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AML: Identifying Practical Concerns With Enasidenib

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: Monday, Feb 19, 2018



Transcript: 

Harry Erba, MD, PhD: I want to get to some practical issues, and we have a lot more to talk about. Let’s focus in on some things that we need our audience to understand. One of them is, if the patients did or did not have an IDH2 mutation at the time of diagnosis, do you retest at the time of relapse?

Alexander E. Perl, MD: It’s often the case that the mutation is present at relapse, but I would generally test because there are patients who will lose it. But that’s uncommon.

Eunice Wang, MD: I wouldn’t generally test.

Alexander E. Perl, MD: I would assume it’s there, but if it wasn’t there I would probably look to see.

Eunice Wang, MD: It’s one of those reasons that we do that testing.

Harry Erba, MD, PhD: You might start the prior authorization for the drug while you’re waiting for the treatment.

Alexander E. Perl, MD: It’s a very expensive drug. If the target isn’t there, I guess you could treat and see what happens.

Eunice Wang, MD: But what percentage of the time is it lost?

Alexander E. Perl, MD: If they respond in the 3 weeks it takes to get the next-generation panel back, you’re going to know. But it can take months to find that out. While it’s well tolerated, you might have to choose an alternate therapy.

Harry Erba, MD, PhD: It is low. I know it was just because you were summarizing a lot of data, but you forgot a very important toxicity that our audience needs to know how to manage, right?

Alexander E. Perl, MD: Very important, right, which is differentiation syndrome.

Harry Erba, MD, PhD: There you go.

Alexander E. Perl, MD: I can’t talk about patients differentiating to a drug without asking, is that a good thing or a bad thing? It’s a good thing because you’re seeing response. It’s a bad thing if they’re getting sick from that response. It occurred in about 10% or 20% of patients on the study that led to the approval of enasidenib, which, mind you, is a phase I/II study. It’s not a phase III study. So, across all these doses, that’s how often they saw this. It led to leukocytosis, it led to patients developing fevers, and it led to pulmonary infiltrates. In some patients, there was concern for cardiotoxicity in terms of pericardial effusions or pleural effusions, and it was steroid responsive. So, it was in many ways similar to what we see in APL when you treat with all-transretinal acid. The ATRA differentiation syndrome and the enasidenib, or really the IDH inhibitor differentiation syndrome, are largely overlapping and the approach was the same.

Once they recognized that this was happening in patients, they quickly initiated dexamethasone 10 b.i.d. until symptoms were controlled. Then they tapered off quickly, so patients don’t wind up on months and months and months of steroids. But you should recognize that this is a risk in your patients, and you should be cautious initiating this drug in patients with preexisting lung problems.

Jorge E. Cortes, MD: There’s another practical element in addition to the management of these symptoms, which is the fact that initially, these may sound like the patient is progressing.

Alexander E. Perl, MD: Yes.

Jorge E. Cortes, MD: We may have, actually, missed some responses initially when we didn’t recognize this, and we thought, “The patient is progressing, lets change to something else.” We need to recognize that we should not only to manage their symptoms, but also know that it may be an expected effect and it may be signaling response to the patient. We use hydroxyurea to try to control that elevation of the white cell count. Let the patients continue and manage the side effects. The other thing that is important that’s a little bit different with this drug, and probably these other drugs to come that have the same aspect, is that these responses will take a while. This is not chemotherapy where if you’re not in remission in the first cycle, you’re not going to respond. Some responses take months before you start seeing something, and even then, they may continue to improve. It may look only like a stable disease or a partial response, but they will get into a complete remission.

Harry Erba, MD, PhD: That’s a very important point. In the study that was presented to the FDA, the median time to first response was 1.9 months, and the median time to best response was almost 4 months. At this congress, there are important data being presented regarding the patients who at 90 days had stable disease, but who remained on therapy. Some of them achieved a complete remission. Practically speaking, Eunice, how do you decide? You’ve got a patient in front of you persistently transfusion-dependent or pancytopenic or in neutropenic infections, how long do you keep them on?

