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How Do Genetic Mutations Inform AML Treatment Options?

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Published on February 27, 2018

Could AML therapies be tailored to specific genetic mutations? Should patients get retested post-treatment? Tune in to hear AML experts, Dr. Lee Greenberger, from The Leukemia & Lymphoma Society, and Dr. Amit K. Verma, from Montefiore Medical Center, cover key mutations for AML patients and their response to treatment. 

This is a Patient Empowerment Network program produced by Patient Power, in partnership with The Leukemia & Lymphoma Society (LLS). We thank Astellas, Celgene Corporation, Novartis, Pfizer and Seattle Genetics for their support.

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Transcript | How Do Genetic Mutations Inform AML Treatment Options?

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:

Dr. Greenberger, I don't want to give people a lot of jargon, but just so they're kind of familiar with the territory, could you mention some of the names or numbers or whatever of some of the key mutations where a doctor may say to a patient, oh, we found this or we found that?  

Dr. Greenberger:

Right.  So I'll give you two examples of which there are drugs.  One is called FLT3, F-L?T-3, and when that gene is mutated we know that it causes tumors to grow.  We've done this in the lab, and we have a newly approved drug, that's midostaurin (Rydapt), to treat an FLT3?mutated patient.  And I'll tell you a little bit more about that in a second. 

And then there's another one called IDH2. IDH2 is mutated in about 10, 15 percent of patients with AML, and there's a newly approved drug, itacitinib, to treat IDH2-mutant patients.  Okay.  So let's say you've got these mutations, right?  And let's say you waited the seven days to get the results back.  The question is what road do you proceed down?  Do you proceed down with saying, okay, we're going to use this new drug, and we're going to treat a newly diagnosed patient with it, or are we going to just go to the conventional cytotoxic therapy and then maybe follow it up by an IDH2 mutation? 

And so that's where these—physician choice becomes so important in terms of evaluating the patient holistically.  How is the patient doing?  What do the cells look like?  What is the mutational status?  You could even imagine a mutation may be detected but it's only in 10 percent of the cells.  Do you treat with an IDH2 mutation inhibitor or not.  That's some of the examples, and I think I'm sure Dr. Verma can amplify on that.

Andrew Schorr:

Yeah.  Why don't you, Dr. Verma.  So give us some of the thinking you're doing based on certain genes.  

Dr. Verma:

Sure.  So these two genes that Dr. Greenberger mentioned are very important because we have medicines for them.  So FLT3, if you have a mutation we now have an approved drug which actually can be given as part of the initial treatment.  The initial chemotherapy that's given for AML or leukemia can include this particular medicine called midostaurin.  And this was approved by the FDA after a big clinical trial was done which showed that if you add this particular medicine to chemotherapy it improves the rates of success and survival in patients who have this FLT3 mutation. 

Now, the other mutation, IDH2, is approved by the FDA, but right now it's approved for patients who, you know, usually fail or relapse after chemotherapy.  This is an oral medicine as—similar to midostaurin, which was an oral medicine.  And, you know, my personal belief from research as well as reading research that other people have done is that if possible these new targeted therapies should be used as early as possible. 

What happens is if you give traditional chemotherapy and the disease comes back, you know, the disease relapses, a lot of times the disease can turn out to be a little bit worse than when it usually—initially had presented. 

And that usually happens because chemotherapy basically works by damaging your DNA.  So it kills DNA.  The cells that are dividing really rampantly like cancer cells get hit by this chemotherapy and die, but some normal cells also get affected by this, as we know.  But what happens is if there are pools of cancer cells, of cancer stem cells that survive—so they have been exposed to the chemotherapy, and then they come back—they can come back with more mutations or with worse mutations, and then it gets a little bit are tougher to bring them in control.  So in the best?case scenario we find the mutation and we have a drug—you know, right now we have two, but we still don't have that many. 

But it is our sincere hope that with the amount of research and stuff that's happening in this field, especially with LLS' support and support of other organizations, we will have more of these drugs.  So when we have more of these drugs we would like them to be given right away if possible because that would be our best chance of a cure.  And you know we all strive for a cure.  We don't control. 

Andrew Schorr:

I have a question about testing.  So Dr. Verma was just talking about trying to give the right treatment right off the bat.  

Dr. Verma:

Right. 

Andrew Schorr:

But cancer changes so for the patient or family member now listening, does this argue, if you're lucky enough to be surviving for a while treated with AML, you should be retested? 

Dr. Greenberger:

Right.  So absolutely, because this particular disease changes, can change rapidly, over a period of months.  After you're done with your therapy you really need to be analyzed.  And we have grants, people that we're funding in the U.S. to look at how these changes occur over time, to basically follow the patient over many months by repeated bone marrow biopsies to ask, genetically, how are these cells changing. 

And, as Dr. Verma said, after the therapy is done you'd have a different—you could have a different disease, and so now the treatment might have to be changed again. 

I'd also like to add one more—one more important comment, and that is why do we think these genetically designed therapies are even going to work.  And so, I think Dr. Verma suggested, they work. 

They typically work a little bit better than the chemotherapy, the cytotoxic therapy we've been using for 30, 40 years.  For some patients they may work very well, but on average they're a little bit better. 

We have seen in other leukemias that there are certain medications that basically can control the disease long term, basically just keep a lid on it for 10, 20 years.  We've seen this with—some patients may know of imatinib mesylate (Gleevec) to treat chronic myelogenous leukemia, and that basically just can totally keep that disease under control for a decade.  And we've seen it with ibrutinib (Imbruvica).  Any CLL patient…

Andrew Schorr:

Right.  I'm living with CLL. 

Dr. Greenberger:

…oral medication.  We take this pill and basically it will keep CLL under control for many, many years.  We don't even know how long, but it's going to be highly effective.  So because of that experience we think that that can also apply to AML. 

But AML is more tricky, because AML can change over time.  It's very clear that this so?called heterogeneity or diverse mutations, it's like whack?a?mole.  You'd knock down one, and then the next one comes up.  And so you have to be able to follow disease over time by repeated sampling to really, we think, the optimal therapy of having the drugs on the shelf, knowing what combinations to use and possibly changing the therapy during the course of treating the disease.  

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.