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Understanding AML: Remission & Relapse
Understanding AML:
Remission & Relapse
Even when morphological remission is achieved, patients with acute myeloid leukemia (AML) are still at risk of relapse.1,2
See one AML patient's experience with remission and relapse, featuring insights from AML expert, Dr DiNardo.
Learn how AML thought leaders are advancing our understanding of remission and relapse.
AML, acute myeloid leukemia.
Although responses to induction therapy are generally high in AML,
responses can be short-lived and most patients relapse.3,4
Experts take a new look at a challenging problem.
Dr DiNardo is a paid consultant for Bristol Myers Squibb.
EXPERT PERSPECTIVES
Courtney D DiNardo, MD
Courtney D DiNardo, MD is an academic clinical researcher with a primary focus on individualized therapy and precision oncology for myeloid malignancies...
WATCH THE EXPERT: AN AML DOCUMENTARY
Featuring an AML patient and his caregiver.
Dr. DiNardo: Acute myeloid leukemia is a cancer of the bone marrow and thus the blood.
Prognosis is definitely better than it was 5 to 10 years ago, but still, our standard of care and our expectations isn’t as great as we would love it.
Patient: You know my retirement came very quickly. My expectations were that I was going to walk every day, get you know, a lot of exercise and go up to my cabin and fish.
I was having trouble reading the newspaper, so I called my eye doctor and they said “Something doesn’t look right. We want you to go back to see your doctor. We’re going to do a blood test.” Less than 45 minutes later I got a call. She said “Go to the emergency room right away.”
Dr DiNardo: The first step is getting the leukemia under control and into remission. And then the second goal, or the second step, is making sure that that remission is able to be a durable one.
Patient: At 55 days, the doctor came in and delivered the news that the blasts were at a level that were acceptable for me to be able to go home. But they told us, you know, it probably wouldn’t hold for a very long period of time.
Dr DiNardo: Unfortunately, the vast majority of patients with AML will relapse, and then we are in a very challenging situation because almost invariably the leukemia that is present at relapse is that much harder to treat, because it has acquired changes that make it less responsive and more resistant to that initial therapy.
Patient: We went to visit the transplant doctor.
Wife: And he said “We just got the last report back, and I’m sorry to tell you that you’re not in remission, and we cannot proceed with a bone marrow transplant.”
If this doesn’t work, we need to have a Plan B and it was not long after that—a couple of weeks—when the oncologist said “Plan B: I found out about a clinical trial.”
Wife: The clinical trial was successful. He was in remission. The doctor said that we don’t know how big this window is of remission.
Dr DiNardo: There are more treatment options available and awareness of different treatment options that are providing increasing benefit for our patients, I think is just such an important part of ongoing leukemia treatment and scientific advancement.
Dr DiNardo: And I have found that people who are able to kind of maintain a positive attitude and have ongoing hope, it really makes a difference.
Dr. DiNardo: Acute myeloid leukemia is a cancer of the bone marrow and thus the blood.
Prognosis is definitely better than it was 5 to 10 years ago, but still, our standard of care and our expectations isn’t as great as we would love it.
Patient: You know my retirement came very quickly. My expectations were that I was going to walk every day, get you know, a lot of exercise and go up to my cabin and fish.
I was having trouble reading the newspaper, so I called my eye doctor and they said “Something doesn’t look right. We want you to go back to see your doctor. We’re going to do a blood test.” Less than 45 minutes later I got a call. She said “Go to the emergency room right away.”
Dr DiNardo: The first step is getting the leukemia under control and into remission. And then the second goal, or the second step, is making sure that that remission is able to be a durable one.
Patient: At 55 days, the doctor came in and delivered the news that the blasts were at a level that were acceptable for me to be able to go home. But they told us, you know, it probably wouldn’t hold for a very long period of time.
Dr DiNardo: Unfortunately, the vast majority of patients with AML will relapse, and then we are in a very challenging situation because almost invariably the leukemia that is present at relapse is that much harder to treat, because it has acquired changes that make it less responsive and more resistant to that initial therapy.
Patient: We went to visit the transplant doctor.
Wife: And he said “We just got the last report back, and I’m sorry to tell you that you’re not in remission, and we cannot proceed with a bone marrow transplant.”
If this doesn’t work, we need to have a Plan B and it was not long after that—a couple of weeks—when the oncologist said “Plan B: I found out about a clinical trial.”
