title: 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.
abstract: 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/B(low)) 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/B(low) 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/B(low) 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.
authors.affiliation: Université Paris Descartes, Hôpital Necker-Enfants-Malades, Assistance Publique-Hopitaux de Paris, Laboratoire d'hématologie and Centre National de la Recherche Scientifique Unité Mixte de Recherche, France.
authors.forename: Raouf
authors.initials: R
authors.lastname: Ben Abdelali
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.forename: Thibaut
authors.initials: T
authors.lastname: Leguay
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boissel
authors.forename: Agnès
authors.initials: A
authors.lastname: Buzyn
authors.forename: Patrice
authors.initials: P
authors.lastname: Chevallier
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
authors.forename: Stephane
authors.initials: S
authors.lastname: Lepretre
authors.forename: Françoise
authors.initials: F
authors.lastname: Huguet
authors.forename: Norbert
authors.initials: N
authors.lastname: Vey
authors.forename: Martine
authors.initials: M
authors.lastname: Escoffre-Barbe
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Tavernier
authors.forename: Oumedaly
authors.initials: O
authors.lastname: Reman
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fegueux
authors.forename: Pascal
authors.initials: P
authors.lastname: Turlure
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousselot
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Cahn
authors.forename: Veronique
authors.initials: V
authors.lastname: Lheritier
authors.forename: Yves
authors.initials: Y
authors.lastname: Chalandon
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Béné
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
mesh_terms: D000293:Adolescent; D000328:Adult; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D002985:Clinical Protocols; D018572:Disease-Free Survival; D044783:F-Box Proteins / Q000235:genetics*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000145:classification / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D051881:Receptor, Notch1 / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG; D016896:Treatment Outcome; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D055815:Young Adult
chemical_list: C442828:BAALC protein, human; D018797:Cell Cycle Proteins; C072312:ERG protein, human; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; D051881:Receptor, Notch1; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D044767:Ubiquitin-Protein Ligases