Dr Wang on the Role of Menin Inhibitors in Genetically Defined AML Subtypes

“One of the big topics at [the 2024 ASH Annual Meeting] was the advent of a new class of targeted therapy for AML: menin inhibitors.”

Eunice S. Wang, MD, a professor of oncology, chief of the Department of Medicine - Leukemia, an assistant member of the Tumor Immunology Program in the Department of Immunology, and leader of the Leukemia Clinical Disease Team at Roswell Park Comprehensive Cancer Center; as well as an associate professor in the Department of Medicine and an academic scholar at the Jacobs School of Medicine and Biomedical Sciences at the State University of New York at Buffalo, discusses the emerging role of menin inhibitors in the treatment of patients with acute myeloid leukemia (AML) harboring KMT2A rearrangements or NPM1 mutations.

Wang explains that menin inhibitors target the interaction between menin and the KMT2A epigenetic complex, a critical driver of leukemogenesis in defined AML subtypes. This mechanism has led to the development of first-in-class agents that selectively disrupt this interaction and restore differentiation in leukemic blasts. At the 2024 ASH Annual Meeting, researchers highlighted the expanding clinical utility of these agents in both monotherapy and combination settings, according to Wang.

Notably, updated results from the phase 2 AUGMENT-101 trial (NCT04065399) evaluating the menin inhibitor revumenib (SNDX-5613) demonstrated sustained clinical activity in patients with relapsed/refractory AML harboring KMT2A rearrangements or NPM1 mutations. Wang notes that the agent produced complete remissions in 17.5% of patients and clinical benefit in approximately two-thirds of patients across both adult and pediatric cohorts.

Wang also highlights the advancement of combination regimens that may improve outcomes beyond single-agent therapy. The phase 1/2 SAVE study evaluated the combination of revumenib, decitabine/cedazuridine (ASTX727), and venetoclax (Venclexta) in patients with relapsed/refractory AML. This regimen achieved an overall response rate of 82% in the overall patient population (n = 33), suggesting synergistic activity between the agents in this regimen and supporting further investigation in frontline and salvage settings.

As more clinical experience is gained, Wang emphasizes the need for biomarker-driven treatment selection and rational sequencing of therapy. Given the genetic specificity of menin inhibitors, molecular profiling for KMT2A rearrangements and NPM1 mutations is critical for identifying appropriate candidates, she explains. The potential for durable responses, particularly when used earlier in the disease course or in combination with other epigenetic agents, is shaping future trials.

Wang concludes that the development of menin inhibition represents a shift toward personalized therapy in AML. As more data become available, these agents may become integral components of treatment for genetically defined subsets of patients, addressing an area of high unmet need in current AML management.