Wife: The clinical trial was successful. He was in remission. The doctor said that we don’t know how big this window is of remission.
Dr DiNardo: There are more treatment options available and awareness of different treatment options that are providing increasing benefit for our patients, I think is just such an important part of ongoing leukemia treatment and scientific advancement.
Dr DiNardo: And I have found that people who are able to kind of maintain a positive attitude and have ongoing hope, it really makes a difference.
Dr Roboz is a paid consultant for Bristol Myers Squibb.
EXPERT PERSPECTIVES
Gail J Roboz, MD
Gail J Roboz, MD is professor of medicine and director of the Clinical and Translational Leukemia Program at the Weill Medical College of Cornell University and the NewYork-Presbyterian Hospital in New York City...
HEAR THE EXPERT: AN AML DISCUSSION
These are the opinions of Dr Gail Roboz and not the views of Bristol Myers Squibb.
While therapeutics for the treatment of acute myeloid leukemia have been improving, especially recently, most patients with this disease unfortunately relapse. There are certain subcategories of AML based on molecular and cytogenetic subgroups in which patients have pretty good long-term survival actually and the chances of relapse are low. But unfortunately that doesn't represent the majority of patients with acute leukemia. The favorable molecular and cytogenetic subtypes are pretty rare, and the majority of the patients actually fall into intermediate or unfavorable groups. And those patients generally relapse. Unfortunately, it can be in some groups and in some ages a virtual certainty that the patient will relapse after a period of remission that can be variable. It can be 9 months, 12 months, 18 months, but generally nowhere near the 5, 10, 20, and 30 years that patients want to hear about when they're first diagnosed with the disease.
So unfortunately the specter of relapse looms over patients, even when they get the good news from their doctor that everything looks okay, blood counts are okay, under the microscope looks okay. Even under those circumstances, patients are very much threatened by relapse and because treatment strategies currently are quite ineffective for curing relapsed AML, the patient's goal if at all possible is to stay in remission. So the problem is that the underlying biology of AML doesn't allow us a lot of options to keep people in remission.
These are the opinions of Dr Gail Roboz and not the views of Bristol Myers Squibb.
The mainstay of therapy is allogeneic stem cell transplantation for patients who achieve first remission. And due to the increased availability of donor procurement strategies as well as the improved tolerability of transplant procedures for older patients, it is certainly possible to take patients at this point well into their 70s into an allogeneic stem cell transplant in first remission.
But transplants are hard, and they have a lot of side effects, and they by far do not cure all patients with AML. In fact, patients are very shocked to hear from their doctors that the cure rates with transplants are maybe 50%, maybe up to 60% in some selected groups. But certainly nowhere near the 100% that patients are expecting to hear when they start thinking about a transplant for cure. So even with our arguably best weapon in the disease of allogeneic stem cell transplantation, we're not curing the majority of patients with AML. And furthermore, for the majority of patients with the disease, allogeneic stem cell transplant is not even feasible due to medical comorbidities or other toxicities which would preclude the procedure. Now, so what else can we do other than a stem cell transplant? Ongoing therapy giving further cycles of chemotherapy, for example, has been tried beyond remission for AML patients, but hasn't been shown to confer a survival advantage.
So usually when patients are treated with intensive chemotherapy, just giving one cycle after another after another, even if chemotherapy in attenuated doses hasn't resulted in a survival benefit, the patients typically stop their treatment and keep their fingers crossed and hope for the best that there isn't a relapse. This is certainly a very difficult time emotionally for patients, because while they are thrilled to be in remission and hopeful it will be ongoing, a lot of patients know from their doctors or from “Doctor Google” or from the internet that the chances of relapse are high. And I can tell you certainly from the office that as people come in and get their monthly blood checks, even when we go to every three months or beyond, they worry every time they see my name on the office door that the disease might have relapsed. I think that for patients who are in remission and who have heard that the possibility of allogeneic stem cell transplant is the only chance for cure; again, it's a step-wise process, so the first process is can they even undergo the procedure?
Is there going to be too high a morbidity and mortality risk for transplant based on their medical comorbidities, concomitant medications and other biologic features of their leukemia. And I should emphasize that the primary risk of transplant still remains relapse of the underlying disease, because there are many aggressive leukemia biologies that manage to come back even after an allo transplant. If the patient is eligible for transplant, they still are worried about relapse because of the high risk of relapse even after allo transplant. But I think that there's certainly a large proportion of younger patients who receive intensive chemotherapy who are going to go down that route. I see a lot of struggle among patients who are in their 70s, even early 70s patients in great shape are very worried about undergoing stem cell transplant without a guarantee for cure, but with a guarantee for substantial morbidity as a minimum for six months after the procedure and for many patients for longer than that depending on graft-versus-host disease or other potential complication.
