Menin Inhibitors in Patients With Advanced AML and Gene Mutations

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Two new studies have demonstrated positive results from novel therapies targeting menin for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) with specific gene mutations, according to findings presented by Jabbour et al (Abstract 57) and Issa et al (Abstract 58) at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition.


The menin inhibitor JNJ-75276617 is a potent and selective inhibitor of the interaction between the scaffolding protein menin and the methyltransferase KMT2A.

The menin inhibitor revumenib is a potent, oral, selective inhibitor of the menin-KMT2A interaction.

“Patients with relapsed or refractory [AML] and KMT2A or NPM1 [mutations] often do poorly on currently available therapies, so there is a need to advance more effective options,” emphasized lead study author of the first study Elias Jabbour, MD, Professor of Leukemia at The University of Texas MD Anderson Cancer Center.

“These advanced and acute leukemias often are very difficult to treat and currently have no approved targeted therapies,” stressed lead study author of the second study Ghayas Issa, MD, Assistant Professor of Leukemia at The University of Texas MD Anderson Cancer Center.

First Study Methods and Results

In a phase I multicenter trial, researchers evaluated the safety and efficacy of a 28-day regimen of oral JNJ-75276617 in 86 patients with a median age of 63 years who had KMT2A- or NPM1-mutated relapsed or refractory AML. They noted that 56% of the evaluable patients had KMT2A-mutated AML and 43% of them had NPM1-mutated AML. The median age

The researchers found that JNJ-75276617 monotherapy showed early clinical activity. Among the 66 patients eligible for evaluation following 1 month of treatment, 71% of them experienced reduced bone marrow disease burden and 50% of them had a decrease in bone marrow blasts of more than 50%. The median time to first response was under 2 months and similar response rates were observed across patient groups with both gene mutations.

The researchers reported that the most common side effect of treatment was differentiation syndrome; however, it was overcome with step-up dosing.

Second Study Methods and Results

In the phase I/II SAVE trial, researchers assigned nine patients aged 12 years and older with relapsed or refractory KMT2A- or NUP98-rearranged (n = 8) or NPM1-mutated (n = 1) advanced AML to receive revumenib in combination with venetoclax and the hypomethylating agent ASTX727.

The researchers discovered that the combination therapy yielded encouraging responses in the patients who participated in the trial. Among the nine evaluable patients, the overall response rate was 100%. Three of the patients achieved complete remission, one of them achieved complete remission with partial hematologic recovery, and three of them achieved had complete remission with incomplete platelet count recovery. Additionally, one of the patients experienced a partial response and one of them had a morphologic leukemia-free state. Measurable residual disease was undetectable in six of the patients.

The researchers reported that the side effects were manageable and consistent with previous studies.


“We are encouraged by the antileukemic activity of this monotherapy, which mimics what we saw in the preclinical setting,” underscored Dr. Jabbour.

“We believe these early results suggest this treatment will be highly effective in advanced leukemias. This is our first look at an entirely oral combination therapy using menin inhibitors, and the results are very encouraging. If sustained in further trials, this could lead to a change in the standard of care for this patient population, with great potential to improve their quality of life,” concluded Dr. Issa.

Both of the studies are currently ongoing to determine the recommended phase II dose of the menin inhibitors both in combination treatments and as monotherapy.

Disclosure: The research in the first study was supported by Janssen Pharmaceuticals. The research in the second study was supported by Syndax and Astex. For full disclosures of the study authors, visit and

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