ISAL 2025 | Menin inhibition in AML: clinical guidance and future directions

Charlie Craddock

Hi. It’s a great pleasure to join VJHemOnc at the ISAL meeting in Munich. I’m Charlie Craddock, I’m a leukemia physician and transplanter from Birmingham in the UK. And I’m here with wonderful colleague from the MD Anderson.

Curtis Lachowiez

I’m Curtis Lachowiez. I formerly was at MD Anderson and now I’m at Oregon Health and Science University in Portland, Oregon. And a pleasure to be here with you.

Charlie Craddock

Great. So I thought we might just start off talking Curtis today, because you’ve got a lot of extensive experience in this space about the really exciting development with menin inhibitors, particularly in the setting of relapsed AML.

Curtis Lachowiez

Sure. I mean, I think everyone in the field is excited about menin inhibitors right now being a new first in class agent, with the recent approval in the States of revumenib, which was FDA approved in December of last year for KMT2A-rearranged AML. And I think just to set the framework, we know that both KMT2A-rearranged AML as well as NPM1-mutated AML is dependent on the menin HOX9a/MEIS1 axis, and interruption of this with a menin inhibitor appears to be a viable therapeutic strategy, working mainly as a differentiating agent where we’ve seen a lot of other successes with molecularly targeted therapies in AML. And particularly it’s effective in, as I mentioned, these molecular subgroups difficult to treat AML, KMT2A-rearranged AML, as well as relapsed and refractory NPM1-mutated AML, where we’re experiencing response rates dependent upon the menin inhibitor of 30 to 40% and duration of response, that’s around 4 to 6 months.

Charlie Craddock

So these are the recently published data that have supported registration and approval by the FDA. Perhaps you could talk about, in your experience, not only the clinical activity, but also potential toxicities and what you look for in terms of preventing toxicities.

Curtis Lachowiez

Sure. Yeah. I mean, so I think the clinical activity seems to be fairly on par with what was seen in the initial AUGMENT-101 study, which was both a pediatric as well as adult population, that ultimately led to approval currently only for KMT2A-rearranged AML, but we anticipate and are looking forward to hopefully also having an approval by the FDA for relapsed/refractory NPM1-mutated AML. In terms of efficacy, like I mentioned before, overall response rates CR CRi rates of around 30 to 40% with the duration of response of around 4 to 6 months, which is important when we think about using these agents potentially as a therapeutic bridge to transplant, curative allogeneic stem cell transplant, and then even as maintenance therapy post-transplant.

As far as toxicities that I think we need to be aware of, there certainly is a slight degree of myelosuppression that I think was unanticipated with the menin inhibitors, given that they are differentiating agents and we don’t see as much myelosuppression with other molecularly targeted differentiating agents, but certainly differentiation syndrome, which is a class effect of a lot of these differentiating agents used for AML. As these leukemic blasts mature, then we see fevers, hypoxia, pulmonary infiltrates, swelling, rashes, weight gain. And so I think the clinician has to be very privy to these signs and symptoms of differentiation syndrome because it can be effectively treated with prompt initiation of corticosteroids.

Charlie Craddock

And so just on the floor, what would you be recommending your fellow would be looking out for in the first 2 or 3 days when you start somebody on a menin inhibitor?

Curtis Lachowiez

Yeah. So I mean, I think you bring up a great point there that usually differentiation syndrome can occur early on in the beginning of therapy as these leukemic blasts mature. But actually the time frame can range anywhere from the first to the third cycle of therapy. So within the first three months of starting someone on this medication, you have to be aware for those symptoms that I mentioned shortness of breath, new onset fevers, rash, peripheral blood leukocytosis that sometimes can be a harbinger of impending differentiation syndrome, acute kidney injury, things of that nature. And if those are suspected, then prompt initiation of high-dose dexamethasone can really rapidly change the course of that and most patients are able to remain on therapy with appropriate treatment.

Charlie Craddock

So really mandates regular daily clinical review. Looking at obs, looking at daily weight and looking at bloods.

Curtis Lachowiez

Yeah, I think so. Yeah I mean I think a prudent clinician would manage it like that.

Charlie Craddock

Certainly doing simple things well. So let me just move on to the last bit, perhaps Curtis, is this is such an exciting new development in relapsed AML. And you talked about two molecular subgroups. But how do you think these agents might be developed in the future? What clinical context?

Curtis Lachowiez

So this is an extremely saturated space in terms of clinical trial development right now. So revumenib was the first in class menin inhibitor that I mentioned. But there’s already three other named menin inhibitors that have joined this space where we’re starting to see a lot of trial development in the relapsed and refractory spaces in combination. So Ghayas Issa from MD Anderson presented some fairly thought-provoking data using the all-oral regimen of revumenib with oral decitabine, cedazuridine combined with venetoclax as a triplet regimen. And in that small, you know, and it’s very preliminary data. But in the initial I believe it was nine patients presented, the overall response rate was 100% compared to the single agent monotherapy response rates of around 30 to 40%. And so it does seem that combination therapy is really the future of these, both in the relapsed refractory setting as well as the frontline setting, both in unfit patients who may utilize, like an HMA venetoclax-based backbone, as well as fit patients with a 7+3-based backbone.

Charlie Craddock

And so from a UK perspective, I mean, we’re excited about opening the relapse trials that are providing more data for registration for the other agents, but we’re participating in the EVOLVE studies where there’s going to be looking at unfit patients with NPM1 and KMT2A mutations, where, as you say, it’s going to be examining the benefit of adding revumenib to an HMA-venetoclax backbone. There’s also the question of adding it to an intensive chemotherapy regimen, but I think also really exciting possibility of using these agents as maintenance post-transplant. This is a big unmet need, and that’s the study we’re developing in the UK AML Group at the moment.

Curtis Lachowiez

Yeah, I think I’d eagerly await that data. And then also, even in the favorable risk NPM1-mutated patients in the frontline setting, we still know today we heard talks that approximately 25 to 30% of those patients that are MRD negative by highly sensitive NPM1 qPCR based assays still relapse. And so maybe there’s even an evolving role for maintenance therapy in that setting also.

Charlie Craddock

It’d be a hell of a big study though. Yeah. Okay. Thanks, Curtis. That was great.

Curtis Lachowiez

Thank you.