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Considerations for CPX-351 in 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: Friday, Feb 09, 2018



Transcript: 

Eunice Wang, MD: Harry, I have a question. This is always a matter of big debate in my center. What about if there’s somebody who’s 50 years old?

Harry Erba, MD, PhD: Again, not in the study but now in the label.

Eunice Wang, MD: Secondary AML in a 50-year-old.

Harry Erba, MD, PhD: Secondary AML.

Eunice Wang, MD: Fifty-five or 59 years old, right?

Harry Erba, MD, PhD: Just to bring everything up-to-date, why was it approved? There were higher CR rates with CPX-351. It met the primary endpoint of overall survival with 9.6 months with CPX-351 versus 6 months with 7-and-3 chemotherapy and lower induction mortality at 30 days, at 60 days. Patients who went on to transplant had better outcomes after CPX-351 than after 7-and-3 chemotherapy. We haven’t seen all the subset data. We’ve seen it for treatment-related AML in the older patients. They also enjoyed a survival benefit. We haven’t seen the data specifically on the molecularly or cytogenetically defined setting. So, we don’t know that it’s better, but we’re hoping it’s not worse. But the question you asked me, “Would you use it in a younger patient with those characteristics?”

Eunice Wang, MD: Because the patients in that trial were not 59.

Harry Erba, MD, PhD: No, and they were patients fit for chemotherapy, patients who you would feel comfortable giving 7-and-3 chemotherapy to. At this meeting, there were some data presented from Japan showing that incorporating an intermediate dose of cytarabine into induction regimens may increase CR rates, not improved overall survival but improved disease-free survival. That’s the trouble. And NCCN guidelines say we could use more intensive regimens with intermediate-dose Ara-C. The EORTC also published data that for patients under 45 years old, there may be a benefit of a regimen including a higher dose of Ara-C. I know at MD Anderson, your typical treatment is to use high-dose Ara-C. I think my answer would be that it is an option, CPX-351. But I know that many would say they don’t know that it’s better than intensifying with chemotherapy, and I think those studies need to be done.

Alexander E. Perl, MD: I would absolutely say the same. I would say biologically, it’s absolutely plausible that you should see the same benefit. The difference is, you can give more intensive regimens comfortably in younger patients, and they make up the difference. And then it gets to the question that you mentioned before, which is, is there a cost benefit to using one approach versus another?

Eunice Wang, MD: I was just going to play the devil’s advocate. There is that landmark analysis showing that with patients on the original phase III trial who got CPX-351 versus 7-and-3 chemotherapy, when they went to transplant, there seemed to be a wide differential between how the patients getting CPX-351 who went to transplant did and those who got 7-and-3 chemotherapy, had a CR, and went to transplant did.
The feelings from some individuals are that CPX-351, because it’s a more potent agent, going into the bone marrow might be inducing a deeper response or, theoretically, a more MRD-negative response, so that patients are going into transplant with a lower disease burden. Now, you can possibly accomplish the same thing with an intensified cytarabine or daunorubicin, but is there something about that particular molar ratio—or liposomal formulations—that gets a better, deeper response? I’m just throwing it out there as a possibility.

Harry Erba, MD, PhD: I think that’s a very important point. Especially with younger patients who you get into transplant, we have the data from the phase III study that they may truly do better, and we do not know why. We need the MRD data. I think you can make a very strong argument for giving CPX-351 to that patient at this point even though they’re younger, and it’s in the label.

Eunice Wang, MD: We just don’t have the exact data.

Harry Erba, MD, PhD: We don’t have the exact data. And the elephant in the room is the cost, right?

Alexander E. Perl, MD: Yes.

Harry Erba, MD, PhD: But you have to be very, very careful about that cost because, as I heard you say recently, you have to consider the entire cost. If a patient doesn’t respond and they’re in the hospital with persistent cytopenias—or the cost of human existence if they never make it to transplant—that is a greater cost. I didn’t say it as elegantly as you said it.

Eunice Wang, MD: Say it costs $50,000 to give this drug versus $8,000, so there’s a $42,000 difference. But if this person with the $42,000 drug can get into CR and there was a difference in CR, this person can go into transplant, and we can save their life. In the long run, if that person relapsed, relapsed, relapsed again, had to have salvage chemotherapy, and then had to have a salvage transplant, what’s the cost benefit? What about that individual patient being able to go straight to a transplant?

Harry Erba, MD, PhD: And on top of that is this age consideration. OK, you challenged me with a 59-, 58-year-old patient. The data from the EORTC and the study here with intermediate or high-dose Ara-C only showed a benefit in the younger of the young patients. So, under 45 years old—almost an AYA (adolescent and young adult) population where you can intensify therapy. I think you can make a very strong argument for using the drug in the labeled indication regardless of the age of the patient.

Alexander E. Perl, MD: One thing we haven’t talked about at all is toxicity. One of the major benefits of this drug was not so much that you saw a higher CR rate but that the treatment-related mortalities were lower, largely because of lower rates of lethal complications.

Eunice Wang, MD: From leukemia, specifically.

Alexander E. Perl, MD: Leukemia wasn’t growing back quickly after CR. If you looked at the rates of infections during aplasia, they were actually higher in the CPX-351 arm, and the duration in years was longer. And yet, other toxicities were lesser. These patients seemed to, at least in our limited experience with it, get less mucositis. They don’t lose their hair. It’s a different pattern of toxicity that we see.

Jorge E. Cortes, MD: I think that goes with the liposomal delivery of drugs in general. I think we know that liposomal amphotericin is less nephrotoxic generally. So, of course, the mucositis and the hair would be important, but can we then have less cardiotoxicity, because this is liposomally encapsulated. That’ll be a great benefit, and it goes back to the concept of intensifying the 3 drugs. Can we intensify these further? There was a limit because at the moment, you had to consider the 1-to-1 equivalent of the anthracycline, and you had that limit, etc. But do you have the same limits when you have this formulation of anthracycline? I don’t know.       

Harry Erba, MD, PhD: I want to be very clear on that. I was an investigator on that trial. It was assumed, and it continues to be assumed by the FDA and the label, that in the absence of data, it’s a 1-to-1 equivalency in terms of cardiotoxicity. You’re right, we really don’t know. And the study, remember, was treatment related, and we had many patients who received anthracyclines who could only receive a certain amount. What I would say about the cardiotoxicity is that if you look at the adverse events, it was a similar rate of nonconduction cardiotoxicity in both 7-and-3 chemotherapy and CPX-351. It was 20%, but that’s much higher than what you’d expect from an anthracycline-induced event. And I think that really was sepsis and transient cardiomyopathy.

Alexander E. Perl, MD: Which evens out over time.

Harry Erba, MD, PhD: It does. Let’s face it, the incidence of cardiotoxicity with 7-and-3 chemotherapy in someone who hasn’t had an anthracycline is only around 1%. So, I think it’s going to be hard to show that benefit. But I will say this: When you compare the cumulative dose of CPX-351 and the cumulative daunorubicin dose with a full course of CPX-351 versus 7-and-3 chemotherapy followed by a 5-and-2 regimen, you’re getting less anthracycline with CPX-351. So, if you do believe they’re equivalent, it may be a way of getting more of the drug in.

Alexander E. Perl, MD: Getting less toxicity at least because of that.

Harry Erba, MD, PhD: At least that, yes.

Eunice Wang, MD: And then, the person’s going to transplant.

Harry Erba, MD, PhD: Right—which is important.

Eunice Wang, MD: We certainly don’t want to have high levels of cardiotoxicity going into transplant.

Transcript Edited for Clarity 

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Transcript: 

Eunice Wang, MD: Harry, I have a question. This is always a matter of big debate in my center. What about if there’s somebody who’s 50 years old?

Harry Erba, MD, PhD: Again, not in the study but now in the label.

Eunice Wang, MD: Secondary AML in a 50-year-old.

Harry Erba, MD, PhD: Secondary AML.

Eunice Wang, MD: Fifty-five or 59 years old, right?

Harry Erba, MD, PhD: Just to bring everything up-to-date, why was it approved? There were higher CR rates with CPX-351. It met the primary endpoint of overall survival with 9.6 months with CPX-351 versus 6 months with 7-and-3 chemotherapy and lower induction mortality at 30 days, at 60 days. Patients who went on to transplant had better outcomes after CPX-351 than after 7-and-3 chemotherapy. We haven’t seen all the subset data. We’ve seen it for treatment-related AML in the older patients. They also enjoyed a survival benefit. We haven’t seen the data specifically on the molecularly or cytogenetically defined setting. So, we don’t know that it’s better, but we’re hoping it’s not worse. But the question you asked me, “Would you use it in a younger patient with those characteristics?”

Eunice Wang, MD: Because the patients in that trial were not 59.

Harry Erba, MD, PhD: No, and they were patients fit for chemotherapy, patients who you would feel comfortable giving 7-and-3 chemotherapy to. At this meeting, there were some data presented from Japan showing that incorporating an intermediate dose of cytarabine into induction regimens may increase CR rates, not improved overall survival but improved disease-free survival. That’s the trouble. And NCCN guidelines say we could use more intensive regimens with intermediate-dose Ara-C. The EORTC also published data that for patients under 45 years old, there may be a benefit of a regimen including a higher dose of Ara-C. I know at MD Anderson, your typical treatment is to use high-dose Ara-C. I think my answer would be that it is an option, CPX-351. But I know that many would say they don’t know that it’s better than intensifying with chemotherapy, and I think those studies need to be done.

Alexander E. Perl, MD: I would absolutely say the same. I would say biologically, it’s absolutely plausible that you should see the same benefit. The difference is, you can give more intensive regimens comfortably in younger patients, and they make up the difference. And then it gets to the question that you mentioned before, which is, is there a cost benefit to using one approach versus another?

Eunice Wang, MD: I was just going to play the devil’s advocate. There is that landmark analysis showing that with patients on the original phase III trial who got CPX-351 versus 7-and-3 chemotherapy, when they went to transplant, there seemed to be a wide differential between how the patients getting CPX-351 who went to transplant did and those who got 7-and-3 chemotherapy, had a CR, and went to transplant did.
The feelings from some individuals are that CPX-351, because it’s a more potent agent, going into the bone marrow might be inducing a deeper response or, theoretically, a more MRD-negative response, so that patients are going into transplant with a lower disease burden. Now, you can possibly accomplish the same thing with an intensified cytarabine or daunorubicin, but is there something about that particular molar ratio—or liposomal formulations—that gets a better, deeper response? I’m just throwing it out there as a possibility.

Harry Erba, MD, PhD: I think that’s a very important point. Especially with younger patients who you get into transplant, we have the data from the phase III study that they may truly do better, and we do not know why. We need the MRD data. I think you can make a very strong argument for giving CPX-351 to that patient at this point even though they’re younger, and it’s in the label.

Eunice Wang, MD: We just don’t have the exact data.

Harry Erba, MD, PhD: We don’t have the exact data. And the elephant in the room is the cost, right?

Alexander E. Perl, MD: Yes.

Harry Erba, MD, PhD: But you have to be very, very careful about that cost because, as I heard you say recently, you have to consider the entire cost. If a patient doesn’t respond and they’re in the hospital with persistent cytopenias—or the cost of human existence if they never make it to transplant—that is a greater cost. I didn’t say it as elegantly as you said it.

Eunice Wang, MD: Say it costs $50,000 to give this drug versus $8,000, so there’s a $42,000 difference. But if this person with the $42,000 drug can get into CR and there was a difference in CR, this person can go into transplant, and we can save their life. In the long run, if that person relapsed, relapsed, relapsed again, had to have salvage chemotherapy, and then had to have a salvage transplant, what’s the cost benefit? What about that individual patient being able to go straight to a transplant?

Harry Erba, MD, PhD: And on top of that is this age consideration. OK, you challenged me with a 59-, 58-year-old patient. The data from the EORTC and the study here with intermediate or high-dose Ara-C only showed a benefit in the younger of the young patients. So, under 45 years old—almost an AYA (adolescent and young adult) population where you can intensify therapy. I think you can make a very strong argument for using the drug in the labeled indication regardless of the age of the patient.

Alexander E. Perl, MD: One thing we haven’t talked about at all is toxicity. One of the major benefits of this drug was not so much that you saw a higher CR rate but that the treatment-related mortalities were lower, largely because of lower rates of lethal complications.

Eunice Wang, MD: From leukemia, specifically.

Alexander E. Perl, MD: Leukemia wasn’t growing back quickly after CR. If you looked at the rates of infections during aplasia, they were actually higher in the CPX-351 arm, and the duration in years was longer. And yet, other toxicities were lesser. These patients seemed to, at least in our limited experience with it, get less mucositis. They don’t lose their hair. It’s a different pattern of toxicity that we see.

Jorge E. Cortes, MD: I think that goes with the liposomal delivery of drugs in general. I think we know that liposomal amphotericin is less nephrotoxic generally. So, of course, the mucositis and the hair would be important, but can we then have less cardiotoxicity, because this is liposomally encapsulated. That’ll be a great benefit, and it goes back to the concept of intensifying the 3 drugs. Can we intensify these further? There was a limit because at the moment, you had to consider the 1-to-1 equivalent of the anthracycline, and you had that limit, etc. But do you have the same limits when you have this formulation of anthracycline? I don’t know.       

Harry Erba, MD, PhD: I want to be very clear on that. I was an investigator on that trial. It was assumed, and it continues to be assumed by the FDA and the label, that in the absence of data, it’s a 1-to-1 equivalency in terms of cardiotoxicity. You’re right, we really don’t know. And the study, remember, was treatment related, and we had many patients who received anthracyclines who could only receive a certain amount. What I would say about the cardiotoxicity is that if you look at the adverse events, it was a similar rate of nonconduction cardiotoxicity in both 7-and-3 chemotherapy and CPX-351. It was 20%, but that’s much higher than what you’d expect from an anthracycline-induced event. And I think that really was sepsis and transient cardiomyopathy.

Alexander E. Perl, MD: Which evens out over time.

Harry Erba, MD, PhD: It does. Let’s face it, the incidence of cardiotoxicity with 7-and-3 chemotherapy in someone who hasn’t had an anthracycline is only around 1%. So, I think it’s going to be hard to show that benefit. But I will say this: When you compare the cumulative dose of CPX-351 and the cumulative daunorubicin dose with a full course of CPX-351 versus 7-and-3 chemotherapy followed by a 5-and-2 regimen, you’re getting less anthracycline with CPX-351. So, if you do believe they’re equivalent, it may be a way of getting more of the drug in.

Alexander E. Perl, MD: Getting less toxicity at least because of that.

Harry Erba, MD, PhD: At least that, yes.

Eunice Wang, MD: And then, the person’s going to transplant.

Harry Erba, MD, PhD: Right—which is important.

Eunice Wang, MD: We certainly don’t want to have high levels of cardiotoxicity going into transplant.

Transcript Edited for Clarity 
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