ASH 2023 | Front-line treatment options for HR-MDS: can we move past azacitidine?

Yeah, sure. So, it was exciting to share the education session for MDS. We first hear about prognostic and molecular classifications that have changed. We then get to hear about lower-risk therapies. And then, really, the focus of my session is high-risk MDS. And we’ve been stuck with azacitidine for, you know, over 15 years now. Can we move past? And unfortunately, it’s still an open question. So, I think really what I go into is I think we have to personalize the treatment of our patients more. Treating an all-comer, high-risk MDS patient population going forward is probably not the most optimal strategy, and I think the one big group of patients we need to separate out is the TP53 mutant group. 

Really, with all standard-of-care therapies, this group has done significantly worse. And so I focus on ways to identify them, some prognostic differences that you can see based on variant allele frequency, allelic status, etc., and really that, although transplant is a curative option, we really need to think about how optimally to get them there. 

We’ve had a lot of struggles in front-line options, and a lot of the critiques have been trial design, heterogeneous patient populations, including patients with other disease, not looking for overall survival. And so, really, there have been three large randomized Phase III trials that have finished accrual. I’ve been fortunate to help lead the magrolimab efforts. And then I think the big setback, you know, just a couple of months ago, is that this did press release to be negative. The data have not been presented. And I think the big question is what are the changes from Phase I to Phase III. Again, do we need to make the eligibility characteristics different? Do we need to think about treatment differences across the group? So still a question on what happened there. 

I think the big excitement, potentially, is with venetoclax right now. We’re all waiting for the Phase III VERONA trial to read out. And, both in large Phase I studies and then real-world data that we’ve recently published, you know, response rates have been in 80% of patients, true complete remissions in over 30%. And we’re hoping that the trial can be positive, but it can cause a lot of toxicities, and there’s still concern in the MDS field. Will we have a positive Phase III trial? But I still think the horizon is quite bright when thinking about that group. We’re also waiting on the readout of the Phase III sabatolimab/azacitidine trial. And the only ongoing accruing trial is a Phase III trial with tamibarotene, which is for RARA overexpressing patients. 

I think going forward we need to potentially better think about synergy resistance mechanisms. I think we need to incorporate measurable residual disease into prospective trials. And again, hopefully we’ll be changing the standard of care soon, but the jury is still out on that.