Acute Myeloid Leukemia: The Path to Personalized Medicine - Episode 7

Liposomal Daunorubicin & Cytarabine for AML


Harry Erba, MD, PhD: Moving on to another FDA approval in the last year or so, we have liposomal daunorubicin/cytarabine, which was approved in August of 2017 for previously untreated adults with either AML [acute myeloid leukemia] with myelodysplasia-related changes, prior MDS [myelodysplastic syndrome], for example, or complex karyotype, multilineage dysplasia; and treatment-related AML. So that drug has now been available for a year. Now again, our audience is probably saying, “Wait, you just went back to chemotherapy.” But this is not just the same old daunorubicin/cytarabine. It was really based on preclinical science showing that the molar ratio of daunorubicin to cytarabine may be very important. And, in fact, the 1 to 5 molar ratio in this liposomal formulation is synergistic and the liposome targets the marrow.

So there is some preclinical data suggesting maybe this is an advantage. The phase III study was a perfect experiment. Lower doses of daunorubicin/cytarabine in the liposomal formulation were compared to the standard 7 and 3 regimen followed by consolidation with the 2, and there was a survival benefit. So there’s something there. Maybe we don’t understand it completely, but Raajit, do you want to talk about some of the subsequent analyses that were presented?

Raajit K. Rampal, MD, PhD: Yes. There are a couple of really interesting analyses that were presented at ASH [the American Society of Hematology meeting] this year [2018], one of which looked at the specific cohort of patients with AML-MRC [acute myeloid leukemia with myelodysplasia-related changes], which certainly are not always the easiest patients to diagnose, given that it is not always a necessity to have a known MDS or CMML [chronic myelomonocytic leukemia] prior to having AML, but it can be found from cytogenetic changes. And so when looking at this subgroup, as opposed to taking out the treatment-related AML patients, there was a benefit to these AML-MRC patients to the liposomal formulation that was reported at this meeting. Again, the larger study had reported on the combination of therapy-related AML and AML-MRC as one group, but now the data here clearly show that the AML-MRC derives benefit from this combination.

One of the really interesting things that emerged was transplant. And, certainly, given the poor natural history of secondary AML, we try to consider transplant whenever possible because that’s the only long-term curative strategy. And the question always remains, can you get a patient to transplant? And one of the interesting things to emerge from the meeting is they are looking at transplant outcomes in patients who had received standard induction versus the liposomal formulation. In fact, there appeared to be a benefit to those patients in terms of their post-transplant outcomes if they had received the liposomal formulation. And so the potential implication of that is, are you getting a deeper response? Are we seeing more MRD [minimal residual disease]-negative response? That data were not presented here but this certainly is one of the implications. But I think it was a very striking finding that there may be a longer-term benefit in terms of how these patients do if you’re going to take them to transplant.

Harry Erba, MD, PhD: So, at your institutions, how do you give liposomal daunorubicin/cytarabine? It’s a 90-minute infusion day 1, 3, and 5. This can be done in an infusion center. Are we ready to do outpatient infusions for induction? Ninety-eight percent of patients in the phase III trial got it as an inpatient.

Mark J. Levis, MD, PhD: We call it the “purple drug.” It’s purple. It’s got anthracycline red and copper blue.

Harry Erba, MD, PhD: I like that color.

Mark J. Levis, MD, PhD: We still give it induction as an inpatient. We regard a newly diagnosed leukemic patient as somebody who warrants an inpatient stay. I don’t think it’s trivial. You do get aplasia and, yes, it’s not anywhere near as toxic. The patient is often sitting there in the corner reading the newspaper, getting this drug. Their hair doesn’t fall out, but there are toxicities. We tend to reserve the outpatient treatment for consolidation, which is actually very convenient. Patients come in quickly, get their consolidation. While there is some neutropenia there, it’s a lot less. It seems to be quite well tolerated, at least in consolidation. So our approach is consolidation.

Naval G. Daver, MD: I think this is similar to the HMA [hypomethylating agent]/venetoclax discussion that we had. Although this is better tolerated and I think overall safer, this is chemotherapy. This is induction therapy. And so I think for 100%, we’re admitting these people like Dr Erba said. The experience of outpatient is anecdotal at best. And I know it’s an insurance reimbursement issue in many places, but we’re admitting them, and the count recovery, as was mentioned, is actually longer than the 7+3 regimen. It’s 35 days versus 28. In spite of that, I think it may be mucositis. We don’t know, but there seems to be a survival benefit; even the 8-week mortality is lower. It’s 10% versus 18%. So I think you have to monitor these people, do transfusions, give them antibiotics. They seem to tolerate it better and have better outcomes, but it’s not because this is low intensity therapy.

Mark J. Levis, MD, PhD: Well, I think you’ll survive better if your leukemia is gone at the completion of all of this awful 8 weeks, and I think that’s probably where this drug is working.

Harry Erba, MD, PhD: The strength of the data that were presented on allotransplant is that this was a randomized phase III study. And, in fact, more patients were able to go on to get a transplant. Even patients over age 70 were able to go on to get a transplant and had, after the liposomal formulation, better outcomes compared to the 7 and 3 option. The difficulty that we will have with analyzing single-center retrospective data is the selection bias. In that north side experience, similar numbers of patients went on to the transplant after 7 and 3 and IDA-FLAG [idarubicin/fludarabine/cytarabine/G-CSF], and yet the outcomes were not as good with 7 and 3. But there may have been some unmeasured covariates there.

Transcript Edited for Clarity