears on the slide.
(00:38:36): Then we looked at yet another cohort of around 1,200 patients transplanted from 2013 to 2017.. Again, the improvement continues in disease-free and overall survival. We are, of course, hopeful that when we look at a fourth decade of patients, from 2023 to 2027, the trend will continue.
(00:38:56): This isn’t to say that transplantation is an easy procedure or risk free, far from it, but it has dramatically improved.
(00:39:12): For patients who are not a good candidate for intensive induction chemotherapy, there are regimens that can prolong life, but are not curative. There are patients who are felt to be unfit for intensive induction chemotherapy. In general, this means patients who are over age 70 and have a comorbidity index of two or greater, or have an ECOG performance status of three or more, but the definitions vary from center to center. There are a number of new regimens being developed for such patients.
(00:39:58): These regimens are not designed as curative therapies. They are designed to try and get a person into remission and keep them there as long as possible. The therapies generally are continued as long as the patient continues to respond. We don't know about the relevance of MRD when we use these less intensive therapies. Also, we are lacking results from a really good prospective randomized study comparing intensive to less intensive induction chemotherapy in AML. Such studies are ongoing, but we do not have the results.
(00:40:41): There have been large retrospective analyses, and we recently published such a study in the journal BLOOD with Mohamed Sorror as the first author. In our study, compared to non-intensive induction, intensive induction therapy was of benefit for older individuals even those in their 70s with comorbidities. Again, that was not a randomized prospective study.
(00:41:08): The regimen that has gotten the most attention is a combination of azacitidine plus venetoclax. That interest came from the so-called VIALE-A trial. Those results are shown in this slide where you have patients who are randomized to the combination of azacitidine plus venetoclax versus azacitidine alone. The CR rates were the composite CR rates, and that includes CR and CRi. They more than doubled with a combination of azacitidine plus venetoclax versus azacitidine alone.
(00:41:47): It generally takes two to three cycles before a maximal response is achieved. The median overall survival with the more effective arm was still only a little over a year, 14.7 months. By a year, about half the patients had died even in a more effective arm, so not where we want to be, but better than where we were.
(00:42:16): Again, the goal here is probably not cure. Although the optimal duration of therapy hasn’t been determined, most physicians continue therapy as long as a response is maintained. Once the therapy fails, unfortunately, survival is quite short. If you do get a CR with azacitidine and venetoclax, there are some patients whose overall performance status dramatically improves because they've gotten into remission with azacitidine and venetoclax. Some of these patients then do go on to transplantation and may be able to be cured in that setting.
(00:43:06): I've been talking for a little less than 45 minutes or so. We want to make sure that we have time for answering questions that the audience may have. I would like to just summarize some of the key points I tried to make during my talk.
(00:43:24): Summary of presentation: First of all, the diagnosis of AML generally requires 20% or more blasts, and this can be from the blood or the marrow. We need to have both morphology and flow cytometry along with cytogenetics and molecular data to appropriately risk stratify patients and to follow them once they get into complete remission.
(00:43:51): In general, we would urge patients to be treated at academic cancer centers if possible. Retrospective analysis suggests that outcomes are improved.
(00:44:03): Once patients get into complete remission, other factors that can influence what is done includes their age, their functional status, how well their counts recover after they were given chemotherapy, and whether they have minimal residual disease.
(00:44:22): For fit patients, we generally recommend intensive induction chemotherapy. We add to that gemtuzumab ozogamicin for good and intermediate risk and midostaurin for FLT3 positive mutated disease.
(00:44:39): There are these new molecularly targeted drugs that have been FDA approved, if patients do not go to transplant, maintenance may be appropriate for many of those.
(00:44:51): We do recommend transplantation for eligible patients who have intermediate or high-risk disease and are fit enough for the procedure.
(00:45:00): The combination of venetoclax and azacitidine looks remarkably effective compared to what we had available to us in the past. Now, whether that is superior to intensive chemotherapy is a big unanswered question.
