Landscape and clinical impact of NOTCH mutations in newly diagnosed acute myeloid leukemia.

Abstract

NOTCH mutations (NOTCH^mut ) are recognized as major oncogenic drivers associated with controversial clinical impact on T-cell acute lymphoblastic leukemia (T-ALL), whereas their clinical value on acute myeloid leukemia (AML) is poorly defined. A study involving 878 consecutive newly diagnosed patients with AML was undertaken in an institution with available clinical data to unravel the impact of NOTCH^mut on prognosis. In the study, NOTCH^mut were discovered in 3.6% (32/878) of included patients with AML and composed substitution-missense, frameshift mutation, substitution-nonsense, and insertion-in frame. These mutations were more commonly associated with low platelet (29 vs 42 × 10⁹ /L, p = .024) count and coexisted with BCOR/BCORL1 (15.6% vs 3.2%, p = .001), DNMT3A (28.1% vs 12.5%, p = .021), and MPL (9.4% vs 0.8%, p = .004) mutations compared with NOTCH wild-type (NOTCH^wt ). No significant difference was observed in treatment responses between NOTCH^mut and NOTCH^wt . The presence of NOTCH^mut was associated with worse overall survival ([OS], 1 year-OS: 68.0% vs 84.2%; 3 year-OS: 48.3% vs 59.6%; p = .059) and relapse-free survival ([RFS], 1 year-RFS: 78.3% vs 85.4%; 3 year-RFS: 54.5% vs 76.9%; p = .018), especially within the European Leukemia Net 2017 intermediate-risk group. Furthermore, allogeneic hematopoietic stem cell transplantation might abrogate the dismal impact of NOTCH^mut on RFS. In multivariate analysis, NOTCH^mut were found to be an independent factor negatively influencing RFS (hazard ratio, 2.153; 95% CI, 1.166-3.975; p = .014). This study suggests that NOTCH^mut may serve as an indicator for poor prognosis of AML. Although NOTCH mutations (NOTCH^mut ) are well studied in T-cell acute lymphoblastic leukemia (T-ALL), less is known about their incidence and prognostic implications in acute myeloid leukemia (AML). A total of 878 newly diagnosed patients with AML was retrospectively analyzed; it was found that the frequency of NOTCH^mut was relatively low but was associated with an adverse prognosis.