Menin inhibition in pediatric UBTF-TD myelodysplastic syndrome: molecular rationale and clinical observation

Abstract Background UBTF tandem duplications (UBTF-TD) define a recently recognized high-risk subtype of pediatric myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). UBTF-TD myeloid neoplasms are driven by a HOX/MEIS1 transcriptional program that depends on the interaction between menin and KMT2A. Preclinical studies have shown sensitivity to menin inhibition, but clinical experience in children with MDS remains scarce. Results We report a ten-year-old girl with MDS with excess blasts harboring UBTF-TD together with NRAS and WT1 mutations. During the first cycle of azacitidine and venetoclax, blood counts did not improve, and the patient remained dependent on platelet and red blood cell transfusions. Revumenib was added to the ongoing treatment. Within two weeks, platelet counts and hemoglobin increased markedly, the patient became transfusion independent, and bone marrow blasts cleared. UBTF-TD also became undetectable by molecular testing. The patient subsequently underwent allogeneic hematopoietic stem cell transplantation and remains in complete remission with full donor chimerism one year after transplantation. Conclusions The rapid hematologic recovery and clearance of both bone marrow blasts and detectable UBTF-TD after initiation of revumenib provide clinical evidence that the menin dependency of UBTF-TD myeloid neoplasms can be therapeutically exploited. The timing and depth of the clinical and molecular response were remarkable.