(00:45:16): With that, I will pause. Thank you for attending the webinar. I also need to thank thousands of AML researchers who have been involved in the development of all this information, and of course, the patients who have been on clinical trials allowing us to amass this knowledge. With that, I will pause and be happy to answer any questions.
(00:45:43) Susan Stewart: Thank you, Dr. Appelbaum. That was an excellent presentation. A great summary of treatment options for patients with AML. Now begins the question and answer session. If you do have a question, please type it into the chat box on the left side of your screen.
(00:46:03): You referred several times to a haploidentical transplant. Can you explain what that is?
(00:46:12 )Dr. Fred Appelbaum: Sure. HLA is a group of genes that are located on chromosome 6, and they're all close together. You get one chromosome 6 from mom and one chromosome 6 from dad. Since mom has two chromosome 6s and dad has two chromosome 6s, the chance that any two siblings will inherit the same two chromosome 6s is one in four. That would be a complete HLA match. We sometimes call it an eight of eight match, because there are 4 HLA genes on each chromosome that are the primary ones of interest.
Sometimes you'll have siblings who will inherit the same chromosome 6 from mom, but different ones from dad. They're matched for one of the chromosomes but not for the other. Those siblings are said to be “haplo-identical”. Everyone is a haplo-identical match to their biologic mother or father because you inherit one of their chromosome 6s and not the other one.
Some years ago it was almost unthinkable to use donors who were mismatched for a whole chromosome 6. Then investigators first in Italy (Velardi and company), using a method of T-cell depletion, and more recently, the group from Hopkins using post-transplant cyclophosphamide, have demonstrated that, in fact, you can use donors who are only haplo matches. That is, mothers [or fathers] for children, and siblings who inherit only one of the two chromosomes from the same parent. Those are haplo matches, and because most people have a parent or a child who might be healthy enough to donate, or a sibling who is a half match, that means that we can now find donors for almost all patients in need.
Now, the outcomes with haplo identical transplants aren't quite as good as with fully matched siblings, although the difference between the two has been shrinking dramatically over the years. There are some institutions where they would use a haplo match rather than a fully matched unrelated donor. There are other institutions that haven't made that switch, and whether haplo identical transplants are better than cord blood is yet another question. The choice of donor between matched sib, matched unrelated, cord blood and a haploidentical donor is a highly debated research topic. It's much better to have that as a research topic than not to have donors at all.
(00:49:04) Susan Stewart: The next person wants to know if you can provide some statistics on survival rates for AML patients who undergo the transplant?
(00:49:16) Dr. Fred Appelbaum: Well, the survival statistics for AML for patients who undergo transplantation depends a great deal on the patient's characteristics. That is, are they younger? Are they older? Are they in a complete remission or do they have minimal residual disease? Are they being transplanted for good risk AML, poor risk AML, and are their donors matched siblings, matched unrelated, or cord blood. There's a wide range. However, if you take our studies in Seattle and you look at our most recent data for AML for patients age 55 and younger, who have been transplanted in first remission from a matched sibling or matched unrelated donor, we have a remarkably good outcome with about an 80% cure rate.
I just want to be sure, Susan, that you heard the caveats I said. Those are patients under age 55 who are getting high-dose myeloablative regimens with matched siblings or matched unrelated donors. This doesn't include patients who are over age 55. It doesn't include patients who have large amounts of residual disease or are getting mismatch transplants. But overall, in every category of transplantation, things are really getting better.
(00:50:40) Susan Stewart: Well, that is encouraging. We have a couple questions about the relationship between age and eligibility for transplant. One person wants to know whether a 76-year old physically fit person can undergo intensive conditioning safely? The other wants to know whether age alone determines whether intense therapy is appropriate, if there are no other comorbidities?
(00:51:05) Dr. Fred Appelbaum: Oh boy, that's such a good question and such a hard one. It's one I do a lot of consults for, and it really does depend on what the patient's life goals are. If you are 76 and have lots of comorbidities, and you have something that you'd like to do in six months that's going to be the most important thing in your life, probably I wouldn't recommend a transplant. But if you're 76, you're healthy, you've gotten into a complete remission and you have the goal of being alive in 10 years, then yes, I would encourage people to consider transplantation.