So I would say that it is certainly a challenge in the field to be able to try to offer patients something other than allogeneic stem cell transplant to prolong their remission. Quality of life does seem to be better for many patients in remission because blood counts are normal. The doctor visits are fewer, they don't need antibiotics and transfusions and they certainly would like to be able to stay in remission. We are happy to have very strong drug development in the field of relapsed AML and there are some options that have been developed recently that were not there several years ago that we're happy to have. But the truth of the matter is that if you asked me my career goal, it would be that nobody relapses with the disease because there's no doubt about it, the curative strategies and even longterm survival strategies for patients with relapsed AML are not good. And I'm not sure that we are going to be in the future able to push the needle that much on curing patients and relapse. What we want to do is prevent the relapse to begin with if at all possible.
These are the opinions of Dr Gail Roboz and not the views of Bristol Myers Squibb.
When patients are initially diagnosed with AML, it's very important to understand that not all AML is the same. In fact, it's an incredibly molecularly and biologically heterogeneous disease. And what we've been doing in recent years is trying to advance our risks stratification systems to include both molecular data and cytogenetic data to try to provide the best possible categorization of the disease with respect to probability for relapse. The European Leukemia Net has guidelines, which have become widely used, which incorporate both molecular and cytogenetic data and into really three groups of favorable, intermediate and unfavorable prognostic risks. And basically what this translates into operationally is that people who are categorized as ELN favorable are not typically offered allogeneic stem cell transplant in first remission because the likelihood of remaining in remission is high enough for those patients that it's not worth the upfront risk of a transplant. Basically everybody who falls into the intermediate and to be unfavorable group is under consideration for allogeneic stem cell transplant at the time of first remission and in those patients very frequently, the duration of the first remission is predicted to be short.
And the problem is that if a patient is unlucky enough to have a really short first remission like 3 or 4 or 5 months, those patients are actually particularly difficult to get back into a second remission and unfortunately outcomes for allogeneic stem cell transplant in patients with active disease are much, much less favorable than if the patient is in remission, even in a second remission. But the hustle to a transplant in first remission for patients who are especially younger and in good shape is that we're not exactly sure we're going to be able to get them back into remission, which is why typically the patients are treated with intensive chemotherapy plus or minus one or two rounds of consolidation while the transplant is being organized and then off they go into an allo transplant in first remission so that we think that that still offers the best chance for cure.
HEAR THE EXPERT: AN AML DISCUSSION
These are the opinions of Dr Gail Roboz and not the views of Bristol Myers Squibb.
While therapeutics for the treatment of acute myeloid leukemia have been improving, especially recently, most patients with this disease unfortunately relapse. There are certain subcategories of AML based on molecular and cytogenetic subgroups in which patients have pretty good long-term survival actually and the chances of relapse are low. But unfortunately that doesn't represent the majority of patients with acute leukemia. The favorable molecular and cytogenetic subtypes are pretty rare, and the majority of the patients actually fall into intermediate or unfavorable groups. And those patients generally relapse. Unfortunately, it can be in some groups and in some ages a virtual certainty that the patient will relapse after a period of remission that can be variable. It can be 9 months, 12 months, 18 months, but generally nowhere near the 5, 10, 20, and 30 years that patients want to hear about when they're first diagnosed with the disease.
So unfortunately the specter of relapse looms over patients, even when they get the good news from their doctor that everything looks okay, blood counts are okay, under the microscope looks okay. Even under those circumstances, patients are very much threatened by relapse and because treatment strategies currently are quite ineffective for curing relapsed AML, the patient's goal if at all possible is to stay in remission. So the problem is that the underlying biology of AML doesn't allow us a lot of options to keep people in remission.
These are the opinions of Dr Gail Roboz and not the views of Bristol Myers Squibb.
The mainstay of therapy is allogeneic stem cell transplantation for patients who achieve first remission. And due to the increased availability of donor procurement strategies as well as the improved tolerability of transplant procedures for older patients, it is certainly possible to take patients at this point well into their 70s into an allogeneic stem cell transplant in first remission.
