Expanding Menin Inhibitors in Acute Myeloid Leukemia

The 2025 European Hematology Association (EHA) Congress spotlighted the growing prominence of menin inhibitors as a promising class of targeted therapies for acute myeloid leukemia (AML). Data presented at the conference extensively covered several menin inhibitors, including revumenib, bleximenib, and ziftomenib, emphasizing their utility across various treatment settings.

These agents are undergoing investigation as monotherapies in the relapsed and refractory (R/R) setting, as well as in combination with intensive and nonintensive therapies in the up-front setting.

Menin inhibitors are particularly relevant for specific subsets of AML, namely those with NPM1 mutations and KMT2A rearrangements, which sustain proliferation.¹ Notably, NPM1 mutations are a significant demographic, occurring in approximately 30% to 40% of patients with AML in the up-front setting, making it a large group amenable to this therapy.²

KMT2A rearrangements are less frequent, found in approximately 5% of the overall adult AML patient population, though they are more common in younger and pediatric patients. Despite being less prevalent in the R/R setting, these targetable alterations still represent a considerable minority of patients who could benefit from menin inhibitor–based treatments.

Revumenib

Results from the phase 1 BEAT AML trial (NCT03013998) revealed that the combination of revumenib (Revuforj), azacitidine (Vidaza), and venetoclax (Venclexta) was safe and feasible across 2 dose levels undergoing evaluation. Investigators from the University of North Carolina School of Medicine reported that the triplet combination led to high remission rates in older patients with newly diagnosed (ND) AML displaying NPM1 mutations or KMT2A rearrangements. Data were presented during the 2025 EHA Congress.³

For patients at dose level 1 who were given revumenib 113 mg every 12 hours on days 1 to 28, the objective response rate (ORR) was 90.5%. At dose level 2 of revumenib 163 mg every 12 hours for days 1 to 28, the ORR was 86.4%. For patients with KMT2A rearrangements, the ORR was 100% vs 85.3% for those with NPM1 mutations. The complete response rates, which included complete responses, hematologic complete responses, and complete remissions with incomplete count recovery, were 81.0%, 81.8%, 88.9%, and 79.4% in the respective cohorts.

After 1 to 2 cycles, no patients had refractory disease. Joshua Zeidner, MD, associate professor of medicine and chief of leukemia research at the University of North Carolina School of Medicine, noted that 84% of evaluable patients achieved remission within 1 cycle of therapy, 100% achieved flow minimal residual disease (MRD)-negative remission, and 31% achieved NPM1-mutated next-generation sequencing–negative remission.

For overall survival (OS), the median follow-up was 6.9 months. For those with KMT2A rearrangements, the median OS was 18.0 months (95% CI, 11.5-not eligible), and for the NPM1-mutated cohort, it was 15.5 months (95% CI, 7.2-19.5). The 1-year OS rate was 63% among all patients, 83% for the group with KMT2A rearrangements, and 55% for the group with NPM1 mutations. “This is the first clinical trial performed on a menin inhibitor plus azacitidine and venetoclax for patients who are newly diagnosed [and] older or unfit with AML who have NPM1 mutations or KMT2A [rearrangements],” Zeidner said during the presentation. “Azacitidine, venetoclax, and revumenib are highly active [in this population].”

The trial enrolled 43 patients who were 60 years or older, unfit for intensive chemotherapy, and had NPM1 mutations or KMT2A rearrangements. The induction phase included revumenib at dose level 1 or 2 plus azacitidine at 75 mg/m2 once daily on days 1 to 7 plus venetoclax per label on days 1 to 28. If patients achieved bone marrow remission, they went on to continue treatment indefinitely. If they had morphologic evidence of AML after the first cycle, patients received induction therapy again. If bone marrow remission occurred following retreatment, they continued the treatment. If it did not, they were taken off the study protocol.

In the dose level 1 cohort (n = 21), the median patient age was 74 years; 47.6% were 75 years or older and 71.4% were women. A majority (71.4%) of patients had an ECOG performance status of 0 or 1. The European LeukemiaNet (ELN) 2024 risk factor criteria showed patients had either favorable- (42.9%), intermediate- (52.4%), or adverse (4.8%)-risk disease.

