Acute Myeloid Leukemia: What to Know, What to Do

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Acute Myeloid Leukemia: What to Know, What to Do

Presenter: Scott Rowley, MD, Professor of Medicine, Georgetown University School of Medicine

October 30, 2024

The presentation is 43 minutes long, followed by 17 minutes of Q&A

Summary:

Acute myeloid leukemia (AML) is a rare disease that is seen most often in older adults, although it can occur in younger people as well. This webinar discusses the symptoms of AML, how it is diagnosed, risk factors for developing AML, and current treatment options.

Many thanks to Syndax whose support helped make this webinar possible.

Key points:

• AML is classified into three main groups: High risk, intermediate risk, and adverse risk.
• The likelihood of relapse after treatment for AML depends on the amount of residual disease that remains after treatment.
• Treatment plans must be individualized for each patient according to their age, other chronic illness they may have, their type of AML, and the risk of their disease progressing.

Highlights:

((00:12:03): A new diagnosis of AML is not a medical emergency for most patients. Treatment can usually wait until laboratory tests are done in the doctor’s office to determine the type of AML and the risk of the disease progressing.

(00:16:07): The likelihood of relapse after treatment is related to the amount of residual disease.

(00:18:03): Supportive care, leukemia remission-induction chemotherapy, and consolidation therapy are treatment options for patients with AML.

(00:23:36): For patients who can tolerate intensive therapy, survival is better for AML patients who have an allogeneic transplant than for those who have either an autologous transplant or standard chemotherapy.

(00:24:28): Graft-versus-host disease (GVHD) and the graft-versus-leukemia effect (GVL) can occur after an allogeneic transplant.

(00:29:42): Older patients and those with other chronic diseases may require a lower-intensity conditioning regimen before an allogeneic transplant.

(00:31:03): Siblings with the same HLA type as the patient are usually the preferred stem cell donor.

(00:32:37): It is possible to use half-matched related donors for transplant.

(00:34:14): Risk factors for developing chronic graft-versus-host disease (GVHD) after transplant include HLA mismatch with the donor, the sex of the donor, older donors, use of peripheral blood stem cells instead of bone marrow and having prior acute GVHD.

(00:39:15): Relapse is the primary cause of transplant failure.

Transcript

(00:00:00): Susan Stewart - Introduction of Speaker, Dr. Scott Rowley. Welcome to the workshop, Acute Myeloid Leukemia: What to Know, What to Do. It's my pleasure to introduce today's speaker, Dr. Scott Rowley.

Dr. Rowley is a Professor of Medicine at Georgetown University School of Medicine in Washington, DC. Now retired, he was the director of the Stem Cell Transplant and Cellular Immunotherapy Program at MedStar Georgetown University Hospital and the medical director of the Cellular Therapy Manufacturing Facilities at Hackensack University Medical Center in New Jersey. His career of over 40 years was dedicated to transplant medicine, and he was on the faculty of the Johns Hopkins Oncology Center in Baltimore and the Fred Hutchinson Cancer Research Center in Seattle.

Dr. Rowley's research focused on developing bone marrow graft processing and cryopreservation techniques and the clinical applications of transplantation in treating cancer and other disorders. Please join me in welcoming Dr. Rowley.

(00:01:15): Dr. Scott Rowley - Overview of Presentation. Thank you very much, Ms. Stewart, for the kind introduction. My presentation is an overview of the diagnosis and treatment of acute myeloid leukemia, what we know about this disease, how the diagnosis and staging of the disease have changed over the past few years and the treatment options that are developing as we get a better understanding of this disease.

Today,  I'm going to discuss what leukemia is, how it is staged, how it is treated, and whether it can be cured. I will also discuss monitoring of what we will call minimal residual disease (MRD), and survivorship after treatment.

(00:02:08):  The definition of acute myeloid leukemia (AML). To start with, what is the definition of acute myeloid leukemia or AML ? The term leukemia is derived from Greek terms that mean white and blood. It was developed back in the mid-1800s, and it reflected the very high white blood cell counts of patients who developed this cancer of the bone marrow.

Myelogenous has to do with the source of the cancer. This is not a stem cell disease in the bone marrow. Your stem cells give rise to all the different types of blood cells. Myeloid leukemia is a cancer that develops specifically in the myeloid lineage that gives rise to the granulocytes, which are infection-fighting cells in your blood. Myeloid leukemia is different from lymphoid leukemia, which involves the lymphocyte-forming lineage.

The term acute is just a term that describes the behavior of the disease if left untreated. Leukemia is either acute or chronic. Chronic leukemias may not require treatment for years after they're diagnosed, but patients with acute leukemia, whether it be AML or ALL, would have a life expectancy measured in weeks if left untreated.

(00:03:31): Symptoms of AML. So, how does the AML present? AML presents with symptoms of bone marrow failure. Patients seek medical attention in the emergency room or in their primary care doctor's office for symptoms of bone marrow failure.

Leukemia prevents or blocks maturation in normal cells, so there'll be a low number of granulocytes, the infecting-fighting cells. Anemia may be present. There may be bruising and bleeding from low platelet counts. Platelets are cells that help prevent bleeding and bruising. So, for example, somebody might come into the emergency room with an infection or bruising that they can't explain.

(00:04:12): How is AML diagnosed? The diagnosis of leukemia is done through blood work or examination of the bone marrow. Rarely, AML is discovered during routine monitoring of another disease. You happen to be in a doctor's office and have a complete blood count CBC) and they find abnormalities in the blood. However, symptoms of bone marrow failure are typically what drive a person to seek medical attention.

(00:04:36): What causes AML? AML is an age-related clonal disease arising after the accumulation of genetic damage to the bone marrow cells. I will show you a slide shortly that demonstrates that this disease is more common in the elderly, and it's probably an accumulation of damage to our DNA over our lifetime.

It's a clonal disease in that a mother cell gives rise to daughter cells, which then accumulate in the bone marrow and prevent the maturation of normal cells.

