Moving Toward Precision Medicine in Adult Acute Myeloid Leukemia - Episode 3

MRD Assessment and Consolidation in AML

Transcript:Elias Jabbour, MD: So, Mark, I want to move to you. We all talk about assessment of minimal disease and how it can affect our choosing therapy; whether we go for chemotherapy, transplantation, clinical trials. Can you tell me where we stand today with MRD assessment in AML?

Mark J. Levis, MD, PhD: Currently, things are still up in the air, but I think a lot of progress is going to be made very soon. We have fairly recent data looking at the value of following an NPM1 mutation. It’s a pretty sensitive test. It’s only applicable right now to the subset of patients who have an NPM1 mutation. And if they’ve got it, you can follow that after they achieve remission and actually predict which patients are going to do well. We don’t know yet what to do about it when we detect it.

Elias Jabbour, MD: Right. But if you don’t have an NPM1 mutation, how do you assess for MRD? Let’s say you don’t have the CBF leukemia nor the APL, where we use PCR for these patients. But for a standard case of AML, you assess MRD by flow cytometry?

Mark J. Levis, MD, PhD: So, the problem is, you’ve got the “taste great, less filling.” You’ve got the flow people on one side, the DNA-based people on the other, and where do you come down? The problem, across the field, is a lack of standardization. If you go around the table of people who assess MRD, they’re mad geniuses. They each know how to do it really well. They ask, “Can you teach someone else, in adding something, to actually do that?” and you get this look that maybe they can’t.

Elias Jabbour, MD: I have a question, then. Let’s say, regardless of how we assess MRD with next-generation sequencing of flow, but you have somebody who has started therapy with bad features. Let’s say, diploid phenotype, FLT3-ITD—positive, or complex karyotype, and they respond very well and they become MRD-negative. Will MRD status trump baseline features in your decision making for transplant?

Mark J. Levis, MD, PhD: Yes. For one thing, the problem is having any form of detectable MRD predicts for a disaster in transplants. So, again, we’re still not sure what to do about MRD when we see it. We know it’s bad. I think, again, the problem that we’re having is a lack of standardization in the techniques. Now, we can agree what MRD is.

Elias Jabbour, MD: Correct.

Mark J. Levis, MD, PhD: So, the regulatory agencies are pushing quite strongly, appropriately, for us to develop a standardized MRD assay for different subtypes of AML. For example, the conventionally available assay to detect a FLT3 mutation is nearly useless for MRD, but there is the technology and there will be very shortly, I believe this year, CLIA—certified assays for an ITD mutation at a level like BCR-ABL.

Elias Jabbour, MD: That brings me to a consolidation approach. Mark, if you have somebody who is MRD-positive or not, when do you decide to go for transplantation? In first remission?

Mark J. Levis, MD, PhD: Actually, allogeneic transplantation, I think, in first remission is our most potent anti-leukemic therapy, even in favorable risk. Elias Jabbour, MD: By favorable, you mean non-CBF?

Mark J. Levis, MD, PhD: No, favorable; even in CBF patients. The problem is in that situation, in general, I think the feeling is that the treatment-related mortality, transplant-related mortality, does not justify. But I think in anyone that has intermediate risk or unfavorable risk, in general, we trying to move toward an allogeneic transplant at first remission, if they’re a suitable candidate and they have a suitable donor.

Elias Jabbour, MD: Okay, and for those who are MRD-positive, do you go for the transplantation? Obviously, we all like to do clinical trials for these patients by default—but for somebody in the community who had induction consolidation and they remain MRD-positive.

Martin S. Tallman, MD: As Mark said, there are emerging data to suggest that those patients fare very unfavorably with allogeneic transplantation. So, I think we do what we can to try to get them into an MRD-negative state.

Richard M. Stone, MD: I want to be clear, though. I think in the community, and even in many academic centers, MRD assessment has not yet, for the reasons that were outlined by Mark, entered the algorithm of how to decide what to do.

Mark J. Levis, MD, PhD: And they’re not standardized.

Richard M. Stone, MD: Right, and even so. So, Mark, what would you do with a patient who had a FLT3-ITD mutation and became MRD-negative by flow cytometry? By Dr. Ward in Seattle, would you not transplant that patient? Of course, you’d still transplant that patient.

Mark J. Levis, MD, PhD: Of course, I would still transplant that patient.

Richard M. Stone, MD: So, we don’t use it is the point.

Transcript Edited for Clarity