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IDH1/2 inhibitors for AML

Panelists: Elias Jabbour, MD, MD Anderson Cancer Center; Martin S. Tallman, MD, Memorial Sloan Kettering Cancer Center; Richard M. Stone, MD, Dana-Farber Cancer Institute; Harry Erba, MD, PhD, University of Alabama; Mark Levis, MD, PhD, Sidney Kimmel Comprehensive Cancer Center
Published: Tuesday, Feb 07, 2017


Transcript:

Elias Jabbour, MD:
That will bring me to the other targets. Mark, you mentioned at the beginning what the minimal workup to be done is, and now we talk about IDH1 and IDH2 mutations. How prevalent are these mutations?

Martin S. Tallman, MD: Overall, IDH1 and IDH2 mutations are in about 20% to 22% of patients; about 15% IDH2 and about 8% IDH1.

Elias Jabbour, MD: And then, these tests are done across the nation, or just only at specific labs, specialized labs?

Martin S. Tallman, MD: Well, it has to be done in a specialized lab, but there are commercial panels that it can be sent, such as Foundation Medicine, for example.

Elias Jabbour, MD: And the test reported, your original report, it’s quantitative or qualitative?

Martin S. Tallman, MD: Qualitative.

Elias Jabbour, MD: Qualitative today. And then, based on this mutation, we have IDH1 and IDH2 inhibitors presented last year from your institution at MD Anderson and other centers as well. Can you update us what is the state of these drugs today?

Martin S. Tallman, MD: I think IDH inhibitors are actually one of the most exciting novel agents that are being studied at the moment. In general, in the relapsed refractory setting in AML and other hematologic malignancies in a phase I and phase II trial, the overall response rate is about 40% and the complete remission rate is about 20%. So, that’s very exciting to have an oral, bioavailable, and relatively nontoxic pill with a complete remission rate in AML; relapse and refractory AML of 20% we think is quite exciting. Also exciting and quite provocative is the mechanism of action, which has been suggested to possibly represent differentiation reminiscent of ATRA (all trans retinoic acid) in APL.

Elias Jabbour, MD: I think in the early stage of the trial, where you start the medication and you have the white blood cell count going up, some investigations did drop this patient because of “progression,” and then later on there was a differentiation and patient responded.

Martin S. Tallman, MD: It’s possible that it may be part of the natural history of the response, as it is in ATRA. With ATRA and arsenic where you see some differentiation, you see leukocytosis that eventually resolves.

Elias Jabbour, MD: But, these are single agents, and you mentioned activity as single-agent oral pills. What is the best for the future: to combine them in elderly people or young people? What is the combination to get an approval?

Martin S. Tallman, MD: Well, I think there are a lot of studies being done. One of the studies I think that’s most important that’s currently available in a number of institutions is combining IDH1 and IDH2 inhibitors with induction chemotherapy, daunorubicin and cytarabine, in previously untreated patients. And I think that’s where we’re anxious to see those results.

Richard M. Stone, MD: If I could just ask Dr. Tallman a question. So, there are also trials, by the way, using low-dose therapy plus the IDH1 and IDH2 inhibitors. But, let’s say the IDH2 inhibitor is available next year because it gets approval based on the wonderful results you just mentioned in the OUTBACK trial patients. You’ve got a patient who’s 45 years old with a relapsed AML with an IDH2 mutation. Will you give them chemotherapy or will you give them an IDH2 inhibitor as a bridge to transplant?

Martin S. Tallman, MD: As first…?

Richard M. Stone, MD: First relapse.

Martin S. Tallman, MD: I think that kind of study has to be done to help guide us. I think it isn’t clear. Certainly, if they fail one reinduction attempt, then I would quickly move to an IDH inhibitor.

Elias Jabbour, MD: But, let’s say the drug is available. Would you give it a single-agent monotherapy, or would you combine it with Ara-C or Vidaza?

Martin S. Tallman, MD: Those studies have to be done, today, in someone that has failed a first induction attempt, a reinduction attempt. Someone relapses, they get the chemotherapy program. If they’re certainly younger, our inclination today, because it’s not commercially available, would to be administer a cycle of chemotherapy. And then, after their first attempt at reinduction, they still have persistent disease, then we would give monotherapy.

