Co-mutation signatures and outcomes in NPM1m AML: A PETHEMA registry study

Results from a retrospective, multicenter, observational Programa Español de Tratamientos en Hematología (PETHEMA) registry study (NCT02607059), evaluating clinical covariates and outcomes in 1,360 patients with newly diagnosed (ND) NPM1-mutated (NPM1m) acute myeloid leukemia (AML), were published in Haematologica by Gil et al. The aims of this study were to chart age- and mutation burden-specific co-mutation networks, define co-occurrence and mutual exclusivity patterns, and examine associations between baseline clinical variables and overall survival (OS).

Key data: Overall, 4,862 mutations were identified; co-mutations were present in 97.2% of patients with a median of three mutations per case. The most common co-mutations were in DNMT3A (45%), FLT3-internal tandem duplication (FLT3-ITD; 42%), and in TET2 (27%), IDH2 (20%), IDH1 (15%), NRAS (15%), and SRSF2 (14%). Trisomy 8 was the most frequently reported cytogenetic abnormality and was significantly associated with DNMT3A mutation (p = 0.012) and FLT3-ITD (p = 0.041). RTK/RAS/MAPK mutation partners were more common in younger vs older adults, while mutations in myelodysplasia-related (MR) genes, splicing/cohesion alterations, and mutation burden increased with age. In prognostic univariate analyses, mutations in SRSF2 (p = 0.006), ETV6 (p = 0.015), and FLT3-ITD (p = 0.020) were associated with poorer OS.

Key learning: Co-mutation signatures were shown to be age-dependent and confer clinically meaningful risk refinement beyond FLT3-ITD in patients with NPM1m AML.