Eunice Wang, MD: I think this brings us to a good point. I think it really depends on the patient. It’s important to remember that this was not a phase III study. This was a phase I/II study. If you speak to the investigators that had this drug on study, the people they put on the study were elderly people, frail people, people with advanced stage MDS who had an IDH2 mutation. These were not 20-, 30-, or 40-year-old young people who had an IDH2 mutation.

Harry Erba, MD, PhD: People who don’t have many other options, either.

Eunice Wang, MD: Right. If I had an older patient, refractory/relapsed, who failed some therapy and was cytopenic and is on this drug—say they’re on for a month and a half—and everyone in my staff says, “They’re not responding. They’re transfusion dependent,” I would persist. I would go out. I would say that as long there are hints of clinical improvement that are independent of white blood cell count and things like transfusion independence and quality of life, patients appreciate being able to take a pill and be an outpatient with decreased infections.

Maybe slowly over time, the ANC (absolute neutrophil count) has risen. Maybe it’s not 100/ mm³ but 500/mm³, and it has risen to the point that they’re not being hospitalized for frequent infections. We’re able to keep them on oral antibiotics. I would persist. I think I would probably give it for at least 3 months. I would say 2 months is a median time to have a response, but I would push it out to 3. And then, if I thought that there weren’t that many options for an older patient and they were potentially having some of those benefits, I would continue.

I have to also point out that if I have a younger patient with refractory/relapsed disease, I’d put them on an IDH inhibitor. I had a patient like this. He had a great response to the IDH2 inhibitor and had clearance of his marrow. He felt great. He was transfusion independent. I said to him, “You need to get a transplant.” And he said, “Dr. Wang, why do I need to get a transplant? I had this great response and I had differentiation syndrome, and patients who get differentiation syndrome and have APL are all cured. Why do I still need a transplant? Why do I need a transplant in the first 6 months? I can’t wait?” I think it’s important to also point out that in the study that led to FDA approval with 140 patients, the median time of duration of the response was 10 months. So, for healthier, younger patients, you have to be cautious that this is not a cure-all.

Harry Erba, MD, PhD: Right. Some patients are relapsing without the IDH2 mutation, another clone grows out there.

Eunice Wang, MD: I think that this is a great agent, and I know there are ongoing studies adding it to chemotherapy. But for right now, you have to remember that if you have a younger patient and they get a CR, this isn’t necessarily the same thing as APL where they’ll be cured.

Harry Erba, MD, PhD: The prescribing information says you should keep people on for at least 6 months, but I agree. It depends on what other options the patient may have. I may, at 3 months or 4 months, do a bone marrow biopsy to make sure things are going in the right direction, because if they’re pancytopenic they may be getting worse. That’s something we’re going to need to learn.

Jorge, clinical investigation. I heard your boss the other day say, “This is A + B. You have 3-and-7 chemotherapy, you have this drug, so add them. Azacitidine, decitabine, add them together.” Are there any concerns about doing that? What’s the rationale?

Jorge E. Cortes, MD: Yes, I do have concerns. That’s been our approach because that’s what we have available, and it sounds like, “OK, well that’s what we do.”

Eunice Wang, MD: Simple.

Jorge E. Cortes, MD: But we’re definitely not there yet. We need to evolve from that because we may take away from the benefits of a drug like this. Not only not get much benefit, but maybe even take away benefit. That’s potentially a possibility. It could be that with 3-and-7 chemotherapy—or whatever variation of that that we use for the younger patients—maybe when you have a drug like this, what you have to combine it with is azacitidine, for example, because of the way they interact. It ends better. So, I think we need to be careful with these combinations and be a little bit more biology oriented, more preclinical. When you combine chemotherapy agents, that’s what you do. If this one works and that one works, that’s fine, because they all work the same way.

Eunice Wang, MD: We got rid of standard chemotherapy from APL treatment, right?

Jorge E. Cortes, MD: Exactly.

Eunice Wang, MD: We actually got away from it.

Jorge E. Cortes, MD: But not with these biologically-directed therapies. I think that we have to be very careful. I’m not convinced that just adding them to 3-and-7 chemotherapy for IDH-mutated patients will give us any benefit.