But transplants are hard, and they have a lot of side effects, and they by far do not cure all patients with AML. In fact, patients are very shocked to hear from their doctors that the cure rates with transplants are maybe 50%, maybe up to 60% in some selected groups. But certainly nowhere near the 100% that patients are expecting to hear when they start thinking about a transplant for cure. So even with our arguably best weapon in the disease of allogeneic stem cell transplantation, we're not curing the majority of patients with AML. And furthermore, for the majority of patients with the disease, allogeneic stem cell transplant is not even feasible due to medical comorbidities or other toxicities which would preclude the procedure. Now, so what else can we do other than a stem cell transplant? Ongoing therapy giving further cycles of chemotherapy, for example, has been tried beyond remission for AML patients, but hasn't been shown to confer a survival advantage.
So usually when patients are treated with intensive chemotherapy, just giving one cycle after another after another, even if chemotherapy in attenuated doses hasn't resulted in a survival benefit, the patients typically stop their treatment and keep their fingers crossed and hope for the best that there isn't a relapse. This is certainly a very difficult time emotionally for patients, because while they are thrilled to be in remission and hopeful it will be ongoing, a lot of patients know from their doctors or from “Doctor Google” or from the internet that the chances of relapse are high. And I can tell you certainly from the office that as people come in and get their monthly blood checks, even when we go to every three months or beyond, they worry every time they see my name on the office door that the disease might have relapsed. I think that for patients who are in remission and who have heard that the possibility of allogeneic stem cell transplant is the only chance for cure; again, it's a step-wise process, so the first process is can they even undergo the procedure?
Is there going to be too high a morbidity and mortality risk for transplant based on their medical comorbidities, concomitant medications and other biologic features of their leukemia. And I should emphasize that the primary risk of transplant still remains relapse of the underlying disease, because there are many aggressive leukemia biologies that manage to come back even after an allo transplant. If the patient is eligible for transplant, they still are worried about relapse because of the high risk of relapse even after allo transplant. But I think that there's certainly a large proportion of younger patients who receive intensive chemotherapy who are going to go down that route. I see a lot of struggle among patients who are in their 70s, even early 70s patients in great shape are very worried about undergoing stem cell transplant without a guarantee for cure, but with a guarantee for substantial morbidity as a minimum for six months after the procedure and for many patients for longer than that depending on graft-versus-host disease or other potential complication.
So I would say that it is certainly a challenge in the field to be able to try to offer patients something other than allogeneic stem cell transplant to prolong their remission. Quality of life does seem to be better for many patients in remission because blood counts are normal. The doctor visits are fewer, they don't need antibiotics and transfusions and they certainly would like to be able to stay in remission. We are happy to have very strong drug development in the field of relapsed AML and there are some options that have been developed recently that were not there several years ago that we're happy to have. But the truth of the matter is that if you asked me my career goal, it would be that nobody relapses with the disease because there's no doubt about it, the curative strategies and even longterm survival strategies for patients with relapsed AML are not good. And I'm not sure that we are going to be in the future able to push the needle that much on curing patients and relapse. What we want to do is prevent the relapse to begin with if at all possible.
These are the opinions of Dr Gail Roboz and not the views of Bristol Myers Squibb.
When patients are initially diagnosed with AML, it's very important to understand that not all AML is the same. In fact, it's an incredibly molecularly and biologically heterogeneous disease. And what we've been doing in recent years is trying to advance our risks stratification systems to include both molecular data and cytogenetic data to try to provide the best possible categorization of the disease with respect to probability for relapse. The European Leukemia Net has guidelines, which have become widely used, which incorporate both molecular and cytogenetic data and into really three groups of favorable, intermediate and unfavorable prognostic risks. And basically what this translates into operationally is that people who are categorized as ELN favorable are not typically offered allogeneic stem cell transplant in first remission because the likelihood of remaining in remission is high enough for those patients that it's not worth the upfront risk of a transplant. Basically everybody who falls into the intermediate and to be unfavorable group is under consideration for allogeneic stem cell transplant at the time of first remission and in those patients very frequently, the duration of the first remission is predicted to be short.
