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Post-ASCO 2019: Identifying and Treating AML Genetic Subtypes

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Published on July 22, 2019

What does mutational status mean for acute myeloid leukemia (AML) patients? How does a patient’s genetic profile impact the course of treatment? AML expert Dr. Eytan Stein, from Memorial Sloan Kettering Cancer Center, breaks down patient subsets of AML and shares research on therapies developed to target specific gene mutations.

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Transcript | Post-ASCO 2019: Identifying and Treating AML Genetic Subtypes

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That's how you’ll get care that's most appropriate for you.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

Andrew Schorr:

Hello and welcome to Patient Power.  I'm Andrew Schorr.  Well, we've had the big ASCO, American Society of Clinical Oncology conference in Chicago, lot of research gets presented.  What does it mean for patients?  

Well, joining us to talk about people with myeloid conditions is a myeloid specialist, a hematologist?oncologist from Memorial Sloan Kettering, and that's Dr. Eytan Stein.  Dr. Stein, welcome to Patient Power.  

Dr. Stein:

Thank you so much for having me.  

Andrew Schorr:

Dr. Stein, so you presented at the ASCO conference on sort of molecular markers and all that for people with myeloid conditions.  So what does that mean exactly?  Is it what genes have gone awry, or what are you looking at?  

Dr. Stein:

Yeah.  So let me tell you a little bit about it. So what's important about knowing about the genetic alterations and, as you mentioned, the genes that have gone awry that have caused the patient to develop a myeloid malignancy or acute myeloid leukemia specifically is that, number one, it can give us some prognostic information about whether we think the patient needs to have extremely aggressive therapy with a stem cell transplant, but maybe more importantly is that over the past three years we've seen a number of drug approvals that are specifically based on the genetic alterations that are found in the bone marrow at the time a patient is diagnosed and if they, God forbid, relapse. 

So, as you probably know, for the past 40 years, or about 40 years before three years ago, we were treating acute myeloid leukemia the same way.  So patients who were what we call fit or younger were getting very strong induction chemotherapy in the hospital, and then those patients who might not be candidates for induction chemotherapy because of some health condition that they might have or if they were just—if their disease was unlikely to respond to induction chemotherapy, those patients were getting hypomethylating agents, a drug like azacitidine (Vidaza) or a drug like—or 5?azacitidine or a drug like decitabine (Dacogen).  

What we now have learned is that some of these molecular genetic alterations can be targeted with specific drugs.  So a good example of that is a mutation that's found in about 30 percent of patients with acute myeloid leukemia, and that's a mutation in a gene called FLT3, we pronounce it "flit three."  And we've seen that if you combine a FLT3 inhibitor called midostaurin (Rydapt) with chemotherapy in patients with this FLT3 alteration when they're first diagnosed, that actually leads to an improvement in survival in patients.  So that's very, very exciting.  

There are other trials that have been done in the relapsed and refractory setting in patients who have mutations in a gene called isocitrate dehydrogenase, also in FLT3, IDH or FLT3, and there are now drugs approved in relapsed and refractory myeloid leukemia for patients with those mutations.  

And what we're trying to do now, and maybe I'm getting ahead of myself, is we're trying to take those drugs that are approved in the relapsed and refractory setting, the patients whose disease has come back or not responded to the initial therapy, and we're trying to move those drugs into the up-front setting.  We're trying to get patients these drugs earlier in combination with chemotherapy because we think that the best shot of getting leukemia cured is when you give your most powerful drugs at the get-go rather than at the time of relapse.   

Andrew Schorr:

Right.  But what you want to do is use the drugs that are right for their version of the disease.  So it would seem that this allows you to give people the most personalized care, if you have a clear picture of their subset.  Not all AML is alike.  

Dr. Stein:

Yeah. Yeah, exactly.  So all AML causes a certain constellation of clinical symptoms, that is, low blood counts and low infection?fighting cell so that patients can get infections.  But really when you look under the hood and you look at that bone marrow it's many different mutations that are causing what we call the phenotype of the disease, so what the patient experiences.  But in order to cure or treat this disease you have to really attack every different subset and every different molecular genetic mutation.  

Andrew Schorr:

And now you are starting to have a range of medicines to do that.  