Harry P. Erba, MD, PhD: I agree with what Marty started with. I think AG120 and AG221, the IDH1 and IDH2 inhibitors, are the most exciting drugs that I’ve seen in AML. But, I think we really need to learn something that’s critically important to which patients are benefiting. Because what’s different about these drugs compared to FLT3 inhibitors is that they don’t inhibit the native IDH1 and IDH2. There would be no energy production in cells since that’s important in the Krebs cycle, and they’re very, very specific. We only see like a 20% complete remission rate. But, in those complete remitters, DiNardo, at this ASH 2016 Congress, is going to show that you can actually show clearance of the mutation, which has not often been done with other inhibitors. But, the issue is, who are these patients? I would imagine that these are patients whose disease is being driven by IDH1 or IDH2. And by turning that off, you can really get at the biology of the disease.

Now the problem with FoundationOne and panels like that, you don’t get the variant’s allelic with frequency of that. What you do get though are the other mutations that are present. I’m going to guess for the future that the patients who have the best responses are the ones who have more simple mutational profiles, where IDH1 and IDH2 mutations are driving the disease.

So, what I’ll finish with is my concern about the way that we have been developing these drugs. If we go about planning the next set of phase III studies of chemotherapy—either a HMA or intensive chemotherapy plus or minus these drugs—and take everyone with an IDH1 and IDH2 mutation and hope to see a benefit in terms of survival, we may be doomed to failure if only a small percentage of those patients actually have the disease driven and are deriving benefit.

Elias Jabbour, MD: Mark, we have the IDH1 and IDH2 inhibitors and we have 2 compounds. Can we combine them? Is there rationale to combine these 2 drugs?

Mark J. Levis, MD, PhD: Combining IDH1 and IDH2 inhibitors? I’ll be honest, I’m not sure. Remember, AML is characterized by having an IDH1 or IDH2 mutation, or a WT1 or WT2 mutation. They’re almost mutually exclusive, right? It’s a complementation group.

Martin S. Tallman, MD: They are mutually exclusive.

Mark J. Levis, MD, PhD: So, you’re not going to see them together.

Transcript Edited for Clarity
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Transcript:

Elias Jabbour, MD:
That will bring me to the other targets. Mark, you mentioned at the beginning what the minimal workup to be done is, and now we talk about IDH1 and IDH2 mutations. How prevalent are these mutations?

Martin S. Tallman, MD: Overall, IDH1 and IDH2 mutations are in about 20% to 22% of patients; about 15% IDH2 and about 8% IDH1.

Elias Jabbour, MD: And then, these tests are done across the nation, or just only at specific labs, specialized labs?

Martin S. Tallman, MD: Well, it has to be done in a specialized lab, but there are commercial panels that it can be sent, such as Foundation Medicine, for example.

Elias Jabbour, MD: And the test reported, your original report, it’s quantitative or qualitative?

Martin S. Tallman, MD: Qualitative.

Elias Jabbour, MD: Qualitative today. And then, based on this mutation, we have IDH1 and IDH2 inhibitors presented last year from your institution at MD Anderson and other centers as well. Can you update us what is the state of these drugs today?

Martin S. Tallman, MD: I think IDH inhibitors are actually one of the most exciting novel agents that are being studied at the moment. In general, in the relapsed refractory setting in AML and other hematologic malignancies in a phase I and phase II trial, the overall response rate is about 40% and the complete remission rate is about 20%. So, that’s very exciting to have an oral, bioavailable, and relatively nontoxic pill with a complete remission rate in AML; relapse and refractory AML of 20% we think is quite exciting. Also exciting and quite provocative is the mechanism of action, which has been suggested to possibly represent differentiation reminiscent of ATRA (all trans retinoic acid) in APL.

Elias Jabbour, MD: I think in the early stage of the trial, where you start the medication and you have the white blood cell count going up, some investigations did drop this patient because of “progression,” and then later on there was a differentiation and patient responded.

