Menin Inhibitors Show Strong Responses in Relapsed Acute Leukemia Across Multiple Trials
2024 ASH data reveals menin inhibitors as monotherapy and in combination achieve response rates up to 89% in relapsed acute leukemia.
Summary
At the 2024 ASH Annual Meeting, nine clinical trials of menin inhibitors—including revumenib, bleximenib, enzomenib, BN-104, and ziftomenib—reported outcomes for relapsed or refractory acute leukemia. These drugs block the KMT2A-menin protein interaction, halting blast proliferation and promoting differentiation in leukemias driven by KMT2A rearrangements, NPM1 mutations, or NUP98 rearrangements. Monotherapy ORRs ranged from 48% to 89%, while combination regimens pairing menin inhibitors with venetoclax, azacitidine, or FLT3 inhibitors pushed ORRs above 80% in some cohorts. Key safety concerns include differentiation syndrome and QTc prolongation, though severity varied across agents. These results collectively underscore menin inhibition as a rapidly maturing therapeutic strategy in hematologic malignancies.
Detailed Summary
Menin inhibitors represent one of the most consequential advances in acute leukemia therapy in recent years, targeting the protein-protein interaction between menin and KMT2A (MLL1) to suppress the HOXA gene cluster and MEIS1 that drive leukemic proliferation. The FDA approval of revumenib for KMT2A-rearranged relapsed/refractory acute leukemia established proof of concept, and the 2024 ASH Annual Meeting provided a comprehensive update on five monotherapy and four combination therapy trials across multiple agents.
In monotherapy settings, revumenib (NCT04065399, n=116 KMT2Ar patients) achieved an ORR of 64% with a CR+CRh rate of 23%; 61% of CR+CRh responders attained MRD negativity. A separate Australian trial (ACTRN12621000439842) explored revumenib in AML patients with MRD or oligoblastic relapse, finding 36% MRD negativity in NPM1-mutated patients. Bleximenib (NCT04811560, n=146) established its recommended phase 2 dose, with ORR reaching 55% at the 150 mg BID dose level and no QTc prolongation observed, though two fatal differentiation syndrome events were reported. Enzomenib (NCT04988555, n=81) achieved a 57% ORR with no therapy-related QTc prolongation or DS-related deaths, and notably produced a CR in a patient with CALM-AF10 fusion, expanding the potential target population. BN-104 (NCT06052813), a newer agent, showed a striking 89% ORR in its dose-escalation phase with no grade ≥3 differentiation syndrome or QTc prolongation.
Combination strategies demonstrated even higher response rates by pairing menin inhibitors with BCL2 inhibitors (venetoclax), hypomethylating agents, or FLT3 inhibitors—all supported by preclinical synergy data. Revumenib plus oral decitabine/cedazuridine (ASTX727) and venetoclax (NCT05360160, n=33) yielded an ORR of 82%, including 100% in NUP98-rearranged patients, though QTc prolongation was notable at 64% all-grade. Ziftomenib combined with venetoclax and azacitidine (NCT05735184, n=54) across three dose levels showed ORRs of 47–53% with no QTc prolongation and low-grade differentiation syndrome. A revumenib plus quizartinib (FLT3 inhibitor) combination in FLT3-mutated AML (NCT05453903) and bleximenib plus venetoclax/azacitidine trials further supported the combination approach, with manageable safety profiles.
Key safety signals across all trials include differentiation syndrome (ranging from 9–27% all-grade), QTc prolongation (largely absent with bleximenib and enzomenib but significant with revumenib combinations), and cytopenias. The varying toxicity profiles suggest meaningful pharmacological differences between agents that may inform patient selection. Most trials enrolled heavily pretreated patients (median 2–3 prior lines), making the response rates particularly noteworthy.
These findings collectively position menin inhibitors as a cornerstone of future acute leukemia treatment, with combination regimens likely to define next-generation frontline and salvage protocols. Ongoing phase 2 and phase 3 trials will be critical to confirm durability of responses and optimize sequencing with transplantation.
Key Findings
- Revumenib monotherapy achieved 64% ORR in KMT2Ar relapsed/refractory acute leukemia; 61% of CR+CRh responders were MRD-negative.
- BN-104 monotherapy showed 89% ORR in early dose-escalation with no grade ≥3 differentiation syndrome or QTc prolongation.
- Revumenib plus venetoclax and oral decitabine achieved 82% ORR, including 100% in NUP98-rearranged AML patients.
- Bleximenib and enzomenib showed no QTc prolongation, differentiating their safety profiles from revumenib-based regimens.
- Combination of menin inhibitors with venetoclax/azacitidine or FLT3 inhibitors demonstrated synergistic activity across multiple trials.
Methodology
This is a correspondence/review article summarizing data from nine clinical trials (phases 1–2) presented at the 2024 ASH Annual Meeting. Data were collected from publicly accessible presentations and posters released by pharmaceutical companies at the meeting, with a collection cutoff of March 1, 2025. Trials enrolled adult and pediatric relapsed/refractory acute leukemia patients with menin-sensitizing genetic alterations.
Study Limitations
All reported trials are early-phase (1–2) with small sample sizes and short follow-up, limiting assessment of response durability and survival benefit. Response rate definitions varied across trials, complicating cross-trial comparisons. The heavily pretreated patient populations may not reflect outcomes in earlier lines of therapy.
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