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

Background: NOTCH mutations (NOTCHmut) 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. Methods: A study involving 878 consecutive newly diagnosed patients with AML was undertaken in an institution with available clinical data to unravel the impact of NOTCHmut on prognosis. Results: In the study, NOTCHmut 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 x 10(9)/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 (NOTCHwt). No significant difference was observed in treatment responses between NOTCHmut and NOTCHwt. The presence of NOTCHmut 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 NOTCHmut on RFS. In multivariate analysis, NOTCHmut were found to be an independent factor negatively influencing RFS (hazard ratio, 2.153; 95% CI, 1.166-3.975; p = .014). Conclusion: This study suggests that NOTCHmut may serve as an indicator for poor prognosis of AML.