In the dose level 2 cohort (n = 22), the median age was 69.5 years; 31.8% were 75 years or older and 36.4% were women, with 68.1% having an ECOG performance status of 0 to 1. Regarding ELN criteria, disease risk was either favorable (59.1%) or intermediate (40.9%); no patient had adverse-risk disease.

Driver Mutations

For those with KMT2A rearrangements (n = 9), the median patient age was 67 years; 11.1% were 75 years or older and 44.4% were women, with 88.9% having an ECOG performance status of 0 or 1. ELN risk included 55.6% of patients with favorable-risk disease, 33.3% with intermediate-risk status, and 11.1% with adverse-risk disease.

For those with NPM1 mutations (n = 34), the median age was 73.5 years; 47.1% were 75 years or older, 55.9% were women, and 64.7% had an ECOG performance status of 0 to 1. ELN risk included 50.0% with favorable-risk disease, 50.0% with intermediate risk, and none with adverse risk. Overall, the median treatment duration cycle was 38.5 days.

Regarding grade 3 or higher adverse effects (AEs), 26% of patients had febrile neutropenia, 19% had acute kidney injury, 14% had dyspnea, 12% had QTcF prolongation, 12% had hypokalemia, and 12% had muscular weakness. The most common grade 1/2 AEs included nausea (60%), constipation (53%), and QTcF prolongation (44%).

Dose reduction with revumenib occurred following grade 4 neutropenia or thrombocytopenia lasting 14 days to the end of the cycle, with dosing reduced to every 21 days for every cycle thereafter for 10 patients.

AUGMENT-101

Updated results from the phase 2 portion of AUGMENT-101 (NCT04065399) evaluated revumenib in patients with R/R AML and NPM1 mutations and were presented by Arellano et al.⁴ The agent was granted priority review by the FDA on June 24, 2025.⁵ A total of 84 patients were evaluated, and 74 patients met efficacy evaluable criteria. The complete response plus complete response with partial hematologic recovery (CR+CRh) rate was 26.0% (95% CI, 16.6%-37.2%), and the ORR was 48.1% (95% CI, 36.5%-59.7%).

The median duration of CR+CRh was 4.7 months (95% CI, 2.1-8.2), and the median time to first CR+CRh response was 2.76 months (range, 0.9-8.8). Of 19 patients who achieved CR+CRh and had MRD status available, 12 (63.2%) were MRD negative (6 by polymerase chain reaction [PCR], 6 by flow cytometry); the median time to MRD negativity was 2.78 months (range, 1.8-4.7).

In the safety population, 66 patients (78.6%) experienced a treatment-related AE (TRAE), and 50 patients (59.5%) experienced a grade 3 or greater TRAE. The most common grade 3 or greater TRAEs were QTc prolongation (18 [21.4%]), anemia (12 [14.3%]), febrile neutropenia (11 [13.1%]), differentiation syndrome (11 [13.1%]; grade 3, 9 [10.7%]; grade 4, 2 [2.4%]), and decreased platelet count (9 [10.7%]). TRAEs led to treatment discontinuation in 4 patients (4.8%) and death in 1 patient (1.2%).

Patients received revumenib 160 mg every 12 hours with a strong CYP3A4 inhibitor or 270 mg every 12 hours without a strong CYP3A4 inhibitor in 28-day cycles. Patients who received 1 or more doses of revumenib comprised the safety population. Patients with centrally confirmed NPM1 mutations were included in the efficacy-evaluable population.

Treatment continued until unacceptable toxicity, disease progression, or lack of response after 4 or more cycles. Primary end points were rate of CR+CRh, safety, and tolerability. Secondary end points included ORR and duration of response. MRD testing was conducted locally by PCR or flow cytometry at the investigator’s discretion.

“Revumenib continues to demonstrate clinically meaningful responses in this heavily pretreated, older R/R population of patients with NPM1[-mutated] AML. The safety profile remains consistent with previous reports. These findings support further investigation of revumenib as a treatment in earlier lines of therapy and in combination,” Arellano et al concluded.