The causes of AML could be radiation exposure, natural radiation such as radon, or radiation given therapeutically, such as for the treatment of lung cancer, breast cancer, or Hodgkin lymphoma. Chemical exposures, such as benzene or other chemicals in our environment, or chemical exposures, such as chemotherapy, could also cause AML.

(00:05:39): Myelodysplastic syndrome (MDS) can evolve into acute leukemia. There's a diagnosis called myelodysplastic syndrome, which was historically called pre-leukemia. It's a distinct disease, but it's a disease that very commonly evolves into what we call secondary acute leukemia, a fairly nasty type of leukemia.

(00:06:08): Leukemia is more common in elderly patients. This slide describes the likelihood of developing leukemia over one’s lifetime. Patients in their 20s,  30s, and 40s have a very low likelihood of developing leukemia, but it becomes more common as we get older, especially over the age of 60.

If you look at the Y axis on this graph, the 30 and 40 you see there is not 35% to 40% of adults in their 70s or 80s who will have leukemia. That is 35 or 40 patients out of a hundred thousand that will develop leukemia. So, even in your 70s and 80s, the likelihood of developing leukemia is much less than 1%.

So, it's a rare disease, but when a leukemia doctor sees a patient with leukemia, it will usually be a patient who's over the age of 60. The approach to treating that older patient will be different than the patient who is younger.

(00:07:16): The diagnosis of leukemia is based on an examination of the blood or bone marrow and the presence of blast cells  in the bone marrow or peripheral blood. On the right-hand side of this slide is a picture of a bone marrow sample with blast cells. Almost every cell in this picture is a leukemic cell, and these cells accumulate and prevent the normal maturation of the other blood cells, leading to the symptoms with which people present. It's diagnosed with microscopic examination of blood or marrow samples. It is usually a disseminated disease [has spread throughout the body] at diagnosis.

(00:07:54): Leukemia is not staged like other cancers. For diseases like breast cancer, colon cancer, lung cancer, etc. people ask "What is the stage of disease? Is it stage 1, 2, 3, 4?"

We do not stage leukemia that way because it's almost always a disseminated disease at diagnosis. Your blood cells travel throughout the body, so it's not surprising that leukemia cells flow throughout the body as well. So, we do not classify it by stages 1, 2, 3, or 4. Rarely, it may present as a solid tumor or what we call a myeloid sarcoma, but that almost always proceeds to the disseminated disease and acute myeloid leukemia in its full-blown form.

(00:08:34): When we first meet a patient that may have leukemia, we need a history. We want to know the patient's age. As I mentioned, older patients are more likely to have leukemia and they will require a different treatment than younger patients. Older patients do not tolerate medical treatments as easily as younger patients. It doesn't matter whether you're talking about cancer, leukemia, or any other diseases such as heart disease, kidney disease, or whatever. The older the patient, the more difficult the treatment may be. You have to avoid side effects.

We will look at the patient's history of chronic illnesses, blood disorders, previous cancer and treatments, and chemical and radiation exposures, all with the intent of putting together a plan of treatment for this individual patient.

(00:09:26): Laboratory tests are done to determine the type of leukemia. The diagnostic testing, the laboratory test I mentioned, is a peripheral blood or bone marrow biopsy. With a bone marrow biopsy, if we look with a microscope and see those blast cells, we know we're dealing with some form of leukemia, but we don't know the type of leukemia that those blast cells represent.

So a variety of tests will be done on a bone marrow sample. Flow cytometry can very easily distinguish between myeloid leukemia versus lymphoid leukemia. Cytogenetics are chromosome breaks that are detected in a proportion of patients that may help classify the risk of the leukemia. FISH studies, I won't talk more about but is another technique to help classify the type of leukemia.

(00:10:03): Next-generation sequencing helps define the leukemia as low-risk, medium-risk, or high-risk. I do want to focus on next-generation sequencing (NGS). This relatively new technique looks for individual breaks in genes or mutations in genes, such as the FLT-3 mutation or IDH mutations. A whole variety of mutations can be discovered. There are over 200 different genes in one commercially-available panel that I use that can be looked at to help classify the leukemia.

(00:10:38): Determining the risk level of the leukemia helps define the treatment plan. The reason why next-generation sequencing is important that AML is not AML is not AML. Back in the 1970s, when I first started treating leukemia, yes, AML was AML, and we treated every single patient the same way.

But now we know that AML is a class of several diseases. The blast cells may all look the same under the microscope, but different AMLs will have different mutations. Those mutations have led to changes in the classification of this disease and have major implications for treatment.

So, on the right-hand side of this slide, you see survival statistics for patients with different mutations. The mutations are shown in the table below the slide. The very top curve, the black line showing the PML-RARA mutation, is acute promyelocytic leukemia, a very favorable-risk leukemia. If you have to have leukemia, this is a leukemia that is easily treated. You can see that most patients—75%—will be alive and in remission 10, 12 years after their diagnosis.

In contrast, patients who present with TP53 mutation, the dark blue line on the bottom of the curve, are patients whose probability of survival is measured in only a few months. So, it's a very aggressive leukemia.

The point here is that next-generation sequencing, trying to classify the leukemia as a more favorable risk or less favorable risk, is very important in developing a treatment plan for the patient.

(00:12:03): For most patients, a new diagnosis of AML is not a medical emergency. Back in the 1970s, we would bring these patients to the hospital and try to get them on treatment as soon as possible.

But if somebody presents with fatigue or bruising today and they're not showing signs of a serious illness, we can delay therapy until we obtain the diagnostic test. So, it's common for a patient to come into the emergency room with symptoms. A blood test is done, leukemia cells are identified, and the patient may be seen by a hematologist. The hematologist may say, "We're going to send you home, and we will see you in the office tomorrow morning so that we can do the bone marrow biopsy and get the appropriate staging studies that can be done in the office, that we may not be able to do in the emergency room."

At that time, we can address and control other medical illnesses, such as infections that might be present. For the younger patients, we can take the opportunity to collect sperm and ova because many of the treatments are sterilizing, which we want to avoid for our younger patients.