Transcript Edited for Clarity 

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Transcript: 

Harry Erba, MD, PhD: I want to get to some practical issues, and we have a lot more to talk about. Let’s focus in on some things that we need our audience to understand. One of them is, if the patients did or did not have an IDH2 mutation at the time of diagnosis, do you retest at the time of relapse?

Alexander E. Perl, MD: It’s often the case that the mutation is present at relapse, but I would generally test because there are patients who will lose it. But that’s uncommon.

Eunice Wang, MD: I wouldn’t generally test.

Alexander E. Perl, MD: I would assume it’s there, but if it wasn’t there I would probably look to see.

Eunice Wang, MD: It’s one of those reasons that we do that testing.

Harry Erba, MD, PhD: You might start the prior authorization for the drug while you’re waiting for the treatment.

Alexander E. Perl, MD: It’s a very expensive drug. If the target isn’t there, I guess you could treat and see what happens.

Eunice Wang, MD: But what percentage of the time is it lost?

Alexander E. Perl, MD: If they respond in the 3 weeks it takes to get the next-generation panel back, you’re going to know. But it can take months to find that out. While it’s well tolerated, you might have to choose an alternate therapy.

Harry Erba, MD, PhD: It is low. I know it was just because you were summarizing a lot of data, but you forgot a very important toxicity that our audience needs to know how to manage, right?

Alexander E. Perl, MD: Very important, right, which is differentiation syndrome.

Harry Erba, MD, PhD: There you go.

Alexander E. Perl, MD: I can’t talk about patients differentiating to a drug without asking, is that a good thing or a bad thing? It’s a good thing because you’re seeing response. It’s a bad thing if they’re getting sick from that response. It occurred in about 10% or 20% of patients on the study that led to the approval of enasidenib, which, mind you, is a phase I/II study. It’s not a phase III study. So, across all these doses, that’s how often they saw this. It led to leukocytosis, it led to patients developing fevers, and it led to pulmonary infiltrates. In some patients, there was concern for cardiotoxicity in terms of pericardial effusions or pleural effusions, and it was steroid responsive. So, it was in many ways similar to what we see in APL when you treat with all-transretinal acid. The ATRA differentiation syndrome and the enasidenib, or really the IDH inhibitor differentiation syndrome, are largely overlapping and the approach was the same.

Once they recognized that this was happening in patients, they quickly initiated dexamethasone 10 b.i.d. until symptoms were controlled. Then they tapered off quickly, so patients don’t wind up on months and months and months of steroids. But you should recognize that this is a risk in your patients, and you should be cautious initiating this drug in patients with preexisting lung problems.

Jorge E. Cortes, MD: There’s another practical element in addition to the management of these symptoms, which is the fact that initially, these may sound like the patient is progressing.

Alexander E. Perl, MD: Yes.

Jorge E. Cortes, MD: We may have, actually, missed some responses initially when we didn’t recognize this, and we thought, “The patient is progressing, lets change to something else.” We need to recognize that we should not only to manage their symptoms, but also know that it may be an expected effect and it may be signaling response to the patient. We use hydroxyurea to try to control that elevation of the white cell count. Let the patients continue and manage the side effects. The other thing that is important that’s a little bit different with this drug, and probably these other drugs to come that have the same aspect, is that these responses will take a while. This is not chemotherapy where if you’re not in remission in the first cycle, you’re not going to respond. Some responses take months before you start seeing something, and even then, they may continue to improve. It may look only like a stable disease or a partial response, but they will get into a complete remission.

Harry Erba, MD, PhD: That’s a very important point. In the study that was presented to the FDA, the median time to first response was 1.9 months, and the median time to best response was almost 4 months. At this congress, there are important data being presented regarding the patients who at 90 days had stable disease, but who remained on therapy. Some of them achieved a complete remission. Practically speaking, Eunice, how do you decide? You’ve got a patient in front of you persistently transfusion-dependent or pancytopenic or in neutropenic infections, how long do you keep them on?

