Revumenib in High-Risk KMT2A-Rearranged Acute Leukemia

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Patients with relapsed or refractory acute leukemia with rearrangement in the lysine methyltransferase 2A gene, a genetic marker known as KMT2A, who were treated with revumenib, a small-molecule inhibitor of menin-KMT2A interactions, saw an overall response rate of 63%, according to results from the phase II Augment-101 trial reported at the 2023 ASH Annual Meeting & Exposition (Abstract LBA-5).

Revumenib is an experimental targeted therapy being studied as a treatment for acute leukemias with certain genetic abnormalities. The trial was stopped early due to the high rate of efficacy meeting a prespecified threshold, suggesting that the drug could offer a new and more effective treatment option for patients with rearrangements in KMT2A.  

Of study participants whose cancer responded to the treatment, 39% proceeded to a stem cell transplant and half had initiated posttransplant maintenance treatment with revumenib at the time of data cutoff. Based on these results, researchers say revumenib provides a promising avenue to allow more patients to proceed to a stem cell transplant—the only known curative treatment for aggressive and hard-to-treat KMT2A-rearranged cancers. 

Ibrahim Aldoss, MD

Ibrahim Aldoss, MD

“Any time you have relapsed or refractory acute leukemia, the only cure is transplant, but to do that, you have to have a response,” said Ibrahim Aldoss, MD, Associate Professor in the Department of Hematology and Stem Cell Transplant at City of Hope National Medical Center, and the study’s lead author. “We observed encouraging durable and meaningful responses, and many of these patients were able to proceed successfully to transplant. We have not seen this level of activity with any other available treatment in this advanced disease setting.”

Study Background

The KMT2A rearrangement genetic abnormality is found in about 10% of acute leukemia cases and can occur in several types of leukemia in both children and adults. KMT2A-rearranged acute leukemia is exceptionally hard to treat, with most patients relapsing after chemotherapy and transplant. In adults, remission rates after relapse as well as median overall survival remain low. Revumenib is a small-molecule drug that targets the pathway that is instrumental in the expression of the KMT2A rearrangement–driven leukemia, with a goal of counteracting its effects. An earlier phase I trial had established the drug’s safety and appropriate dosing strategy.

Phase II Study

For the phase II trial, researchers administered revumenib orally to 94 patients, both pediatric and adult, with relapsed or refractory KMT2A-rearranged acute leukemias in 28-day cycles. Most (83%) had acute myeloid leukemia, and the rest had acute lymphoblastic leukemia or mixed phenotype acute leukemia. All participants had received previous cancer treatments, but their cancer had either not responded to or had come back after the initial treatments; about half had previously received a stem cell transplant. 

An interim analysis of the drug’s efficacy was conducted on 57 participants with centrally confirmed KMT2A rearrangement and was performed 6 months after the last of these patients enrolled, a timepoint selected to allow sufficient time for response to the drug to take place. This analysis revealed that the best responses, defined as a complete response or complete response with hematologic recovery, occurred in 23% of patients. That proportion exceeded the prespecified threshold for efficacy, so the trial was stopped early. 

Among the 36 patients who attained a response, 25 were characterized as having a complete response. Of these 25 patients, 22 had testing at their institution for measurable residual disease (MRD), and 15 (68%) achieved MRD negativity. 

“A majority of responders achieved MRD-negative status, which is a deep remission, indicating that these patients responded exceptionally well to the treatment,” said Dr. Aldoss. “The results demonstrate that targeting the menin protein in leukemias with [KMT2A rearrangement] genetic abnormality results in clinical benefit for patients, regardless of age, and this benefit was observed across different [KMT2A-rearranged] leukemia [types].”

Treatment-related adverse events occurred in 82% of patients, the majority of which were manageable, according to Dr. Aldoss. Nausea, differentiation syndrome, and reversible QTc prolongation were the most common. About half of patients experienced grade ≥ 3 treatment-related adverse events. Data showed 6.4% of patients discontinued the therapy as a result of adverse events, with no patients discontinuing due to differentiation syndrome or QTc prolongation.  

This research is limited in that it was a single-arm study using historical standard of care as control to compare results with, rather than a randomized controlled trial. Several additional studies are ongoing to test the use of revumenib in combination with other standard-of-care acute leukemia treatments.  

Disclosure: The study was funded by Syndax, maker of revumenib. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.