Activating NOTCH1 Mutations Predict Favorable Early Treatment Response and Long Term Outcome in Child- hood Precursor T-Cell Lymphoblastic Leukemia Short Title: NOTCH1mutations predict outcome in pediatric T-ALL

Activating mutations of the transmembrane receptor NOTCH1 are common in precursor Tcell 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 NOTCH1 mutations 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 favorable MRD kinetics, which was independent from gender, age, white blood cell count, and Tcell 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 NOTCH1 mutations predict a more rapid early treatment response and a favorable long term outcome in children with T-ALL. For personal use only. by guest on June 6, 2013. bloodjournal.hematologylibrary.org From