Eunice Wang, MD: I think this brings us to a good point. I think it really depends on the patient. It’s important to remember that this was not a phase III study. This was a phase I/II study. If you speak to the investigators that had this drug on study, the people they put on the study were elderly people, frail people, people with advanced stage MDS who had an IDH2 mutation. These were not 20-, 30-, or 40-year-old young people who had an IDH2 mutation.

Harry Erba, MD, PhD: People who don’t have many other options, either.

Eunice Wang, MD: Right. If I had an older patient, refractory/relapsed, who failed some therapy and was cytopenic and is on this drug—say they’re on for a month and a half—and everyone in my staff says, “They’re not responding. They’re transfusion dependent,” I would persist. I would go out. I would say that as long there are hints of clinical improvement that are independent of white blood cell count and things like transfusion independence and quality of life, patients appreciate being able to take a pill and be an outpatient with decreased infections.

Maybe slowly over time, the ANC (absolute neutrophil count) has risen. Maybe it’s not 100/ mm³ but 500/mm³, and it has risen to the point that they’re not being hospitalized for frequent infections. We’re able to keep them on oral antibiotics. I would persist. I think I would probably give it for at least 3 months. I would say 2 months is a median time to have a response, but I would push it out to 3. And then, if I thought that there weren’t that many options for an older patient and they were potentially having some of those benefits, I would continue.

I have to also point out that if I have a younger patient with refractory/relapsed disease, I’d put them on an IDH inhibitor. I had a patient like this. He had a great response to the IDH2 inhibitor and had clearance of his marrow. He felt great. He was transfusion independent. I said to him, “You need to get a transplant.” And he said, “Dr. Wang, why do I need to get a transplant? I had this great response and I had differentiation syndrome, and patients who get differentiation syndrome and have APL are all cured. Why do I still need a transplant? Why do I need a transplant in the first 6 months? I can’t wait?” I think it’s important to also point out that in the study that led to FDA approval with 140 patients, the median time of duration of the response was 10 months. So, for healthier, younger patients, you have to be cautious that this is not a cure-all.

Harry Erba, MD, PhD: Right. Some patients are relapsing without the IDH2 mutation, another clone grows out there.

Eunice Wang, MD: I think that this is a great agent, and I know there are ongoing studies adding it to chemotherapy. But for right now, you have to remember that if you have a younger patient and they get a CR, this isn’t necessarily the same thing as APL where they’ll be cured.

Harry Erba, MD, PhD: The prescribing information says you should keep people on for at least 6 months, but I agree. It depends on what other options the patient may have. I may, at 3 months or 4 months, do a bone marrow biopsy to make sure things are going in the right direction, because if they’re pancytopenic they may be getting worse. That’s something we’re going to need to learn.

Jorge, clinical investigation. I heard your boss the other day say, “This is A + B. You have 3-and-7 chemotherapy, you have this drug, so add them. Azacitidine, decitabine, add them together.” Are there any concerns about doing that? What’s the rationale?

Jorge E. Cortes, MD: Yes, I do have concerns. That’s been our approach because that’s what we have available, and it sounds like, “OK, well that’s what we do.”

Eunice Wang, MD: Simple.

Jorge E. Cortes, MD: But we’re definitely not there yet. We need to evolve from that because we may take away from the benefits of a drug like this. Not only not get much benefit, but maybe even take away benefit. That’s potentially a possibility. It could be that with 3-and-7 chemotherapy—or whatever variation of that that we use for the younger patients—maybe when you have a drug like this, what you have to combine it with is azacitidine, for example, because of the way they interact. It ends better. So, I think we need to be careful with these combinations and be a little bit more biology oriented, more preclinical. When you combine chemotherapy agents, that’s what you do. If this one works and that one works, that’s fine, because they all work the same way.

Eunice Wang, MD: We got rid of standard chemotherapy from APL treatment, right?

Jorge E. Cortes, MD: Exactly.

Eunice Wang, MD: We actually got away from it.

Jorge E. Cortes, MD: But not with these biologically-directed therapies. I think that we have to be very careful. I’m not convinced that just adding them to 3-and-7 chemotherapy for IDH-mutated patients will give us any benefit.

Transcript Edited for Clarity 
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