The exception are patients who have a very elevated white blood cell count over 100,000. The blood just doesn't pump. It becomes very honey-like or sludge-like, and that needs to be addressed urgently.

Or there's a type of AML called acute promyelocytic leukemia (APL) where patients are at very high risk of stroke so the treatment starts immediately. Even if you merely suspect that a patient has APL, we start the treatment right then and there.

(00:13:52): AML is classified into three major groups. I showed you all the different genetic changes, but they can be broadly classified into favorable, intermediate, or adverse risk groups by their genetic features. The favorable risk leukemias are easily cured with standard treatments. You do not want to go into highly toxic treatments if you can avoid them and their long-term side effects, such as chronic graft-versus-host disease after an allogeneic transplant (a transplant using donor cells).

On the other hand, patients with adverse risk cytogenetics will relapse very quickly. Therefore, the treatment plan has to be much more intensive to try to cure this disease. The individual's risk group will define the treatment plan.

(00:14:42): What is the therapeutic ratio? So, let me go over some definitions here. The therapeutic ratio is the ability to kill the leukemia cells without killing the normal cells. It's a ratio of toxicity. We want to kill the abnormal cells but don't want to kill the normal cells. An example is this: you can very easily use bleach to kill bacteria that might be on your kitchen counter, but you don't want to inject it into your bloodstream to treat an infection because the therapeutic ratio is just not there.

(00:15:11): So, with the chemotherapy drugs we use and the radiation we might use to treat leukemia, there is a ratio between our ability to kill the abnormal cells and the damage it will do to our normal cells. Thus, a treatment plan will look at the therapeutic ratio of the plan to minimize damage to normal cells while maximizing the ability to kill abnormal cells.

Fortunately, scientists are developing targeted agent drugs that specifically target a mutation while sparing normal cells that don't have that mutation. Currently, we have commercially available FLT-3 inhibitors and multiple drugs approved by the FDA to treat patients with FLT-3-mutated AML. We also have a couple of inhibitors for IDH mutations.

(00:16:07): The likelihood of relapse is related to the amount of residual disease after treatment. Another concept we're going to discuss is minimal residual disease. This is the disease that remains after treatment. It may not be detected by current techniques but can still cause leukemia relapse.

The likelihood of relapse is related to the amount of residual disease after treatment. The curve on the right illustrates this. On the X axis, you can see "treatment" on the left side and "after-treatment," or the monitoring phase that would go on after the treatment was stopped, on the right side.

The top line, the red line, is a person who received treatment that killed only 90 to 95% of the leukemia cells. They still had persistent blast cells in the blood or the bone marrow after treatment. They have refractory disease, and other treatments will be needed.

The more effective the treatment, the more cells we'll kill. We'll go up to 99%, 99.9%, 99.999%. As we kill more and more of these cells, the remission may last longer, but until we completely destroy the minimal residual disease, we believe the disease will eventually return. So that's the concept of minimal residual disease that's so important to us.

(00:17:30): Other principles guiding the treatment choice for AML. I've already covered therapeutic ratio and targeted agents. Combinations of agents: Multiple drugs can be used together to be more effective without causing overlapping toxicity. We want to avoid long-lasting organ damage, such as organ failure, which includes sterility. The treatments that we develop should be tolerable for older people or people with chronic illnesses such as heart disease, lung disease, kidney disease, and diabetes.

(00:18:03): Treatment options for AML are supportive care, leukemia remission-induction chemotherapy, and consolidation therapy.

(00:18:19): Supportive care. Supportive care is similar to hospice care. We want to manage the symptoms of bone marrow failure, but supportive care doesn't prevent the disease from progressing. We're not doing anything to kill the leukemia blast cells.

Supportive care is a component of everything we do to treat leukemia. There are some patients, however, particularly older patients in their late 80s into their 90s, or patients with other serious illnesses, patients with very, very adverse risk cytogenetic features to whom we would say "Your likelihood of survival is better without chemotherapy than it would be with chemotherapy."

For these patients, we give blood transfusions, medications, and maybe low-dose chemotherapy to help slow the growth of the disease, but we're not attempting to achieve a cure. This requires a close discussion with the patient and the patient's family about the treatment goals and the expected survival lifespan.

(00:19:26): Remission-induction chemotherapy. We use remission-induction chemotherapy to get a patient into remission, which is successful in about 60 to 80% of patients. Patients with a higher-risk disease will be more towards the 60%, and patients with a lower-risk disease will be more towards the 80%.

Historically, this involves intensive chemotherapy, a regimen called “7 and 3,” which we were using back in the 1970s when I first started my medical practice. However, some novel agents and approaches are now being developed for patients who are not candidates for this very intensive regimen.

“7 and 3” is an intensive regimen. The idea is to kill the leukemia cells, but there may be many side effects, particularly for older patients and patients with comorbidities. After approximately a four-week stay in the hospital receiving the “7 and 3” regimen, the doctor may do a bone marrow biopsy and say to the patient, "You are in remission, but this remission does not equal a cure. So we need to proceed with "consolidation therapy."

(00:20:34): Examples of remission-induction chemotherapy. These are just some examples of leukemia remission-induction chemotherapy. You can download these slides and look them over in more detail. “7 and 3” regimen is cytarabine and some form of anthracycline; 5-azacytidine and venetoclax are regimens that are more commonly used for older patients.

(00:20:41): Consolidation therapy is intended to kill the minimal residual disease that remains in the patient after remission. There are a variety of options. You can give additional cycles of chemotherapy, usually two to four cycles, with drugs such as high-dose cytarabine. There are targeted agents that can be used longer. If you have a disease that has FLT-3 mutation, one or two years of a targeted medication may be adequate to remove minimal residual disease. And then, of course, an allogeneic stem cell transplant is a treatment for minimal residual disease that we'll get to in a minute or so.

There are also research studies using immunological techniques such as CAR-T cells to treat AML patients. There are nine active studies in the United States as of a few days ago when I looked.

