title: Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia.
abstract: With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10(-4) and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.
authors.affiliation: Department of Hematology and.
authors.forename: Kheira
authors.initials: K
authors.lastname: Beldjord
authors.affiliation: Department of Biostatistics, University Paris Diderot, Institut Universitaire d'Hématologie, EA-3518 and UMR-S-717, University Hospital Saint-Louis, Assistance Publique - Hôpitaux de Paris, Paris, France;
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chevret
authors.affiliation: Laboratory of Oncohematology, AP-HP, Hôpital Necker Enfants-Malades, University Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades, Institut National de Recherche Médicale U1151, Paris, France;
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.affiliation: Department of Hematology, University Hospital Purpan, Toulouse, France;
authors.forename: Françoise
authors.initials: F
authors.lastname: Huguet
authors.affiliation: Department of Hematology, University Hospital, Rennes, France;
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Boulland
authors.affiliation: Department of Hematology, University Hospital Haut-Lévèque, Bordeaux, France;
authors.forename: Thibaut
authors.initials: T
authors.lastname: Leguay
authors.affiliation: Department of Hematology, University Hospital Lyon Sud, Lyon, France;
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
authors.affiliation: Department of Hematology and.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Cayuela
authors.affiliation: Department of Hematology, University Hospital Claude Huriez, Lille, France;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Grardel
authors.affiliation: Department of Hematology, University Hospital, Geneva, Switzerland;
authors.forename: Yves
authors.initials: Y
authors.lastname: Chalandon
authors.affiliation: Department of Hematology and.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boissel
authors.affiliation: Department of Hematology, University Hospital, Zürich, Switzerland;
authors.forename: Beat
authors.initials: B
authors.lastname: Schaefer
authors.affiliation: Department of Hematology, University Hospital Purpan, Toulouse, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Delabesse
authors.affiliation: Department of Hematology, University Hospital Robert Debré, Assistance Publique - Hôpitaux de Paris, Paris, France;
authors.forename: Hélène
authors.initials: H
authors.lastname: Cavé
authors.affiliation: Department of Hematology, University Hospital, Nantes, France;
authors.forename: Patrice
authors.initials: P
authors.lastname: Chevallier
authors.affiliation: Laboratory of Oncohematology, AP-HP, Hôpital Necker Enfants-Malades, University Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades, Institut National de Recherche Médicale U1151, Paris, France;
authors.forename: Agnès
authors.initials: A
authors.lastname: Buzyn
authors.affiliation: Department of Hematology, University Hospital, Rennes, France;
authors.forename: Thierry
authors.initials: T
authors.lastname: Fest
authors.affiliation: Department of Hematology, University Hospital, Caen, France;
authors.forename: Oumedaly
authors.initials: O
authors.lastname: Reman
authors.affiliation: University Hospital Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, Paris, France;
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Vernant
authors.affiliation: GRAALL Coordination Office, University Hospital Lyon Sud, Lyon, France;
authors.forename: Véronique
authors.initials: V
authors.lastname: Lhéritier
authors.affiliation: Department of Hematology, University Hospital, Nantes, France;
authors.forename: Marie C
authors.initials: MC
authors.lastname: Béné
authors.affiliation: Department of Genetics, Aix-Marseille University, Marseille, France; and.
authors.forename: Marina
authors.initials: M
authors.lastname: Lafage
authors.affiliation: Laboratory of Oncohematology, AP-HP, Hôpital Necker Enfants-Malades, University Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades, Institut National de Recherche Médicale U1151, Paris, France;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
authors.affiliation: Department of Hematology, University Hospital, INSERM U892/CNRS 6299, Angers, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.affiliation: Department of Hematology and.
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D018365:Neoplasm, Residual; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor