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Treatment of AML With Myelodysplasia-Related Changes

Panelists: Harry Erba, MD, PhD, Duke University; Jorge E. Cortes, MD, MD Anderson Cancer Center; Alexander E. Perl, MD, MS, Hospital of The University of Pennsylvania; Daniel Pollyea, MD, MS, University of Colorado, Anschutz Medical Campus; Eunice Wang, MD, Roswell Park Comprehensive Cancer Center
Published: Thursday, Aug 22, 2019



Transcript: 

Harry Erba, MD, PhD: We need to get on to all of the excitement with the new drugs that are targeting, and I’m going to let my esteemed colleagues be the leads on each of those. But I’m going to take one for the team first, and I’m going to talk about chemotherapy because chemotherapy still cures patients. It’s just not been optimized or has not been able to cure the majority of patients. But it doesn’t mean we don’t have still things to do there. We all know that there’s been 40 years of attempts to improve on the outcomes with 7 and 3 [cytarabine and daunorubicin] and consolidation. And the majority of the studies have been negative.
 
Recently, there’s been an exception, and that is giving daunorubicin and cytarabine, except in a new formulation, a liposomal encapsulation of a magical 1 to 5 ratio of daunorubicin to cytarabine. So this is liposomal daunorubicin cytarabine. The investigators, we all called it CPX-351. This came from very good preclinical work showing that the molar ratio of the 2 drugs is very important at being synergistic for cell kill in leukemia cell lines, and some molar ratio is actually antagonistic. The liposomal formulation allows you to keep that 1 to 5 molar ratio. The liposome that is part of this agent actually targets the leukemic cells better than normal cells and targets the bone marrow.

This drug was actually tested first in a randomized phase II study versus [cytarabine and daunorubicin] and in patients between 60 and 75 [years old]. And in that initial randomized phase II study, there was no statistically significant benefit. But in a subset analysis, patients with poor-risk disease, antecedent hematologic disorders—CML [chronic myeloid leukemia] , CMML [chronic myelomonocytic leukemia], MDS [myelodysplastic syndrome], or treatment-related AML [acute myeloid leukemia]—those patients appeared to have higher CRs [complete responses], better relapse-free survival, better overall survival, and lower induction toxicity, mortality. But the numbers weren’t sufficient to make it statistically significant, and it was a post hoc analysis.

And so the perfect experiment was done, a well designed phase III study of liposomal daunorubicin cytarabine versus 7 and 3 [cytarabine and daunorubicin], followed by 2 cycles of consolidation with 5 and 2 [cytarabine and daunorubicin] or liposomal daunorubicin cytarabine. And the study was positive. Overall survival, median was increased from chemotherapy of 6 months up to 9.5 months with the liposomal product. The induction mortality was lower with the liposomal product. The response rates, both CR, and CR plus CRi [complete response with incomplete hematologic recovery], were higher with the liposomal formulation. In terms of toxicity, no apparent difference in nonhematologic toxicity, maybe a little bit less mucositis, but a slightly longer time to count recovery with the liposomal product. But patients did achieve CR, CRi, meaning their counts did recover.

What was most intriguing is that in this group of patients between 60 and 75 with poor-risk disease, a large number of them went on to transplant, more of them went on to transplant after the liposomal product. And by landmark analysis, the survival of those patients was superior to patients who went on to transplant after 7 and 3 [cytarabine and daunorubicin] approach. A large randomized phase III study that led to a drug approval. So I really do believe that in that group of patients with secondary AML, the way I call it, that labels AML with myelodysplasia-related changes or therapy-related AML, we really need to consider the use of this agent to help improve outcomes of our patients. So 40 years later we’re still optimizing daunorubicin/cytarabine. But I think there really is something to this formulation. Any comments?

Jorge E. Cortes, MD: I agree. I emphasize the fact that the safety profile was actually pretty good, very consistent with the chemotherapy. If anything, a few things you saw, for example, they saw alopecia and things like that. A little bit more myelosuppression but nothing consistent. And actually there were fewer deaths related to sepsis and things like that. It’s a good agent. As you said, the mechanism is still the same, but these agents are directed more into the leukemic blasts and they maintain that molar ratio that’s been found to be optimal. So for that population it’s good. The question is can we expand that and take it into de novo AMLs and others. Those studies are going to be happening and we’ll see. Right now the indication is what you mentioned, and that’s where we are using it. But it will be intriguing to see if we can help optimize the chemotherapy in other areas.

