Dr Stein on the Emerging Role of Menin Inhibitors in Frontline Combinations for AML

"One rationale for combining menin inhibitors, specifically with chemotherapeutic agents, is that one of the issues with menin inhibitors is that they can cause fairly severe differentiation syndrome. [Therefore], if you can actually debulk the leukemia a little bit [with chemotherapeutic agents] before you introduce your menin inhibitor, that may lower the rates of differentiation syndrome overall and [reduce the incidence of] grade 3 or higher differentiation syndrome."

Eytan M. Stein, MD, chief of Leukemia Service Director, Program for Drug Development in Leukemia, Division of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center, discussed how menin inhibitors could fit into combination treatment strategies for for the frontline treatment of certain subsets of patients with acute myeloid leukemia (AML).

According to Stein, the rationale for these combinations is based on the complementary mechanisms of action between menin inhibitors and existing chemotherapeutic backbones and other systemic agents. Agents such as cytarabine and venetoclax (Venclexta) exert broad cytotoxic effects; menin inhibitors such as revumenib (Revuforj) specifically inhibit menin and disrupt the its interaction with other proteins. This dual approach is designed to simultaneously promote leukemic cell death and differentiation, and the goal of moving targeted agents like menin inhibitors to frontline combinations could help boost remission rates in that setting.

The frontline combinations aim to build on the efficacy and safety of menin inhibitors in the relapsed/refractory setting. In November 2024, the FDA approved revumenib for the treatment of adult and pediatric patients aged 1 year and older with relapsed or refractory acute leukemia and a KMT2A translocation. The regulator agency also granted priority review to a supplemental new drug application seeking the approval of revumenib for the treatment of patients with relapsed/refractory, NPM1-mutant AML. Ziftomenib (KO-539) has also been granted priority review for the treatment of adult patients with relapsed/refractory AML harboring an NPM1 mutation.

Stein noted that one of the challenges of menin inhibition is the risk of differentiation syndrome; however, incorporating the agents into treatment with chemotherapy up-front may help reduce leukemic burden, which could lower the risk of differentiation syndrome, Stein said.

Findings from the phase 1b portion of the BEAT AML trial (NCT03013998) showed that older patients with newly diagnosed AML harboring NPM1 mutations or KMT2A rearrangements treated with revumenib plus azacitidine and venetoclax (n = 43) experienced a complete remission (CR) rate of 67%, a composite CR rate of 81%, and an overall response rate of 88%.

Ultimately, Stein explained that menin inhibitor–based combinations could expand therapeutic options in AML, particularly for biomarker-selected patients. As more data become available, he expects further refinement in patient selection and management strategies that incorporate both molecularly targeted agents and cytotoxic therapies to improve clinical outcomes in AML subgroups.