Understanding Driver Mutations in AML: What Is Next-Generation Sequencing?

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Topics include: Treatments

How can we better understand acute myeloid leukemia (AML)? As genetic testing becomes more and more prevalent in determining which treatments are right for specific types of AML, we break it down with experts on what you need to know. The best course of action is to get genetic testing done and work with your doctor to understand and determine which treatment path will be best for you. 

This is a Patient Empowerment Network program produced by Patient Power. We thank Daiichi Sankyo and Jazz Pharmaceuticals for their support.

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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.

Esther Schorr:

If one relapses with AML, in that scenario, do they need to be then retested to the…

Dr. Ritchie:                  

…yes.

Esther Schorr:             

Because I know, in some of the other leukemias, that’s the case.

Dr. Ritchie:                  

The NCCN guidelines really recommend that there is a mutational panel done at diagnosis. But if we’re going to send someone to transplant, there’s a lot of sort of disagreement about how you measure minimal residual disease. But one of the things I think most people are beginning to have a consensus about is repeating the molecular panel to see whether or not we still see those molecular abnormalities, in addition to other things. 

Andrew Schorr:          

It’s the driver gene.

Dr. Kadia:                    

Exactly. So, I think, what we realize is that this is a disease that’s constantly evolving. So, we hit it with chemotherapy. It evolves to progress. We hit it again with something else, it evolves. So, the evolution happens either through chromosome abnormalities or to mutations. So, it’s important to recheck some of these mutations to see now, hey, they didn’t have the FLT3 before, but now they do. Now, we can target it with something else.

Andrew Schorr:          

Dr. Kadia, so we’ve mentioned a couple of these cancer genes. IDH, FLT3, I think. So, these are oncogenes, right?

Dr. Kadia:                    

Right. So, what’s been great, and I think this has been greatly summarized by my colleagues, but we’ve had sort of a revolution in how we treat AML and many cancers, but particularly AML and the liquid tumors. With the advent of what we call next-generation sequencing, we’re able to really get the mutations and the data from the leukemia cells. We find that there are recurrent mutations. Mutations are changes in the DNA that happen over and over and over again, in different people with leukemia. So, it made us realize that, if these mutations keep happening in AML, they must drive the AML.

There must be something about them that makes the AML happen. And, in fact, that’s the case. So, in a handful of those mutations, things that people have really studied, we now know that things like FLT3 or “flit 3” is a mutation that really drives proliferative AML. And so, people said, well, if that drives it, can we develop a drug target inhibitor of that mutation to shut the leukemia down? And indeed we can. We used to use a drug call Sorafenib last year, over a year ago. A drug called midostaurin (Rydapt) was approved with chemotherapy in the front line. And just recently, as was describe, just a week ago, gilteritinib (Xospata) was approved in patients who have the FLT3 mutation, but they’ve had relapsed disease.  

So, that’s just one example. The second you said IDH, right, isocitrate dehydrogenase, another mutation. We didn’t know what it meant. But people worked and worked and figured it out. And they found out there’s two mutations, an IDH1 and an IDH2 mutation. Each of those drives that particular subset of leukemia. And it turns out you can make inhibitors to each of those, and they work. An oral medication you take once a day for people with relapsed disease actually works. 

And it doesn’t work like regular chemotherapy. We describe intensive chemotherapy. You put them in the hospital, their hair falls out. They have mouth sores and diarrhea and nausea and vomiting. We don’t see that, with these pills. We do see some side effects. And, certainly, the patient and the family member need to recognize those side effects. So, there are side effects. But they’re different. They’re more tolerable. They’re more manageable. And so, that’s what we’ve been able to do, get people home, take these medications, and target these specific mutations. 

So, among the many mutations we’ve discovered, we found drugs for probably two to three of those targets. But we also found that some of these mutations will predict for responses to other drugs like venetoclax (Venclexta). 

Andrew Schorr:          

Let’s talk about testing. How do you know? 

Esther Schorr:             

I was just going to say it really sounds like you have to be tested. 

Dr. Lee:                       

Yes.

Esther Schorr:             

To know where you fall.

Dr. Ritchie:                  

And I think that’s one of the big barriers right now that I feel the insurance industry has not really caught up to what it is that we’re doing in AML. So, every patient who is getting or has a suspicion that patient has AML, that patient, when they have a bone marrow biopsy and they see a doctor should have a next-generation sequencing sent.

The problem is this costs thousands of dollars. Now, some insurance companies are not—they don’t really care or aren’t really cognizant of the quality of the different NGS panels. And they make deals to cover with one or not cover at all. So, it can be a hassle for the patient. And it can be thousands of dollars expense. So, that’s something that I think the whole industry is working on to try and enlighten insurance companies and to make them pay for this particular sequencing. MD Anderson has their own in house. And you probably have worked out a deal with insurance companies.

Dr. Kadia:                    

No, we have. So, I think more and more, insurance companies are beginning to realize that this is a part of the disease treatment. If you have pneumonia, you’re going to get a chest X-ray. If you have AML, it’s becoming standard.

 It has for years. We do FLT3 mutations. We do something called NPM1 mutations. For years, we’ve been doing this in AML. Now, what they need to realize is that we need to expand that to what we call a sequencing panel, which are 80 different genes, which are commonly mutated. Why? Not just because we’re interested and we’re curious, but because these mutations play an important role in telling the patient this is your prognosis. And this is the drug that we’re going to treat it with.

Dr. Ritchie:                  

Or even, if this patient—and just because you’re older doesn’t mean you’re not a candidate to be a bone marrow transplant candidate, there are some mutations that we find that really propel us to wanting to have that patient.

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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Page last updated on July 2, 2019