Revumenib is a first in class oral menin inhibitor that targets a central oncogenic dependency shared across KMT2Ar, NPM1m, and NUP98r AML. In addition to suppressing leukemogenic transcriptional programs and promoting leukemic differentiation, menin inhibition has been shown to modulate epigenetic states linked to antigen presentation and immune recognition. These properties provide a strong biological rationale for evaluating revumenib as maintenance therapy following alloHCT, with the goal of suppressing residual leukemic clones while preserving or enhancing GVL activity during immune reconstitution.
Menin is a critical cofactor for oncogenic transcriptional programs in AML subsets driven by KMT2A rearrangements, NPM1 mutations, and NUP98 rearrangements. The interaction between menin and KMT2A promotes aberrant expression of HOX and MEIS genes, maintaining leukemic self-renewal and blocking differentiation. Revumenib is a potent, selective, oral small-molecule inhibitor of the menin-KMT2A interaction that has demonstrated clinical activity in relapsed or refractory AML. Beyond its direct anti-leukemic effects, emerging preclinical data indicate that menin inhibition may favorably modulate leukemia-immune interactions in the post-transplant environment. Menin inhibition has been shown to induce myeloid differentiation and increase expression of antigen presentation machinery, including MHC class II, in KMT2Ar and NPM1m AML. This effect is mediated through activation of interferon-related signaling pathways and results in enhanced recognition of leukemia cells by donor T cells. In parallel, menin inhibition has been shown to augment donor T-cell effector function and reduce T-cell exhaustion, collectively strengthening the GVL response without directly increasing alloreactivity against normal tissues.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
TRIPLE
Enrollment
146
Relapse free survival (RFS) in KMT2Ar, NPM1m, and NUP98r AML in the Intent-to-Treat (ITT) population with a minimum of 1 year of follow-up post-randomization.
RFS is defined as the time from randomization to the date of relapse or the date of death from any cause, whichever comes first.
Time frame: From randomization to the date of event occurrence, assessed for a minimum of 1 year post-randomization.
RFS in the modified ITT (mITT) population
Relapse free survival rate in modified intent to treat population
Time frame: From randomization to the date of event occurrence, assessed for a minimum of 1 year post-randomization
Rate of overall survival (OS) in the ITT population
Overall survival rate in the intent-to-treat population
Time frame: From randomization to the date of event occurrence, assessed for a minimum of 1 year post-randomization.
Incidence of relapse in the ITT population
Incidence of relapses in intent-to-treat participant population
Time frame: From randomization to the date of event occurrence, assessed for a minimum of 1 year post-randomization.
Rate of event-free survival (EFS) in the ITT population
Events such as relapse/progression, death from any cause, graft failure, use of donor lymphocyte infusion which have occurred from time from the date of randomization to the date of event occurrence.
Time frame: From randomization to the date of event occurrence, assessed for a minimum of 1 year post-randomization
Rate of non-relapse mortality (NRM) in the ITT population
Death in participants in the absence of disease progression or relapse
Time frame: From randomization to the date of event occurrence, assessed for a minimum of 1 year post-randomization.
Frequency, duration, and severity of Treatment-Emergent Adverse Events (TEAEs), Treatment-Related Adverse Events (TRAEs), Adverse Events of Special Interest (AESIs), and Serious Adverse Events (SAEs) in the Safety Analysis population
Documentation of number of treatment related of adverse events; their frequencies, duration, and severity
Time frame: From date of randomization to end of treatment, assessed for a minimum of 1 year post-randomization
Change from baseline in other observations related to safety for electrocardiograms (ECGs) measuring QT intervals.
Documentation and comparison of abnormal ECGs from baseline measurements in relationship to safety
Time frame: From date of randomization to end of treatment, assessed for a minimum of 1 year post-randomization.
Change from baseline in other observations related to safety for vital signs.
Documentation and comparison of abnormal vital signs from baseline measurements in relationship to safety
Time frame: From date of randomization to end of treatment, assessed for a minimum of 1 year post-randomization.
Change from baseline in other observations related to safety for performance status in the Safety Analysis population
Documentation and comparison of abnormal performance from baseline measurements in relationship to safety
Time frame: From date of randomization to end of treatment, assessed for a minimum of 1 year post-randomization.
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