leukemia and long term outcome in child-hood precursor T-cell lymphoblastic Activating NOTCH1 mutations predict favorable early treatment response

Abstract Activating mutations of the transmembrane receptor NOTCH1 are common in precursor T-cell lymphoblastic leukemia (T-ALL). We systematically analyzed the impact of activating NOTCH1 mutations on early treatment response and long-term outcome in 157 patients with T-ALL of the pediatric ALL-BFM 2000 study. We confirm previous results that NOTCH1mutations occur in > 50% of T-ALL in children. In 82 patients (82/157; 52.2%), activating NOTCH1 mutations were identified either in the heterodimerization (55/82; 67.1%), in the PEST (13/82; 15.9%), or in both domains (14/82; 17.0%), respectively. The presence of NOTCH1 mutations was significantly correlated with a good prednisone response and favor-able MRD kinetics, which was independent from gender, age, white blood cell count, and T-cell immunophenotype at the time of diagnosis. Furthermore, activating NOTCH1 mutations specified a large subgroup of patients with an excellent prognosis. These findings indicate that in the context of the ALL-BFM 2000 treatment strategy