One thing that's happened is we have developed preparative regimens here in Seattle and elsewhere that are relatively non-toxic, such as one composed of fludarabine and low-dose TBI. We can do that transplant as an outpatient. Oftentimes, patients never even get hospitalized. Now there can be problems with graft-versus-host disease and infection, so it's not a walk in the park. I would never want to tell someone that it is, but it can be remarkably non-toxic in some patients. Just this last year, I was attending on two patients who were age 78 and 79, both of whom went through the transplant without major problems. I've also seen patients in their early 70s that have quite a few complications, and there is a mortality rate of up to 20% due to complications of the transplant over the first two years. It's not an easy choice. In Seattle, we would not rule someone out on age alone up until probably they get to 80 or so.
(00:53:25) Susan Stewart:: All right. This person just had a transplant in July. She's a 52-year old female. She had FLT3 very low ratio, wants to know a couple things. Would she be considered a favorable risk or an intermediate risk? She's also commenting that today's day 90. She just had bone marrow biopsy and she's wondering if she should be put on a targeted drug for FLT3. If so, what would it be and for how long?
(00:54:00) Dr. Fred Appelbaum: The studies are not definitive yet. Some people would err on the side of comission and use a drug. Some people would say, "Well, the studies aren't totally known yet and the drugs do have toxicity, so let’s wait until we know definitively." In Seattle, we would err towards putting patients on FLT3 inhibitor after the transplant if they had FLT3 positive AML. Now, she said that she was a low allelic ratio initially. Is that right?
(00:54:33) Susan Stewart : Correct.
(00:54:35) Dr. Fred Appelbaum : How low?
(00:54:37)Susan Stewart : She didn't say.
(00:54:39) Dr. Fred Appelbaum: I want to caution people. I'm not seeing the patient, I'm not reading their chart. I hate to give individual patient advice without actually being responsible for taking care of the patient. I think those are important caveats. My choice would depend on the allelic ratio. It also depends on what other mutations the patient has along with the FLT3. If they're NPM1 negative, for example, then that still is a higher risk that if they were NPM1 positive. Currently, patients who are NPM1 positive with low allelic ratio of FLT3 are generally considered to be relatively good risk.
(00:55:27) Susan Stewart: The next person said he has been doing well for over a year now on azacitidine and venetoclax, and wonders when you would consider a transplant? Wait till relapse or earlier? He is fit and is 73.
(00:55:47) Dr. Fred Appelbaum: Well, again, if he waits till he relapses, the chance of a transplant working is low. He's unlikely to get back into a complete remission. The transplants carried out for people that have active disease just don't do nearly as well. If he ever wants to consider a transplant, he should do it while he's in remission. That doesn't mean he should do a transplant. I'm just saying that if he is someone who thinks that they want to have a transplant at some point they ought to get it while they're in remission. Waiting until relapse, it's unlikely that they'll be able to get an effective transplant because once you relapse, it's very hard to get people back in remission after they fail a year of azacitidine and venetoclax. If you try to do a transplant with active disease, the chance of the transplant working is much, much less.
(00:56:43) Susan Stewart: This next person has a donor question. She wants to know if you're 62 years old and you had a choice between a 12 out 12 matched related sibling... Actually, she's 64, the sibling is 62 years old and is a 12 out of 12 match…or she could choose a 20-year old who is a 10 out of 10 matched unrelated donor. Any opinion on that?
(00:57:09) Dr. Fred Appelbaum: Well, there have been multiple research articles published about this question. Half go one way and half go the other way. There's still a lot of debate about this, about whether an older sibling or younger matched unrelated donor is preferable. I don't think that the answer is clear-cut. It also depends on what kind of transplant the person is going to undergo, what preparative regimen is planned, and what form of GVHD prophylaxis is anticipated. There's no easy answer for this one. Different transplant centers may give you a different answers.
(00:57:56) Susan Stewart: The next person wants to know if you have a better chance of survival if your AML is caught early versus late?
