Subtype- and functional class-dependent prognostic impact of CSF3R mutations in acute myeloid leukaemia: A cohort study of 2500 patients.

Abstract

Colony-stimulating factor 3 receptor (CSF3R) mutations occur in acute myeloid leukaemia (AML), but their prognostic significance remains unclear. We analysed 2500 patients with newly diagnosed de novo non-acute promyelocytic leukaemia (APL) AML treated with intensive induction therapy. CSF3R^mut were identified in 3.5% and frequently co-occurred with CCAAT/enhancer-binding protein alpha bZIP domain (CEBPA-bZip) mutations and RUNX family transcription factor 1::RUNX1 partner transcriptional co-repressor 1 (RUNX1::RUNX1T1) fusions. In the entire cohort, CSF3R^mut were associated with inferior relapse-free survival (RFS), but not overall survival (OS) or event-free survival (EFS). The prognostic impact was context-dependent. The adverse association was most consistent in CEBPA-bZip AML, with inferior OS, EFS (hazard ratio [HR], 2.76; p = 0.001) and RFS (HR, 2.66; p = 0.002) and persisted after multivariable adjustment and time-dependent modelling of transplantation. Membrane-proximal activating mutations (MPM) were associated primarily with inferior RFS (HR, 2.27; p = 0.001) in the overall cohort, whereas cytoplasmic-tail truncating mutations (CTTM) showed no consistent adverse effect. In CEBPA-bZip AML, both MPM and CTTM showed adverse EFS and RFS associations, although the CTTM subgroup was small. The prognostic impact of CSF3R^mut in AML depends on molecular context and functional mutation class, with the strongest adverse associations observed in CEBPA-bZip AML.