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Consolidation Strategies in AML

Panelists: Harry Erba, MD, PhD, Duke University; Jorge E. Cortes, MD, MD Anderson Cancer Center; Alexander E. Perl, MD, MS, Hospital of The University of Pennsylvania; Daniel Pollyea, MD, MS, University of Colorado, Anschutz Medical Campus; Eunice Wang, MD, Roswell Park Comprehensive Cancer Center
Published: Tuesday, Aug 13, 2019



Transcript: 

Harry Erba, MD, PhD: Well, as long as you have the floor, let’s turn back to the intensively treated patient. So you’ve gotten through induction and they’re in a complete remission. Do you know how much consolidation to give those patients and how do you determine that? And who would you think about for transplant?

Daniel Pollyea, MD, MS: Right. Here’s where we need to go back to that information that we collected at the time of diagnosis. This is why it was so important to get that next-generation sequencing panel and to know every piece that you can about the underpinnings of their disease and what’s making their disease tick. Because now’s when you need to use that information, to make decisions about the next step. And if you didn’t get that information at the time of diagnosis, it’s gone. So you’re going to be trying to do this blindly, which is impossible.

At our institution, we would assess, once a patient is in a remission, what is their fitness for transplant, what is the availability for donors? And certainly, if they have any high-risk features, that would be a patient who we would steer toward a transplant in first remission, assuming they’re good candidates for that type of a procedure. The good-risk patients, the core binding factor patients, which we should have identified very early because of the data to support use of gemtuzumab at the time of induction, or other patients that we feel have good-risk disease biology, those are patients that we would recommend going on to consolidation. If they had a gemtuzumab-based regimen, then we would follow the induction plan with incorporating gemtuzumab with the chemotherapy elements for the duration of the consolidation. That would dictate the number of cycles, etcetera. At least that’s how we do things.

Harry Erba, MD, PhD: Maybe this is a role for MRD [minimal residual disease]. We can’t see the disease anymore, should we use MRD to determine how many cycles?

Daniel Pollyea, MD, MS: Yes. I think there’s a great study from a couple of years ago from the Chinese group with patients with core binding factor AML [acute myeloid leukemia] doing a very sensitive PCR [polymerase chain reaction] test for that abnormality after 2 cycles and then I believe if it was negative, doing a third and final cycle. So yes, I think incorporating MRD into the decision making not only for how many cycles of consolidation should a patient get. But also more importantly, at our institution if a patient is on track to just receive consolidation with no transplant but at some predetermined point still has MRD, we’ll take them off that path and back onto a transplant path, regardless of what their upfront disease biology was. If it was quite favorable but they’re proving in real time to not be having very deep responses, then those are patients who probably don’t have a chance of being cured with just chemotherapy and should be reassessed for a transplant.

Jorge E. Cortes, MD: I think part of the problem is that there hasn’t been really much in terms of prospective studies, and we all have our own preferences in terms of how much consolidation you’re going to give them. We have regimens that we give them, 6 cycles of consolidation. But there’s been some analyses that have shown that 1 cycle of consolidation is enough for most patients. In some of the core binding factor leukemias, perhaps there’s a little bit more solid information that they probably benefit from more consolidation, perhaps 4 [cycles]. But that also comes, most of it, from retrospective analysis of 4 versus 1 and things like that. So the evidence is not very strong. Now, you mentioned MRD and following by MRD. But you could argue that if a patient, if given a couple of cycles of consolidation, induction and consolidation, they still have MRD, is that same consolidation really going to get rid of that MRD or is it time to change to something else? Now, we talked earlier, we don’t have that eraser of blinatumomab or something, so change is fine, but change for what? The point is that, if induction and 2 consolidations have not gotten rid of MRD, is that really the answer?

Harry Erba, MD, PhD: Yes, I like Dan’s approach there. I’m beginning to adopt that as well. That’s where I might use MRD, at least for these non-DTA mutations, to decide if the patient should then go on to a transplant. And sometimes patients are very reluctant to accept transplant in first remission. If you have real data that the disease is still there, that might help.

Daniel Pollyea, MD, MS: But then we go back to the argument that sending a patient to a transplant with MRD, a nihilistic person could look at the data there and get very discouraged, and I think it’s a bad predictor for an outcome after a transplant. But what else are you going to do?

Jorge E. Cortes, MD: I think we have to differentiate, it is a bad predictor for transplant, but the statistics for transplant look worse in a patient like that. The statistics for a patient with that look better with a transplant than without a transplant. So in that perspective, that’s the best today we can do for our patient.

Daniel Pollyea, MD, MS: There is a curative option with that plan, yes.

