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MRD's Potential Role in Treating Acute Myeloid Leukemia

Panelists: Harry Erba, MD, PhD, University of Alabama at Birmingham; Jorge E. Cortes, MD, MD Anderson Cancer Center; Alexander E. Perl, MD, Perelman School of Medicine; Eunice Wang, MD, Roswell Park Cancer Institute
Published: Thursday, Mar 01, 2018



Transcript: 

Harry Erba, MD, PhD: One thing that I promised our audience we were going to talk about is the use of some assay flow cytometry, next-generation sequencing, to look at minimal residual disease. Let me give you an example of something at this congress that was presented by Dr. Lambert: a really nice oral presentation looking at WT1 overexpression, which is informative in every leukemia patient. You don’t have to worry about flow phenotypes, immunophenotypes. You don’t have to worry about specific fusions or mutations to follow. You can look at WT1 overexpression using an RT-PCR (reverse transcription polymerase chain reaction)-based assay.

And so, she presented a very nice study looking at the prognostic significance of that. What she found was that at the end of induction, if the patient did not have a certain amount of reduction in the expression level of WT1, that they had a worse outcome. To me, that sounds like responding is better than nonresponding. But on top of that, this effect was also seen in patients who went to transplant. This is the important point I’d like us to discuss.

So, you have a patient who has minimal residual disease by whatever assay, and most studies show a worse outcome if they go to transplant with minimal residual disease. But there appears to be a benefit of transplant in the MRD-negative patients. Do you think MRD assessment, by whatever means, is ready for primetime in decision making for transplant?

Alexander E. Perl, MD: No.

Eunice Wang, MD: Well, OK.

Alexander E. Perl, MD: With the caveat that I think we need an assay we can use everywhere. I think we need an assay that gives us a clear answer. We need to have an assay where we say, “Based on these results, we can change what we do,” and it changes the outcome. That’s what I think we need. Now, do we have data that are informative and help us make decisions? Clearly. Do we have data on various assays that have been validated intracenter? Clearly. Do we have something that we can use for everybody, where we say our standard approach is X and it leads to better outcomes because it informs the next choice that leads to a change in the natural history? I don’t think we’re there yet.

Eunice Wang, MD: I use the information as, if I get an MRD-positive patient—I know obviously our institute standard is not commercialized—I do think, “Maybe I need to give them another consolidation cycle.” If they’ve been getting cytarabine-based therapy, maybe I want to give them a hypomethylating agent to get that to be MRD-negative. And the transplanters are very interested because even from their point of view, I’m going to try to get them MRD-negative before transplant. If the patient goes into transplant MRD-positive, that certainly affects what kind of immunosuppressive therapy they’re going to use.

Alexander E. Perl, MD: That’s a good point.

Eunice Wang, MD: It may affect what type of transplant they’re going to use because haploidentical transplants are very much in vogue and we use a lot of them. But they’re associated with a higher risk of relapse. So, for somebody coming in with MRD disease, it might be more beneficial to do a myeloablative approach. With that information right now, though it’s not ready for prime time—I wouldn’t advocate that everybody do it, and it’s clearly not commercialized or generally available—it is informative on an individual patient basis.

Harry Erba, MD, PhD: Let me tell you why I would push back a little on that. I think that’s a very valid way of doing it, but there’s a caveat. We don’t know that if a patient is MRD-positive after induction, pursuing some other therapy to make them MRD-negative gives them a better prognosis.

Eunice Wang, MD: We don’t.

Jorge E. Cortes, MD: I was going to say, I view this from a different perspective. Certainly, the patients who go to transplant without detectable residual disease do better. They do better with chemotherapy only. My problem is that with the patients who don’t get to that stage, pursuing more chemotherapy can backfire big time. You could get them very sick, and of course you don’t even know that it’s going to make them MRD-negative. They don’t do as well with transplant versus if they were MRD-negative. But that’s probably the best they can do for that patient. So, I think what we need to do is figure out, what do we do to improve the outcome of those patients after transplant? What do we need to give them? I don’t know, we’ve been doing azacitidine. There are other options.

Eunice Wang, MD: Right. Maybe give them something before transplant. Would it affect the transplant regimen and your posttransplant regimen? Would you put them on a TKI or something posttransplant? What would you do?

Alexander E. Perl, MD: I think maintenance is a really great question when we’re dealing with MRD-positive patients going in.

Eunice Wang, MD: To try to decrease posttransplant.