(00:21:28): Why is allogeneic transplantation used to treat some patients with acute myeloid leukemia (AML)? Let me turn to transplantation and a few concepts I want to cover. Why are we talking about allogeneic transplantation? Why not autologous transplantation, which is commonly used to treat other diseases?

We'll talk about the transplant conditioning regimen, selection of donors, minimal residual disease monitoring, how we manage relapse, as well as some of the complications of treatment, including graft-versus-host disease.

Transplantation started in the 1950s, before chemotherapy was commonly available. There was only one chemotherapy drug at that time. However, it was recognized that radiation is very effective at killing cancer and that total body radiation applied to the entire bone marrow space could kill leukemia quite nicely.

(00:22:15): Leukemia is very sensitive to radiation. Unfortunately, so are normal cells. So, when you give a patient total body irradiation it kills the leukemia but also damages the good cells. It is similar to taking a rototiller to the yard to eliminate the weeds. You get rid of the weeds, but you also get rid of the good grass. That only works if you have more grass seeds to regrow the lawn.

So, transplantation started with the concept that we could give these very high doses of radiation and subsequent chemotherapy, or chemotherapy and radiation to ablate the bone marrow, get rid of the leukemia cells, and then use cells from a donor to regrow the bone marrow. So, stem cell transplantation was required to regrow the bone marrow after the marrow-destructive effects of a very intense transplant regimen.

What was recognized in the 1980s is that allogeneic transplantation is a very robust form of immunotherapy. I've told many leukemia patients that if I were to do a bone marrow biopsy on them and inject their bone marrow into me, I would not develop leukemia because my immune system knows "me," and it knows what is "not me" and you're "not me."  If I were the donor for that patient, my immune system could go into the patient, recognize the patient and the leukemia as "not me," and attack the leukemia cells, potentially curing the patient of the disease.

(00:23:36): Survival is better for AML patients who had an allogeneic transplant than for those who only had an autologous transplant or standard chemotherapy. Some studies conducted in the 1990s, comparing chemotherapy to autologous transplant to allogeneic transplant, showed this. In a recently published follow-up study, so we're talking 20, 30 years later, survival is still much better for patients who received allogeneic transplantation.

In the bottom curve, you see that patients who had an allogeneic transplant were much less likely to relapse than the patients who received only chemotherapy.  As a consequence, in the top graph, the patients who received an allogeneic transplant were several times more likely to be alive 20 years later than the patients who received standard chemotherapy. So, this is why we treat patients who have acute leukemia with allogeneic transplantation.

(00:24:28): Graft-versus-host disease (GVHD) and graft-versus-leukemia effect (GVL). So, some more definitions: graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect. I mentioned that the immune system is very powerful but it is not very bright. It does not distinguish between the host's (patient’s) normal cells and the leukemia cells.

When I put stem cells into the patient, I'm putting in a new immune system. I hope the new immune system will attack the leukemia cells, but the immune cells may also attack the patient’s normal cells. An analogy is if you take a quarter out of your pocket and assume the quarter is the new immune system going into the patient, heads on the quarter is the graft-versus-leukemia effect, and tails is graft-versus-host disease. We cannot separate the two. So, we have to deal with the toxicity of the graft-versus-host disease while trying to achieve the graft-versus-leukemia effect that ultimately will cure this disease.

This was recognized back in the 1980s. This slide shows the risk of relapse after an allogeneic transplant for patients with acute leukemia. The top curve shows the patients who had no GVHD. They didn't develop skin rash or other manifestations of GVHD. These patients were twice as likely to relapse as patients who did develop GVHD. So, this again demonstrates the immune system's power to fight leukemia.

(00:26:01): The transplant conditioning regimen aims to kill cancer cells and prevent the patient’s immune system from rejecting the donor cells. The early transplant-conditioning regimen back in the 1950s was total body irradiation. The intent was to kill the leukemia cells. But the other side of the conditioning regimen, and why it is called the conditioning regimen and not a chemotherapy regimen, is that it conditions the host (the patient) by ablating the patient's immune system so that it does not reject the donor's cells.

We want to accomplish two things with the conditioning regimen: kill the cancer cells and reduce the patient's powerful immune system so that it can't reject the donor's cells.

Conditioning regimens are usually given over four to seven days. Different transplant programs use different regimens. The bone marrow cells will be depleted, especially with the more intensive conditioning regimens. It takes 14 to 21 days after the conditioning regimen for the bone marrow to recover and start producing new blood cells, allowing the patient to be discharged from the hospital.

(00:27:00): Side effects of the conditioning regimen. During that time, we see side effects. High-dose chemotherapy and radiation can affect other growing cells, such as the lining of the stomach and the mouth, causing mucositis. There can be other organ toxicities, infections, and so forth. All of these are common during the first 14 and 21 days, but once the bone marrow cells start recovering, patients can be discharged from the hospital. A key point is that older patients don't tolerate the more intensive regimens as well as younger patients.

(00:27:32): We classify conditioning regimens into three broad groups. The myeloablative regimens are the rototillers of treatment. These regimens may include high-dose total body irradiation or a drug called busulfan, which is absolutely perfect for ablating bone marrow when given in high doses. So these are your myeloablative regimens. Hopefully, they completely ablate the bone marrow and kill as many leukemia cells as possible.

At the other extreme are the non-myeloablative regimens. The mildest non-myeloablative regimen was developed at the Fred Hutchinson Cancer Center in Seattle and involved just one dose of radiation. People came in, got their dose of radiation, went upstairs, got their transplant, and then were discharged to an apartment near the hospital on the same day. Many never spent an overnight in the hospital. So, it is a very, very low-intensity regimen.

The intent of the non-myeloablative regimen is not to kill cancer but to suppress the immune system, and this regimen is very effective at doing that. It uses the graft-versus-leukemia effect to cure the disease. Your transplant physician can use various combinations of the drugs on this slide depending on how aggressive your particular disease is, your age, and your comorbidities.

