Balancing benefit and burden: treatment intensification in paediatric KMT2A rearrangements acute myeloid leukaemia.

Background and purpose: Chromosomal rearrangements involving KMT2A (KMT2A-r) occur in 20% of paediatric acute myeloid leukaemia (AML). Previous studies reported that the outcome depends on the specific fusion partner. The study aimed to report the outcomes of paediatric KMT2A-r AML patients and to assess the impact of different fusion partners. Patient/material and methods: We retrospectively analysed 610 paediatric patients with intermediate-risk (IR) AML diagnosed at Children's Cancer Hospital Egypt, from January 2008 to December 2021. Patients were assigned to four groups based on fusion partner.

Results: Of 610 patients diagnosed with IR-AML, 150 (24.6%) had KMT2A rearrangements. KMT2A-r was significantly associated with hyperleukocytosis (P = 0.029), central nervous system (CNS) disease (P = 0.003), monocytic differentiation (P = 0.001), additional cytogenetic abnormalities (ACA) (P = 0.04), and complex karyotype (P = 0.001). Fusion partner, t(9;11) (p22;q23) (9p22/KMT2A::MLLT3 fusion) was most prevalent (40.8%). KMT2A-r was an independent predictor of relapse with a cumulative incidence of relapse (CIR) of 46% versus 30% in KMT2A negative group (P = 0.006). Within the KMT2A-r group, ACA and complex karyotype adversely affected the outcome with 5-year overall survival (OS) of 34% versus 53% (P = 0.027) and 26% versus 51% (P = 0.004), respectively. Outcome varied depending on fusion partner. Event-free survival (EFS) ranged from 50% to 17%, OS from 54% to 27%, and CIR from 75% to 38%.

Interpretation: KMT2A-r is an independent prognostic factor for relapse, and presence of ACA and a complex karyotype in KMT2A-r patients is associated with poorer outcomes, emphasising the need for aggressive and innovative therapeutic strategies.