Eunice Wang, MD: But there’s an argument to be made from the transplanters that they don’t want to transplant that person because they say that that patient is going to relapse post-transplant. That unless they have potentially a myeloablative option, if you don’t do a fully myeloablative transplant for that person, the risk of relapse with a reduced intensity, or a haploid transplant, is going to be extremely high. And they’re going to come to me, and they’ve said this, they will say, “Fine, I will transplant your patient as MRD-positive. What are you planning to do after transplant? How are we going to maintain that person in a remission?”

And we do have the luxury, I think, in some cases to have targetable mutations, which I would advocate that we always recheck the FLT3 and the IDH1 and IDH2 at relapse because there is a percentage of patients for which we didn’t detect it at diagnosis, either because it was subclonal at a very low VAF [variant allele frequency]  or something. Because we have the option sometimes and there are ongoing studies looking at FLT3 inhibitors, and IDH1/IDH2 inhibitors post-transplant. But I think that that puts us in a difficult position because the transplanters will say, “Well, I don’t know if I want to take them.” And they say, “OK, I will prepare your patient for transplant, but what are you going to do in the 6 to 8 weeks in between to prevent that patient from progressing, and what are you going to do afterwards?” And I think that makes us all uncomfortable. Again, I don’t know that we have an answer to that, but it is an ongoing discussion.

Daniel Pollyea, MD, MS: Well, it’s a clinical trials question, it really is.

Alexander E. Perl, MD, MS: And there are trials. One example I can think of is the CTN 1506 study, which is looking at the addition of gilteritinib post-transplant but not enrolling patients post-transplant, enrolling them pre-transplant, so that you can figure out is MRD going into transplant? What predicts who needs that kind of a drug?

Daniel Pollyea, MD, MS: That’s the way to do that type of a study. That’s the important question.

Eunice Wang, MD: But I think that brings up the question, yes, gilteritinib is not approved in the post-transplant setting, but there are off-label FLT3 inhibitors.

Alexander E. Perl, MD, MS: Sure.

Eunice Wang, MD: And there are data even in a randomized phase II study, albeit, but there are data that even off-label FLT3 inhibitors could have positive effects, specifically sorafenib. So the argument I get when I try to put my patient on that type of gilteritinib versus placebo trial is, “Well, I don’t feel comfortable with that, my patient has MRD-positivity, I would like them to get a FLT3 inhibitor,” based mostly on a gut feeling or on maybe the data with Ph-positive ALL [Philadelphia chromosome-positive acute lymphoblastic leukemia] where we do put patients on TKI [tyrosine kinase inhibitor] post-transplant. I think those are difficult things that we’re really struggling with. I think the MRD has been valuable, but it’s opened up more therapeutic dilemmas now that we didn’t have before.

Transcript Edited for Clarity

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Transcript: 

Harry Erba, MD, PhD: Well, as long as you have the floor, let’s turn back to the intensively treated patient. So you’ve gotten through induction and they’re in a complete remission. Do you know how much consolidation to give those patients and how do you determine that? And who would you think about for transplant?

Daniel Pollyea, MD, MS: Right. Here’s where we need to go back to that information that we collected at the time of diagnosis. This is why it was so important to get that next-generation sequencing panel and to know every piece that you can about the underpinnings of their disease and what’s making their disease tick. Because now’s when you need to use that information, to make decisions about the next step. And if you didn’t get that information at the time of diagnosis, it’s gone. So you’re going to be trying to do this blindly, which is impossible.

At our institution, we would assess, once a patient is in a remission, what is their fitness for transplant, what is the availability for donors? And certainly, if they have any high-risk features, that would be a patient who we would steer toward a transplant in first remission, assuming they’re good candidates for that type of a procedure. The good-risk patients, the core binding factor patients, which we should have identified very early because of the data to support use of gemtuzumab at the time of induction, or other patients that we feel have good-risk disease biology, those are patients that we would recommend going on to consolidation. If they had a gemtuzumab-based regimen, then we would follow the induction plan with incorporating gemtuzumab with the chemotherapy elements for the duration of the consolidation. That would dictate the number of cycles, etcetera. At least that’s how we do things.

Harry Erba, MD, PhD: Maybe this is a role for MRD [minimal residual disease]. We can’t see the disease anymore, should we use MRD to determine how many cycles?

Daniel Pollyea, MD, MS: Yes. I think there’s a great study from a couple of years ago from the Chinese group with patients with core binding factor AML [acute myeloid leukemia] doing a very sensitive PCR [polymerase chain reaction] test for that abnormality after 2 cycles and then I believe if it was negative, doing a third and final cycle. So yes, I think incorporating MRD into the decision making not only for how many cycles of consolidation should a patient get. But also more importantly, at our institution if a patient is on track to just receive consolidation with no transplant but at some predetermined point still has MRD, we’ll take them off that path and back onto a transplant path, regardless of what their upfront disease biology was. If it was quite favorable but they’re proving in real time to not be having very deep responses, then those are patients who probably don’t have a chance of being cured with just chemotherapy and should be reassessed for a transplant.