(00:28:47): Examples of a non-myeloablative conditioning regimen. This slide shows an example of a non-myeloablative regimen. This is the low-dose regimen developed in Seattle. Total body irradiation happens about a third of the way along the timeline, and the transplant happens on the same day. Johns Hopkins modified it by adding chemotherapy before the transplant and cyclophosphamide after the transplant for patients whose donor was only half-matched. After the cyclophosphamide is given, patients start on long-term antirejection medications for several months, such as tacrolimus and mycophenolate mofetil. Then, at monthly intervals, their bone marrow or blood is tested for what's called chimerism. Do we see the donor cells in there or any minimal residual disease? Do we still see cancer cells that we need to address?

(00:29:42): Comorbidity may require us to use a lower-intensity conditioning regimen. Patients come to us at an older age now. Some patients have diabetes or high blood pressure. They may have had a heart attack, or they may have kidney, lung, or liver dysfunction. Your doctor will put together a comorbidity score for you, based on points for each of these.

(00:30:10): Here is a curve showing that patients with higher comorbidity scores are more likely to die of treatment-related complications. This is not relapse; this is just death due to treatment complications.

In this particular study, patients with comorbidity scores of three or higher had almost a 30% chance of dying from treatment complications. This is another reason why we have these less intensive conditioning regimens for patients with these high comorbidity scores. We want to reduce the intensity of the regimen and use more of the graft-versus-leukemia effect to cure their disease.

What I mean by this is that transplantation is not limited to 21-year-olds in perfectly good health. We do transplant patients in their 50s, 60s, and 70s and those with higher comorbidity scores.

(00:31:03): Siblings with the same HLA type as the patient are usually the preferred donor. Transplantation started with HLA-matched sibling donors. Your tissue type is your HLA type, and that is the primary factor when considering who to select as the patient’s donor. We prefer to deal with donors who are an HLA match with the patient, and sibling donors are our primary donor option, particularly if they are young.

The problem is that a sibling has a one-in-four chance of matching another sibling. This is just the genetics of how tissue type is inherited. The average family size in the United States is 2.2 children, meaning that three-quarters of our patients do not have an HLA-matched sibling donor. So, we need to look for alternate donors for them to use.

(00:31:51): Age is a factor when choosing a donor. If we have the luxury of more than one potential donor, then we look at other factors. Age is an important one. Older donors have a higher risk of inducing graft-versus-host disease in the patient. Older donors may have an undiagnosed cancer that can be transmitted to the patient. These are all factors that your physician will consider when selecting a donor for you and putting together your treatment plan.

(00:32:20): Unrelated donors are an option if a related donor is not available or suitable. Fortunately, we have alternate donor options. The unrelated donor program has, I think, over 16 million donors in the registry. I used to be in the registry, and my wife was also there until we aged out, because age makes a difference.

(00:32:37): It is possible to use half-matched related donors for transplant. Investigators at Johns Hopkins developed a technique to use half-matched donors. A half-matched donor would be, for example, your child or your parent. By definition, you are a half-match with each one of those. You may have a brother or sister who's a half-match or a grandparent, grandchild, or cousin who is half-matched. The most distant relative I have used for a transplant patient was the son of a cousin. I don't know what degree relative that is, but it is far beyond a first-degree relative.

(00:33:07): Ethnicity is a factor when searching for an unrelated donor. I'm going to briefly discuss this slide. It looks at ethnicity and the fact that, although we have a fairly good chance of finding donors for people who are Caucasian and have a European background, our ability to find an unrelated donor for patients who are part of a different ethnic group is lower. So, this is where half-matched donor transplants become very important because unless you're truly an orphan and you have no family and you have no children, then a half-matched transplant is an option.

(00:33:39): Survival is similar after half-matched transplants and unrelated donor transplants. This is a study from our transplant center comparing half-matched donor transplants to unrelated donor transplants. In this particular patient population, the survival curves were the same. So, we offer half-matched transplants if we feel that's the best donor option for a patient.

(00:34:09): This is a graph looking at transplants up to about 2018. The orange curve at the bottom shows the number of half-matched transplants being used, which has continued to rise rapidly.

(00:34:14): Risk factors for developing graft-versus-host disease (GVHD) after transplant. So now let me talk about graft-versus-host disease (GVHD) - a complication after transplant. What are the risk factors for GVHD?

One is HLA mismatch. If you have a seven out of eight antigen-matched donor rather than an eight out of eight antigen-matched donor, you're more likely to develop difficult-to-manage graft-versus-host disease.

If the sex of the donor and patient are different, particularly for a male patient, that may induce a higher risk of a GVHD.

Older age of the donor and the choice of conditioning regimen intensity can affect the risk of developing GVHD.

Another factor that can increase the risk of developing difficult-to-control GVHD is having acute GVHD that progresses to chronic GVHD.

Using peripheral blood stem cells from the donor rather than bone marrow has advantages, but a disadvantage is that it may increase the risk of developing difficult-to-control chronic graft-versus-host disease.

(00:35:15): Treatment plans that reduce the risk of developing GVHD. There are prophylactic regimens to reduce the risk of developing GVHD. We talked about the conditioning regimen. That is only half the treatment regimen before the transplant. When you sit down with your transplant physician, they'll say, "Okay, we're going to use an ablative or non-ablative-conditioning regimen, and this is what we're going to give you to prevent the GVHD."

Options include chemotherapy such as methotrexate, or post-transplant cyclophosphamide using the technique that was developed at Johns Hopkins Center.

We can remove the T-lymphocytes, the cells that cause graft-versus-host disease, from the donor cells. However, this is not commonly done because when you remove the - lymphocytes to prevent graft-versus-host disease, you also remove the T-lymphocytes that help kill the tumor cells. If you think back to that example with the quarter: you cannot separate heads and tails from that immune system with our current technology.

(00:36:08): Symptoms of acute graft-versus-host disease (aGVHD). Acute GVHD typically manifests on the skin, in the liver, and the upper or lower GI systems. It starts 14 to 100 days after transplant. These statements are generalizations.