Martin S. Tallman, MD: It’s possible that it may be part of the natural history of the response, as it is in ATRA. With ATRA and arsenic where you see some differentiation, you see leukocytosis that eventually resolves.

Elias Jabbour, MD: But, these are single agents, and you mentioned activity as single-agent oral pills. What is the best for the future: to combine them in elderly people or young people? What is the combination to get an approval?

Martin S. Tallman, MD: Well, I think there are a lot of studies being done. One of the studies I think that’s most important that’s currently available in a number of institutions is combining IDH1 and IDH2 inhibitors with induction chemotherapy, daunorubicin and cytarabine, in previously untreated patients. And I think that’s where we’re anxious to see those results.

Richard M. Stone, MD: If I could just ask Dr. Tallman a question. So, there are also trials, by the way, using low-dose therapy plus the IDH1 and IDH2 inhibitors. But, let’s say the IDH2 inhibitor is available next year because it gets approval based on the wonderful results you just mentioned in the OUTBACK trial patients. You’ve got a patient who’s 45 years old with a relapsed AML with an IDH2 mutation. Will you give them chemotherapy or will you give them an IDH2 inhibitor as a bridge to transplant?

Martin S. Tallman, MD: As first…?

Richard M. Stone, MD: First relapse.

Martin S. Tallman, MD: I think that kind of study has to be done to help guide us. I think it isn’t clear. Certainly, if they fail one reinduction attempt, then I would quickly move to an IDH inhibitor.

Elias Jabbour, MD: But, let’s say the drug is available. Would you give it a single-agent monotherapy, or would you combine it with Ara-C or Vidaza?

Martin S. Tallman, MD: Those studies have to be done, today, in someone that has failed a first induction attempt, a reinduction attempt. Someone relapses, they get the chemotherapy program. If they’re certainly younger, our inclination today, because it’s not commercially available, would to be administer a cycle of chemotherapy. And then, after their first attempt at reinduction, they still have persistent disease, then we would give monotherapy.

Harry P. Erba, MD, PhD: I agree with what Marty started with. I think AG120 and AG221, the IDH1 and IDH2 inhibitors, are the most exciting drugs that I’ve seen in AML. But, I think we really need to learn something that’s critically important to which patients are benefiting. Because what’s different about these drugs compared to FLT3 inhibitors is that they don’t inhibit the native IDH1 and IDH2. There would be no energy production in cells since that’s important in the Krebs cycle, and they’re very, very specific. We only see like a 20% complete remission rate. But, in those complete remitters, DiNardo, at this ASH 2016 Congress, is going to show that you can actually show clearance of the mutation, which has not often been done with other inhibitors. But, the issue is, who are these patients? I would imagine that these are patients whose disease is being driven by IDH1 or IDH2. And by turning that off, you can really get at the biology of the disease.

Now the problem with FoundationOne and panels like that, you don’t get the variant’s allelic with frequency of that. What you do get though are the other mutations that are present. I’m going to guess for the future that the patients who have the best responses are the ones who have more simple mutational profiles, where IDH1 and IDH2 mutations are driving the disease.

So, what I’ll finish with is my concern about the way that we have been developing these drugs. If we go about planning the next set of phase III studies of chemotherapy—either a HMA or intensive chemotherapy plus or minus these drugs—and take everyone with an IDH1 and IDH2 mutation and hope to see a benefit in terms of survival, we may be doomed to failure if only a small percentage of those patients actually have the disease driven and are deriving benefit.

Elias Jabbour, MD: Mark, we have the IDH1 and IDH2 inhibitors and we have 2 compounds. Can we combine them? Is there rationale to combine these 2 drugs?

Mark J. Levis, MD, PhD: Combining IDH1 and IDH2 inhibitors? I’ll be honest, I’m not sure. Remember, AML is characterized by having an IDH1 or IDH2 mutation, or a WT1 or WT2 mutation. They’re almost mutually exclusive, right? It’s a complementation group.

Martin S. Tallman, MD: They are mutually exclusive.

Mark J. Levis, MD, PhD: So, you’re not going to see them together.

Transcript Edited for Clarity
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