IDH Inhibitors and MDS

Harry Paul Erba, MD, PhD: Let me come back to Mark’s point about picking ivosidenib for the previously untreated patient, maybe an older patient who couldn’t tolerate a myelosuppression. How about the patients who’ve had MDS [myelodysplastic syndrome] and been on a hypomethylating agent [HMA]? Is that another niche for the IDH inhibitors?

Mark J. Levis, MD, PhD: So, I can’t comment from trial data. There are trial data looking at, for example, IDH inhibitors, as you know, in MDS. You all have used it; I know you have, I have. And, actually, it works. It’s highly effective. It’s the same disease. Who cares if it’s 9% blasts; it’s going to be the same disease. In fact, my impression is it works a little better than if it’s AML [acute myeloid leukemia]. If you’ve got an IDH-mutant high-grade MDS, I love an IDH inhibitor in that setting, to be honest.

Harry Paul Erba, MD, PhD: But that’s basically what I’m asking, though. This is an MDS patient progressed to AML, and now you find an IDH mutation. Do you add VEN [venetoclax] to an HMA? Do you add an IDH inhibitor to an HMA?

Mark J. Levis, MD, PhD: No, I would probably go with the IDH inhibitor at that point. That’s been my practice.

Harry Paul Erba, MD, PhD: Panel: Anyone dissent?

Daniel Pollyea, MD, MS: I mean, there are some data that Amer presented at ASH [American Society of Hematology], Amer Zeidan, MBBS, Yale School of Medicine, showing the utility of addition of venetoclax to a hypomethylator failure MDS situation. And they were pretty promising data. It’s still early, but I think it’s a bit of a dealer’s choice at that point.

Mark J. Levis, MD, PhD: Yeah. AZA failed, so then add VEN. IDH failed; add AZA/VEN, it worked great. AZA/VEN failed; add IDH. I mean, we have choices.

Daniel Pollyea, MD, MS: Yeah, options.

Harry Paul Erba, MD, PhD: But I want to be very clear about Amer Zeidan’s presentation about adding venetoclax to HMAs, and HMA failure patients who still have MDS. You know what was most impressive to me about those responses that he saw was that these were mostly more marrow CRs [complete responses] with an AML we would call a morphologic leukemia-free-state. In his ECOG presentation, he tried very hard to say that there is some hematologic improvement, which he showed. But I would say that the real benefit there is if you have, these are high-risk patients, right? MDS progressing to AML. Their only long-term outcome is going to be good with, if they undergo allogeneic transplant. So it may be a way of cytoreducing the marrow and making your transplanter happy that the blasts are gone even if the disease isn’t.

Mark J. Levis, MD, PhD: Yeah, I just did it with a guy who failed 3 cycles of AZA who was sent to me; we added VEN. Great; his counts normalized. He looked like he was in CR. The marrow still shows MDS. He’s going to transplant, but this is a high-risk transplant.

Gail J. Roboz, MD: That happens with some frequency, actually. I do think that we should make the point, because you were talking about MDS transformations, there are perhaps a surprising proportion of patients with antecedent MPN [myeloproliferative neoplasms] who also seem to pop an IDH mutation. And those patients have historically been particularly difficult to manage and get into remission. So that’s another scenario where if you have an antecedent MPN, it may be worth it to wait an extra minute and get back your mutation studies.

Mark J. Levis, MD, PhD: Yeah, the responses to the IDH mutant inhibitors in those patients are extraordinary.

Gail J. Roboz, MD: They’re really good. So, yes, that’s a group where other therapies are particularly not good, so there’s no need to rush to launch something ineffective for those patients.

Transcript Edited for Clarity