GVHD can be very mild. I've had many patients come into the clinic, and I look at them and say, "Okay, you have skin GVHD," and they say, "Where?" Because there's just some mild erythema (rash) and a little redness of skin that looks like they've been in the sun about an hour too long. And I say, "Okay, the bad news is that you’ve got GVHD. The good news is that your risk of relapse just went down by 50% because you have GVHD."

But acute GVHD can also be very severe, with patients developing severe diarrhea that requires hospitalization. And acute GVHD can be fatal in a small proportion of patients.

(00:36:54): Symptoms of chronic graft-versus-host disease (cGVHD). Chronic GVHD is a multiorgan system disease, and it can be very severe. It can cause chronic scarring of the skin, liver failure, dry eyes, and dry mouth, affecting the quality of life. This usually occurs later after treatment, one year, maybe earlier, maybe later, and it is also staged and graded by the severity of the disease.

(00:37:19): The treatment for acute and chronic GVHD has historically been steroids, prednisone or methylprednisolone, steroids, steroids, steroids. These are high-dose steroids, dosages that your physicians would not normally use to treat other conditions. Unfortunately, steroids have lots and lots of side effects, so we are constantly looking for steroid-sparing agents.

(00:37:40): New steroid-sparing medications help reduce reliance on steroids to treat GVHD. Fortunately, in the modern era of transplantation, we are getting new steroid-sparing agents. One such drug has been FDA-approved specifically for the treatment of acute graft-versus-host disease, and three drugs are now FDA-approved for the treatment of chronic graft-versus-host disease. These drugs allow us to use fewer steroids.

(00:37:58): Why do we want to avoid using steroids to treat GVHD? Why are steroids so important? Why do we want to avoid them?

Steroids increase the risk of infections. We can see nutritional issues with steroids, especially if a person has GVHD in the colon and has a lot of diarrhea.

There are other complications with steroids, such as steroid muscle weakness. I've seen people unable to stand up out of a chair or climb out of a car because of steroid myopathy.

Steroids can also lead to insulin resistance and bone damage. So, there are a lot of issues with steroids, and these steroid-sparing agents have been a godsend for patients with GVHD.

(00:38:37):  Pictures of chronic GVHD symptoms. On the left-hand side are some pictures of chronic GVHD. This is scarring chronic graft-versus-host disease in which the skin becomes leather-like. People may not be able to extend their arms straight. Fortunately, we don't see this often. If you go on the internet, you'll see this kind of picture.

(00:38:54):  GVHD is not a major cause of death after transplant. I want to point out that GVHD is not a major cause of death. It's a major cause of morbidity. A patient's quality of life is dramatically affected by GVHD, but the major cause of death after transplant is relapse of disease, as shown in the blue sections of the pie charts.

(00:39:15): Relapse is the primary cause of transplant failure. Minimal residual disease (MRD) before transplant or at any point after transplant increases the risk of relapse. I believe that monitoring for relapse should occur early after transplantation, as early as day 28, using the test called cell-free DNA that looks for evidence of malignancy. We want to treat the minimal residual disease as soon as possible. The problem is that the treatments for minimal residual disease can be toxic and may increase the risk of GVHD or bone marrow failure, so we don't use them for everyone.

(00:39:57): There is no standard approach to treating minimal residual disease or relapse. This slide shows that patients who come to transplantation with evidence of disease have a much higher risk of relapse, and the treatment plan has to take that into account.

There is no standard approach to treating minimal residual disease or relapse. Your physician will discuss various options with you, such as withdrawing immunosuppression, "Let's take the reins off the donor immune system." If we do this, we may have to deal with graft-versus-host disease, but hopefully, we will see a stronger graft-versus-leukemia effect.

There are targeted agents, such as the FLT-3 or IDH inhibitors. We can give low-dose chemotherapy using non-targeted agents, such as 5-azacytidine and decitabine. Donor lymphocyte infusions that rev up the immune system can be tried, as can a variety of options currently being researched, such as CAR-T cells or modifications to donor leukocyte infusion (DLI) to reduce its side effects.

(00:40:53): On the right side of this slide is a graph showing survival for patients in one study who were given donor leukocyte infusion (DLI) versus those who did not receive DLI. It shows that revving up the immune system will reduce the risk of relapse but, unfortunately, can cause more GVHD.

(00:41:10): There are many possible health issues after transplantation. I refer you back to the BMT InfoNet and the 2023 Survivorship Symposium. This material was covered very extensively including specifics about graft-versus-host disease, dry eyes, dry mouth, sexual functioning, fatigue, depression, etc. You can visit their website (bmtinfonet.org) and look at presentations on all these subjects.

(00:41:41): Planning for post-transplant survivorship is an issue. You should receive information about what testing should be performed and how often, looking for minimal residual disease or complications of treatment. Recommended chemopreventive therapies, information about the possible long-term side effects of treatment, and information you need when you return to your referring physician.

(00:42:06): So, in summary, AML is not AML. You need a treatment plan. Define the disease at its diagnosis: "Is this a high-risk disease based on these mutations? Is it a more favorable risk?"

Plan an induction and consolidation regimen, and monitor for treatment complications.

Perform MRD testing using a sensitive technique, such as NGS sampling of bone marrow or cell-free DNA testing of blood. Plan treatments and long-term care.

(00:42:38): The scientific advances in the biology of AML are leading to new treatments. Allogeneic transplantation continues to be the most likely treatment to cure patients with high-risk AML. We can now classify patients as having high-risk disease versus those who have low-risk disease who don't need to take on the risks associated with transplantation.

(00:42:56): The key issue after transplantation is relapse. We are working on how to monitor and treat minimal residual disease.

And you are an individual. You need an individual treatment plan to address how best to treat your leukemia and avoid possible side effects. I'm going to end at this point and take questions. Thank you very much.

Question and Answer Session

(00:43:24): Susan Stewart  - Thank you very much, Dr. Rowley. That was an excellent presentation. You covered quite a bit of ground. We will now begin the question and answer session.

(00:43:44): The first question is, "Does the patient need zero minimum residual disease to be considered in remission?"