And the problem is that if a patient is unlucky enough to have a really short first remission like 3 or 4 or 5 months, those patients are actually particularly difficult to get back into a second remission and unfortunately outcomes for allogeneic stem cell transplant in patients with active disease are much, much less favorable than if the patient is in remission, even in a second remission. But the hustle to a transplant in first remission for patients who are especially younger and in good shape is that we're not exactly sure we're going to be able to get them back into remission, which is why typically the patients are treated with intensive chemotherapy plus or minus one or two rounds of consolidation while the transplant is being organized and then off they go into an allo transplant in first remission so that we think that that still offers the best chance for cure.
Dr Stone is a paid consultant for Bristol Myers Squibb.
EXPERT PERSPECTIVES
Richard Stone, MD
Dr Stone is the Chief of Staff and Director of the Adult Acute Leukemia Program at Dana-Farber Cancer Institute, and Professor of Medicine at Harvard Medical School...
HEAR THE EXPERT: AN AML DISCUSSION
These are the opinions of Dr Richard Stone and not the views of Bristol Myers Squibb.
Most patients are going to relapse—even if they have a stem cell transplant, some will relapse. So, I think it’s just intrinsically disease.
It is a clonally complex disease, so therapy may be able to get rid of 99.9 percent of the cells but we have that one lurking clone that can’t be killed by therapy.
That’s very important. Complete remission in AML is generally thought to be necessary but not sufficient to achieve a cure. If the goal in this, let’s say, younger patient is cure, which it generally always is in younger patients and sometimes even in older patient but anyway if cure is the goal, remission of some sort is necessary to get to that goal.
Far and away the most important reason why people who achieve remission don’t survive normal natural history is because they relapse after the consolidation therapy. And why do they relapse? They relapse because they have some clones, presumptively, or cells just are not completely enough eradicated by the initial therapy and that’s where the rubber meets the road.
MRD is alternatively called minimal residual disease, but most of us prefer to call it measurable residual disease because we’ve always measured it. We’ve measured it with a bone marrow test that was fairly not sensitive. Now we can measure it by asking whether the immunophenotypic clone that was present at diagnosis is still present at the time of morphological remission.
Of those in remission, probably about half have an MRD-positive remission where they can still have detectable disease at the time of this morphologic remission. And that’s a tough—it’s all well and good to be able to detect them but the real problem is what the heck do we do about it once we see it?
These are the opinions of Dr Richard Stone and not the views of Bristol Myers Squibb.
I stand by that statement and I think we can learn a little bit, maybe, from ALL in this regard. So what we need is an effective MRD eraser, I think, to change people from detectable disease to undetectable disease. I mean, there’s a lot of leaps here.
Our cutoff for morphological disease is still less than 5 percent blasts. I already mentioned that’s just part of the equation—even if we’re just looking at things like the bone marrow and the blood counts because we still want full hematopoiesis if possible. If we get partial restoration of hematopoiesis, it probably means the remission is not as deep if you can measure the actual leukemic burden, although we don’t know that for certain and it seems likely, so evolution of morphological remission hasn’t changed very much in all those years.
If you’re more of a guy who likes to keep their eyes open, then you should probably measure it because we’re learning about what to do about it. It does have prognostic information which might be helpful to patients.
The problem is the techniques themselves are not standardized in the US and not easily measured for logistical reasons. So it’s a tricky, tricky question. I still recommend that they be measured but what to do about it is very controversial. I guess I would try to marry the upfront prognostic data with this outback after two cycles of chemotherapy MRD data and try to figure out what the heck we should do with our patients. But we have to acknowledge that it’s far from set in stone.
These are the opinions of Dr Richard Stone and not the views of Bristol Myers Squibb.
That’s the problem. The answer is there is no level that’s reassuring enough because even people with MRD-negative disease...some of the people with MRD-negative disease still will relapse. And that’s simply because we don’t measure every last leukemic cell. We measure a lot more leukemic—or we can pick up a lot more leukemic cells by using one of these new techniques but it doesn’t—it’s not perfect. It’s just a matter of odds if you have MRD-negative disease you’re less likely to relapse. That’s it.
So, takeaway number one, it’s probably going to be a very important and routinely measured issue soon, once we standardize the technique. And, number two, because PCR is a Next Gen sequence that’s kind of patient specific and if you can do flow cytometry you can apply it to almost everybody. I suspect in the most commonly used technique will be flow cytometry. Three, and the most important thing, is that at the moment we don’t know what—we know that it’s better to not have measurable disease by a sensitive technique but we don’t know what to do with it yet in AML. And we’re learning about that. All of us would like to get rid of the residual disease and hopefully that will lead to a better natural history.
