VIDEO: Treatments in the pipeline for myelodysplastic syndrome

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So, you know, I'm definitely most excited still about, again changing the frontline paradigm for patients, again, novel combinations with azacitidine. I think, you know, the big trial that we are awaiting readout now is the VERONA trial, which is this azacitidine venetoclax trial. And you know, maybe could we have data end of this year or 2024? Because this has changed the paradigm in elderly acute myeloid leukemia and actually a lot of patients with AML. And so if this is positive, I think we have a new backbone. And again, thinking about triplet combinations is something that I'll be, you know, very excited about in the near future. A lot of research that I've been focused on is also looking at the impact of having a TP53 mutation. It's a molecular subgroup with really the poorest of outcome and we really argue no standard of care and even if venetoclax, you know, does have an approval, it's really a group that we really need to think about, even from frontline, what is the best combination therapy? And really going forward this group really needs to always be by itself. So I think we really need to have p53 mutant and p53 Wild-Type trials. We do know in this subgroup of patients that MDS and AML is a huge overlap. Actually we argue for patients with really more than 5% blast, that it's really a homogeneous entity. And so there is again, still with hope for, you know, magrolimab, the anti-CD47 therapy. There is the ENHANCE-2 trial, which is in acute myeloid leukemia patients. This is azacitidine venetoclax versus azacitidine magrolimab. But I think a positive would actually change the MDS space in parallel.

I think outside of that, you know, I'm excited about, in lower risk MDS, thinking about targeting the really underlying biology or what is known as sort of inflammasome activation, which is this inflammatory cell death that is quite central to the pathogenesis of myelodysplastic syndrome.There have been some initial drugs like canakinumab, MD Anderson, our center, have had a study for. There are going to be what are called NLRP3 inhibitors and further development of the IRAK-1/4 inhibitors that I think are kind of exciting in this space. And I think we'll get into, you know, the probably greatest unmet need is, once we do fail HMA-based therapy, particularly for higher risk myelodysplastic syndrome patients, there's really nothing. I think the one exception and something that I am excited about are, you know, IDH1/2 mutations definitely can occur. They're very rare in MDS, probably 5% in total for both of those molecular subgroups. We are hopeful, based on an ongoing US study with ivosidenib (Tibsovo, Agios), that this will ultimately get an approval for essentially HMA failure MDS patients. I think at the same time though, you know, we and others have presented and published some data showing that if you use these drugs earlier you may even get better responses and maybe really prevent these diseases from ever becoming higher risk or AML. Something that I consider, in the off-label setting, not infrequently.

And there's actually two trials, one being coordinated by WashU with Dr. Kelly Bolton and one at Sloan Kettering with Dr. Eyton Stein, where they're looking at using IDH1/2 inhibitors respectively in the pre-MDS state or what we call CCUS or clonal cytopenia of undetermined significance. They're pretty landmark trials targeting CCUS that I'm excited about. But outside of that, you know, the barn is open. We really need exciting therapies in this space. I'm hopeful for sort of immune therapies, bispecific, CAR-T, other cellular therapies. I think these trials have been more AML biased. But MDS patient population actually may represent a really good subgroup, but we're very very in our infancy in that setting.