Bleximenib

Results from an ongoing phase 1b dose-finding study (NCT05453903)⁶ evaluating bleximenib activity in NPM1-mutated or KMT2A-rearranged AML determined that the 100-mg, twice-daily dose was the appropriate recommended phase 2 dose in combination with venetoclax and azacitidine for patients with KMT2A-rearranged or NPM1-mutated AML who were R/R or ND.

R/R patients received venetoclax/azacitidine in combination with oral bleximenib twice daily at 15 mg to 150 mg or 30 mg to 100 mg if they were ND over a 28-day cycle and during count recovery. Bleximenib was started at day +4 without the need for step-up dosing. Safety analysis included all dosed patients. An analysis of the intention-to-treat population included patients with AML with NPM1 mutations or KMT2A rearrangements. These patients received 50 mg, 100 mg, or 150 mg of bleximenib twice daily in combination with venetoclax/azacitidine, and included patients who discontinued prior to first disease evaluation.

As of February 2025, 120 patients received bleximenib with venetoclax/azacitidine (R/R, n = 86; ND, n = 34). The median age was 66.5 years (range, 19-88); 52 patients had KMT2A rearrangements and 68 had NPM1 mutations.

In the safety analysis (n = 120), the most common all-grade treatment-emergent AEs (TEAEs) were nausea (60%), thrombocytopenia (55%), and anemia (51%). The most common grade 3 or greater TEAEs were thrombocytopenia (53%), anemia (48%), and neutropenia (46%). Investigators reported 5 events of differentiation syndrome (4%), with 4 patients experiencing grade 2 to 3 and 1 patient with grade 5 (adverse karyotype and progressive disease), which met dose-limiting toxicity (DLT) criteria. A DLT of grade 3 diverticulitis was also reported. No QT prolongation related to study treatment has been reported to date. Safety profiles were comparable among dose groups, disease subtypes, and settings.

Pharmacodynamic data demonstrated robust reduction in target gene expression, with a more rapid reduction in NPM1 mutational burden and elimination of CD11b-positive blasts in the bleximenib 100 mg vs bleximenib 50 mg cohort.

In the R/R efficacy data set, the ORR and composite complete response (cCR) rates for the 50 mg cohort were 76% and 32%, respectively. In the 100 mg cohort, the ORR and cCR rates were 79% and 54%, respectively. There was no further improvement in efficacy observed in the 150 mg cohort. In ND patients (bleximenib 50 mg, n = 13; 100 mg, n = 13), the ORR and cCR rates were also lower with bleximenib 50 mg (77% and 62%) vs 100 mg (92% and 85%); data continue to mature. In ND and R/R settings, there were no observed differences in response rates between KMT2A rearrangements and NPM1 mutations.

Wei AH et al reported that evaluation of safety, efficacy, and tolerability data informed bleximenib 100 mg twice daily as the recommended phase 2 dose in combination with venetoclax/azacitidine for both R/R and ND patients with KMT2A-rearranged or NPM1-mutated AML. Bleximenib in combination with venetoclax/ azacitidine has an acceptable safety profile, with no QTc prolongation signal observed to date. The combination of bleximenib with venetoclax/azacitidine support further exploration for KMT2A rearrangements and NPM1 mutations in the phase 3 cAMeLot-2 study (NCT06852222).

Ziftomenib

Two studies involving another menin inhibitor, ziftomenib, were presented during the 2025 EHA Congress: KOMET-007 and KOMET-001. The FDA has granted priority review to the agent, with a Prescription Drug User Fee Act target action date of November 30, 2025.⁷

KOMET-007

KOMET-007 (NCT05735184) is a phase 1a/1b dose-escalation and dose-expansion study evaluating ziftomenib in combination with venetoclax/azacitidine, venetoclax alone, or cytarabine and daunorubicin in patients with AML with either NPM1 mutations or KMT2A rearrangements.⁸

Investigators reported robust clinical activity and deep responses in ND patients with NPM1-mutated (n = 49) or KMT2A-rearranged (n = 33) AML. For patients with NPM1 mutations, the composite complete remission (CRc) was 93.0% vs 89.0% for patients with KMT2A rearrangements.