Minimal Residual Disease (MRD) as a Predictor of Relapse in AML
HEAR THE EXPERT: AN AML DISCUSSION
These are the opinions of Dr Richard Stone and not the views of Bristol Myers Squibb.
Most patients are going to relapse—even if they have a stem cell transplant, some will relapse. So, I think it’s just intrinsically disease.
It is a clonally complex disease, so therapy may be able to get rid of 99.9 percent of the cells but we have that one lurking clone that can’t be killed by therapy.
That’s very important. Complete remission in AML is generally thought to be necessary but not sufficient to achieve a cure. If the goal in this, let’s say, younger patient is cure, which it generally always is in younger patients and sometimes even in older patient but anyway if cure is the goal, remission of some sort is necessary to get to that goal.
Far and away the most important reason why people who achieve remission don’t survive normal natural history is because they relapse after the consolidation therapy. And why do they relapse? They relapse because they have some clones, presumptively, or cells just are not completely enough eradicated by the initial therapy and that’s where the rubber meets the road.
MRD is alternatively called minimal residual disease, but most of us prefer to call it measurable residual disease because we’ve always measured it. We’ve measured it with a bone marrow test that was fairly not sensitive. Now we can measure it by asking whether the immunophenotypic clone that was present at diagnosis is still present at the time of morphological remission.
Of those in remission, probably about half have an MRD-positive remission where they can still have detectable disease at the time of this morphologic remission. And that’s a tough—it’s all well and good to be able to detect them but the real problem is what the heck do we do about it once we see it?
These are the opinions of Dr Richard Stone and not the views of Bristol Myers Squibb.
I stand by that statement and I think we can learn a little bit, maybe, from ALL in this regard. So what we need is an effective MRD eraser, I think, to change people from detectable disease to undetectable disease. I mean, there’s a lot of leaps here.
Our cutoff for morphological disease is still less than 5 percent blasts. I already mentioned that’s just part of the equation—even if we’re just looking at things like the bone marrow and the blood counts because we still want full hematopoiesis if possible. If we get partial restoration of hematopoiesis, it probably means the remission is not as deep if you can measure the actual leukemic burden, although we don’t know that for certain and it seems likely, so evolution of morphological remission hasn’t changed very much in all those years.
If you’re more of a guy who likes to keep their eyes open, then you should probably measure it because we’re learning about what to do about it. It does have prognostic information which might be helpful to patients.
The problem is the techniques themselves are not standardized in the US and not easily measured for logistical reasons. So it’s a tricky, tricky question. I still recommend that they be measured but what to do about it is very controversial. I guess I would try to marry the upfront prognostic data with this outback after two cycles of chemotherapy MRD data and try to figure out what the heck we should do with our patients. But we have to acknowledge that it’s far from set in stone.
These are the opinions of Dr Richard Stone and not the views of Bristol Myers Squibb.
That’s the problem. The answer is there is no level that’s reassuring enough because even people with MRD-negative disease...some of the people with MRD-negative disease still will relapse. And that’s simply because we don’t measure every last leukemic cell. We measure a lot more leukemic—or we can pick up a lot more leukemic cells by using one of these new techniques but it doesn’t—it’s not perfect. It’s just a matter of odds if you have MRD-negative disease you’re less likely to relapse. That’s it.
So, takeaway number one, it’s probably going to be a very important and routinely measured issue soon, once we standardize the technique. And, number two, because PCR is a Next Gen sequence that’s kind of patient specific and if you can do flow cytometry you can apply it to almost everybody. I suspect in the most commonly used technique will be flow cytometry. Three, and the most important thing, is that at the moment we don’t know what—we know that it’s better to not have measurable disease by a sensitive technique but we don’t know what to do with it yet in AML. And we’re learning about that. All of us would like to get rid of the residual disease and hopefully that will lead to a better natural history.
HEAR THE EXPERT:
AN AML DISCUSSION
These audio clips and transcripts are excerpts from a paid interview with Dr Richard Stone, sponsored by Bristol Myers Squibb. These are the opinions of Dr Richard Stone and not the views of Bristol Myers Squibb.
These are the opinions of Dr Richard Stone and not the views of Bristol Myers Squibb.
Most patients are going to relapse—even if they have a stem cell transplant, some will relapse. So, I think it’s just intrinsically disease.
It is a clonally complex disease, so therapy may be able to get rid of 99.9 percent of the cells but we have that one lurking clone that can’t be killed by therapy.