Harry Erba, MD, PhD: I think that’s the bottom line here. This is on us, right? We need to develop studies that will look at a different approach—not chemotherapy, but a different approach, whether it be immunomodulation antibodies, tyrosine kinase, biologic therapies, pre- or posttransplant—to improve the outcome of these patients. 

Transcript Edited for Clarity 

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Transcript: 

Harry Erba, MD, PhD: One thing that I promised our audience we were going to talk about is the use of some assay flow cytometry, next-generation sequencing, to look at minimal residual disease. Let me give you an example of something at this congress that was presented by Dr. Lambert: a really nice oral presentation looking at WT1 overexpression, which is informative in every leukemia patient. You don’t have to worry about flow phenotypes, immunophenotypes. You don’t have to worry about specific fusions or mutations to follow. You can look at WT1 overexpression using an RT-PCR (reverse transcription polymerase chain reaction)-based assay.

And so, she presented a very nice study looking at the prognostic significance of that. What she found was that at the end of induction, if the patient did not have a certain amount of reduction in the expression level of WT1, that they had a worse outcome. To me, that sounds like responding is better than nonresponding. But on top of that, this effect was also seen in patients who went to transplant. This is the important point I’d like us to discuss.

So, you have a patient who has minimal residual disease by whatever assay, and most studies show a worse outcome if they go to transplant with minimal residual disease. But there appears to be a benefit of transplant in the MRD-negative patients. Do you think MRD assessment, by whatever means, is ready for primetime in decision making for transplant?

Alexander E. Perl, MD: No.

Eunice Wang, MD: Well, OK.

Alexander E. Perl, MD: With the caveat that I think we need an assay we can use everywhere. I think we need an assay that gives us a clear answer. We need to have an assay where we say, “Based on these results, we can change what we do,” and it changes the outcome. That’s what I think we need. Now, do we have data that are informative and help us make decisions? Clearly. Do we have data on various assays that have been validated intracenter? Clearly. Do we have something that we can use for everybody, where we say our standard approach is X and it leads to better outcomes because it informs the next choice that leads to a change in the natural history? I don’t think we’re there yet.

Eunice Wang, MD: I use the information as, if I get an MRD-positive patient—I know obviously our institute standard is not commercialized—I do think, “Maybe I need to give them another consolidation cycle.” If they’ve been getting cytarabine-based therapy, maybe I want to give them a hypomethylating agent to get that to be MRD-negative. And the transplanters are very interested because even from their point of view, I’m going to try to get them MRD-negative before transplant. If the patient goes into transplant MRD-positive, that certainly affects what kind of immunosuppressive therapy they’re going to use.

Alexander E. Perl, MD: That’s a good point.

Eunice Wang, MD: It may affect what type of transplant they’re going to use because haploidentical transplants are very much in vogue and we use a lot of them. But they’re associated with a higher risk of relapse. So, for somebody coming in with MRD disease, it might be more beneficial to do a myeloablative approach. With that information right now, though it’s not ready for prime time—I wouldn’t advocate that everybody do it, and it’s clearly not commercialized or generally available—it is informative on an individual patient basis.

Harry Erba, MD, PhD: Let me tell you why I would push back a little on that. I think that’s a very valid way of doing it, but there’s a caveat. We don’t know that if a patient is MRD-positive after induction, pursuing some other therapy to make them MRD-negative gives them a better prognosis.

Eunice Wang, MD: We don’t.

Jorge E. Cortes, MD: I was going to say, I view this from a different perspective. Certainly, the patients who go to transplant without detectable residual disease do better. They do better with chemotherapy only. My problem is that with the patients who don’t get to that stage, pursuing more chemotherapy can backfire big time. You could get them very sick, and of course you don’t even know that it’s going to make them MRD-negative. They don’t do as well with transplant versus if they were MRD-negative. But that’s probably the best they can do for that patient. So, I think what we need to do is figure out, what do we do to improve the outcome of those patients after transplant? What do we need to give them? I don’t know, we’ve been doing azacitidine. There are other options.

Eunice Wang, MD: Right. Maybe give them something before transplant. Would it affect the transplant regimen and your posttransplant regimen? Would you put them on a TKI or something posttransplant? What would you do?

Alexander E. Perl, MD: I think maintenance is a really great question when we’re dealing with MRD-positive patients going in.

Eunice Wang, MD: To try to decrease posttransplant.

Harry Erba, MD, PhD: I think that’s the bottom line here. This is on us, right? We need to develop studies that will look at a different approach—not chemotherapy, but a different approach, whether it be immunomodulation antibodies, tyrosine kinase, biologic therapies, pre- or posttransplant—to improve the outcome of these patients. 

Transcript Edited for Clarity 
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