Jorge E. Cortes, MD: I think part of the problem is that there hasn’t been really much in terms of prospective studies, and we all have our own preferences in terms of how much consolidation you’re going to give them. We have regimens that we give them, 6 cycles of consolidation. But there’s been some analyses that have shown that 1 cycle of consolidation is enough for most patients. In some of the core binding factor leukemias, perhaps there’s a little bit more solid information that they probably benefit from more consolidation, perhaps 4 [cycles]. But that also comes, most of it, from retrospective analysis of 4 versus 1 and things like that. So the evidence is not very strong. Now, you mentioned MRD and following by MRD. But you could argue that if a patient, if given a couple of cycles of consolidation, induction and consolidation, they still have MRD, is that same consolidation really going to get rid of that MRD or is it time to change to something else? Now, we talked earlier, we don’t have that eraser of blinatumomab or something, so change is fine, but change for what? The point is that, if induction and 2 consolidations have not gotten rid of MRD, is that really the answer?

Harry Erba, MD, PhD: Yes, I like Dan’s approach there. I’m beginning to adopt that as well. That’s where I might use MRD, at least for these non-DTA mutations, to decide if the patient should then go on to a transplant. And sometimes patients are very reluctant to accept transplant in first remission. If you have real data that the disease is still there, that might help.

Daniel Pollyea, MD, MS: But then we go back to the argument that sending a patient to a transplant with MRD, a nihilistic person could look at the data there and get very discouraged, and I think it’s a bad predictor for an outcome after a transplant. But what else are you going to do?

Jorge E. Cortes, MD: I think we have to differentiate, it is a bad predictor for transplant, but the statistics for transplant look worse in a patient like that. The statistics for a patient with that look better with a transplant than without a transplant. So in that perspective, that’s the best today we can do for our patient.

Daniel Pollyea, MD, MS: There is a curative option with that plan, yes.

Eunice Wang, MD: But there’s an argument to be made from the transplanters that they don’t want to transplant that person because they say that that patient is going to relapse post-transplant. That unless they have potentially a myeloablative option, if you don’t do a fully myeloablative transplant for that person, the risk of relapse with a reduced intensity, or a haploid transplant, is going to be extremely high. And they’re going to come to me, and they’ve said this, they will say, “Fine, I will transplant your patient as MRD-positive. What are you planning to do after transplant? How are we going to maintain that person in a remission?”

And we do have the luxury, I think, in some cases to have targetable mutations, which I would advocate that we always recheck the FLT3 and the IDH1 and IDH2 at relapse because there is a percentage of patients for which we didn’t detect it at diagnosis, either because it was subclonal at a very low VAF [variant allele frequency]  or something. Because we have the option sometimes and there are ongoing studies looking at FLT3 inhibitors, and IDH1/IDH2 inhibitors post-transplant. But I think that that puts us in a difficult position because the transplanters will say, “Well, I don’t know if I want to take them.” And they say, “OK, I will prepare your patient for transplant, but what are you going to do in the 6 to 8 weeks in between to prevent that patient from progressing, and what are you going to do afterwards?” And I think that makes us all uncomfortable. Again, I don’t know that we have an answer to that, but it is an ongoing discussion.

Daniel Pollyea, MD, MS: Well, it’s a clinical trials question, it really is.

Alexander E. Perl, MD, MS: And there are trials. One example I can think of is the CTN 1506 study, which is looking at the addition of gilteritinib post-transplant but not enrolling patients post-transplant, enrolling them pre-transplant, so that you can figure out is MRD going into transplant? What predicts who needs that kind of a drug?

Daniel Pollyea, MD, MS: That’s the way to do that type of a study. That’s the important question.

Eunice Wang, MD: But I think that brings up the question, yes, gilteritinib is not approved in the post-transplant setting, but there are off-label FLT3 inhibitors.

Alexander E. Perl, MD, MS: Sure.

Eunice Wang, MD: And there are data even in a randomized phase II study, albeit, but there are data that even off-label FLT3 inhibitors could have positive effects, specifically sorafenib. So the argument I get when I try to put my patient on that type of gilteritinib versus placebo trial is, “Well, I don’t feel comfortable with that, my patient has MRD-positivity, I would like them to get a FLT3 inhibitor,” based mostly on a gut feeling or on maybe the data with Ph-positive ALL [Philadelphia chromosome-positive acute lymphoblastic leukemia] where we do put patients on TKI [tyrosine kinase inhibitor] post-transplant. I think those are difficult things that we’re really struggling with. I think the MRD has been valuable, but it’s opened up more therapeutic dilemmas now that we didn’t have before.

Transcript Edited for Clarity
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