Harry Erba, MD, PhD: And a new backbone of chemotherapy upon which to test novel agents that we’re about to talk about.

Jorge E. Cortes, MD: Absolutely.

Eunice Wang, MD: Right.

Alexander E. Perl, MD, MS: Yes. I thought this was a very courageous study because they really looked at a very high-risk population, one in which you really would have to go to transplant to expect good outcomes. There are 2 takeaways I have from this. The first is, the choice of induction matters. You got more people to transplant and the transplant worked better. But the second is, transplant you can give to older patients and see good outcomes. This is one of the few prospective studies that actually had a fairly high rate of transplantation in older patients, and actually that’s what was intended and what was delivered on the study. That’s encouraging because the transplant outcomes in patients even over the age of 70 were really quite good, and that encourages us to be aggressive with these patients and hopefully offer them curative therapy.

Eunice Wang, MD: I wanted to add one important point and this touches back on Sasha [Alexander] when we talked about the initial diagnoses of these patients, that at his institute they specifically do FISH [fluorescence in situ hybridization] for chromosome 5 and 7 abnormalities to look for this particular entity. So if you look at the terminology and the use of this agent, I have a feeling that maybe people are not aware or don’t use the drug as much because there’s this new entity that they sort of have defined as AML with MDS-related changes.

I think going back again to our initial discussion, to get the benefit of this drug, which is a proven benefit in this phase III clinical trial for this subset of patients, it is essential that at the time of diagnosis that your hematopathologist and the clinicians are specifically looking for MDS-related changes, whether it’s a prior history, a prior history of myelotoxic chemotherapy for any reason, or cytogenetic abnormalities, which are diagnostic of the MDS-related changes. In fact, people often use the word secondary AML because that’s something we’re more familiar with, but it may be that specific number of patients with this particular entity are not recognized and are therefore going ahead and getting 7+3 [cytarabine/daunorubicin] as their initial induction chemotherapy instead of the liposomal. And I think that’s something we need to be aware of and we need to specifically ask for in addition to FLT3, IDH1, IDH2. We need to talk to our pathologists and our cytogeneticists and clarify, is this an MDS-related entity?

Harry Erba, MD, PhD: Yes. Again, a very good argument for waiting for this information to help you pick the best therapy, and day 1 matters. I think that’s what we’re saying.

Transcript Edited for Clarity

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Transcript: 

Harry Erba, MD, PhD: We need to get on to all of the excitement with the new drugs that are targeting, and I’m going to let my esteemed colleagues be the leads on each of those. But I’m going to take one for the team first, and I’m going to talk about chemotherapy because chemotherapy still cures patients. It’s just not been optimized or has not been able to cure the majority of patients. But it doesn’t mean we don’t have still things to do there. We all know that there’s been 40 years of attempts to improve on the outcomes with 7 and 3 [cytarabine and daunorubicin] and consolidation. And the majority of the studies have been negative.
 
Recently, there’s been an exception, and that is giving daunorubicin and cytarabine, except in a new formulation, a liposomal encapsulation of a magical 1 to 5 ratio of daunorubicin to cytarabine. So this is liposomal daunorubicin cytarabine. The investigators, we all called it CPX-351. This came from very good preclinical work showing that the molar ratio of the 2 drugs is very important at being synergistic for cell kill in leukemia cell lines, and some molar ratio is actually antagonistic. The liposomal formulation allows you to keep that 1 to 5 molar ratio. The liposome that is part of this agent actually targets the leukemic cells better than normal cells and targets the bone marrow.

This drug was actually tested first in a randomized phase II study versus [cytarabine and daunorubicin] and in patients between 60 and 75 [years old]. And in that initial randomized phase II study, there was no statistically significant benefit. But in a subset analysis, patients with poor-risk disease, antecedent hematologic disorders—CML [chronic myeloid leukemia] , CMML [chronic myelomonocytic leukemia], MDS [myelodysplastic syndrome], or treatment-related AML [acute myeloid leukemia]—those patients appeared to have higher CRs [complete responses], better relapse-free survival, better overall survival, and lower induction toxicity, mortality. But the numbers weren’t sufficient to make it statistically significant, and it was a post hoc analysis.

