Harry Erba, MD, PhD:In the phase III study of liposomal daunorubicin/cytarabine versus 7 + 3, patients received those agents as induction. The dose of daunorubicin was 60 mg/m2, that was a reasonable dose in an older patient population over the age of 60. And then, they received consolidation with the same agents, either liposomal daunorubicin/cytarabine or 5 + 2 with cytarabine and daunorubicin for 2 cycles. And patients could undergo allogeneic transplant.
The primary endpoint of the study was overall survival. To get on the study, patients had to be fit for chemotherapy, performance status of 0 to 2, ages 60 to 75, and have either therapy-related AML, de novo AML with cytogenetic abnormalities of MDS, or a history of myelodysplastic syndrome, or CMML, that had been treated or not.
Some might criticize that study and ask, “Well, why wasn’t high-dose cytarabine used in that population of patients during consolidation?” In fact, in the NCCN guidelines, 5 + 2 is a perfectly appropriate consolidation, especially in this high-risk group of patients where it’s not clear that just intensifying consolidation is actually going to improve outcomes. It’s really allogeneic transplant that’s important.
So, it turns out to be a perfect experiment. And what was done in this experiment was daunorubicin/cytarabine, an induction in consolidation, was compared in the 7 + 3 and 5 + 2 regimens to 3 doses during induction of the liposomal formulation, or 2 doses during each of the 2 consolidation cycles. And in fact, if you add up the total doses of daunorubicin and cytarabine in the induction consolidation in both arms, there was less daunorubicin, less cytarabine, in the liposomal arm compared with the standard 7 + 3 arm. So, what were the results of that study?
Well, the primary endpoint was met. The median survival was improved from 6 months to 9.6 months. And that was statistically significant. The other way of looking at it is 1-year survival: 44% of patients were still alive after liposomal daunorubicin/cytarabine at 1 year compared with 28% with 7 + 3. Other efficacy endpoints were also superior with the liposomal formulation, including complete remission rate, and complete remission rate with incomplete count recovery where it was 48% with liposomal formulation and 33% with 7 + 3.
And again, in terms of toxicity, there was actually lower 30- and 60-day mortality with the liposomal formulation than with the 7 + 3. At 60 days, the mortality was 21% with the 7 + 3 arm, and it was 12% or 13% with the liposomal formulation. Similar rates of mortality at 30 and 60 days due to adverse events, but the difference really was in better control of the disease on the liposomal arm compared with the 7 + 3 arm.
Another very important efficacy endpoint is, as I said earlier, that the only curative option for this group of patients is to get them to an allogeneic stem cell transplant in a complete remission. Well, in that study, 20% of patients underwent allogeneic stem cell transplant and complete remission after Vyxeos (daunorubicin and cytarabine). So, 20% of the patients in the Vyxeos arm and 12% in the 7 + 3 arm. So, more patients after Vyxeos were able to go to transplant in first remission. And then the second part of that is, OK, so what were the outcomes after transplant? The patients who went to transplant who received an allotransplant in first remission after liposomal daunorubicin/cytarabine had improved survival compared with those who got 7 + 3 and induced that remission.
It’s not clear why there’s this difference. Some have speculated that maybe there’s less minimal residual disease after the liposomal formulation since it targets the marrow. We don’t know yet. Some have speculated that maybe it’s the toxicity profile and patients are better able to undergo allogeneic transplant after the liposomal formulation versus 7 + 3. We don’t know the reason, but the observation based on a landmark analysis is there.
In terms of the other side of the coin, in terms of toxicity, the toxicities were very similar between 7 + 3 and liposomal daunorubicin/cytarabine, the things that you might expect in terms of mucocytes, in terms of infectious complications. There was a slightly higher incidence of fatal CNS hemorrhage with liposomal formulation2% versus 7 + 3, where it was 0.7%. And all grades of hemorrhage were more commonly seen with liposomal formulation than 7 + 3, most of that being accounted for by nasal epistaxis that could be easily controlled.
If there’s 1 difference that needs to be stressed between the liposomal formulation and 7 + 3, it is that even though the doses of those agents are lower in the liposomal formulation, actually the duration of myelosuppression tended to be longer in patients who received the liposomal formulation. This may be because the drug is targeting the bone marrow and that there is some uptake by normal stem cells. So, in managing these patients, I think keeping an eye on their blood counts for longer, they may require more transfusion support and you may need to wait a bit longer before you go on to consolidationmake sure that the platelets are over 50,000, the neutrophil counts are over 500. And between cycles, consolidation weight at least 5 to 8 weeks be in cycle 1 and cycle 2 consolidation.
Transcript edited for clarity.
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