Single-Drug Targeted Therapy May Improve Proportion of Patients With Hard-to-Treat Leukemias Proceeding to Transplant

TON - February 2024 Vol 17, No 1

San Diego—Patients with relapsed or refractory acute leukemia with rearrangement in the KMT2Ar gene, an aggressive and difficult-to-treat leukemia, had an overall response rate of 63% when treated with the investigational agent revumenib, according to data from the single-arm pivotal phase 2 AUGMENT-101 study presented by Ibrahim Aldoss, MD, associate professor, Department of Hematology and Stem Cell Transplant, City of Hope National Medical Center, Duarte, California, at the 65th American Society of Hematology Annual Meeting.

In addition, of study participants who experienced a response, 39% proceeded to a stem cell transplant. The trial was stopped early after meeting the primary efficacy end point at the predefined interim analysis, suggesting that revumenib could offer a new and more effective treatment option for patients with rearrangements in the KMT2Ar gene, said Dr Aldoss.

Currently, no targeted therapies for KMT2A disease have been approved. “A New Drug Application for KMT2Ar leukemia has been initiated under the FDA Real-Time Oncology Review program based on these data,” said Dr Aldoss.

The menin-KMT2A interaction is a key driver of leukemogenesis. Revumenib is a small-molecule inhibitor of menin-KMT2A interactions with activity in patients with relapsed or refractory KMT2Ar and NPM1 mutated acute leukemias. The KMT2Ar genetic abnormality is found in about 10% of acute leukemias and can occur in several types of leukemia in children and adults. Most patients with KMT2Ar-positive acute leukemia relapse after chemotherapy and transplant, and in adults, remission rates after relapse and median overall survival remain low.

“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,” said Dr Aldoss. “Any time you have relapsed or refractory acute leukemia, the only cure is transplant, but to do that, you have to have a response.”

The portion of the AUGMENT-101 study reported here enrolled patients aged ≥30 days with no upper age limit who had relapsed or refractory KMT2Ar acute leukemia. (A second cohort of NPM1-mutated AML is still enrolling patients.) The primary end points of the study were complete remission (CR) or CR with partial hematologic recovery (CRh). Treatment was continued until unacceptable toxicity or lack of at least morphological leukemia-free state after 4 treatment cycles.

The efficacy population consisted of 57 patients and the safety analysis included 94 who had received ≥1 dose of revumenib. Of the entire cohort, more than 80% had acute myeloid leukemia (AML). “A quarter of the patients were refractory and never achieved remission, and over half of the patients were refractory to their last salvage therapy, regardless if they achieved remission before or not,” said Dr Aldoss. “These are heavily pretreated patients. Close to half [46%] had ≥3 prior lines of therapy, three-quarters had prior venetoclax, which is used frequently in AML, and almost half had prior allogeneic stem cell transplant, including 10% who had 2 transplants.”

Over a median follow-up of 6.1 months, the CR plus CRh rate was 23% (P=.0036), thus meeting the primary end point. A total of 70% (7 of 10) who achieved a CR plus CRh rate and 68% (15 of 22) who achieved a composite CR achieved negative measurable residual disease status. “Half of patients were able to continue revumenib therapy after their transplant,” he said.

Responses were observed across all preidentified subgroups and across KMT2A rearrangements. Median time to CR or CRh was 1.9 months, and the median duration of response was 6.4 months. The median duration of remission was 6 months. Median overall survival was 8.0 months.

The most common any-grade treatment-emergent adverse events (TEAEs) were nausea (27.7%), differentiation syndrome (26.6%), and QTc prolongation (23.4%). Dose reduction was necessary in 9% of patients, and 6% discontinued therapy due to TEAEs.

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