Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia

Abstract

Severe congenital neutropenia (SCN) is a heterogeneous bone marrow failure syndrome predisposing to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML). We studied 82 North American and Australian SCN patients enrolled in the Severe Chronic Neutropenia International Registry who were on long-term treatment with granulocyte colony-stimulating factor and for whom the neutrophil elastase (ELA2) gene was sequenced. There was no significant difference in the risk of MDS/AML in patients with mutant versus wild-type ELA2: the respective cumulative incidences at 15 years were 36% and 25% (P = 0.96). Patients with either mutant or wild-type ELA2 should be followed closely for leukaemic transformation.

Fig 1

Granulocyte colony-stimulating factor (G-CSF) dose and absolute neutrophil count (ANC) response in patients with SCN, by ELA2 mutation status. Average ANC on therapy during the 6–18 month follow-up period on G-CSF, for patients with wild-type (blue) and mutant (black) ELA2, according to G-CSF dose (μg/kg/d) at 6 months. Dose was analysed on the log₂ scale and ANC on the log₁₀ scale. Solid lines show mean values from a generalized linear model that allows for a different linear relationship in patients with mutant versus wild-type ELA2. Shaded areas correspond to 95% point-wise confidence limits. Reference line at 1·5 × 10⁹ cells/l shows the therapeutic target ANC. Median G-CSF dose was 5·2 μg/kg/d in patients with wild-type ELA2 and 9·9 μg/kg/d in patients with mutant ELA2.

Fig 2

Cumulative incidence of MDS/AML in patients with SCN, by ELA2 mutation status. Cumulative incidence, by years on G-CSF therapy, and 95% confidence intervals at selected years (error bars), in patients with mutant (black) and wild-type (blue) ELA2. The Kaplan–Meier actuarial method was used to estimate the cumulative incidence curves.