gilteritinib + valemetostat

**Gilteritinib + valemetostat** is an investigational oral combination therapy for FLT3-mutated acute myeloid leukemia (AML), particularly FLT3-ITD subtypes. Gilteritinib is a selective small-molecule tyrosine kinase inhibitor targeting **FMS-like tyrosine kinase 3 (FLT3)**, approved as monotherapy for relapsed/refractory FLT3-mutated AML, while valemetostat (DS-3201) is a dual inhibitor of **enhancer of zeste homolog 1 (EZH1)** and **enhancer of zeste homolog 2 (EZH2)**, key components of the Polycomb repressive complex 2 (PRC2) that mediates H3K27me3-dependent gene silencing. Preclinical studies demonstrate synergy, where FLT3 inhibition modulates PRC2 activity by reducing EZH2 expression, and the combination reduces leukemic blasts, leukemia stem cells (LSCs), and colony-forming activity in patient-derived FLT3-ITD AML cells while sparing or enhancing normal hematopoiesis (e.g., increased CFU-GM). In vivo, it decreases leukemic burden in FLT3-ITD AML mouse models. Developed through academic research collaborations, it shows promise for overcoming FLT3 inhibitor resistance via EZH1/2 targeting.[1][2][8]