Current perspectives on KMT2A fusion proteins and menin inhibition in paediatric acute myeloid leukaemia

The therapeutic landscape of acute myeloid leukaemia (AML) has evolved beyond the classic '7 + 3'/DA regimen, through the approval and incorporation of targeted treatments in both front-line and relapsed/refractory settings. Indeed, the use of selective BCL-2 antagonists (e.g. venetoclax) and FLT3 inhibitors (e.g. midostaurin, gilteritinib) which target specific molecular characteristics of leukaemic cells, has enhanced outcomes and survival rates. Arguably one of the most exciting advancements has been the clinical development of menin inhibitors for the treatment of patients harbouring specific genetic aberrations. These abnormalities include rearrangements of the lysine methyltransferase 2A (KMT2A) gene, and they occur in approximately one fifth of childhood/paediatric (i.e. infant, adolescent and young adult) AML patients. Spurred on by the recent FDA approval of revumenib, menin inhibitors hold the potential to further shift the treatment paradigm for this patient population. Here, we aim to provide a comprehensive overview of the pathogenesis of KMT2A rearrangements, with a focus on KMT2A fusion genes and proteins within paediatric AML patients. Additionally, we summarise the challenges arising from resistance to menin inhibitors, and we touch on the potential of combination therapies to expand the efficacy of menin inhibition and mitigate some of the resistance mechanisms employed by leukaemic clones.