Prognostic Significance of MRD in AML



Harry Erba, MD, PhD: These are very costly tests though and we do a lot of bone marrow [biopsies] on our patients. When do we actually need to do these tests? What do you think?

Alexander E. Perl, MD, MS: It’s a great question there. The actionable question versus the database are 2 important questions, and they may not be the same questions. We need all the information that we’re going to need down the road to make the transplant decision, but we don’t need all of that information right from the start. The information you need to make a treatment decision is basically what I’ve stated. Some centers have actually done a limited next-generation panel, or a PCR [polymerase chain reaction] panel, or a combination of these to say let me give you all the information you need right now, and then you get a full panel later on.

At our institution, we get one but then we’ve pulled out the things that we need front line, as I’ve just described. You do need a certain amount of information right up front, but you’ll still need a full database later on to say I didn’t need to know before starting 7+3 [cytarabine/daunorubicin], does this patient have a RUNX1 mutation, but I might want to use that if I’m making a transplant decision. So you need that eventually, and that’s why we would send that at diagnosis to get a full, at our institution, 68-gene panel. If a patient relapses, we want to have that information back again.

We also might be following that once they’re in remission to know did the leukemia-associated clones go away? Because there’s emerging data that if they don’t, at least for mutations that aren’t clonal hematopoiesis-associated, such as DNMT3A, ASXL1, or TET2, the persistence of mutations associated with the leukemia is a really bad prognostic sign and it effectively is like minimal residual disease [MRD]. So you can use that to say are we seeing clearance of the disease that we’re treating and if not, do we need to escalate our therapy?

Harry Erba, MD, PhD: Well, you just opened a can of worms there. Go ahead. We’re going to come back to it.

Jorge E. Cortes, MD: I was going to mention, it starts getting complex, no question, because there are many other aspects that we need to consider. Number 1, and this takes us back to the diagnostic, is that we’re talking about these mutations, but they don’t happen in isolation. There are these co-mutations that occur in many instances. And the way 1 mutation happens when it happens by itself, whereas when it happens in combination with another mutation, is different. NPM1, for example, just having NPM1 is one thing, having NPM1 in the presence of FLT3, it’s a completely different beast. You need to understand this and see how that affects the prognosis, number 1.

Then as you continue the treatment, and as Sasha [Alexander] was mentioning, these mutations, you can eliminate clones and whatever, but you can also select clones. As the patient develops recurrence, or resistance, or whatever, the clone may be completely different. And Sasha has actually done very nice work with the FLT3-mutated patients. As they relapse, now they have RAS mutation, for example. And this is still [being researched] and some of these you can only do with very sophisticated assays and all of that. But still it’s important to understand the fact that a patient was FLT3-mutated at the beginning, on the relapse you could be facing a completely different scenario.

That’s why it’s very important to repeat that panel to see what exactly are you facing, and does it makes sense to, for example, try another FLT3 inhibitor, or are you dealing with something else where you need to consider a different approach? So it is important to consider the fluidity and the changing nature of the disease as the treatment progresses.

Alexander E. Perl, MD, MS: One frustration I’ve always had with data looking at patients with relapsed AML [acute myeloid leukemia] is that often the only data that they have about them comes from the diagnostic specimen. It’s not re-sampled when they go on the study or the analysis at relapse. So it’s a limited dataset if something is going to change between point A and point B.

Harry Erba, MD, PhD: I want to come back to a very important point that you brought up. Testing at the time of remission, so the counts have recovered after your initial therapy, you think the patient’s in remission. We learned a long time ago that persistence of an abnormal cytogenetic clone is associated with a poor outcome. Did we learn what to do about that? Because I don’t remember knowing except do what we always do.

Alexander E. Perl, MD, MS: Transplant.

Harry Erba, MD, PhD: Send them to transplant, right?

Eunice Wang, MD: Right.

Harry Erba, MD, PhD: Well, here’s the point. I’m going to get to Dan then for his discussion of MRD by flow and by mutational analysis. But I don’t know what to do with that information, and my concern is that Dan will tell us about how this is prognostically important with a transplant. And this is important to them because transplant centers get accredited based on their outcomes in different disease states. So the patient is apparently in a complete remission, but we all know they have persistent disease by cytogenetics or maybe some other tests we’ll talk about. And we know that their relapse rate will be higher. So the transplant center might say back to you, “I’d really like you to give them more therapy to get them into a deeper response, and then their outcome with transplant will be better.” And that might be true, might not be true.

Eunice Wang, MD: Right.

Harry Erba, MD, PhD: But I don’t know what to give.

Jorge E. Cortes, MD: The thing that we understand more and more is that bad diseases are bad diseases with everything. A patient with a p53 mutation, their outcome after transplant is also very poor, and maybe it’s the best thing you can do for the patient. But compared to a transplant for somebody who doesn’t have a p53 mutation, those patients do very poorly. The problem is our biggest needs we haven’t been able to solve. The patient with persistent MRD, they still have a worse prognosis with outcome. The patients with p53 mutations, they still have a poor prognosis with outcome. So these bad scenarios, our instinct has been to send to transplant. Our solution is not there.

Harry Erba, MD, PhD: Exactly.

Eunice Wang, MD: But I think the timing is unsure because if you have somebody who’s MRD-positive who has persistent disease, even though they’re morphologically or clinically in a remission, we don’t have a good agent. So that might be the person we’re in the absence of knowing whether they had MRD-positive or negative. You would send them to transplant because they have minimal level disease. If you then delay the transplant and try to give them some type of therapy, you run the risk, which has happened in my practice, where then the disease explodes, and now you have no option of doing a transplant because they have overt disease.

Jorge E. Cortes, MD: But my transplant colleagues will tell me, get them to MRD-negative. I say, number 1, tell me how. Number 2, if I have them MRD-negative, I probably wouldn’t be calling you anyway.

Harry Erba, MD, PhD: That I agree. I get that. And there’s the problem, we don’t have what we have in B-cell ALL [acute lymphocytic leukemia], we don’t have the blinatumomab of AML.

Eunice Wang, MD: We don’t have the molecular eraser, right?

Harry Erba, MD, PhD: That’s right. We don’t have the molecular eraser, and so I think we all agree that clinical research really has to look at what to do about MRD, something different than chemotherapy.

Transcript Edited for Clarity

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