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Resistance Mechanisms in AML and Treatment Decisions

Panelists: Naval G. Daver, MD, The University of Texas MD Anderson Cancer Center; Harry Erba, MD, PhD, Duke University; Mark J. Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center; Alexander Perl, MD, Abramson Cancer Center, University of Pennsylvania; Raajit K. Rampal, MD, PhD Memorial Sloan Kettering Cancer Center
Published: Wednesday, Feb 20, 2019



Transcript:

Harry Erba, MD, PhD:
You’ve brought up this contrast between a type 1 FLT3 inhibitor like gilteritinib that hits both the ITD [internal tandem duplication] and the TKD [tyrosine kinase domain], and quizartinib, a type 2, which is just the ITD. Does that matter, in terms of mechanisms of resistance? What are we seeing in terms of resistance to these drugs? Does the TKD matter, and is that how we should choose?

Alexander Perl, MD: Well, I think it does matter for 2 reasons. There’s also a difference between having a TKD only and having a TKD on the background of an ITD, particularly if you’ve had prior exposure to a FLT3 inhibitor, and then that shows up. If the TKD shows up on the background of a FLT3-ITD, those patients, across the board, don’t respond to drugs like quizartinib or sorafenib.

The TKD-only—we don’t know how driven that is by FLT3. It may be present but not a major driver. There’s some controversy on this, and I know we’ve talked about whether there are patients with TKD where it is a driver mutation, perhaps a high allele burden, in that setting where they’re going to respond to a drug. And we have seen responses to gilteritinib in that setting.

Harry Erba, MD, PhD: But not on the label.

Alexander Perl, MD: It’s not on the label. It’s not something you can readily get in any laboratory. You’d have to do an assay to say that. So we really are left with a yes-no question there. So, again, you have both mutations. I think that’s an indication where you would really favor using a type 1 inhibitor. If you had one or the other, then we’ve got to look at the drugs and see what’s better.

Mark J. Levis, MD, PhD: But the simple truth is, in the relapsed/refractory setting, a single agent might give you a response. It’s not going to give you a response for very long. Gilteritinib is a great drug and inhibits both types of mutations, and then you’re just going to get a RAS mutation that’s going to make you resistant. We’ve got to combine them and move them up earlier.

Naval G. Daver, MD: But you know with the TKD, I think that was something that we were a little surprised about because I reviewed the initial Lancet Oncology article a little bit. We don’t see, clinically, much of it, and it’s rare. It’s 5% of all patients. But with a single agent TKD, you had 12 and then 12, and it’s like 1 or 2 responders. So, I don’t know. Do we think crenolanib or midostaurin are going to be more active? Do we have data for that? Or we just don’t have anything that hits TKD alone.

Mark J. Levis, MD, PhD: We do have drugs that hit TKD alone. My impression is you have to have a high allelic ratio. It’s got to be a driver for that patient, and, even then, the response rate is clearly lower than the ITD.

Harry Erba, MD, PhD: And that’s probably the most important observation on the subset analyses from the RATIFY trial. The hazard ratio for survival was actually greatest in the TKD population, making you wonder, is it really FLT3 that we’re inhibiting?

Before we leave this topic of FLT3 inhibitors, I wanted to touch on one thing. Would one of you like to comment on FLT3 inhibitors in combination with less intensive therapy like gilteritinib with azacitidine?

Mark J. Levis, MD, PhD: Well, in fact, the MD Anderson Cancer Center headline….

Naval G. Daver, MD: Well, not with gilteritinib though. But with AZA [azacitidine]/quizartinib, which Jorge Cortes, MD, and some of our Fellows presented last year, we saw the response rate. Now these are frontline and relapsed FLT3-ITD mutated. And AZA/quizartinib in the frontline setting actually gave us, it was 80%, 82%. It was small numbers. About 21 patients. And the survival was actually 21 months. So these are the AZA/venetoclax group of patients, not failed induction.

So I think that’s really exciting. We’re continuing to enroll HMA [hypomethylating agent]/ quizartinib. I know there’s an HMA/gilteritinib, and this could be very potent. And, of course, we may or may not get to this, but can you add venetoclax there? You have to dose reduce, interrupt, but you may really get a blockbuster effect there.

Mark J. Levis, MD, PhD: But not using chemotherapy. If I give you chemotherapy, Harry, I’m afraid I’d do 2 things. I’d make you very upset and your hair would fall out.

Harry Erba, MD, PhD: We’re not friends any more.

Mark J. Levis, MD, PhD: But in addition, a FLT3 ligand would rocket up in you a few weeks later. That ligand is a cytokine like G-CSF [granulocyte colony-stimulating factor]. The body is trying to regenerate your bone marrow. It directly impedes these FLT3 inhibitors. You don’t see that effect when you combine it with the low intensity agents. So, again, this perhaps is the origin of my bias with backing away from these intensive chemotherapies and going less intense.