(00:43:52): Dr. Scott Rowley  - Yes. Our current concept is that if we see evidence of leukemia, then that leukemia eventually will relapse at some point in the future. It gets a little confusing because there are genetic changes that are not pre-leukemic, something called clonal hematopoiesis of indeterminate prognosis, that also becomes more common as we get older. At my age, I have about a 10% likelihood I'm carrying one or more mutations, but that doesn't mean I have cancer; I just carry these mutations. And so when you're looking at mutations after transplantation, you might see mutations that are not leukemic. But if we see the leukemia mutations, the mutations that define leukemia, then my answer is that I would suspect that the patient will relapse.

(00:44:43): Susan Stewart -  The next question, "I had AML and was very fortunate to be involved in a clinical study using targeted radiation instead of full-body irradiation. Will targeted radiation minimize damage to the organs and the eyes? Will it become the new standard of treatment for patients with AML going through transplant?"

(00:45:08): Dr. Scott Rowley  - Yes. When we give total body irradiation, we cut the dose or withhold the dose to avoid toxicity to the kidneys. Kidneys are very radiation sensitive. We block the lungs. Lungs are very sensitive to radiation. And then we try to radiate the entire bone marrow space. By doing this targeted radiation, you get radiation of the bone marrow and hopefully avoid the other organs, improving the outcome by minimizing the side effects.

(00:45:38): Susan Stewart  - The next question is, "I was my sister's bone marrow donor in 1987. Can you explain how current treatment compares and contrasts and if survival rates have improved?"

Dr. Scott Rowley (00:45:52): Dr. Scott Rowley - I didn't show a slide, but yes, the survival rate of transplant patients for acute leukemia has improved year after year after year. And this is despite the fact that  transplant services now accept patients who are older with comorbidities.  Given that, we would expect that the survival rates would go down. But the treatment has improved dramatically since the 1980s. We have a better understanding of conditioning regimens. We have non-myeloablative regimens instead of fully myeloablative regimens. We have a better understanding of GVHD. We have new medications. We have new antibiotics.

(00:46:32): Susan Stewart -  Next question is, "What can be done for leukemia cutis and its progression?"

(00:46:40):Dr. Scott Rowley - Leukemia cutis is an organ involvement with leukemia. The leukemia cells infiltrate into the skin with very classic appearing, multiple skin nodules. If we do a biopsy, we see leukemia cells in the skin. It's like a solid tumor with leukemia. These patients will develop frank bone marrow-involvement with leukemia if they don't have it at that time. So, we want to treat patients with leukemia cutis to induce remission. It may not be evident in the bone marrow yet, but it will be, and it's certainly in the skin.

(00:47:18): Susan Stewart  - All right, next question, "I was treated for AML and received a BMT in 2015. Is it possible to now determine what type of AML I had based on new genetic testing?"

(00:47:33): Dr. Scott Rowley - That is very unlikely unless the transplant program collected a sample of your blood and cells before you underwent treatment. Some transplant programs do that. When I worked at Hutchinson Center in Seattle, we routinely collected blood samples from the patients and the donors and we could go back to 10 years ago and do further testing on these blood samples. But without those tests, we would not be able to know what kind of leukemia you had at that time because, presumably, you do not have any of those mutations now.

(00:48:09): Susan Stewart - Next question, "In your experience, are there some ways that we can decrease the chance of a recurrence?"

(00:48:18): Dr. Scott Rowley - That is the $60 million question: How do we prevent relapse after transplantation? Many patients are cured of their disease. The cure rates are 40 to 60%, maybe as high as 70 or 80%, depending on the patient's disease and other patient characteristics as well as the treatment we're giving. Most patients are cured, but the majority of patients who die after transplant die of relapse, and we want to prevent that. That, to me, is the primary issue.

So, scientists are working very diligently on the best way of detecting minimal residual disease after treatment, whether it be standard leukemia therapy or transplantation or any other therapy for leukemia, and how to treat that particular minimal residual disease.

(00:49:13): Susan Stewart - The next question, "I've relapsed after my second transplant. I've had no major GVHD. We will probably do more chemo and then a DLI, donor leukocyte infusion. Is there something we should do to increase my chance of GVHD?"

(00:49:32): Dr. Scott Rowley - I do not know how we can increase the chance of GVHD. So you're talking about a treatment that I did not address, like what happens after a person relapses? Do we do a second transplant or just give a donor lymphocyte infusion? I'm a believer in donor lymphocyte infusion. A second transplant can be very toxic. For the adult patient, we do not want to do a second transplant within one year of the first transplant. It's just very toxic and very difficult.

But we can rev up the immune system. We can give a certain amount of chemotherapy to put people in remission. This may be low-dose chemotherapy or higher-dose chemotherapy. We want to get the person into remission. That's half the purpose of the conditioning regimen we use for transplants to kill cancer cells.

(00:50:20): But the other half is the immune system, and that means giving the patient donor lymphocyte infusions. A second transplant and donor lymphocyte infusions are equal in their ability to cure the disease. So, I agree with donor lymphocyte infusions as in your case. I'm not exactly certain how we could do more, but maybe there would be some maintenance therapy after you get the lymphocyte infusions.  They may want to give multiple doses of DLI at monthly or six-week intervals.

(00:50:54): Susan Stewart - The next question is, "I'm 40 years post-allogeneic transplant." Congratulations. "What would be my chances of relapse?"

(00:51:04): Dr. Scott Rowley -  Almost zero. If you had a disease that comes back now, our immediate reaction would be, "This is some other disease." You just happened to be struck by lightning twice instead of once. Relapse is rare after about two years after transplantation. We have seen patients relapse four or five years later. Those leukemias are fairly benign. They're fairly easy to treat. We get people back into remission, and they have a good chance of being cured with a second go-around. But once you get beyond two years after transplantation, the likelihood of relapse is close to zero.

(00:51:53): Susan Stewart  - All right, the next question, "I've had hairy cell leukemia since 1996 but was stricken with AML in March 2015. I'm at day 75 post-allo transplant. Will the transplant cure me of hairy cell leukemia?"

