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The single-drug therapy provides clinical benefit and could help more patients with hard-to-treat leukemias proceed to stem cell transplant

: Revumenib Monotherapy in Patients with Relapsed/Refractory KMT2Ar Acute Leukemia: Topline Efficacy and Safety Results from the Pivotal Augment-101 Phase 2 Study

(SAN DIEGO, Dec. 12, 2023) – Patients with relapsed or refractory acute leukemia with rearrangement in the lysine methyltransferase 2a gene, a genetic marker known as KMT2Ar, who were treated with revumenib saw an overall response rate of 63%, according to results from a phase II trial being reported during the 65th ÎÚÑ»´«Ã½ (ASH) Annual Meeting and Exposition. 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 the KMT2Ar gene.  

Of study participants whose cancer responded to the treatment, 39% proceeded to a stem cell transplant and half had initiated post-transplant maintenance treatment with revumenib at the time of the 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 KMT2Ar cancers. 

“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, 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.”

The KMT2Ar genetic abnormality is found in about 10% of acute leukemias and can occur in several types of leukemia in both children and adults. KMT2Ar acute leukemia is exceptionally hard to treat, with most patients relapsing after chemotherapy and transplant. In adults, remission rates after relapse and median overall survival remain low. Revumenib is a small molecule drug that targets the pathway that is instrumental in the expression of the KMT2A-rearranged driven leukemia with a goal of counteracting its effects. An earlier phase I trial had established the drug’s safety and appropriate dosing strategy.

For the phase II trial, researchers administered revumenib orally to 94 patients, both pediatric and adult, with relapsed or refractory KMT2Ar 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 KMT2Ar, and performed six 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 (meaning the cancer is gone and blood cell counts have returned to normal or adequate levels) 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, meaning that fewer than 5% of marrow cells were cancerous as seen under the microscope. Of these 25 patients, 22 had testing at their institution for measurable residual disease (MRD), another marker that indicates the depth of cancer eradication, 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 KMT2Ar genetic abnormality results in clinical benefit for patients, regardless of patients’ age, and this benefit was observed across different KMT2Ar leukemia [types].”

Treatment-related adverse events occurred in 82% of patients, the majority of which were manageable, according to Dr. Aldoss. Nausea, differentiation syndrome (a group of symptoms indicating a reaction to cancer treatment in which cancer cells mature to become normal cells), and reversible QTc prolongation (a measure of effects on the heart electricity waves) were the most common. About half of patients experienced treatment-related adverse events of grade three or higher. 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.  

The study was funded by Syndax, maker of revumenib. 

Ibrahim Aldoss, MD, of City of Hope National Medical Center, will discuss this study in the Late-Breaking Abstracts Session on Tuesday, Dec. 12, 2023, at 9:00 a.m. Pacific time in Hall A (San Diego Convention Center).

The ÎÚÑ»´«Ã½ (ASH) (hematology.org) is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 60 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology.

ASH’s flagship journal, Blood () is the most cited peer-reviewed publication in the field, and Blood Advances () is an open-access, online journal that publishes more peer-reviewed hematology research than any other academic journal worldwide. Two new journals will be joining the Blood Journals portfolio in 2024, Blood Neoplasia () and Blood Vessels, Thrombosis & Hemostasis ().

Contact:  
Melissa McGue, ASH, [email protected]
Kira Sampson, ASH, [email protected] 
Brianne Cannon, FleishmanHillard, [email protected]