A multicenter phase 1 trial evaluating the safety and preliminary efficacy of revumenib as post-transplant maintenance after allogeneic hematopoietic cell transplant in patients with KMT2A-rearranged or NPM1-mutated acute leukemia Free

Background and Significance Allogeneic stem cell transplant (alloSCT) is a potentially curative post-remission therapy for patients with acute leukemia; however, chromosomal rearrangements involving the lysine methyltransferase 2A (KMT2A) gene and Nucleophosmin 1 (NPM1) gene mutations with concomitant high-risk features increase the risk of post-alloSCT relapse and shorter survival. Revumenib is an oral potent menin inhibitor, which targets the MLL binding pocket on menin to disrupt the MLL-Menin interaction. In KMT2A rearranged (KMT2Ar) and NPM1m leukemia models, menin inhibition displaced menin from chromatin complexes, abrogated the aberrant expression of HOX and MEIS1, and prolonged overall survival. Additionally, menin inhibition induces epigenetic changes leading to increased expression of antigen presentation complexes, MHC class I and II, to enhance the sensitivity of leukemia blasts to T-cell-mediated cytotoxicity (Sparbier CE et al. Nat Cell Biol. 2023; Hogeling SM et al. Haematologica. 2025). In a phase 1 study in patients with relapsed or refractory KMT2Ar or NPM1m acute leukemia, treatment with revumenib led to an impressive CR/CRh rate of 30% with 78% of responding patients achieving MRD-negative remissions by flow cytometry (Issa GC et al. Nature. 2023). The safety of revumenib as maintenance therapy after alloSCT and preliminary efficacy in preventing post-alloSCT relapse has yet to be evaluated.

Study Design and Methods This will be a multicenter, open-label, single-arm, phase 1 investigator-initiated study to investigate the safety and preliminary efficacy of revumenib as post-alloSCT maintenance therapy (NCT06575296). Key eligibility criteria include age ≥2 years, diagnosis of acute leukemia by WHO 5^th edition, the presence of KMT2Ar or NPM1m with high-risk features (FLT3-ITD co-mutation, pre-alloSCT MRD positivity by flow cytometry or NPM1 molecular MRD, or second or later complete remission). Enrollment can start from day +30 to day +120 after alloSCT in fully engrafted patients in morphologic remission with no evidence of active grade 2-4 acute graft-versus-host disease (GVHD). Revumenib is given orally twice daily over a 28-day cycle, starting on day 50 to 150, and continued for 2 years at one of 3 potential dose levels. Each dose level includes adjustment for pediatric patients' weight <40 kg and for concomitant use of a strong CYP3A4 inhibitor antifungal. The primary objective is to determine the safety and RP2D of revumenib as post-alloSCT maintenance. Secondary objectives include assessing preliminary efficacy, alloSCT toxicity (NRM, acute and chronic GVHD), pharmacokinetics, and minimal residual disease (MRD). Correlative studies include investigating immune reconstitution, inflammatory cytokine profiles, and novel methods of MRD detection for NPM1 mutations and KMT2A rearrangements.

The study consists of two segments: 1) a dose escalation cohort to determine the maximum tolerated dose and the RP2D, followed by 2) a dose expansion cohort to better characterize the safety of the combination as well as the preliminary efficacy of revumenib as post-alloSCT maintenance. Dose escalation/de-escalation will follow a Bayesian optimal interval design with a target DLT rate of 0.2, with up to 9 evaluable patients to be treated at a dose level. Among pediatric patients < 40kg, enrollment in dose escalation will be staggered until each patient has proceeded through the DLT period. The DLT period will be the first cycle of treatment (28 days). A DLT is defined as any hematologic toxicity, regardless of NCI CTCAE, v5.0 grade, resulting in receipt of <75% of planned dose intensity, all non-hematologic toxicities CTCAE, v5.0 ≥grade 3 not clearly resulting from disease progression, intercurrent illness, or known external causes, any grade ≥3 QTcF prolongation, or cases of potential drug-induced liver injury as defined by Hy's law. Additionally, adverse events of special interest, severe GVHD, and non-relapse mortality will be monitored throughout the study with stopping boundaries based on the Bayesian toxicity monitoring rule.

This proposed phase 1 trial will establish the safety and RP2D for revumenib as post-alloSCT maintenance therapy for patients with KMT2Ar and high-risk NPM1m acute leukemias. Additional pharmacokinetic, MRD, and immune profiling studies will also inform RP2D and the future phase 2 trial. The trial is actively recruiting at City of Hope and the Dana-Farber Cancer Institute.