Potential of Menin Inhibitors Is Focus of AML Session

Eytan M. Stein, MD

Menin inhibitors are showing improvements in overall response by patients with relapsed/refractory AML, said Eytan M. Stein, MD, who discussed his recent research in this area ahead of the upcoming 10th Annual Meeting of the Society of Hematologic Oncology (SOHO 2022). Stein was lead author on AUGMENT-101 (NCT04065399), a first-in-human, phase 1/2 study in patients with relapsed/refractory acute leukemia.¹

Stein is a hematologic oncologist and director of the Program for Drug Development in Leukemia, Division of Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York.

He specializes in acute and chronic leukemias, myelodysplastic syndrome, myeloproliferative neoplasms, and the development of novel therapies for acute myeloblastic leukemia (AML). Stein is a principal investigator across many clinical trials for the treatment of AML and focuses on new therapies, such as small molecule inhibitors, to better target AML.

The SOHO Daily News: What does the current leukemia landscape look like?

Stein: The current leukemia landscape is very exciting. For many years, we had very few treatment options for patients with [AML]; during the past 7 years, a slew of drugs has been approved and many more are in clinical development, some of which are likely to be approved. The landscape was such that for about 40 years we were wandering in the desert, where we had no treatment or minimal treatment; we have, in some ways, reached the “promised land” of much treatment. A lot of that treatment came from these elegant studies conducted 10 to 15 years ago to help us understand the genetic basis of [AML] and how patients can have different genetic abnormalities that can lead to their disease. Understanding the biology of those genetic abnormalities has led to targeted therapies that have improved survival for our patients.

Looking forward, what approaches are you most excited to learn or hear about within the next 1 to 3 years?

There are a number of approaches. I think we’re continuing to build on successes with small molecules that block mutated proteins and protein-protein interactions that lead to the development of AML. That’s very exciting. We now have backbone therapies that are very effective—specifically, the combination of azacitidine (Vidaza) with the BCL2 inhibitor venetoclax (Venclexta) that is a therapeutic modality that is incredibly effective for our patients, [especially] our older patients with AML. Many of the studies being done now are adding a third agent and sometimes even a fourth in backbone treatment. The idea [is] that by adding these agents that work in slightly different ways, you’re going to increase efficacy. I’m also excited because I think the combination of azacitidine and venetoclax is indicated for use in patients who are 75 years or older, or who are ineligible for intensive induction chemotherapy in newly diagnosed AML.2 But I think it’s so effective that we’re going to start using that regimen in younger patients as well. The other thing I’m excited about, which hasn’t completely panned out yet, is the idea of [cellular therapies] for patients with [AML]. There are efforts being made to develop CAR T cells for AML. That’s something that has been a bit challenging, but there are some new approaches. It may be that just like we have CAR T cells for acute lymphoblastic leukemia [ALL], for lymphoma, and for myeloma, we may in the next 1 to 3 years be on the way to having a CAR T-cell program for patients with [AML] as well.

Do any clinical challenges occupy space in your mind?

I painted a rosy picture, but you can look at the glass half empty also in that we have all these new drugs, and all or many of them are leading to improvements in overall survival, but [most] patients will still end up relapsing and dying. There’s an opportunity to think about getting these patients cured rather than just incrementally improving overall survival. I think the patient population we struggle with most is that group of patients who fall into the unfavorable risk category by European LeukemiaNet Criteria,3 especially those patients who have a complex karyotype and/or a TP53 mutation. Those are patients that we struggle with and who really don’t do very well with our available therapies, and we need to do better with those patients.

Is there anything you want other attendees to know about you and what you’ve been doing lately for the upcoming meeting?

I spend a lot of time working on the inhibition of isocitrate dehydrogenase, which is mutated in patients with AML. But recently, I’ve really been focusing my efforts on inhibiting a protein called menin. Menin is a protein that is intricately involved in the pathogenesis of a certain subtype of AML and ALL that has rearrangements involving a chromosome locus called the MLL locus. These are called MLL rearrangements. There are all these really interesting small molecule inhibitors that target this menin protein, and the early clinical results show really fantastic outcomes. The data that we presented for one of these compounds, from a company called Syndax, led to an overall response rate of 55% in patients with relapsed and refractory AML and ALL.1 [Those are] the kind of data we don’t see very frequently. I’m all-in on menin inhibitors, and I’m looking forward to continuing [helping] with their development.

What are you most looking forward to during the meeting?

I miss in-person meetings; the problem with virtual meetings is you don’t get that personal interaction where you’re able to run into someone in the hallway and talk about life and have the scientific interaction that you can’t really get on a scheduled virtual call. There are many international leaders in acute leukemia [who] attend and present at SOHO, and the personal interaction allows [you to speak with them] when they’re done presenting. You can just go up to them and ask a question and say, “Hey, you want to grab a cup of coffee and talk about some ideas I have? Or talk about other studies and other things we can do to improve the lives of our patients?” You can’t really do that in a virtual meeting. I’m a strong advocate [for] doing as many in-person meetings as we can.

_REFERENCES:

_{1. Stein EM, Aldoss I, DiPersio JF, et al. Safety and efficacy of menin inhibition in patients (pts) with MLL-rearranged and NPM1 mutant acute leukemia: a phase (ph) 1, first-in-human study of SNDX-5613 (AUGMENT 101). American Society of Hematology Annual Meeting & Exposition 2021. Blood. 2021;138(suppl 1):699. doi:10.1182/blood-2021-146944}

_{2. FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia. FDA. October 16, 2020. Accessed August 23, 2022. https://bit.ly/3QFWKbc}

_{3. Boddu PC, Kadia TM, Garcia-Manero G, et al. Validation of the 2017 European LeukemiaNet classification for acute myeloid leukemia with NPM1 and FLT3-internal tandem duplication genotypes. Cancer. 2019;125(7):1091-1100. doi:10.1002/cncr.31885}