(00:58:11) Dr. Fred Appelbaum: We don't know that to be honest. There is no way to do that study because you don't know if it's caught early or late. What you know is what the white count is at diagnosis, but is that because the disease is growing more rapidly? If your count is very high, does that mean the disease was caught late versus early? Now it does, of course, make intuitive sense that finding it a little earlier when there are fewer leukemic cells should be of some advantage. That's hard to prove. In mouse models, if you inoculate fewer leukemic cells, you can cure the mouse more easily both with chemotherapy and with the allogeneic transplants. So that suggests that there might be some advantage to early diagnosis. But we really can't prove that definitively.
(00:59:33) Susan Stewart: The next question comes from a 55-year-old female who had a stem cell transplant from a 100% matched sibling donor, but she relapsed seven months after transplant. She's now considering a trial using CAR T-cell therapy. Can you comment on CAR T-cell therapy to treat patients with AML?
(00:59:54) Dr. Fred Appelbaum: Unfortunately, it's been much more difficult to develop effective CAR T-cells for AML than it was to develop CAR T-cells for ALL, CLL, and lymphoma. The ALL, CLL and lymphoma CAR T-cell studies targeted something called CD19, which was expressed heavily on the malignant cells. You could wipe out the CD19 cells, whether they're malignant or normal, without a great deal of toxicity to the patient. It's surprising, but you can live pretty normally without any normal B cells for some period of time. In addition, the CLL cells and ALL cells just are intrinsically more sensitive to the killing by a CAR T-cell.
In AML, we don't have that good a target. People have been trying to find what is an optimal target for AML. Unfortunately, most of the targets that people have studied, the three most commonly being CD33, CD123, and WT1, are also expressed on normal early hematopoietic cells, at least CD33 and CD123 are. A result is that patients get significant pancytopenia with the CAR T-cell, because you are eliminating normal blood forming cells. In addition, AML cells don't seem to be quite as sensitive to direct killing.
Now, having said that, there's a lot of incredible science that's going into the development of new cell immunotherapy. No T cell therapy for AML has been FDA approved. But there are clinical trials ongoing, and if a patient has access to such a trial, I would encourage participation.
(01:03:16) Susan Stewart: The next person has a question about cord blood transplant. They want to know whether cord blood has to be HLA matched like marrow or stem cells.
(01:03:26) Dr. Fred Appelbaum: Actually no. In fact, that's one of the really important points about cord blood. When we first started doing cord blood transplants, almost all the cord blood transplants were done using incompletely matched cords - well, the unrelated cord blood transplants, I should say. There were some related cord blood transplants that were done using matched cord, but those are almost all for infant or childhood diseases. For adults, the cord bloods that were being done, were all mismatched for one or two antigens.. Surprisingly, we did not see a big increase in graft-versus-host disease. In fact, if anything with cord blood transplants, we saw less, certainly less chronic GVHD than we saw with unrelated donor transplants. Today we are able to perform cord transplants that are mismatched for two or more antigens. That has been really important, particularly for patients without matched siblings or matched unrelated donors.
Of course, I think most people know that it's much harder to find a matched unrelated donor for people from ethnic minorities, whether it be Hispanic or Black, and for people of mixed racial background. Now the reason for that is an interesting story of anthropology. Modern humanity began on the African continent. Every HLA type is represented there. With time, populations of individuals left and carried only a subset of HLA types with them.
There are HLA types that are relatively homogenous within certain populations. For example, among the Japanese, there's a smaller number of HLA types comparatively. There's just much, much more heterogeneity in African individuals or people in the United States of African descent, similarly among Hispanics. With all that heterogeneity, it's tougher to find a matched related donor, which makes cord blood an important source of stem cells. Now, with the development of haploidentical transplants, though, many people are starting to favor haplo over cord, although whether that's really the right thing to do is still, I think, debatable. Each has its own advantages and disadvantages in particular situations.
