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Menin Inhibitors in AML
Rethinking AML Therapy: Menin Inhibitors as a New Paradigm in Precision Hematology

Released: October 08, 2025

Eytan M. Stein
Eytan M. Stein, MD
Eunice S. Wang
Eunice S. Wang, MD
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Key Takeaways
  • Routine molecular and cytogenetic testing is essential at diagnosis and relapse to identify candidates for menin inhibitor therapy.
  • Menin inhibitors such as revumenib and ziftomenib induce differentiation and subsequent cell death of leukemia cells resulting in clinical remissions in genetically defined AML subsets (mNPM1, KMT2Ar).
  • Combination regimens of menin inhibitors with venetoclax/azacitidine or intensive chemotherapy demonstrate high response rates and tolerability.
  • Vigilant surveillance and management of differentiation syndrome is essential for patients to achieve maximal clinical benefit on menin inhibitors.

Acute myeloid leukemia (AML) remains one of the most challenging hematologic malignancies to manage, with high relapse rates and limited treatment options for genetically defined subgroups like KMT2A-rearranged (KMT2Ar) and NPM1-mutant (mNPM1) AML. Over the past decade, clinical advances have illuminated the central role of transcriptional dysregulation in driving leukemogenesis. This discovery sparked the development of menin inhibitors, a new class of targeted therapies designed to disrupt oncogenic transcriptional programs and restore normal myeloid differentiation. Clinical successes with these agents have transformed the treatment landscape. In this expert commentary, Eytan Stein, MD, and Eunice Wang, MD, review the scientific rationale, clinical advances, challenges, and future directions shaping this paradigm-shifting class of drugs.

Understanding the Science: Why Menin?

Eytan Stein, MD:
Menin is a transcription adaptor protein that plays a pivotal role in transcriptional regulation. It binds with KMT2A (formerly MLL1) and subsequently drives the aberrant expression of HOX genes, a hallmark of both KMT2Ar and mNPM1 AML. These leukemias are critically dependent on the menin-KMT2A axis. This mechanism of action drives the effective treatment of 2 genetically distinct yet mechanistically linked forms of AML. KMT2Ar is often associated with therapy-related AML or infant leukemias, and NPM1 is the most commonly mutated gene in de novo AML, representing up to 30% of cases. By disrupting the interaction of menin and KMT2A, menin inhibitors shut down oncogenic transcriptional activity and induce differentiation of leukemic blasts into functional myeloid cells.

These subsets share a reliance on menin-driven gene expression, making them ideal candidates for this targeted approach.

Clinical Advances: Revumenib and Ziftomenib

Eunice Wang, MD:
Revumenib (approved in 2024) was the first menin inhibitor to gain FDA approval for the treatment of relapsed/refractory (R/R) acute leukemia with a KMT2A translocation in adult and pediatric patients aged 1 year and older. In the phase I/II AUGMENT-101 trial, revumenib demonstrated a 23.4% complete response (CR)/complete response with partial hematologic recovery (CRh) rate with an impressive 64% measurable residual disease (MRD) negativity among responding adult patients with R/R KMT2Ar AML. Although QTc prolongation and differentiation syndrome (DS) remain notable potential adverse events, these events are largely manageable with appropriate monitoring and early initiation of steroid use, respectively.

Ziftomenib is currently under FDA review for R/R mNPM1 AML. Ziftomenib has demonstrated a 25% CR/CRh rate in adult patients with R/R mNPM1 AML. These responses appear to be durable, with a median overall survival of 16.4 months. Of importance, ziftomenib shows a favorable safety profile, with limited QTc prolongation and manageable DS (13% grade 3 events, no grade 4 or 5), positioning it as an attractive monotherapy option.

Beyond Monotherapy: The Power of Combinations

Eunice Wang, MD:
Although single-agent data are compelling, the future of AML treatment lies in combination regimens. Phase I/II studies such as BEAT AML and SAVE have evaluated revumenib or ziftomenib in combination with azacitidine and venetoclax. These studies reported objective response rates exceeding 88.4% and 82%, respectively. The CR rate in the BEAT AML trial was 67.4%, and the CR/CRh rate in the SAVE trial was 48%.

Combination strategies also extend to intensive chemotherapy. The phase I KOMET-007 study, in which ziftomenib was added to intensive (7+3) chemotherapy in newly diagnosed KMT2Ar and mNPM1 AML patients, showed a complete hematologic recovery (CRc) rate of 92% and measurable residual disease negativity in 76% of responders. These regimens were well tolerated, without significant additional toxicities including manageable differentiation syndrome and no QTC prolongation. This opens the door for broader adoption of menin inhibitors in frontline therapy. 

Navigating Challenges: DS, Testing, and Resistance

Eytan Stein, MD:
The implementation of molecular testing is challenging but critical for the proper use of menin inhibitors. Although we are accustomed to screening for FLT3 and IDH mutations, routine fluorescence in situ hybridization (FISH) or molecular testing for KMT2A rearrangements and rapid polymerase chain reaction for mNPM1 must become standard at AML diagnosis and certainly at relapse. This is especially important in therapy-related AMLs and patients who have previously received solid-tumor chemotherapy.

DS is the most concerning toxicity across all menin inhibitors. It typically presents early in treatment and can escalate rapidly. Healthcare professionals should maintain a high level of suspicion for DS, and early steroid intervention (often dexamethasone 10 mg twice daily) is the standard of care. Owing to how critical DS surveillance is, prophylactic steroids are being considered in high-risk cases.

Finally, resistance mutations are emerging. At Memorial Sloan Kettering Cancer Center, we have observed MEN1 mutations that disrupt drug binding, particularly in patients treated with revumenib. Each menin inhibitor binds differently, suggesting that cross-resistance may not be absolute and could be exploited to develop second-line sequencing strategies.

The Horizon: New Agents and Future Trials

Eunice Wang, MD:
Other menin inhibitors such as bleximenib and enzomenib are quickly advancing through clinical trials. Bleximenib has shown a high overall CRc rate of 75% in R/R mNPM1 and promising tolerability, when combined with venetoclax and azacitidine. Enzomenib is a chemically distinct agent that may cause less DS, with early results suggesting CRc rates after monotherapy use in patients with R/R KMT2Ar and mNPM1 AML of 30.4% and 47.1%, respectively.

Randomized phase III trials evaluating menin inhibitors plus standard-of-care therapies (7+3 or ven/aza) vs standard of care alone are currently underway, and the results will be crucial in determining whether these agents will become integral parts of first-line AML therapy for these genetically defined subsets of patients.

Summary: From Relapse to First Line and Beyond

Eytan Stein, MD:
Menin inhibitors have rapidly transformed from an experimental class into a new standard of care for specific AML subsets. Their role in inducing deep molecular remissions in high-risk populations, particularly R/R mNPM1 and KMT2Ar AML, is apparent. As we integrate them into frontline regimens and test combinations with other targeted agents, they may redefine the way we treat AML altogether.

Your Thoughts
Are you currently testing for KMT2Ar and mNPM1 at diagnosis? What barriers exist in your institution to integrating menin inhibitors into frontline therapy? Could DS management protocols be standardized? Post a comment to join the discussion.

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