Revumenib Alters the Treatment Landscape for KMT2A-Rearranged Leukemia

Academic Background

Leukemia is a malignant disease caused by abnormalities in the hematopoietic system, with KMT2A-rearranged (KMT2A-r) leukemia being a common subtype, particularly in pediatric and adult acute myeloid leukemia (AML). Rearrangements of the KMT2A gene (lysine methyltransferase 2A gene) lead to its fusion with over 100 different genes, forming oncogenic KMT2A fusion proteins. These fusion proteins maintain the expression of stem cell-associated genes (such as HOX and MEIS1) by recruiting chromatin complexes, thereby promoting leukemogenesis.

Menin is a protein that interacts with KMT2A and is crucial for maintaining the oncogenic function of KMT2A fusion proteins. Therefore, inhibitors targeting the Menin-KMT2A interaction are considered a potential therapeutic strategy. In recent years, Menin inhibitors, as a novel class of small-molecule drugs, have gradually become a research hotspot in the treatment of KMT2A-r leukemia.

This article, written by Emily B. Heikamp and Scott A. Armstrong, was published on November 7, 2024, in the Journal of Clinical Oncology (JCO). It details the groundbreaking progress of the Menin inhibitor Revumenib in the treatment of KMT2A-r leukemia and explores its potential applications in other types of leukemia.

Research Process and Results

1. Mechanism of Action of Menin Inhibitors

Menin inhibitors disrupt the interaction between Menin and KMT2A fusion proteins, leading to the dissociation of Menin and KMT2A fusion proteins from chromatin, thereby inhibiting the expression of oncogenic genes. Revumenib is a protein-protein interaction inhibitor (PPI) that binds to Menin, competitively preventing the attachment of KMT2A. This mechanism not only downregulates oncogenic genes but also promotes the differentiation of leukemia cells.

2. Preclinical Studies

In preclinical studies, Revumenib demonstrated significant anti-leukemic activity in patient-derived xenograft models of KMT2A-r leukemia. Research showed that Revumenib effectively eradicated leukemia cells and induced cell differentiation. These results laid the foundation for the clinical translation of Revumenib.

3. Clinical Trial (AUGMENT-101)

AUGMENT-101 is a phase I/II clinical trial for KMT2A-r leukemia, aimed at evaluating the safety and efficacy of Revumenib. The trial included a large number of heavily pretreated patients with relapsed/refractory (R/R) disease. The results showed that Revumenib achieved an overall response rate (ORR) of 63.2%, with a complete remission (CR) or CR with partial hematologic recovery (CRh) rate of 22.8%. Notably, many patients who achieved CR subsequently underwent hematopoietic stem cell transplantation (HSCT), offering the potential for cure.

4. Gene Expression as a Biomarker

Researchers also evaluated gene expression as a pharmacodynamic biomarker of Revumenib response. The results showed that Revumenib treatment significantly downregulated direct target genes of the KMT2A fusion protein (such as MEIS1, HOXA9, FLT3, and PBX3) and upregulated myeloid differentiation markers (such as CD11b, CD13, and CD14). However, these changes in gene expression did not effectively distinguish responders from non-responders.

5. Safety

Revumenib demonstrated a favorable safety profile, with the main adverse event being differentiation syndrome, which occurred in approximately 25% of patients, with only one grade 4 event. All cases were successfully treated with corticosteroids and/or hydroxyurea.

Conclusions and Significance

Revumenib, as a novel Menin inhibitor, has shown significant clinical efficacy in the treatment of KMT2A-r leukemia. Its unique mechanism of action disrupts the Menin-KMT2A interaction, inhibits the expression of oncogenic genes, and promotes the differentiation of leukemia cells. The results of the AUGMENT-101 trial indicate that Revumenib not only provides a new treatment option for relapsed/refractory patients but also creates conditions for subsequent curative treatments, such as hematopoietic stem cell transplantation.

Furthermore, Menin inhibitors have shown potential therapeutic effects in other types of leukemia, such as NPM1-mutant and NUP98-rearranged leukemia. Although single-agent therapy may face resistance issues, combination therapies (e.g., with hypomethylating agents or Venetoclax) are expected to further improve efficacy.

Research Highlights

1. Breakthrough Treatment: Revumenib is the first targeted drug to show significant efficacy in KMT2A-r leukemia, offering new hope for relapsed/refractory patients.
2. Unique Mechanism of Action: By disrupting the Menin-KMT2A interaction, Revumenib not only inhibits oncogenic gene expression but also promotes leukemia cell differentiation.
3. Broad Application Prospects: Menin inhibitors are effective not only in KMT2A-r leukemia but may also have applications in other types of leukemia and certain solid tumors.
4. Potential of Combination Therapy: Although single-agent therapy may face resistance issues, combination therapies are expected to further improve efficacy and offer the potential for long-term cure.

Future Outlook

Although the efficacy of Revumenib in KMT2A-r leukemia is encouraging, future research needs to address resistance issues and explore its applications in other types of leukemia and solid tumors. Additionally, clinical trials of combination therapies are underway, offering hope for more patients.

The emergence of Revumenib marks an important milestone in the field of leukemia treatment, providing patients with new treatment options and hope for a cure.