Menin Inhibitors: A New Treatment Option for Some Leukemia Patients

The excitement around menin inhibitors, a new class of targeted therapy for leukemia, is building. And for good reason: these new oral medications are showing promising results for patients with specific genetic changes in their leukemia cells.

"Menin inhibitors are a very exciting new type of therapy," explains Dr. Amer Zeidan, Professor of Medicine and Chief of Hematologic Malignancies at Yale University. "They are pills that target specific alterations that occur in around 40% of patients with acute leukemia."

A Treatment Twenty Years in the Making

The story of menin inhibitors began almost two decades ago, initially driven by pediatric oncologists seeking better treatments for infants with a particularly challenging type of acute lymphoblastic leukemia (ALL). Through years of careful research, scientists discovered that blocking the interaction between two proteins - menin and KMT2A - could force leukemia cells to mature into normal cells. This fundamental discovery has now led to a new class of treatments that could help both children and adults with certain types of leukemia.

What Are Menin Inhibitors and Who Could Benefit?

Menin inhibitors are targeted therapies - meaning they're designed to attack specific features of leukemia cells while largely sparing healthy cells. Your doctor might consider a menin inhibitor if your leukemia has specific genetic features:

• NPM1 mutations: These are more common in younger patients and in those whose leukemia cells look normal under the microscope (what doctors call "normal karyotype"). About 30% of AML patients have this mutation.
• KMT2A rearrangements: These occur in 5-10% of patients with acute leukemia. Your doctor might particularly suspect this if you've had previous chemotherapy for another cancer, especially breast cancer or lymphoma. These changes often occur in young children with ALL and in a type of AML where the leukemia cells look like monocytes (a type of white blood cell).

"Between these two alterations, around 40% of patients will have one of those changes. This targeted therapy follows the path of other targeted therapies we have used in AML, such as IDH inhibitors and FLT3 inhibitors," notes Dr. Zeidan.

The Current Landscape: Multiple Menin Inhibitors in Development

Early clinical trials with different menin inhibitors are showing some consistent patterns:

• About 60% of patients show some response to treatment
• Around 25% or more achieve a complete remission
• For those who respond, the benefits typically last about 6.5 months
• Many patients who respond can proceed to stem cell transplant, which might provide longer-term control of their leukemia
• The primary difference between menin inhibitors may be largely related to their safety profile

Several menin inhibitors are being studied:

Revumenib:

The first FDA-approved menin inhibitor (We'll have a detailed article about revumenib coming soon!)

Ziftomenib:

• Combined with standard chemotherapy (7+3) in newly diagnosed AML patients
• Impressive early results:
  • Overall, 91% of patients responded to this treatment.
  • The majority of patients (>80% in all subgroups) showed a complete remission of leukemia cells, including both NPM1-mutated patients and those with KMT2A rearrangements
  • 76% of patients achieved MRD negativity (no detectable disease using sensitive testing)

Based on the encouraging early results, there are now multiple trials underway investigating ziftomenib for both newly diagnosed and relapsed patients with acute leukemia. Additionally, an expanded access program has been established for patients with acute leukemia who have exhausted all other treatment options.

Bleximenib:

• The latest results are from a study with 146 patients with relapsed/refractory acute leukemia, mostly AML
  • Nearly 50% overall response rate, 38% of patients achieved complete remission, and 14% of patients were able to proceed to transplant so far, although the study is still ongoing
• When administered in combination with intensive chemotherapy to treat patients with newly diagnosed AML:
  • Almost all patients quickly showed some level of response, and 86% achieved a complete remission

Bleximenib is also moving forward in clinical development and is currently being studied in multiple clinical trials. The investigators shared that they are very excited to see these response rates, but that they are still on the learning curve with these agents and hypervigilant to make sure they are administered safely to patients who can benefit the most.

Enzomenib:

• Enzomenib was designed to improve its specificity to hit its target, potentially reducing the side effects
• It has shown activity both when administered alone and when combined with other medications
• Response rates:
  • 65.2% in KMT2A-rearranged leukemia
  • 58.8% in NPM1-mutated leukemia
• Some patients (34% with KMT2A and 12% with NPM1) were able to proceed to allogeneic transplant
• Notably, researchers did not have to alter the dose of enzomenib when prescribing an antifungal medication (also called an azole), which are frequently used to prevent infections in patients with leukemia.

Enzomenib is being studied in an international phase 1/2 study, which is still recruiting participants as of April 2025

What to Know About Menin Inhibitors Side Effects

While each menin inhibitor has its own safety profile, your healthcare team will help you monitor for and manage potential side effects. Here's what you need to know:

Differentiation Syndrome (DS):

• Occurs in 10-15% of patients, and it is due to the rapid death of a large number of leukemia cells
• Signs include: fever, breathing difficulties, fluid retention or swelling, rashes, low blood pressure, or even kidney failure

When treated early, it is manageable with temporary treatment interruption and steroids, so it is key that patients report any symptoms as soon as possible so the care team can treat them early.

Blood Count Changes:

• Changes are common, especially when menin inhibitors are given in combination with chemotherapy
• Patients take regular blood tests to monitor the cell counts
• Significant changes in cell counts may lead to adjustments in the medication doses.

General Side Effects:

• Nausea and vomiting (particularly with some agents)
• Generally manageable with supportive care
• Patients need to take their temperature twice daily

Managing Expectations

While the early results with menin inhibitors are encouraging, leading experts emphasize the importance of careful research. Experts are eagerly waiting for results from larger and randomized trials, which compare new treatments directly with current standards. These are essential to understand truly:

• How long do responses last
• Whether patients live longer with this treatment
• Long-term side effects
• Who benefits most from these treatments

As Dr. Laura Michaelis from the Medical College of Wisconsin notes, "All the data we have so far comes from non-comparative studies [there is no control arm]. We need to wait for randomized trials to really know the impact of these new treatments."

Find Open Clinical Trials with Menin Inhibitors

"When you have a good drug that is active, you try to combine it in earlier lines of treatment with other standard of care treatments," explains Dr. Zeidan.

This is exactly what's happening with menin inhibitors:

• Studies combining them with standard chemotherapy
• Trials with venetoclax and azacitidine combinations
• Thoroughly being studied for newly diagnosed patients, relapsed/refractory, and also as maintenance after transplant

With HealthTree's Clinical Trial Finder, you can review all the clinical trials with menin inhibitors that are currently looking for patients with leukemia. If you connect your medical records, our Patient Navigators will also be able to assist you in understanding your eligibility to participate in these studies. Create a free Cure Hub account below and start exploring all your options:

Find Open Studies with Menin Inhibitors

Watch our full interview below with Dr. Zeidan, who discusses the latest menin inhibitor research.

What This Means for Patients

If you have AML or ALL, your doctor might test your leukemia cells for NPM1 mutations or KMT2A rearrangements. This testing helps determine if a menin inhibitor might be right for you now or in the future.

Remember: This is an exciting time in leukemia treatment, with new options becoming available for specific genetic changes. Talk to your healthcare team about whether genetic testing and menin inhibitors might be right for your situation.

Continue learning about menin inhibitors from the experts. Click here to listen to Dr. Joshua Zeidner's experience with these revolutionary new treatments.

Continue Reading Leukemia News

Sources: 

• Drawing First Blood: Will Menin Inhibitors Revolutionize the Treatment of AML?
• Ziftomenib Combined with Intensive Induction (7+3) in Newly Diagnosed NPM1-m or KMT2A-r Acute Myeloid Leukemia: Interim Phase 1a Results from KOMET-007
• Phase 1 Results: First-in-Human Phase 1/2 Study of the Menin-MLL Inhibitor Enzomenib (DSP-5336) in Patients with Relapsed or Refractory Acute Leukemia
• Bleximenib Dose Optimization and Determination of RP2D from a Phase 1 Study in Relapsed/Refractory Acute Leukemia Patients with KMT2A and NPM1 Alterations
• Phase 1b Study of Menin-KMT2A Inhibitor Bleximenib in Combination with Intensive Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia with KMT2Ar or NPM1 Alterations