Pediatric-inspired intensified therapy of adult T-ALL reveals the favorable outcome of NOTCH1/FBXW7 mutations, but not of low ERG/BAALC expression: a GRAALL study

• Published in: Blood 2011-11, Vol.118 (19), p.5099-5107
• Main Authors: Ben Abdelali, Raouf, Asnafi, Vahid, Leguay, Thibaut, Boissel, Nicolas, Buzyn, Agnès, Chevallier, Patrice, Thomas, Xavier, Lepretre, Stephane, Huguet, Françoise, Vey, Norbert, Escoffre-Barbe, Martine, Tavernier, Emmanuelle, Reman, Oumedaly, Fegueux, Nathalie, Turlure, Pascal, Rousselot, Philippe, Cahn, Jean-Yves, Lheritier, Veronique, Chalandon, Yves, Béné, Marie-Christine, Macintyre, Elizabeth, Dombret, Hervé, Ifrah, Norbert
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Biological and medical sciences; Cancer; Cell Cycle Proteins; Cell Cycle Proteins - genetics; Child; Clinical Protocols; Disease-Free Survival; F-Box Proteins; F-Box Proteins - genetics; F-Box-WD Repeat-Containing Protein 7; Female; Gene Expression; Hematologic and hematopoietic diseases; Humans; Kaplan-Meier Estimate; Leukemia-Lymphoma, Adult T-Cell; Leukemia-Lymphoma, Adult T-Cell - classification; Leukemia-Lymphoma, Adult T-Cell - drug therapy; Leukemia-Lymphoma, Adult T-Cell - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Life Sciences; Male; Medical sciences; Middle Aged; Mutation; Neoplasm Proteins; Neoplasm Proteins - genetics; Predictive Value of Tests; Prognosis; Prospective Studies; Receptor, Notch1; Receptor, Notch1 - genetics; Trans-Activators; Trans-Activators - genetics; Transcriptional Regulator ERG; Treatment Outcome; Ubiquitin-Protein Ligases; Ubiquitin-Protein Ligases - genetics; Young Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-02-334219

Despite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/Blow) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/Blow in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatric-inspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/Blow and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatric-inspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup.