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CPX-351 for Secondary AML

Panelists: Harry Erba, MD, PhD, Duke Cancer Institute; Naval Daver, MD, The University of Texas MD Anderson Cancer Center; Rami Komrokji, MD, H. Lee Moffitt Cancer Center; Mark Levis, MD, PhD, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center; Dan Pollyea, MD, MS, University of Colorado Cancer Center
Published: Thursday, Feb 27, 2020



Transcript: 

Harry Erba, MD, PhD: Let’s not forget about chemotherapy and advances there. I’d like to talk about liposomal daunorubicin cytarabine. Rami?

Rami Komrokji, MD: Sure. CPX-351 is a liposomal cytarabine daunorubicin that’s packaged in a way that allows delivery of a 5:1 ratio of the drug with better bone marrow penetration and leukemia cell kill, in vitro at least. We’ll take the phase I and phase II studies, and there was a signal of survival benefit in patients with secondary AML [acute myeloid leukemia], a term used to combine therapy-related AML as well as AML for antecedent hematologic diseases. In the phase III randomized clinical trial led by Jeff Lancet, randomized patients who had either therapy-related AML, AML from MDS [myelodysplastic syndrome], or AML with MDS-like cytogenetics, as well as randomized patients between the CPX-351 and 7+3 [cytarabine, daunorubicin], the standard chemotherapy. It showed a survival advantage for CPX-351 over the intensive chemotherapy: higher remission rates and a 1-year survival in the range of 40% versus 27%, 28%. The drug was approved in that setting for patients with secondary AML.

It still goes through what we’ve been discussing. It goes through the same exercise. If I decided to induce a patient who is a candidate for intensive chemotherapy, and the patient happens to be a secondary AML patient, then I will use CPX-351 [liposomal cytarabine daunorubicin] over 7+3 [cytarabine, daunorubicin] in that setting. That’s how I position the treatment. At this year’s ASH [American Society of Hematology 2019 Annual Meeting & Exposition], we’ve seen some subset analyses of our data from the original study. The original study, by the way, included 300 patients. We saw data on the molecular profile for those patients and how they fared. Not all the patients on the study had samples, and those were not serial samples. Those were just at diagnosis.

The message from that is probably that patients with TP53 did not do well, as well. For the patients who had TP53 mutation, in the study, the response rate and overall survival looked the same as 7+3 [cytarabine, daunorubicin]. Mark had alluded to that, and I completely agree with him. It’s my practice, if somebody has TP53, to go all away completely from intensive chemotherapy. I don’t give intensive chemotherapy even if they are younger patients. The message from the molecular analysis was like that. The other groups were too small to make a firm conclusion, and some of the subsets they looked at the TET2, SSL1 mutated. The CR [complete remission] rates seemed equivalent, but then there was some survival advantage. I don’t know what to make of that data. The only thing I can say is, like in the TP53, the message should be this: we should be enrolling those patients in clinical trials, novel combinations. They don’t do well with intensive chemotherapy.

There was another analysis done looking at the patients with AML with MDS-like changes who got consolidation and got to transplant. There have been signals in many of the subset studies looking at patients, even the patients who go into remission. When they get consolidation with CPX-351 [liposomal cytarabine daunorubicin] compared with 7+3 [cytarabine, daunorubicin] or they go to transplant, their outcome has been better with the CPX-351 [liposomal cytarabine daunorubicin]. People are speculating about that. Are we actually getting better MRD [minimal residual disease] status or not? There was a landmark analysis presented at this meeting as well for that subset of patients showing that patients who went to transplant receiving CPX-351 [liposomal cytarabine daunorubicin] and the induction consolidation of 7+3 [cytarabine, daunorubicin] did better with the transplant.

Mark Levis, MD, PhD: The thing with CPX-351 [liposomal cytarabine daunorubicin] that I’m seeing cause some confusion among practitioners is your secondary AML. Is the patient borderline fit for intensive therapy? Are you going to use HMA-VEN [hypomethylating agents, venetoclax], or are you going to use CPX-351 [liposomal cytarabine daunorubicin]? The data would suggest that CPX-351 [liposomal cytarabine daunorubicin] is clearly associated with taking an intensive route. Maybe even transplanting the patient is the approach, yet there’s this default of going with HMA-VEN [hypomethylating agents, venetoclax] because it’s easier.

Dan Pollyea, MD, MS: As Harry pointed out, a significant percentage of patients who weren’t thought to be candidates for intensive chemotherapy in the setting of HMA [hypomethylating agents]–venetoclax went to a transplant and have had good outcomes. What I find interesting about CPX-351 [liposomal cytarabine daunorubicin] is that it already has a pretty narrow indication, and now we’re supposed to say, “OK, it’s secondary AML and it’s treatment-related AML, but not the TP53.” The message is that it’s chemotherapy, right? The same rules apply to standard of care. It seems as if the risk factors for poor response to chemotherapy are applicable to CPX-351 [liposomal cytarabine daunorubicin], and it’s chipping away at the patients who should get it.

Harry Erba, MD, PhD: I’ll remind you: in that phase III study that was for patients ages 60 to 75—so not young people—more patients were able to get to transplant. Although it’s a completely different study, more patients than in the HMA-VEN [hypomethylating agents, venetoclax] studies went to transplant, of course different studies. The outcome after transplant was superior than after chemotherapy. It comes down to a very long conversation. While you’re waiting for this mutational data to come back, figure out what your patient wants. For the 70-year-old, are they looking for maintenance therapy and just living another year? Or are they looking to be cured? If it’s a curative route, then I use chemotherapy, and  liposomal daunorubicin cytarabine has an advantage there if you’re going to take them to transplant. It’s a long discussion.

Mark Levis, MD, PhD: That’s been our approach too.

Harry Erba, MD, PhD: If they do get an HMA-VEN [hypomethylating agents, venetoclax], don’t forget about the value of transplant.

Dan Pollyea, MD, MS: For a remission, this is a big maybe. I don’t know the quality of a remission after a lower-intensity therapy versus a higher-intensity therapy and how that might be testing for a post-transplant outcome. It’s a provocative consideration right now, and if you’re in that situation, Harry, I agree: don’t rest on your laurels, that may be someone who could go on to benefit.

Naval Daver, MD: Interestingly now, are we going to think about maintenance with oral AZA [azacitidine] after CPX-351 [liposomal cytarabine daunorubicin]? Then there’s going to be just another because that is going to come up next.

Dan Pollyea, MD, MS: Or after HMA-VEN [hypomethylating agents, venetoclax]. Any remission may be amenable to a maintenance.

Harry Erba, MD, PhD: That’s right. Now that it’s available, or will be available, we need to be able to study this. Before we leave this section, just 1 word about another drug that was approved in the last couple of years: glasdegib, the hedgehog inhibitor. It was approved based on a randomized phase II study in older patients unfit for chemotherapy: low-dose cytarabine or low-dose cytarabine with glasdegib. There was a longer survival, almost double, from 5 to 9 months. There was a higher remission rate with the combination with glasdegib.

It has not caught on, at least in my practice. What I’ve seen, partly because—and I know we’re not supposed to do this—but when you look at the data with HMA-VEN [hypomethylating agents, venetoclax] and LoDAC-VEN [low-dose cytarabine–venetoclax], the responses and duration responses appear greater. There is some GI [gastrointestinal] toxicity, hair loss, and muscle cramps that you see with it. Hopefully, the phase III studies that are being done will be designed in a way that will show the actual benefit of this drug for our patients.

Transcript Edited for Clarity

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Transcript: 

Harry Erba, MD, PhD: Let’s not forget about chemotherapy and advances there. I’d like to talk about liposomal daunorubicin cytarabine. Rami?

Rami Komrokji, MD: Sure. CPX-351 is a liposomal cytarabine daunorubicin that’s packaged in a way that allows delivery of a 5:1 ratio of the drug with better bone marrow penetration and leukemia cell kill, in vitro at least. We’ll take the phase I and phase II studies, and there was a signal of survival benefit in patients with secondary AML [acute myeloid leukemia], a term used to combine therapy-related AML as well as AML for antecedent hematologic diseases. In the phase III randomized clinical trial led by Jeff Lancet, randomized patients who had either therapy-related AML, AML from MDS [myelodysplastic syndrome], or AML with MDS-like cytogenetics, as well as randomized patients between the CPX-351 and 7+3 [cytarabine, daunorubicin], the standard chemotherapy. It showed a survival advantage for CPX-351 over the intensive chemotherapy: higher remission rates and a 1-year survival in the range of 40% versus 27%, 28%. The drug was approved in that setting for patients with secondary AML.

It still goes through what we’ve been discussing. It goes through the same exercise. If I decided to induce a patient who is a candidate for intensive chemotherapy, and the patient happens to be a secondary AML patient, then I will use CPX-351 [liposomal cytarabine daunorubicin] over 7+3 [cytarabine, daunorubicin] in that setting. That’s how I position the treatment. At this year’s ASH [American Society of Hematology 2019 Annual Meeting & Exposition], we’ve seen some subset analyses of our data from the original study. The original study, by the way, included 300 patients. We saw data on the molecular profile for those patients and how they fared. Not all the patients on the study had samples, and those were not serial samples. Those were just at diagnosis.

The message from that is probably that patients with TP53 did not do well, as well. For the patients who had TP53 mutation, in the study, the response rate and overall survival looked the same as 7+3 [cytarabine, daunorubicin]. Mark had alluded to that, and I completely agree with him. It’s my practice, if somebody has TP53, to go all away completely from intensive chemotherapy. I don’t give intensive chemotherapy even if they are younger patients. The message from the molecular analysis was like that. The other groups were too small to make a firm conclusion, and some of the subsets they looked at the TET2, SSL1 mutated. The CR [complete remission] rates seemed equivalent, but then there was some survival advantage. I don’t know what to make of that data. The only thing I can say is, like in the TP53, the message should be this: we should be enrolling those patients in clinical trials, novel combinations. They don’t do well with intensive chemotherapy.

