High-Risk MDS: Clinical Efficacy Data

Yazan Madanat, MD: Mikkael, can you tell us about treatment options for higher-risk MDS [myelodysplastic syndrome], going into detail about clinical trial efficacy and how you would select 1 over the other in your practice?

Mikkael A. Sekeres, MD: Sure. It’s easy to remember. I’m proof of principle that you don’t have to be a genius to know all the trial data in MDS because there aren’t a lot of great trial data. There’s only 1 prospective randomized trial that has ever shown a survival advantage in higher-risk MDS, and that’s the AZA-001 study that you mentioned, Yazan. In that trial, patients with higher-risk disease as defined by IPSS [International Prognostic Scoring System] were randomized to receive azacitidine or conventional care regimens. Conventional care regimens consisted of 60% of patients receiving best supportive care. The remaining 40% received either low-dose cytarabine or classic 7+3 intensive AML [acute myeloid leukemia]–type therapy.

On that study, patients who were randomized to receive azacitidine survived a median of 24 months compared with 15½ months for those who received conventional care regimens. That difference was statistically significantly different. That was dramatic. This is now the standard of care. There’s no arguing about it.

Azacitidine and decitabine are very similar structurally and in how they behave biologically. In fact, 1 is a prodrug for the other. A similar study that was conducted in Europe looked at decitabine in higher-risk patients with MDS. Patients were randomized to getting decitabine or best supportive care. It wasn’t exactly the same as the AZA-001 study, because it wasn’t conventional care regimens, but it was similar to the 60% of patients on AZA-001 who got best supportive care. In the decitabine study, however, the median survival for those who received decitabine was 10.1 months vs 8.5 months for those who got best supportive care. That was not a significant difference between those 2 arms.

This has had us wringing our hands for years. Why is it that we had such a dramatic survival benefit in 1 study but not the other? The answer is in the control groups. If you look at the control group on the AZA-001 study, they lived for 15½ months. For those on the decitabine randomized trial, they lived for only 8½ months. That has to get to patient selection on the studies. These were simply very different patient populations who were enrolled in 1 study vs the other.

Another explanation for the big difference between the 2 studies is that I always say there must have been some magic dust that they sprinkled on those patients in the AZA-001 study, because no randomized trial has ever been able to recapitulate that median survival of 24 months for patients who received azacitidine. Much more typical is the median survival that we saw in the United States in North American Cooperative Group studies that compared azacitidine to azacitidine plus entinostat on the ECOG study, or azacitidine plus lenalidomide or vorinostat in the North American Intergroup Study. On both of those studies, the median survival for a patient receiving azacitidine with higher-risk MDS was about a year and a half. That is what our comparison should be.

Those are the trial data justifying our use. Yazan, you and I are pretty supportive of using azacitidine as first-line therapy in patients with higher-risk MDS. We have this new oral decitabine-cedazuridine combination. It was approved by the FDA in a study that was a little complicated in how it was structured. Patients with higher-risk disease or intermediate 1 risk disease—lower risk was included in that—were randomized to receive oral decitabine or IV [intravenous] decitabine. There wasn’t a placebo control group. There wasn’t another arm getting another different type of therapy. They both got decitabine. They got that for 1 cycle, and then they could switch over and get IV decitabine.

When you look at the response rates on this trial, it was about what we’ve seen for decitabine or azacitidine. When you look at the PK [pharmacokinetics] and PD [pharmacodynamics] data, they’re very similar for oral decitabine and IV decitabine. When you look at the median overall survival, it’s about a year and a half which, in my mind was a little low for a study that included patients with lower-risk MDS. I would have thought it would have been in the 20- to 24-month range. That being said, we’re seeing similar outcome data for oral decitabine vs IV decitabine, but we haven’t seen a true comparative study of oral decitabine vs conventional care regimens or placebo. I’m still voting for higher-risk MDS. My level 1 data is with treating them with azacitidine up front.

Transcript Edited for Clarity