Promising New Combo Treatment Shows High Remission Rates in AML Patients with NPM1 and KMT2A Mutations | Harry Erba, MD | #EHA2025

Hello, I'm Harry Erba.

I'm professor of medicine and director of the leukemia program at Duke University in Durham, North Carolina.

And I'm here today in Milan, Italy, for the EHA, European Hematologic Association.

Meeting, where I will be presenting data, for, KOMET-007 study of ziftomenib in combination with intensive chemotherapy for newly diagnosed patients with MPN1 mutated or KMT to a rearranged AML.

Wow, that's a mouthful.

What does this all mean?

Well, let's break it down.

We know that all cancers are due to acquired mutations in the normal cells of our body that cause them to go awry, grow out of control, stop developing normally into the cells.

They should be, They don't stay where they're supposed to be.

They move out of those tissues.

And this is all due to acquired genetic changes that happen.

And these are mistakes of nature.

Okay.

Maybe not associated with anything that you've done in your lifetime.

And ones we're talking about are not inherited.

So although there are heritable, genetic changes that lead to leukemia, the majority of patients do not have those heritable genetic changes.

And the two that I'm going to tell you about, NPM1 and KMT2A rearrangements are not inherited.

They occur in the bone marrow cells and lead to leukemia.

And these lead to leukemia because they interact with a protein in the bone marrow cells called menin, and cause the cells to turn off all of the genes that are important for those primitive bone marrow cells to develop normally into red cells, white cells, and platelets.

That's what these mutations do.

NPM1 mutation KMT2A fusion proteins from the rearrangements.

They will bind to menin and block normal differentiation at the same time upregulate increase the production of genes that cause proliferation and overgrowth of those cells and keep them from dying.

Okay. And that's what leukemia is.

And so if you think about it, maybe we can improve outcomes of people with leukemia.

If we develop drugs that don't allow these genetic changes to do their damage, by blocking that interaction between Menin and the mutated NPM1 which is present in 30% of AML patients or the mutated KMT2A rearranged proteins, which is present in 5 to 10% of patients with AML, and even more patients with acute lymphoblastic leukemia.

So why is this important?

Because we're making some headway with chemotherapy.

But a lot of patients still don't respond.

Many will relapse and we need to do better.

And so this is an attempt to do better by being smarter about how we deliver treatment.

And we already know that a whole group of drugs that are in development called menin inhibitors can, as single agents, single drugs, get a person into remission.

Unfortunately, it's the minority of patients get into remission.

And those remissions typically don't last long.

So we're trying to do better by combining things that we know work in those two diseases.

We know chemotherapy works.

We know these menin inhibitors work.

And this is not pie in the sky.

It's something that happened late in the future or in the far future.

We already have a drug on the market revumenib that is approved by the FDA for the KMT2A rearrangements in patients with acute leukemias that have already had the disease come back after standard treatment.

So these drugs show great promise.

And when I'm excited about is being here at this Congress to talk about, what we have seen by combining this pill ziftomenib with the standard chemotherapy we've been using for the past 50 years.

And what I'm going to present is that the response rates that we have seen are 90% of the patients.

Almost all of the patients responded.

Many of these patients could then continue and receive ziftomenib as a maintenance therapy if they didn't undergo allogeneic transplant.

And importantly, we did this without seeing a change in the toxicity profile to chemotherapy.

There was nothing new that we saw.

And everything that was there is manageable by doctors who know how to take care of patients undergoing chemotherapy for leukemia with curative intent.

So we're excited about this.

And we believe that the data I'm about to present later this afternoon, is a good basis for the study that we will be starting by the end of this year, where we compare that triplet of the two chemo drugs, cytarabine and daunorubicin, and with ziftomenib to cytarabine and daunorubicin, and without ziftomenib with a placebo.

Because what we hope to show there is that we're going to not only increase the number of remissions, but improve the number of patients surviving this disease and potentially surviving the disease without a need for an allergenic transplant to help them survive the disease.

So this is a very early times, but very exciting, at this Congress, and many, current meetings, menin inhibitors are the forefront of what we're talking about as the next class of drugs that may, change the outcomes, that we are seeing for our patients with acute leukemia, both AML and ALL. Thank you.