Moving Toward Precision Medicine in Adult Acute Myeloid Leukemia - Episode 2

CPX-351 for Older Patients with AML

Transcript:Elias Jabbour, MD: Marty, there was the presentation at the ASH meeting about CR, CRi, CRp. So, we have different criteria of responses. Are they all equivalent? Or at least in somebody where we would give 3+7 intensive chemotherapy, we should limit our responses to CR, or CRp at the most, but not the marrow CR and others.

Martin S. Tallman, MD: There’s some new information that is being presented at this ASH 2016 meeting from the Eastern Cooperative Oncology Group that suggest that response parameters less than CR may not be as good as CR, particularly CRi, both with chemotherapy and the novel agent clofarabine. So, I think that we have to reevaluate those additional response parameters.

Elias Jabbour, MD: Definitely, I agree with you. I want to go to Harry. You’ve done a lot of studies with the new agents, Harry, and then as we’ve started discussing, there’s not much for these elderly patients. We have the HMA therapy. I want to focus on a group of patients who had poor prognosis; they have therapy-related secondary AML. I know there was a trial looking at CPX-351, a liposomal formulation. Can you tell me more about it?

Harry P. Erba, MD, PhD: So, CPX-351 is a liposomal formulation of cytarabine (Ara-C) and daunorubicin. And there are 2 interesting components of this agent. The first is that the way that these 2 drugs were put together in the liposome were informed by preclinical data showing that you get best activity of these 2 drugs when you have delivered them at a molar ratio of 5:1. And so, in the liposome, the cytarabine is present in a molar ratio of 5:1 of the daunorubicin. And the second is the liposomal formulation itself. There are preclinical data and correlative data showing that this agent gets incorporated into the bone marrow and daunorubicin and cytarabine are released in the bone marrow.

There was a large phase III study comparing CPX-351 as an induction and as a consolidation versus 3+7, followed by 2+5 chemotherapy as a consolidation. No high-dose Ara-C there. The patients who were eligible were between the ages of 60 and 75, and they had to have a secondary AML, which was defined as treatment-related AML—AML that was following MDS either pretreated with a hypomethylating agent or not or AML with complex or MDS-related cytogenetic changes. That was the patient population.

It was a positive study. The remission rates were higher with CPX-351 versus 7+3. The mortality at day 30 was lower. The mortality at day 60 was lower with CPX-351. And when they looked at cause of mortality, more patients had persistent disease who were dying at day 60 with 3+7 versus the CPX-351. But the endpoint of the study was survival, and again, there was a statistically significant improvement in overall survival in the patients who received CPX-351. When they looked at the subset of patients who went on to receive an allogeneic transplant in that first remission, the outcome of allogeneic transplant was better in patients who had achieved their first remission with CPX-351 than with 3+7. So, they were pretty compelling data that this is a benefit for patients that are defined clinically as having secondary AML, at least in that age group.

Elias Jabbour, MD: So, do you think this drug will get an approval in the future?

Harry P. Erba, MD, PhD: I do think it will be approved.

Elias Jabbour, MD: And once approved, do you think there’s any subset of patients who will do better with CPX-351? I know, across the board, the randomization favors CPX-351. But among the patients who receive the CPX, for example, somebody who failed the decitabine or azacitidine, did they respond well to CPX? How about the subset?

Harry P. Erba, MD, PhD: They did. So, when they looked at patients who had previously received a hypomethylating agent, it didn’t seem to impact the response rates. An interesting question that will come up, though, is, are the molecular subsets in this patient population? Dr. Coleman at Dana-Farber did an analysis of the genetics of older AML samples that appear to be de novo AMLs, but found that the molecular signature was very similar to patients who had clinically secondary AML. It will be interesting to look at these data from the phase III study or other data with CPX-351 and see if there’s a particular subset that can be defined by a molecular panel or mutational panel that might benefit.

Elias Jabbour, MD: And beyond this study, where do you see the drug once it’s approved? What is the next step to use it, where to combine it?

Harry P. Erba, MD, PhD: Well, I think it’s an interesting time for us because with this drug, and midostaurin that we’ll talk about later, the way we develop future drugs in AML is really going to change dramatically. I think we are going to, for the first time in 30 or 40 years, have new standards-of-cares for subsets of our patients. So, I would imagine, in terms of just the age population, there are safety data of CPX-351 in younger patients in the relapse refractory setting. In fact, I believe your colleague, Dr. Cortez, published that. And so, the agent may be given also to younger patients. But I would caution that because, remember, in this trial, the postremission treatment did not include high-dose cytarabine. And so, the full benefit in younger patients who might be able to tolerate more intensive therapies is still unknown.

Mark J. Levis, MD, PhD: If I could just interject, the interesting point about CPX-351: we know in a younger patient population, it appears equivalent from an overall survival standpoint to our conventional 7+3. But we also know from prior studies when we tried to incorporate other agents into 7+3, sometimes the toxicity is too much. By lowering the toxicity, but getting the same efficacy, are we going to have a safer platform to explore more new agents?

Harry P. Erba, MD, PhD: I think that’s possible. So, it gets back to looking at the toxicity of CPX-351 versus 3+7 in that phase I study. And there were less infectious deaths with CPX-351, but there actually was more myelosuppression with CPX-351—at least during the induction, it took longer for counts to recover than with 3+7—and so, that’s definitely going to be something that needs to be considered if, for other agents that have myelosuppressive abilities, you try to add them to CPX-351.

Transcript Edited for Clarity