CRc MRD negativity was 68% for patients with NPM1 mutations at a median of 4.7 weeks and 83.0% for those with KMT2A rearrangements at a median of 4.1 weeks. After a median follow-up of 25 weeks, 96% of patients with NPM1 mutations remained alive and continued on the study. At a median follow-up of 16 weeks, 88% of patients with KMT2A rearrangements remained alive and continued on the study.

“Taken together, these data support the phase 3 advancement of ziftomenib combination in newly diagnosed NPM1-mutated and KMT2A-rearranged AML,” concluded lead investigator Harry Erba, MD, professor of medicine, Duke University School of Medicine, and colleagues.

KOMET-001

Findings from the phase 1/2 KOMET- 001 trial (NCT04067336) revealed that the agent achieved clinically meaningful, MRD-negative responses in a heavily pretreated population of R/R patients with AML with NPM1 mutations.⁹

During the conference, the phase 2 portion of the trial was reported, which included a pooled supportive analysis that included 112 patients, with 20 patients from phase 1b and 92 patients from phase 2.

As of the data cutoff of December 20, 2024, a total of 9 patients in the phase 2 portion were receiving ziftomenib and 83 had discontinued due to progressive disease (n = 34), AEs (n = 17), lack of efficacy (n = 12), and patient withdrawal (n = 8). All patients from phase 1b discontinued treatment.

Overall, menin inhibitors look promising in the R/R AML setting, with significant clinical findings exhibited in patient subsets.

REFERENCES:

1. Nadiminti KVG, Sahasrabudhe KD, Liu H. Menin inhibitors for the treatment of acute myeloid leukemia: challenges and opportunities ahead. J Hematol Oncol. 2024;17(1):113. doi:10.1186/s13045-024-01632-8

2. Sharma N, Liesveld JL. NPM 1 mutations in AML-the landscape in 2023. Cancers (Basel). 2023;15(4):1177. doi:10.3390/cancers15041177

3. Zeidner J. Azacitidine, venetoclax, and revumenib for newly diagnosed older adults with acute myeloid leukemia (AML) and NPM1 mutation or KMT2A rearrangement: updated results from the BEAT AML consortium. Presented at: EHA 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract S138.

4. Arellano ML, Thirman M, DiPersio J, et al. Patients with relapsed or refractory (R/R) nucleophosmin 1-mutated (NPM1m) acute myeloid leukemia (AML): updated results from the phase 2 AUGMENT-101 study. Presented at: EHA 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract PS1467.

5. Syndax announces FDA priority review of sNDA for Revuforj (revumenib) in relapsed or refractory mNPM1 acute myeloid leukemia. News release. Syndax Pharmaceuticals. June 24, 2025. Accessed June 25, 2025. https://tinyurl.com/nnfc84sh

6. Wei AH, Reyner JE, Garciaz S, et al. RP2D determination of bleximenib in combination with venetoclax/azacitidine: phase 1b study in ND & R/R AML with KMT2A/NPM1 alterations. Presented at: EHA 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract S137.

7. Kura Oncology and Kyowa Kirin announce FDA acceptance and priority review of new drug application for ziftomenib in adults with relapsed or refractory NPM1-mutant AML. News release. Kura Oncology. June 1, 2025. Accessed June 3, 2025. https://tinyurl.com/42pup9zu

8. Erba H, Wang ES, Fathi AT, et al. Ziftomenib combined with intensive induction chemotherapy (7+3) in newly diagnosed NPM1-m or KMT2A-r acute myeloid leukemia: Updated phase 1a/b results from KOMET-007. Presented at: EHA 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract S136.

9. Fathi AT, Montesinos P, Issa GC, et al. Ziftomenib in relapsed/refractory NPM1-mutant acute myeloid leukemia: phase 1b/2 clinical activity and safety results from the pivotal KOMET-001 study. Presented at: EHA 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract PF473.