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Blood, 15 August 2006, Vol. 108, No. 4, pp. 1151-1157.
Prepublished online as a Blood First Edition Paper on April 13, 2006; DOI 10.1182/blood-2005-12-4956.
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CLINICAL TRIALS AND OBSERVATIONS
Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia
Stephen Breit,
Martin Stanulla,
Thomas Flohr,
Martin Schrappe,
Wolf-Dieter Ludwig,
Gabriele Tolle,
Margit Happich,
Martina U. Muckenthaler, and
Andreas E. Kulozik
From the Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg; the Department of Pediatric Hematology and Oncology, Hannover Medical School; the Institute of Human Genetics, University of Heidelberg; the Department of General Pediatrics, University Medical Centre Schleswig-Holstein, Campus Kiel; and the Department of Hematology, Oncology, and Tumor Immunology, Robert-Rössle-Clinic at the HELIOS Clinic Berlin-Buch, Charité Medical School, Berlin, Germany.
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–Berlin-Frankfurt-Munster (BFM) 2000 study. We confirm previous results that NOTCH1 mutations occur in more than 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%). The presence of NOTCH1 mutations was significantly correlated with a good prednisone response and favorable minimal residual disease (MRD) kinetics, which was independent from sex, 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, NOTCH1 mutations predict a more rapid early treatment response and a favorable long-term outcome in children with T-ALL.
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