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Haematologica. 2015 Mar;100(3):324-30. doi: 10.3324/haematol.2014.114157. Epub 2015 Jan 16.

ASXL1 mutations in younger adult patients with acute myeloid leukemia: a study by the German-Austrian Acute Myeloid Leukemia Study Group.

Author information

1
Klinik für Innere Medizin III, Universitätsklinikum Ulm, Germany.
2
Klinik für Hämatologie, Onkologie und Klinische Immunologie, Universitätsklinikum Düsseldorf, Germany.
3
Klinik für Onkologie und Hämatologie, Klinikum Oldenburg, gGmbH, Germany.
4
Medizinische Klinik und Poliklinik III, Universitätsklinikum Bonn, Germany.
5
Medizinische Klinik und Poliklinik, Innere Medizin I, Universitätsklinikum des Saarlandes, Homburg, Germany.
6
II. Medizinische Klinik und Poliklinik, Universitätsklinikum Schleswig-Holstein, Kiel, Germany.
7
Medizinische Klinik III, Städtisches Klinikum Karlsruhe gGmbH, Germany.
8
III. Medizinische Klinik, Klinikum rechts der Isar der Technischen Universität München, Germany.
9
Universitätsklinik für Innere Medizin V, Medizinische Universität Innsbruck, Austria.
10
III. Medizinische Klinik und Poliklinik, Universitätsmedizin Mainz, Germany.
11
Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Medizinische Hochschule Hannover, Germany.
12
Klinik für Innere Medizin III, Universitätsklinikum Ulm, Germany konstanze.doehner@uniklinik-ulm.de.

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.

PMID:
25596267
PMCID:
PMC4349270
DOI:
10.3324/haematol.2014.114157
[Indexed for MEDLINE]
Free PMC Article

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