A Phase II Study of the Menin Inhibitor Revumenib in Leukemia Associated with Upregulation of HOX Genes: Trial in Progress
Authors: Issa Ghayas C. , Chin Kuo-Kai , Blachly James S. , Farhat Aziz , Xiao Lianchun , Ning Jing , Cuglievan Branko , Shukla Neerav , Sasaki Koji , Loghavi Sanam , Cai Sheng , Kantarjian Hagop M. , Stein Eytan M. 
Published: December 2024

Background and Significance: The homeobox (HOX) genes and their DNA-binding cofactor MEIS1 are aberrantly expressed in up to 60% of acute myeloid leukemia (AML) (Spencer DH, Leukemia 2015) in addition to other subsets of acute leukemia of various lineages. The interaction of menin with lysine methyltransferase 2A (KMT2A) is a dependency in acute leukemia with either rearrangement of KMT2A or mutation of the nucleophosmin 1 gene (NPM1), which in turn causes an aberrant expression of HOX and a differentiation arrest. The menin inhibitor revumenib reverses this aberrant expression, leading to hematopoietic differentiation and an overall response rate of 53% in highly refractory leukemias with these genotypes (Issa GC, Nature 2023). However, a growing list of other leukemia subsets characterized by upregulation of HOX genes have a demonstrated preclinical susceptibility to menin inhibition including leukemias with rearrangements of NUP98 (Heikamp EB, Blood 2022), MN1-fusions (Libbrecht C, Leukemia 2021) or UBTF-tandem duplication (TD) (Barajas JM, Blood 2024). Therefore, we designed this phase II clinical trial to evaluate the efficacy of revumenib in patients with relapsed or refractory (R/R) acute leukemias associated with upregulation of HOX genes.
Study Design and Methods: This isa single-arm, open label, multicenter, investigator-initiated study using revumenib orally at 163 mg with strong CYP3A inhibitors or 276 mg without strong CYP3A inhibitors every 12 hours in continuous 28-day cycles (NCT06229912).Given the lack of clinically validated assays for measurement of HOX expression, we relied instead on identification of genetic abnormalities with demonstrated prior evidence of HOX overexpression in pre-clinical studies for eligibility including: NUP98 rearrangements, KMT2A-PTD, NPM1::MLF1 or t(3;5)(q25;q34), SET::NUP214 or t(9;9)(q34;q34), RUNX1::EVI1 or t(3;21)(q26;q22), KAT6A-CREBBP or t(8;16)(p11;p13), CDX2::ETV6 or t(12;13)(p13;q12), PICALM::MLLT10 or t(10;11)(p12;q14-21); MN1::ETV6 or t(12;22)(p13;q12) and UBTF-TD. Patients age ≥ 12 years with weight ≥ 40Kg with any R/R acute leukemia, of either myeloid, lymphoid, or mixed lineages, with these abnormalities are eligible.
The primary objective is efficacy assessed as the overall response rate within 5 cycles of treatment initiation. Secondary objectives include assessment of duration of response, event-free and overall survival, rates of measurable residual disease negativity by flow and cytogenetic remission (in those with baseline cytogenetic abnormalities). Exploratory objectives include evaluation of HOX/MEIS expression as a biomarker of response, and the rate of acquired mutations in the MEN1 gene that disrupt binding of revumenib as a mechanism of resistance (Perner F, Nature 2023), among other molecular and cellular markers that may be predictive of antitumor activity and/or resistance.
The planned sample size is 40 patients across 5 tertiary centers in the United States. We plan to employ Bayesian monitoring of futility and toxicity where enrollment will be stopped early if there is more than 97.5% probability that the CR/CRh rate is less than 10% or there is more than 80% probability that the unacceptable toxicity rate is more than 20%.
This study may identify multiple leukemia subsets susceptible to menin inhibition. If this occurs, expansion cohorts in those subsets will be started. In addition, HOX/MEIS1 expression may become a genotype-agnostic method of identifying patients who will benefit from menin inhibition.