That’s very important. Complete remission in AML is generally thought to be necessary but not sufficient to achieve a cure. If the goal in this, let’s say, younger patient is cure, which it generally always is in younger patients and sometimes even in older patient but anyway if cure is the goal, remission of some sort is necessary to get to that goal.
Far and away the most important reason why people who achieve remission don’t survive normal natural history is because they relapse after the consolidation therapy. And why do they relapse? They relapse because they have some clones, presumptively, or cells just are not completely enough eradicated by the initial therapy and that’s where the rubber meets the road.
MRD is alternatively called minimal residual disease, but most of us prefer to call it measurable residual disease because we’ve always measured it. We’ve measured it with a bone marrow test that was fairly not sensitive. Now we can measure it by asking whether the immunophenotypic clone that was present at diagnosis is still present at the time of morphological remission.
Of those in remission, probably about half have an MRD-positive remission where they can still have detectable disease at the time of this morphologic remission. And that’s a tough—it’s all well and good to be able to detect them but the real problem is what the heck do we do about it once we see it?
These are the opinions of Dr Richard Stone and not the views of Bristol Myers Squibb.
I stand by that statement and I think we can learn a little bit, maybe, from ALL in this regard. So what we need is an effective MRD eraser, I think, to change people from detectable disease to undetectable disease. I mean, there’s a lot of leaps here.
Our cutoff for morphological disease is still less than 5 percent blasts. I already mentioned that’s just part of the equation—even if we’re just looking at things like the bone marrow and the blood counts because we still want full hematopoiesis if possible. If we get partial restoration of hematopoiesis, it probably means the remission is not as deep if you can measure the actual leukemic burden, although we don’t know that for certain and it seems likely, so evolution of morphological remission hasn’t changed very much in all those years.
If you’re more of a guy who likes to keep their eyes open, then you should probably measure it because we’re learning about what to do about it. It does have prognostic information which might be helpful to patients.
The problem is the techniques themselves are not standardized in the US and not easily measured for logistical reasons. So it’s a tricky, tricky question. I still recommend that they be measured but what to do about it is very controversial. I guess I would try to marry the upfront prognostic data with this outback after two cycles of chemotherapy MRD data and try to figure out what the heck we should do with our patients. But we have to acknowledge that it’s far from set in stone.
These are the opinions of Dr Richard Stone and not the views of Bristol Myers Squibb.
That’s the problem. The answer is there is no level that’s reassuring enough because even people with MRD-negative disease...some of the people with MRD-negative disease still will relapse. And that’s simply because we don’t measure every last leukemic cell. We measure a lot more leukemic—or we can pick up a lot more leukemic cells by using one of these new techniques but it doesn’t—it’s not perfect. It’s just a matter of odds if you have MRD-negative disease you’re less likely to relapse. That’s it.
So, takeaway number one, it’s probably going to be a very important and routinely measured issue soon, once we standardize the technique. And, number two, because PCR is a Next Gen sequence that’s kind of patient specific and if you can do flow cytometry you can apply it to almost everybody. I suspect in the most commonly used technique will be flow cytometry. Three, and the most important thing, is that at the moment we don’t know what—we know that it’s better to not have measurable disease by a sensitive technique but we don’t know what to do with it yet in AML. And we’re learning about that. All of us would like to get rid of the residual disease and hopefully that will lead to a better natural history.
VIEW SLIDE DECK
MRD as a Predictor of Relapse in AML
A slide presentation covering remission and relapse in AML and the importance of detecting and monitoring MRD.
EXTERNAL AML-RELATED ARTICLE
Very poor long-term survival in past and more recent studies for relapsed AML patients: The ECOG-ACRIN experience
References: 1. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447. 2. San Miguel JF, Martínez A, Macedo A, et al. Immunophenotyping investigation of minimal residual disease is a useful approach for predicting relapse in acute myeloid leukemia patients. Blood. 1997;20(6):2465-2470. 3. Meyers J, Yu Y, Kaye JA, Davis KL. Medicare fee-for-service enrollees with primary acute myeloid leukemia: an analysis of treatment patterns, survival, and healthcare resource utilization and costs. Appl Health Econ Health Policy. 2013;11(3):275-286. 4. Luskin MR, Stone RM. Can minimal residual disease determination in acute myeloid leukemia be used in clinical practice? J Oncol Pract. 2017;13(8):471-480.
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