(01:06:05) Susan Stewart: This person has a question about what is considered full recovery of blood counts after a stem cell transplant. For example, four years ago he had a transplant and his platelet count currently hovers around 150 or slightly less. Other blood counts are not too bad. He's considered immunocompromised by the oncologist, and he wonders is that considered for sufficient blood counts or does he need more?
(01:06:37) Dr. Fred Appelbaum: I'd have to know more about the specific patient. A platelet count of 150,000 is just fine, and that would be considered normal. That in and of itself wouldn't by any means represent any kind of compromise in function, either immune or blood clotting or anything else, so 150,000 platelets is fine..
(01:07:14) Susan Stewart: This gentleman wants to know when TET2 is present, does that pose a problem in transplant?
(01:07:23) Dr. Fred Appelbaum: TET2 is one of those mutations that we talked about. TET2 by itself doesn't really influence things very much. It would depend on what else it's with and what the other characteristics of the disease are. TET2 is not something that by itself independent of everything else, would have a huge influence.
(01:07:56) Susan Stewart: I think this gentleman is asking a question that I've heard from a number of patients, why is it so difficult to learn the outcome of clinical trials? As an AML transplant survivor. I participated in three clinical trials over five years ago and have no idea of their success.
(01:08:16) Dr. Fred Appelbaum: Well, I would call the center where I was treated and get the result. Certainly, they owe it to people. Now, I would say that there might not yet be results from a trial someone participated in five years ago. Remember that for a study to have its result, all the patients have to be accrued, right? You might have to randomize hundreds of patients and if you're patient number 10, you still have quite a few patients to go. It can take a long time to accrue those other patients. Once those patients are accrued, then they have to be followed for a certain length of time to reach the endpoint. Once the endpoint is reached, then you have to go through all the data. There have to be audits to make sure all the data is accurate, reviewed. The statisticians have to go through it to summarize all the data. Then finally, only when the data is accrued, reviewed and published can the data be released. That's generally the rules of the game. It may be that the final results of that study are just not available yet. Now, having said that, if the results are done and the study is finished and the manuscript is written, then certainly the data should be made available to the patients as well.
(01:10:04) Susan Stewart: This final question is rather a general question. The person wants to know whether you have any suggestions about nutrition and what role that plays in the success of treatment.
(01:10:22) Dr. Fred Appelbaum: Let me start by just making a broad, broad statement. We do know that patients who are either way too heavy or way too thin, do more poorly with AML induction and with transplantation. Patients who are very obese or very underweight have poorer outcomes. That's just a global statement. We do know that obesity and diabetes adds to comorbidity index, which means that outcomes of treatment are poorer. We also know that hypertension is a risk factor, another one of those comorbidities. It takes a long time, but almost certainly people who have high fat diets, high salt diets, taking too many calories tend to get diabetes and tend to be hypertensive. All that does certainly contribute to poorer outcomes.
If you're trying to get more granular than that and talk about do people that take in a bit more whatever vitamin C or vitamin D or something else, does that have any outcome influence? It's much, much harder to see that. Studying diet and studying nutrition is a really, really hard thing to do. Some people roll their eyes, why don't you know? Taking dietary histories that are accurate is very, very difficult. In the past it's been shown to be highly inaccurate. You have to do careful feeding studies to try and get at those results. We do know that during the course of treatment, that people who are undergoing transplantation, if they do not have any GI intake, there's more damage to the GI tract during transplantation. We do encourage continued oral feedings during the procedure to allow for more rapid recovery.
The literature on nutrition, I can't possibly begin to summarize it in an answer to a question. I can say that t we rely heavily on our dietitians.... When I attend on the transplant service at the Hutch, I have a team with me. I have a pharmacist, a dietitian, a physician's assistant and a nurse and scheduler. If I didn't have the dietitian and the pharmacist with me, I wouldn't do nearly as good a job in taking care of my patients. They really do play a key role in the course of transplantation.
(01:13:42) Susan Stewart: With that, I'm afraid our time is up. We're going to need to wrap up. Thank you again, Dr. Appelbaum, for a very enlightening presentation, and thank you, the audience, for your excellent questions.This article is in these categories: This article is tagged with: