Emerging Role of Venetoclax in the Treatment of MDS

Gail Roboz, MD: For clinical trials. We've all avoided TP53. We have all kinds of made faces. We know the patients that we're not helping correctly. They have complex karyotype, they have TP53, MDS therapies, in general, are not where we want them, so I do want to take us into the clinical trials land. I think everybody on this call will nod if you say, what's the right answer for an MDS patient, a clinical trial. Everybody here wants that, but what can we talk about of some that are kind of new, not available yet? You can't write the prescriptions yet, but that look promising. Anyone want to take? Rami, maybe I'll throw you just preliminarily. Venetoclax and HMA combinations have literally flipped the switch in AML. We are now talking about totally different outcomes. Is that happening for MDS? Are we going to be adding Venetoclax to all of this and solving our problems?

Rami Komrokji, MD: Yeah. I think obviously, as you mentioned, I'll stress that, particularly now in the landscape of the clinical trials, we've never had a time where we had like four or five randomized phase 3 clinical trials and higher risk. I know it sounds theoretical, but I would encourage everybody listening to this, whenever your patients logistically have access to a clinical trial, please send them because they are really trials that are gonna change the landscape of MDS. We totally understand that there are sometimes patients that will not go trials, logistically cannot travel to a center, but that's a key. I think in the coming time, we're going to be covering several of those. Let's pick on Venetoclax first. You asked me to do that. Obviously, the data in AML looks great. It's changed the practice. I'll have to say the natural thing in MDS is we follow immediately after AML so it's already made its way into practice actually, without the data completely supporting it. There is a phase 3 randomized clinical trial going on that hopefully would show us the benefit. It's one of the studies that the primary endpoint is overall survival, which I know Dr. Raza appreciates much more than any other endpoint. Then to be honest, I think the Venetoclax, there are caveats about it. It's not less intense therapy. It is type of intensive therapy. You may think of intensive chemotherapy, and we think hypomethylating agents. I think HMA event is more to the intensive chemotherapy. We know from the phase 1/2 studies that the dosing is different in MDS so it's two weeks, not four weeks. We know that the CRs look promising. I'm hoping that the phase 3 will be positive. I've used it outside the context of trial which I'll probably not recommend in any place in general practice unless you really have very good infrastructure to support monitoring those patients closely. Yes, we use it. I think of it is going to be maybe a good transplant preparing regimen in MDS. HMA then getting good response is like the hammer you'll head get MRD, go to transplant, have toxicity that you have to be aware of, particularly in the beginning. There are days where we repeat bone marrow after four cycles of Aza. Not there if you are doing Aza-Ven. You have to do it early, back off the dosing of the Venetoclax, a lot of things. That's what I- There are trials going on. Hopefully, they'll be positive. My thinking on it, it's going to be particularly in patients that you want to hit hard, almost like an intensive regimen. The last thing, just to mention about it, that at least from the AML data, it's not going to be a home run in the P53. Unfortunately, even in the AML, the median survival Aza or Aza-Ven was the same. I tend not to use Ven even if I'm doing out-of-the-box in patients with P53.

Gail Roboz, MD: I think that I just want to get kind of a nod from everyone, which I think I'm going to get but if I don't, I will explore that. I'm thinking that we are not recommending to the audience here that you just take every high-risk MDS patient and pop them on to a hypomethylating agent combined with Venetoclax even if you can get it. I think we all are- everybody is kind of agreeing that there are at least reservations about that. There's myelosuppression to deal with. I think the dose and schedule that are for AML are not necessarily going to be what they are for MDS. I think it's worth mentioning that the complexity of that. In the United States with all of the choices available, which I love, and I'm thrilled for but the choices can be complicated and we do have oral hypomethylating agents available. I think that there is a temptation that, oh, if I can just take this pill and this pill just to keep in mind that it might be able to be done, but it's actually not so easy. We're going to watch the myelosuppression there. I'm going to come back to oral hypo methylators in a minute for some other discussion, but just be careful dumping things together.

Transcript Edited for Clarity