Future Directions in MDS

Mikkael A. Sekeres, MD: Are there newer types of therapies that you’re excited about in particular for higher-risk MDS [myelodysplastic syndromes]?

Yazan Madanat, MD: Yes, there are a few in later stages of development that I hope to see on the market if the outcomes prove them to be effective. The combination of azacitidine with venetoclax is now in an ongoing phase 3 trial with promising phase 1b data that were presented at the last few meetings. Magrolimab with azacitidine vs azacitidine-placebo is also in a randomized phase 3 trial. The phase 3 trial for pevonedistat has completed accrual, and we’re waiting for the survival outcomes.

There are many drugs in later stages of development or that we’re waiting for results on. A TIM3 inhibitor, sabatolimab, is also in phase 3 trial development. There are many newer drugs. You led some of those studies. Do you want to tell us about what excites you the most of these compounds and how you think everything will pan out? Because they definitely have different toxicities, tolerability, efficacy outcomes, and end points.

Mikkael A. Sekeres, MD: We’re all eagerly awaiting the results of these trials. A lot of big studies are going to hit home in the next year and a half. As you mentioned, 1 of them is the azacitidine and pevonedistat study. That’s a trial that I led. What I was encouraged about is that, particularly in the higher-risk MDS group, there was a significant improvement in event-free survival for those who got the combination vs those who got azacitidine alone. One of the secrets to this study doing well, at least in a lower-phase randomized setting, is that the pevonedistat was tolerable.

We wrote the protocol. We learned from the North American Intergroup trial. I led the North American Intergroup trial and would receive emails from folks around the country who were participating in it, who said they had already lowered the dose of a combination of drugs because of an adverse effect in the patient and were asking if they should lower it again for another adverse effect. I would say, “The protocol didn’t say that. You weren’t supposed to lower it based on that.” But the damage had already been done. We studied that and found that it was significantly more likely that a combination arm would be lowered by ways that didn’t follow the specifications in the protocol. We were much more rigid in how we wrote the azacitidine and pevonedistat protocol with much more direction to consult with a medical monitor before adjusting any doses. That may have helped with some of the improvements we saw, at least in the earlier-phase trial.

As you mentioned, there’s a combination of azacitidine and venetoclax that Jacqueline Garcia presented at ASH [American Society of Hematology Annual Meeting] that had encouraging overall response rates for the combination. But I always keep in mind that the phase 2 setting combinations always seem to do very well. In our phase 2 azacitidine and lenalidomide study, we reported an overall response rate of 72%. That’s similar to what we’re seeing for the combination of azacitidine and venetoclax in the phase 1b trial. Let’s see what happens in the randomized setting.

The same is true of azacitidine and magrolimab, where the overall response rate was reported as very high. Of course, you have to subtract the marrow CRs [complete remission] from that because, as you know, I’m not a believer in marrow CRs, as you elegantly described earlier. But when you subtract those out, you still have an overall response rate of around 70%. It’s still good, but it’s similar to what we saw in the phase 2 azacitidine and lenalidomide study. I’m excited about all these. Eventually, the secret to this will be some combination of therapies to treat higher-risk MDS. I’m just waiting to see which of these is going to be the first to hit home.

Yazan, our time is up. It’s been an absolute delight getting to spend this time with you. Thanks so much for joining me and talking about the management of myelodysplastic syndromes in high-risk patients.

Yazan Madanat, MD: It was a pleasure connecting with you and seeing you again, Mikkael. This was a great discussion. I always learn from you. I hope our audience found this helpful and enjoyed the discussion.

Transcript Edited for Clarity