(00:52:12): Dr. Scott Rowley - Yes, in theory, it can. We have not used transplantation for hairy cell leukemia. If you go into the medical literature, you'll find small series of case reports and so forth, but my thoughts are that the graft-versus-tumor effect will be effective against this lymphoid malignancy as much as it may be for the myeloid leukemia. However, I would have to go back to the medical literature to see what the current results of transplantation are. It's not a typical treatment that we use for hairy cell leukemia.

(00:52:46): Susan Stewart - The next question is, "How do you know if joint deterioration is GVHD-related or age-related?

(00:52:56): Dr. Scott Rowley - Joint deterioration, if it's related to GVHD, it is related to the treatment of GVHD. The corticosteroids can induce something called avascular necrosis, bone death. It's seen primarily in the hips and may also be seen in the knees and the shoulders, the big joints in the body.

This is diagnosed with an MRI. MRIs can confirm whether there has been bone death, and if so, the treatment is to get off the steroids to try to prevent it from progressing. Typically, it will require bone replacement therapy, a hip replacement, a knee replacement, or even a shoulder replacement. It is a devastating complication of the treatment of GVHD, and that's why we're looking for steroid-sparing agents, but the answer will be an MRI. An MRI will be able to distinguish between just plain old arthritis that comes with aging and the bony necrosis that comes with steroids.

(00:54:07): Susan Stewart - This individual wanted to know, "What are the FDA-approved medications that are used to treat GVHD?"

(00:54:16): Dr. Scott Rowley - Oh, there's belumosudil. That's for chronic GVHD. Ruxolitinib is for both acute and chronic graft-versus-host disease. Ibrutinib has been used. I'm not a firm believer in it, but it was approved based on mouse studies for the treatment of chronic GVHD. So those are three FDA-approved drugs, and they're very, very good medications to use in the management of GVHD.

(00:55:08): Susan Stewart - The next person wants to know, "Is there a simple way to determine the risk of relapse for AML patients?"

(00:55:17): Dr. Scott Rowley - I'm a believer - not all doctors believe in this - of monitoring disease after treatment using cell-free DNA. I'm not a believer in doing bone marrow biopsies frequently after transplantation. They're painful and not very sensitive for identifying minimal residual disease. If you do not pick up the leukemia cells at one site and move the needle just to the side a few centimeters, you might get a different result.

Cell-free DNA is a brand-new technique using a NGS test that looks for mutations in the blood. This technique is used for all sorts of cancer: colon, lung, breast, and leukemia. When leukemia cells in your body die, they release DNA into the bloodstream, and you can look for genetic mutations in the bloodstream.

So, I'm a firm believer in looking at NGS monthly after transplantation using cell-free DNA, and then maybe at three-month intervals for the first couple of years after that. If a person has detectable mutations, then we become more involved in trying to treat this. If they become NGS-negative or MRD-negative, then we can extend the intervals. And once we get beyond two years, the likelihood of relapse becomes much less.

(00:56:45): Susan Stewart—This person wants to know about extramedullary myeloid sarcomas after relapse after transplant and how they are treated.

(00:56:59): Dr. Scott Rowley - You're going to be treated with chemotherapy, and I would love to be able to do some local radiation therapy if I could. This is a phenomenon I don't think is well understood. We can see “solid” forms of “liquid” tumors develop in patients who have had a graft-versus-tumor effect. We see this in leukemia. We see this in myeloma when patients get an allogeneic transplant. There is no evidence of disease in the bone marrow, but suddenly, we see this extramedullary disease, this myeloid sarcoma, develop in the setting of a graft-versus-tumor effect.

I'm not enthusiastic about trying to treat those with a second transplant or DLI. I want to use chemotherapy, radiation to try to manage those. Other doctors may have different opinions though and I will recognize that this is a subject that will require some intensive consultation.

(00:58:04): Susan Stewart - This gentleman wants to know, "Do you have an age cutoff for related donors who are matched related?"

(00:58:14): Dr. Scott Rowley - I start getting nervous when I have donors over the age of 35 or 40, believe it or not. I would much rather have a younger donor. At my age, if I were to develop leukemia, I have five siblings. There is a strong likelihood that I will have a sibling match. But they're all in their 60s and 70s and I do not want a transplant from them. Instead, I have a daughter who's in her 30s; she's a half-match. I would much rather have her as my donor. So I start looking at different donor options as we get above the age of 30 or 35 years of age. And the other side of that, I will not transplant patients who are 80 and above. Transplant is just way too toxic, even with the reduced intensity regimens nowadays.

(00:59:04): Susan Stewart - This will have to be our last question. "I was diagnosed with AML at 25. I was otherwise healthy and not exposed to large amounts of radiation that I know of. I also worked from home and was not exposed to chemicals. What could have caused it?"

(00:59:23): Dr. Scott Rowley - Well, we are constantly exposed to radiation. There's radon in the ground, and if you bought a house or sold a house, particularly in the areas of the country with a lot of granite, they would insist on radon testing in your basement.

We are exposed to solar radiation. We are also exposed to chemicals in the environment. You may not have had any chemical exposures that you are aware of, benzines and so forth, but there are other exposures, and sometimes it is just, as best I can say, it's just bad luck: why you, as opposed to somebody else?" If you have a family history of a hematologic disease, we say, "Okay, this is related to your genetics," but if you don't have such a family history, then we have to say that, "It will not be explained. It just happened. You can be cured of this disease and can get on with your life."

Sorry, that's a very cold way of answering it. I apologize for being so cold, but I hope that you are cured of your disease. If we look back and ask, "Why did it occur?" We just won't have the answer.

(01:00:37): Susan Stewart—With that, we will need to wrap up the workshop. I want to thank Dr. Rowley for an excellent presentation, Syndax, whose support helped make this presentation possible, and you, the audience, for your excellent questions.

Please email BMT InfoNet at help@bmtinfonet.org if we can help you in any way, or call us toll-free at (888) 597-7674. Thank you, and have a great day.