And so the perfect experiment was done, a well designed phase III study of liposomal daunorubicin cytarabine versus 7 and 3 [cytarabine and daunorubicin], followed by 2 cycles of consolidation with 5 and 2 [cytarabine and daunorubicin] or liposomal daunorubicin cytarabine. And the study was positive. Overall survival, median was increased from chemotherapy of 6 months up to 9.5 months with the liposomal product. The induction mortality was lower with the liposomal product. The response rates, both CR, and CR plus CRi [complete response with incomplete hematologic recovery], were higher with the liposomal formulation. In terms of toxicity, no apparent difference in nonhematologic toxicity, maybe a little bit less mucositis, but a slightly longer time to count recovery with the liposomal product. But patients did achieve CR, CRi, meaning their counts did recover.

What was most intriguing is that in this group of patients between 60 and 75 with poor-risk disease, a large number of them went on to transplant, more of them went on to transplant after the liposomal product. And by landmark analysis, the survival of those patients was superior to patients who went on to transplant after 7 and 3 [cytarabine and daunorubicin] approach. A large randomized phase III study that led to a drug approval. So I really do believe that in that group of patients with secondary AML, the way I call it, that labels AML with myelodysplasia-related changes or therapy-related AML, we really need to consider the use of this agent to help improve outcomes of our patients. So 40 years later we’re still optimizing daunorubicin/cytarabine. But I think there really is something to this formulation. Any comments?

Jorge E. Cortes, MD: I agree. I emphasize the fact that the safety profile was actually pretty good, very consistent with the chemotherapy. If anything, a few things you saw, for example, they saw alopecia and things like that. A little bit more myelosuppression but nothing consistent. And actually there were fewer deaths related to sepsis and things like that. It’s a good agent. As you said, the mechanism is still the same, but these agents are directed more into the leukemic blasts and they maintain that molar ratio that’s been found to be optimal. So for that population it’s good. The question is can we expand that and take it into de novo AMLs and others. Those studies are going to be happening and we’ll see. Right now the indication is what you mentioned, and that’s where we are using it. But it will be intriguing to see if we can help optimize the chemotherapy in other areas.

Harry Erba, MD, PhD: And a new backbone of chemotherapy upon which to test novel agents that we’re about to talk about.

Jorge E. Cortes, MD: Absolutely.

Eunice Wang, MD: Right.

Alexander E. Perl, MD, MS: Yes. I thought this was a very courageous study because they really looked at a very high-risk population, one in which you really would have to go to transplant to expect good outcomes. There are 2 takeaways I have from this. The first is, the choice of induction matters. You got more people to transplant and the transplant worked better. But the second is, transplant you can give to older patients and see good outcomes. This is one of the few prospective studies that actually had a fairly high rate of transplantation in older patients, and actually that’s what was intended and what was delivered on the study. That’s encouraging because the transplant outcomes in patients even over the age of 70 were really quite good, and that encourages us to be aggressive with these patients and hopefully offer them curative therapy.

Eunice Wang, MD: I wanted to add one important point and this touches back on Sasha [Alexander] when we talked about the initial diagnoses of these patients, that at his institute they specifically do FISH [fluorescence in situ hybridization] for chromosome 5 and 7 abnormalities to look for this particular entity. So if you look at the terminology and the use of this agent, I have a feeling that maybe people are not aware or don’t use the drug as much because there’s this new entity that they sort of have defined as AML with MDS-related changes.

I think going back again to our initial discussion, to get the benefit of this drug, which is a proven benefit in this phase III clinical trial for this subset of patients, it is essential that at the time of diagnosis that your hematopathologist and the clinicians are specifically looking for MDS-related changes, whether it’s a prior history, a prior history of myelotoxic chemotherapy for any reason, or cytogenetic abnormalities, which are diagnostic of the MDS-related changes. In fact, people often use the word secondary AML because that’s something we’re more familiar with, but it may be that specific number of patients with this particular entity are not recognized and are therefore going ahead and getting 7+3 [cytarabine/daunorubicin] as their initial induction chemotherapy instead of the liposomal. And I think that’s something we need to be aware of and we need to specifically ask for in addition to FLT3, IDH1, IDH2. We need to talk to our pathologists and our cytogeneticists and clarify, is this an MDS-related entity?

Harry Erba, MD, PhD: Yes. Again, a very good argument for waiting for this information to help you pick the best therapy, and day 1 matters. I think that’s what we’re saying.

Transcript Edited for Clarity
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