title: ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German-Austrian Acute Myeloid Leukemia Study Group.
abstract: We studied 1696 patients (18 to 61 years) with acute myeloid leukemia for ASXL1 mutations and identified these mutations in 103 (6.1%) patients. ASXL1 mutations were associated with older age (P<0.0001), male sex (P=0.041), secondary acute myeloid leukemia (P<0.0001), and lower values for bone marrow (P<0.0001) and circulating (P<0.0001) blasts. ASXL1 mutations occurred in all cytogenetic risk-groups; normal karyotype (40%), other intermediate-risk cytogenetics (26%), high-risk (24%) and low-risk (10%) cytogenetics. ASXL1 mutations were associated with RUNX1 (P<0.0001) and IDH2(R140) mutations (P=0.007), whereas there was an inverse correlation with NPM1 (P<0.0001), FLT3-ITD (P=0.0002), and DNMT3A (P=0.02) mutations. Patients with ASXL1 mutations had a lower complete remission rate (56% versus 74%; P=0.0002), and both inferior event-free survival (at 5 years: 15.9% versus 29.0%; P=0.02) and overall survival (at 5 years: 30.3% versus 45.7%; P=0.0004) compared to patients with wildtype ASXL1. In multivariable analyses, ASXL1 and RUNX1 mutation as a single variable did not have a significant impact on prognosis. However, we observed a significant interaction (P=0.04) for these mutations, in that patients with the genotype ASXL1(mutated)/RUNX1(mutated) had a higher risk of death (hazard ratio 1.8) compared to patients without this genotype. ASXL1 mutation, particularly in the context of a coexisting RUNX1 mutation, constitutes a strong adverse prognostic factor in acute myeloid leukemia.
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Germany.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Germany.
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Germany.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Herzig
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Aulitzky
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Späth
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Teleanu
authors.affiliation: Klinik für Hämatologie, Onkologie und Klinische Immunologie, Universitätsklinikum Düsseldorf, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kündgen
authors.affiliation: Klinik für Onkologie und Hämatologie, Klinikum Oldenburg, gGmbH, Germany.
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.affiliation: Medizinische Klinik und Poliklinik III, Universitätsklinikum Bonn, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
authors.affiliation: Medizinische Klinik und Poliklinik, Innere Medizin I, Universitätsklinikum des Saarlandes, Homburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Held
authors.affiliation: II. Medizinische Klinik und Poliklinik, Universitätsklinikum Schleswig-Holstein, Kiel, Germany.
authors.forename: Heinz-A
authors.initials: HA
authors.lastname: Horst
authors.affiliation: Medizinische Klinik III, Städtisches Klinikum Karlsruhe gGmbH, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Ringhoffer
authors.affiliation: III. Medizinische Klinik, Klinikum rechts der Isar der Technischen Universität München, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Götze
authors.affiliation: Universitätsklinik für Innere Medizin V, Medizinische Universität Innsbruck, Austria.
authors.forename: David
authors.initials: D
authors.lastname: Nachbaur
authors.affiliation: III. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kindler
authors.affiliation: Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Medizinische Hochschule Hannover, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Heuser
authors.affiliation: Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Medizinische Hochschule Hannover, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Thol
authors.affiliation: Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Medizinische Hochschule Hannover, Germany.
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Klinik für Innere Medizin III, Universitätsklinikum Ulm, Germany konstanze.doehner@uniklinik-ulm.de.
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D005260:Female; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000090243:Nucleophosmin; D011379:Prognosis; D011446:Prospective Studies; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D012737:Sex Factors; D016019:Survival Analysis; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
chemical_list: C473949:ASXL1 protein, human; D000970:Antineoplastic Agents; D050676:Core Binding Factor Alpha 2 Subunit; C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; C493728:RUNX1 protein, human; D012097:Repressor Proteins; D000090243:Nucleophosmin; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3