IDH Mutations in AML

Harry Paul Erba, MD, PhD: I’m going to have Gail take the lead on this because we’re going to switch gears and talk about the 20% of AML [acute myeloid leukemia] patients that have mutations of IDH.

Gail J. Roboz, MD: Well, the land of IDH, you know, brought us back to all of our nightmares of organic chemistry and Krebs cycle and everybody kind of got through that year where we actually learn this again. And everybody took their medications and learned about IDH inhibitors. Revolution No 1 was the identification of course of the mutations in AML. Then, all of a sudden, wait a minute: AML, relapsed AML, isn’t necessarily completely the land of the lost. We have been suffering so enormously with poor therapies for patients with relapsed AML.

We have been pummeling them for decades with lots of different chemotherapy combinations without success. And then there are data emerging for ivosidenib and for enasidenib: ivosidenib being a potent IDH1 inhibitor, an orally available drug; ivosidenib an orally local inhibitor or mutant IDH2, showing actually quite high response rates as well as durable remissions, a single-agent, pretty well-tolerated drug in relapsed AML; not curing the patients.

We are not talking years in remission, but we are talking durable remissions in the 6-to-12-month zone, with a single agent. Toxicity profile has been a little bit glitchy for these drugs. You have to watch for differentiation syndrome, which we’ll have to talk about a little bit. You have to look at QT. But basically these are orders of magnitude different from standard chemotherapies. They have better response rates than chemo in these groups, and we thought, “OK, this is huge; let’s move them to the up-front setting.”

So there we also had some interesting data. The ivosidenib trial allowed some patients with newly diagnosed disease to be treated. And actually, there’s the CR-CRH [complete remission and CR with partial hematologic recovery] of about 40% in those patients. Some of those, if you look at the swim plots, were actually durable remissions. These are patients who might not actually have been offered anything. They were the patients that you’re talking about, Harry, who are older and may have fallen into the nihilism trap of, “Oh, you can’t get anything.” And yet here they are in a durable remission. So the data are very similar for enasidenib. So these are single agents that can be used both up front and in relapsed disease to be remitters; they induce remission.

Of course, then the question is: What about combining them with standard chemotherapy? What about combining them with azacitidine? But actually the world was moving at the same time, and what we started seeing as this tremendous success was evolving was that actually venetoclax was particularly affective in the IDH subgroups, in IDH1 and IDH2.

So, this is confusing, and I’m sure you’re going to want to initiate some discussion about this, because now you have choices: “Well, how do I pick a combination of venetoclax and azacitidine, or which ivosidenib and azacitidine, or which 1 if we have a little bit of too many choices?” And I would say the summary that we’ve seen so far out of EHA and out of ASCO [American Society of Clinical Oncology]. So we know that IVO plus azacitidine works. That is an effective regimen for up-front disease.

We think that ENA plus azacitidine might be a little bit less resoundingly good. It didn’t look like there’s a survival benefit over azacitidine alone, but there was still high response rates. So the question on everybody’s mind is: Why would you choose one of those instead of AZA and venetoclax? And I think we can deliberate that a little bit. I think there are individual patient characteristics that may lead to 1 combination versus the other.

But I think the most interesting part is that we were telling everybody, all of us on this call, on this kind of conference—although we didn’t use to use Zoom, but we were all telling people: “Wait, calm down; wait for the mutational profile. AML [acute myeloid leukemia] doesn’t have to be treated for everybody in 5 seconds; let’s apply our inhibitors.” Certainly in the relapsed setting, this is absolutely true, and the last thing we want to be doing is pummeling on chemotherapy.

But in the newly diagnosed patients, I think the question is: Do you wait? Or do you say, “Well, venetoclax kind of fixes everything, and then we’ll see who didn’t get fixed and deal with an inhibitor later.” And I think that’s kind of where we are right now for newly diagnosed patients who are older patients who are not going for intensive induction.

Mark J. Levis, MD, PhD: I might interject, though, that in the really unfit, or the really elderly patients, I kind of want to know if they have an IDH mutation, because I honestly would rather do HMA/IDH if I have the choice. So I agree with you for the most part.

Gail J. Roboz, MD: No, I think that’s exactly what I was alluding to, though, that in certain specific situations where you really don’t think that the myelosuppression is going to fly, might you wait for the IDH? Because both the single agent and the combination with venetoclax of IDH inhibitors are less myelosuppressive. And, actually, Courtney presented some data that some of those people seemed to recover counts faster, actually.

So I think those might be the right patients. The question is, though: How quickly are people getting their data back? And I think that is a major issue. Some people are getting the IDH data back quickly from PCR in 72 hours. Others are still taking 2 weeks. And I do think that, you know, 2 weeks of hanging around and waiting—one does have to be a little bit careful when you do have AZA/VEN as a potential compelling option. If the patient absolutely can’t tolerate it, then you can wait.

Transcript Edited for Clarity