ASH 2025 | Findings from the Phase II AMMO trial of ASTX727 in CMML and other MDS/MPN overlap syndromes

I’ve presented the first results of the UK randomized trial called AMMO, which stands for ASTX727, which is versus hydroxycarbamide and best supportive care in MDS-MPN overlap syndromes. So this was a Phase II trial in which we randomized patients with MDS-MPN overlaps in a two-to-one fashion to either receive ASTX727, which is an oral formulation of decitabine with cedazuridine, which is a cytidine deaminase inhibitor which allows it to be taken orally. And the standard of care for pretty much all of these diseases for decades has been hydroxycarbamide, but that’s not particularly disease-modifying. The results are not very good. It doesn’t particularly delay progression, and it can actually exacerbate the other cytopenias that these patients often have by virtue of being overlapped. So we know that hypomethylating agents work in these diseases. What we don’t have or didn’t have is any prospective randomized data against that standard of care. So we took 77 patients recruited across 13 sites geographically spread across the UK. A very simple design and we just treated them in a two-to-one ratio with 727 or they were able to receive best supportive care that in almost all cases included hydroxycarbamide. We gave them six cycles of ASTX727 or control, at which point those who were responding could continue until progression. If they weren’t responding, they would come off study. There was no crossover from the best supportive care arm. We met our primary endpoint, which was great. The overall response rate was 54% for the experimental arm versus 27% for hydroxycarbamide. Not very many CRs, I think 10% versus 3.8%, which was basically one patient on the hydroxycarbamide arm, which is actually fairly modest data, but probably what you’d expect for a hypomethylating agent in these diseases. But what was really pleasantly surprising, I think, was that the secondary endpoints of survival were all met with a significant advantage in the ASTX727 arm. For example, overall survival for the full modified intention to treat population was 24.2 months for ASTX727, but only 17 months in the hydroxycarbamide arm. And the hazard ratio was 0.45, which did reach significance. And we saw the same and sometimes better figures for progression-free survival, transformation-free survival, and again, slightly better results when we just looked at the majority of patients with CMML who took part in the study. So, you know, I think the question is why have we seen an advantage when other studies with hypomethylating agents, for example, the Phase III Dacota trial of IV decitabine, why have we seen significance? And, you know, I think one of the answers to that is to do with the fairly permissive dose reductions and dose delays and the better tolerability of the drug. This is an oral agent. IV decitabine is quite hard going for these quite elderly comorbid patients. And I think that’s reflected in the fact that the median number of treatment cycles received by our patients was 10 versus around five in Dacota. And we were quite liberal about dose reductions from the initial five day to four to three and often down even to two days per cycle, almost a sort of maintenance type approach. And as such, we’ve got responders still going on cycle 35 and beyond. And so I think that’s probably part of it. And the tolerability profile was, as you might expect, this drug has been used widely in the US and elsewhere. And, you know, we saw 24% of patients with 727 suffered febrile neutropenia, typical but very manageable hematological toxicity. So we’re really quite excited by this, it’s a small advance perhaps but it’s the first randomized survival advantage for any drug in any MDS-MPN overlap syndrome for almost 30 years, the first one since hydroxycarbamide itself. And so, you know, we believe that this should be a new standard of care for advanced proliferative MDS-MPN overlaps beyond just CMML who need treatment.

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