Harry Erba, MD, PhD: Very interesting.

Transcript edited for clarity.
 

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Transcript:

Harry Erba, MD, PhD:
You’ve brought up this contrast between a type 1 FLT3 inhibitor like gilteritinib that hits both the ITD [internal tandem duplication] and the TKD [tyrosine kinase domain], and quizartinib, a type 2, which is just the ITD. Does that matter, in terms of mechanisms of resistance? What are we seeing in terms of resistance to these drugs? Does the TKD matter, and is that how we should choose?

Alexander Perl, MD: Well, I think it does matter for 2 reasons. There’s also a difference between having a TKD only and having a TKD on the background of an ITD, particularly if you’ve had prior exposure to a FLT3 inhibitor, and then that shows up. If the TKD shows up on the background of a FLT3-ITD, those patients, across the board, don’t respond to drugs like quizartinib or sorafenib.

The TKD-only—we don’t know how driven that is by FLT3. It may be present but not a major driver. There’s some controversy on this, and I know we’ve talked about whether there are patients with TKD where it is a driver mutation, perhaps a high allele burden, in that setting where they’re going to respond to a drug. And we have seen responses to gilteritinib in that setting.

Harry Erba, MD, PhD: But not on the label.

Alexander Perl, MD: It’s not on the label. It’s not something you can readily get in any laboratory. You’d have to do an assay to say that. So we really are left with a yes-no question there. So, again, you have both mutations. I think that’s an indication where you would really favor using a type 1 inhibitor. If you had one or the other, then we’ve got to look at the drugs and see what’s better.

Mark J. Levis, MD, PhD: But the simple truth is, in the relapsed/refractory setting, a single agent might give you a response. It’s not going to give you a response for very long. Gilteritinib is a great drug and inhibits both types of mutations, and then you’re just going to get a RAS mutation that’s going to make you resistant. We’ve got to combine them and move them up earlier.

Naval G. Daver, MD: But you know with the TKD, I think that was something that we were a little surprised about because I reviewed the initial Lancet Oncology article a little bit. We don’t see, clinically, much of it, and it’s rare. It’s 5% of all patients. But with a single agent TKD, you had 12 and then 12, and it’s like 1 or 2 responders. So, I don’t know. Do we think crenolanib or midostaurin are going to be more active? Do we have data for that? Or we just don’t have anything that hits TKD alone.

Mark J. Levis, MD, PhD: We do have drugs that hit TKD alone. My impression is you have to have a high allelic ratio. It’s got to be a driver for that patient, and, even then, the response rate is clearly lower than the ITD.

Harry Erba, MD, PhD: And that’s probably the most important observation on the subset analyses from the RATIFY trial. The hazard ratio for survival was actually greatest in the TKD population, making you wonder, is it really FLT3 that we’re inhibiting?

Before we leave this topic of FLT3 inhibitors, I wanted to touch on one thing. Would one of you like to comment on FLT3 inhibitors in combination with less intensive therapy like gilteritinib with azacitidine?

Mark J. Levis, MD, PhD: Well, in fact, the MD Anderson Cancer Center headline….

Naval G. Daver, MD: Well, not with gilteritinib though. But with AZA [azacitidine]/quizartinib, which Jorge Cortes, MD, and some of our Fellows presented last year, we saw the response rate. Now these are frontline and relapsed FLT3-ITD mutated. And AZA/quizartinib in the frontline setting actually gave us, it was 80%, 82%. It was small numbers. About 21 patients. And the survival was actually 21 months. So these are the AZA/venetoclax group of patients, not failed induction.

So I think that’s really exciting. We’re continuing to enroll HMA [hypomethylating agent]/ quizartinib. I know there’s an HMA/gilteritinib, and this could be very potent. And, of course, we may or may not get to this, but can you add venetoclax there? You have to dose reduce, interrupt, but you may really get a blockbuster effect there.

Mark J. Levis, MD, PhD: But not using chemotherapy. If I give you chemotherapy, Harry, I’m afraid I’d do 2 things. I’d make you very upset and your hair would fall out.

Harry Erba, MD, PhD: We’re not friends any more.

Mark J. Levis, MD, PhD: But in addition, a FLT3 ligand would rocket up in you a few weeks later. That ligand is a cytokine like G-CSF [granulocyte colony-stimulating factor]. The body is trying to regenerate your bone marrow. It directly impedes these FLT3 inhibitors. You don’t see that effect when you combine it with the low intensity agents. So, again, this perhaps is the origin of my bias with backing away from these intensive chemotherapies and going less intense.

Harry Erba, MD, PhD: Very interesting.

Transcript edited for clarity.
 
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