NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study

作者：Vahid Asnafi, Agnès Buzyn, Sandrine Le Noir, Frédéric Baleydier, Arnauld Simon, Kheïra Beldjord, Oumédaly Reman, Francis Witz, Thierry Fagot, Emmanuelle Tavernier, Pascal Turlure, Thibaut Leguay, Françoise Huguet, Jean‐Paul Vernant, Francis Daniel, Marie C. Béné, Norbert Ifrah, Xavier Thomas, Hervé Dombret, Elizabeth A. Macintyre · 发表于：Blood · 年份：2008 · DOI：10.1182/blood-2008-10-184069 · 被引用次数：246 · 研究领域：Acute Lymphoblastic Leukemia research、Acute Myeloid Leukemia Research、Chronic Myeloid Leukemia Treatments

Many somatic genetic abnormalities have been identified in T-cell acute lymphoblastic leukemia (T-ALL) but each individual abnormality accounts for a small proportion of cases; therapeutic stratification consequently still relies on classical clinical markers. NOTCH1 and/or FBXW7 mutations both lead to activation of the NOTCH1 pathway and are among the most frequent mutations in T-ALL. We screened 141 adult diagnostic T-ALL samples from patients treated on either the Lymphoblastic Acute Leukemia in Adults (LALA)-94 (n = 87) or the GRAALL-2003 (n = 54) trials. In 88 cases (62%) there were demonstrated NOTCH1 mutations (42% heterodimerization [HD], 10% HD+proline glutamate serine threonine [PEST], 6% PEST, 2% juxtamembrane mutations, 2% transactivation domain [TAD]) and 34 cases (24%) had FBXW7 mutations (21 cases had both NOTCH1 and FBXW7 mutations); 40 cases (28%) were wild type for both. There was no significant correlation between NOTCH1 and/or FBXW7 mutations and clinico-biologic features. Median event-free survival (EFS) and overall survival (OS) were 36 versus 17 months (P = .01) and not reached versus 32 months (P = .004) in patients with NOTCH1 and/or FBXW7 mutations versus other patients, respectively. Multivariate analysis showed that the presence of NOTCH1/FBXW7 mutations was an independent good prognostic factor for EFS and OS (P = .02 and P = .01, respectively). These data demonstrate that NOTCH1 pathway activation by either NOTCH1 or FBXW7 mutation identifies a l...