There was another analysis done looking at the patients with AML with MDS-like changes who got consolidation and got to transplant. There have been signals in many of the subset studies looking at patients, even the patients who go into remission. When they get consolidation with CPX-351 [liposomal cytarabine daunorubicin] compared with 7+3 [cytarabine, daunorubicin] or they go to transplant, their outcome has been better with the CPX-351 [liposomal cytarabine daunorubicin]. People are speculating about that. Are we actually getting better MRD [minimal residual disease] status or not? There was a landmark analysis presented at this meeting as well for that subset of patients showing that patients who went to transplant receiving CPX-351 [liposomal cytarabine daunorubicin] and the induction consolidation of 7+3 [cytarabine, daunorubicin] did better with the transplant.

Mark Levis, MD, PhD: The thing with CPX-351 [liposomal cytarabine daunorubicin] that I’m seeing cause some confusion among practitioners is your secondary AML. Is the patient borderline fit for intensive therapy? Are you going to use HMA-VEN [hypomethylating agents, venetoclax], or are you going to use CPX-351 [liposomal cytarabine daunorubicin]? The data would suggest that CPX-351 [liposomal cytarabine daunorubicin] is clearly associated with taking an intensive route. Maybe even transplanting the patient is the approach, yet there’s this default of going with HMA-VEN [hypomethylating agents, venetoclax] because it’s easier.

Dan Pollyea, MD, MS: As Harry pointed out, a significant percentage of patients who weren’t thought to be candidates for intensive chemotherapy in the setting of HMA [hypomethylating agents]–venetoclax went to a transplant and have had good outcomes. What I find interesting about CPX-351 [liposomal cytarabine daunorubicin] is that it already has a pretty narrow indication, and now we’re supposed to say, “OK, it’s secondary AML and it’s treatment-related AML, but not the TP53.” The message is that it’s chemotherapy, right? The same rules apply to standard of care. It seems as if the risk factors for poor response to chemotherapy are applicable to CPX-351 [liposomal cytarabine daunorubicin], and it’s chipping away at the patients who should get it.

Harry Erba, MD, PhD: I’ll remind you: in that phase III study that was for patients ages 60 to 75—so not young people—more patients were able to get to transplant. Although it’s a completely different study, more patients than in the HMA-VEN [hypomethylating agents, venetoclax] studies went to transplant, of course different studies. The outcome after transplant was superior than after chemotherapy. It comes down to a very long conversation. While you’re waiting for this mutational data to come back, figure out what your patient wants. For the 70-year-old, are they looking for maintenance therapy and just living another year? Or are they looking to be cured? If it’s a curative route, then I use chemotherapy, and  liposomal daunorubicin cytarabine has an advantage there if you’re going to take them to transplant. It’s a long discussion.

Mark Levis, MD, PhD: That’s been our approach too.

Harry Erba, MD, PhD: If they do get an HMA-VEN [hypomethylating agents, venetoclax], don’t forget about the value of transplant.

Dan Pollyea, MD, MS: For a remission, this is a big maybe. I don’t know the quality of a remission after a lower-intensity therapy versus a higher-intensity therapy and how that might be testing for a post-transplant outcome. It’s a provocative consideration right now, and if you’re in that situation, Harry, I agree: don’t rest on your laurels, that may be someone who could go on to benefit.

Naval Daver, MD: Interestingly now, are we going to think about maintenance with oral AZA [azacitidine] after CPX-351 [liposomal cytarabine daunorubicin]? Then there’s going to be just another because that is going to come up next.

Dan Pollyea, MD, MS: Or after HMA-VEN [hypomethylating agents, venetoclax]. Any remission may be amenable to a maintenance.

Harry Erba, MD, PhD: That’s right. Now that it’s available, or will be available, we need to be able to study this. Before we leave this section, just 1 word about another drug that was approved in the last couple of years: glasdegib, the hedgehog inhibitor. It was approved based on a randomized phase II study in older patients unfit for chemotherapy: low-dose cytarabine or low-dose cytarabine with glasdegib. There was a longer survival, almost double, from 5 to 9 months. There was a higher remission rate with the combination with glasdegib.

It has not caught on, at least in my practice. What I’ve seen, partly because—and I know we’re not supposed to do this—but when you look at the data with HMA-VEN [hypomethylating agents, venetoclax] and LoDAC-VEN [low-dose cytarabine–venetoclax], the responses and duration responses appear greater. There is some GI [gastrointestinal] toxicity, hair loss, and muscle cramps that you see with it. Hopefully, the phase III studies that are being done will be designed in a way that will show the actual benefit of this drug for our patients.

Transcript Edited for Clarity
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