FLT3 Triplet Regimens for AML

Harry Paul Erba, MD, PhD: Mark, I’m a leukemia doctor because I’ve only had to deal with giving 2 drugs at once, and that’s all I can do—7 and 3—40 years of that. And now we’re talking about triplets over the doublets. I feel like they’re trying to make me a myeloma doctor. It’s making me very anxious. Well, what’s your thought about adding in FLT3 inhibitors to HMA/VEN [hypomethylating agents/venetoclax] or HMA with a FLT3 inhibitor alone?

Mark J. Levis, MD, PhD: So we’ve been wrestling with that a fair amount. Obviously, we know that a FLT3 mutation, you don’t respond as well or you don’t respond for as long with an HMA /VEN combination. However, we’ve already just spent all this time talking about the myelosuppression with AZA [azacitidine]/VEN, and it’s real.

FLT3 is important for normal marrow to reconstitute. That multipotent progenitor cell has FLT3 on it; it wants to regenerate all those nice neutrophils and start that process. You inhibit FLT3, you are going to impair that. And when we combined gilteritinib with venetoclax, we saw some profound aplasias.

So what we do at my institution is a little bit different. We will pop the patient into remission with AZA/VEN if they have a FLT3, and then we actually sequence with AZA/GILT, and then we go back to AZA/VEN.

I don’t like using that triplet. I recognize that’s a great interest. A lot of people say, “Of course; it’s perfectly safe to do.” That hasn’t been quite our experience with the profound aplasias. So that’s been our approach; I don’t know the answer.

Harry Paul Erba, MD, PhD: Yeah, I agree with you, Mark. The triplet can be very myelosuppressive. I’ve had experiences where I gave the AZA/VEN. I clear an IDH clone only to be left with a FLT3 clone, and then give gilteritinib [GILT] and kind of had an almost bounce between the 2 regimens because it’s hard to give them at the same time.

Mark J. Levis, MD, PhD: Yeah, so we’ve been sequencing AZA, AZA/VEN, AZA/GILT.

Harry Paul Erba, MD, PhD: So, before we leave this combination, any final thoughts about HMA/VEN that you want to bring up? Any of you.

Gail J. Roboz, MD: Yeah, I would think that a cautionary tale is to not sound like we want to be advocating tons of mixing and matching. Because I think that it’s really hard to do sometimes, and I think that we are a victim a bit of our own success in having a lot of these drugs available. And I worry, actually, that it’s going to be very hard to learn what to sequence and how to change these doses and schedule if everybody kind of makes it up. And I philosophize about this a little bit because I’m not sure what the right answer is.

We’re in the middle of COVID-19 [coronavirus disease 2019]. People can’t get to centers. You want to try to do things that make sense. You have a smattering of data from here and there. So I understand that, and I do that, too. But at the same point, I think it’s going to actually be very difficult for us to answer the fundamental questions of which triplet? And is it an IDH inhibitor up front, or is it venetoclax up front? Or are you doing, are you alternating between them, or is 1 of the agents to be continued indefinitely? It’s really hard to answer this if we don’t do some studies.

Harry Paul Erba, MD, PhD: Gail, I’m going to come back to you when we get to the IDH inhibitors for that very thought about the triplet combination there. Dan, I think you wanted to ask something.

Daniel Pollyea, MD, MS: Yeah. I mean, it actually dovetails nicely with what Gail said. I mean, something you said earlier. You know: Pay attention to that plateau curve at the end, and let’s dig into who those patients are and how, what had made them be able to have this very long-term remission. And let’s learn about who those people are, and if they are people whose disease is being driven by a FLT-3 mutation, then let’s add a FLT.

If they are not the patients with a FLT3 mutation, then those are patients we should probably be leaving alone. And so understanding who those patients are and leaving them alone and giving them this very potent and reasonably well-tolerated, reliable therapy is the way to go. And then learning who the patients are who aren’t staying in these long long-term remissions and doing something like what Mark said makes a lot of sense to me. You know, sort of alternating therapies and sort of pushing on 1 clone versus another to try to prolong the remission. But like Gail said, I mean, I would really discourage us throwing everything in at the beginning because you can see, there’s 20%, maybe 30%, of patients for whom that will only represent overtreatment and excess toxicity.

Harry Paul Erba, MD, PhD: Dan, that dovetails into the question I wanted to ask you. You presented previously data from the HMA/VEN combination with clearance of leukemic stem cells. So my question for you is: Is there any data from any of the venetoclax data that a deeper remission, an MRD [minimum residual disease]-negative CR [complete response], means anything more than an MRD-positive CR? Is there any difference in survival that we know of between those two qualitatively different CRs?

Daniel Pollyea, MD, MS: Not that I’m aware of at this time, but I will say that I don’t think that the appropriate studies have necessarily been done. Or to answer that specific question: In the very near future, that’s going to be an extremely relevant question that we need to answer.

Transcript Edited for Clarity