Mikkael Sekeres, MD, MS: Were there things at the 2019 ASH [American Society of Hematology Annual Meeting & Exposition] that jumped out at you in terms of different potential therapeutic approaches for treating MDS [myelodysplastic syndrome] or targeting specific genetic abnormalities? Rami, maybe I’ll start with you.

Rami Komrokji, MD: There are several obviously exciting data. Maybe I will summarize the APR-246, for example. But as you mentioned, there are different themes. One of them is targeted therapy, and actually there is 1 session that is dedicated to looking at targeted therapy. We are going from a subset of patients who have SF3B1 mutation but remain transfusion-dependent all the time. Luspatercept could be an option here, but to the other extreme, patients who have a p53 mutation unfortunately have poor outcome. The median survival typically is 4 to 6 months, and there are poor outcomes with transplant and short duration of response. These had been an area of unmet need for patients with MDS.

Several of us had been working with this compound APR-246. That’s a drug that restores the wild function of p53. It originally was tested in ovarian cancer looking at resensitizing ovarian cancer for cisplatin because that’s part of the mechanism. We looked at this preclinically, showed some additive effect with azacitidine, and did the phase I study through the MDS Clinical Research Consortium. At this ASH meeting, we’ve seen 2 phase II studies presented, 1 from our group here and 1 from our colleagues in France with a similar design.

Both studies included around 50 patients. All patients had p53 mutation and complex karyotype. Both studies actually show overall responses more than 80%, more than 50% complete responses, and in the range of 18%, 17% marrow CR [complete response], plus hematologic improvement. Almost half the patients became NGS [next-generation sequencing] negative for the p53 mutation. Again, that’s not minimal residual disease. That’s clearance of the mutation because the NGS panel threshold is variable, somewhere from 5% to 2%.

The median overall survival for those patients at least looks around a year compared with historically 6 months. One-third of the patients went to transplant, and their outcome was better. It’s very exciting. The phase III is ongoing. Hopefully that will confirm those results we are seeing, and it can become an available option for patients with unmet needs.

Mikkael Sekeres, MD, MS: I totally agree. Patients with MDS who have a p53 abnormality are just in a horribly tight spot, and with a median survival that’s terrible. There have been studies that have shown that people with p53 abnormalities seem to actually be very responsive to hypomethylating agents [HMAs] but not for very long. That’s the dirty little secret about that. You can see response rates that may be 60%, 70% with a hypomethylating agent, but they last only 3 or 4 months. So that may be potentially useful if you’re trying to get somebody to a transplant but not for the majority of patients with MDS, who aren’t transplant eligible, for treating them long term. Ellen, are there…?

Ellen K. Ritchie, MD: I thought that the CD47 antibody—which is something that Rami, you have also been working on at your institution—was also very exciting for the p53-mutated patients. That is in the early studies, the patients who were treated up front with this compound had a 100% response rate and a very low number of patients. But these are exciting initial data. As this goes forward, it will be interesting to see if this is another tool in our box to be able to treat patients with a p53 mutation, who really have this dismal prognosis, with something new. So I was pretty excited about that data. You can probably comment more on that particular trial, Rami, because it was started at your institution. But I think that’s an interesting drug.

Rami Komrokji, MD: Right. The anti-CD47 monoclonal antibody is a novel way of targeting macrophages. So, it’s a checkpoint inhibitor. It targets a receptor signal that is usually the “don’t eat me” signal, basically evading the immune surveillance from macrophages. It has been tested in patients with MDS as well as AML [acute myeloid leukemia]. Particularly in MDS, in combination with azacitidine, there is early signal of very promising activity. As you mentioned, originally there were almost 100% responses—more than 50%, 60% CRs, one-third MRD. The results of the update were presented at ASH. It looks very promising, even in patients with p53. That’s also being moved forward. The main toxicity with it actually is on-target hemolysis that you see early on. There is a single dose given early on because the receptor is on the red blood cells. You see hemolysis, and then the patients will have improvement. It looks promising as well, and the studies are moving toward phase III study with the compound.

Jamile M. Shammo, MD: There are also some interesting data in the frontline setting. Because we always complain about patients who get hypomethylating agents indefinitely and that oral hypomethylating agents may be the way to go. For this compound, ASTX727, we participated in those studies. It is a combination of oral decitabine coupled with cytidine deaminase inhibitor, cedazuridine. It’s a fixed dosage. Essentially it’s a tablet that somebody can take for 5 days every 28 days. The study essentially compared that and actually had 2 different arms, but they were relatively identical except with a different sequence of the oral versus IV [intravenous].

After cycle 3, everyone had received the oral compound. That would be really interesting to see. That may take the place of parenteral hypomethylating agents, so that’s interesting. There’s also a combination with pevonedistat and azacitidine in frontline and also in the relapsed setting that was presented at ASH. Combination study is very interesting, and we’ll see what the future might hold for that.

Rami Komrokji, MD: That study is very interesting. I was going to say we will not leave Mikkael out because he led all the efforts, so maybe he will tell us about where we are with the pevonedistat. But we’ve had the trials originally, and we saw some promising activity as well.

Mikkael Sekeres, MD, MS: I’m a big fan of combination studies, but the challenge with them is that when you’re adding drugs together to an older population, it’s hard to keep people on those drugs. What we saw in the North American intergroup study looking at combinations of azacitidine with lenalidomide or azacitidine and vorinostat was that doctors would lower the doses because they were worried about adverse effects. Or they would stop 1 of the drugs, and that would compromise the efficacy.

We are seeing promising data with pevonedistat added to azacitidine. It’s completed a large international randomized study also looking at outcomes. We’ll see if those data are positive. What we tried to build into that protocol were stricter guidelines about not lowering doses of the therapy and not stopping the therapy prematurely. We believe that if patients are going to see a response to hypomethylating agents, they need to be on those drugs for at least 6 cycles or 6 months.

Ellen K. Ritchie, MD: There was an interesting Chinese abstract buried in all the abstracts from 2019 in which they looked at over 1000 patients—mainly patients who received HMA alone versus HMA combinations in China. They found that there was a higher rate of complete response in patients who received combinations. But the overall survival was the same in patients who received HMA alone versus HMA in combination. It’s hard to know whether those combinations got the full dose of those drugs or what happened there, but it’s interesting to look at that large population study and see that the overall survival was the same, whether they got the HMA or the combination.

There are a lot of challenges when we present combinations to be able to keep those patients on drug at appropriate dosing. That might account for the fact that the overall survival was the same. But that is an interesting large population study—a lot of our MDS studies are not at such a large population—looking at the outcomes of combination or single HMA.

Mikkael Sekeres, MD, MS: Great point.

Transcript Edited for Clarity