Dr. Stein:

Absolutely right. So as I mentioned earlier, we have these FLT3 inhibitors.  We have ideation inhibitors, and there are many, many other drugs that are being developed for specific subsets of patients with AML.   

Andrew Schorr:

Okay.  So I know you're combining medicines, and you want to use them earlier, but let's go into the lab for a minute.  You said that there are others in development.  So for people who are lucky enough to have their AML treated successfully now but not cured, they're saying, well, what medicines could come to be available that could help me later on?  What's going on?  

Dr. Stein:

Yeah.  So what's going on in clinical trials and actually very exciting.  I'll just talk about two specific classes of drugs that we're very excited about.  So one is that there are a lot of patients with AML that will actually have mutations in a category the genes called splicing factor genes, and in the laboratory actually now in early clinical trials there are drugs that are targeting these specific splicing factor mutations, and these drugs are very, very active in the laboratory.  We're now bringing them in to patients, and hopefully they're going to be as active in patients.  

There's another drug that we're very excited about which targets a mutation in a gene called p53.  P53 is a gene that when mutated can be involved in a lot of different types of cancer. And it tends to be involved in AML in a particularly nasty subset of disease that may not respond very well to chemotherapy.  

So there is a drug now that's being investigated in the laboratory called APR?246, and that's a drug that takes mutant p53 protein and actually sort of rehabilitates it and makes it act normally again.  In the early clinical studies, it's been very, very promising and this would be something that we're very, very excited about to get into later case studies.  

I think I would be remiss if I didn't talk about a clinical trial that's being done specifically to—for personalized medicine to target specific gene mutations in all patients, and that's a clinical trial called the Beat AML trial.  It's being sponsored by The Leukemia & Lymphoma Society.  And on this clinical trial what happens is if the patients with newly diagnosed AML, they come in, they get their bone marrow profiled for whatever mutations they have, and then depending on those mutations patients get allocated or sent to a specific sub protocol that is personalized for their type of leukemia, for their type of AML.  

And that trial is exciting not only because we get many, many drugs to patients quickly, it's also exciting because it's a trial that is very adaptable.  So if there is a new drug that we think is exciting, it can be added into the trial, and then patients can get access to it more quickly.  

Andrew Schorr:

Okay.  So let's really pull all this together.  At the ASCO conference you spoke to your peers and researchers about really probably the importance of molecular testing, really knowing what's going on with an individual AML patient, what therapy follows from that, and then going forward for the patients, our patient audience, is really making sure that they have the workup so that they and their doctor, whether it's with existing therapies, new combinations, or even what may be in a trial, may make sense for them.  Did I get it right?  

Dr. Stein:

That's exactly right.  

Andrew Schorr:

Okay.  So given that we went 40 years with not much going, how do you feel about the pace of change now offering hope to people affected by AML?  

Dr. Stein:

I think it's—I would except to see many, many more advances, and hopefully it's not going to take another 40 years.  I think within the next five years we're going to see additional advances with new drugs for AML.  

And the other thing that I think is important is that this has been a wonderful partnership, not only within the academic community and with our industry partners but also really with its government, with the Food and Drug Administration, which has been working extremely hard to get these new drugs to patients and get them approved as quickly as possible.  

I think part of what has allowed us to have these drugs approved quickly is that the FDA has been very open to thinking about new end points that are clinically meaningful for patients that might be the basis of a drug approval.  An example of this is with the ideation inhibitors one of the bases of these drug approvals were that patients would become transfusion independent.  The FDA recognized that the patients don't like coming in every twice a week or three times to get transfusions, and that that is an important quality of life measure if you can reduce the number of transfusions the patients are getting.  

Andrew Schorr:

So, Dr. Stein, a hopeful time, collaboration.  You mentioned the government.  You mentioned the Beat AML initiative with the Leukemia Society and patients who are watching and researchers such as yourself working together to make more progress than ever before.  That's a good thing.  

Dr. Stein:

Very good thing. Very good.  

Andrew Schorr:

Thanks for your devotion to patients and your hopeful message.  Thanks for being with us.  

Dr. Stein:

Thank you so much for the opportunity.  

Andrew Schorr:

I'm Andrew Schorr.  Remember, knowledge can be the best medicine of all.  

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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