Paschka Peter, Schlenk Richard F, Gaidzik Verena I, Herzig Julia K, Aulitzky Teresa, Bullinger Lars, Späth Daniela, Teleanu Veronika, Kündgen Andrea, Köhne Claus-Henning, Brossart Peter, Held Gerhard, Horst Heinz-A, Ringhoffer Mark, Götze Katharina, Nachbaur David, Kindler Thomas, Heuser Michael, Thol Felicitas, Ganser Arnold, Döhner Hartmut, Döhner Konstanze
Klinik für Innere Medizin III, Universitätsklinikum Ulm, Germany.
Klinik für Hämatologie, Onkologie und Klinische Immunologie, Universitätsklinikum Düsseldorf, Germany.
Haematologica. 2015 Mar;100(3):324-30. doi: 10.3324/haematol.2014.114157. Epub 2015 Jan 16.
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.
我们对1696例年龄在18至61岁的急性髓系白血病患者进行了ASXL1突变研究，在103例（6.1%）患者中发现了这些突变。ASXL1突变与年龄较大（P<0.0001）、男性（P=0.041）、继发性急性髓系白血病（P<0.0001）以及骨髓（P<0.0001）和循环中（P<0.0001）原始细胞比例较低相关。ASXL1突变出现在所有细胞遗传学风险组中：正常核型（40%）、其他中间风险细胞遗传学（26%）、高风险（24%）和低风险（10%）细胞遗传学。ASXL1突变与RUNX1（P<0.0001）和IDH2（R140）突变（P=0.007）相关，而与NPM1（P<0.0001）、FLT3-ITD（P=0.0002）和DNMT3A（P=0.02）突变呈负相关。ASXL1突变患者的完全缓解率较低（56%对74%；P=0.0002），与野生型ASXL1患者相比，无事件生存期（5年时：15.9%对29.0%；P=0.02）和总生存期（5年时：30.3%对45.7%；P=0.0004）均较差。在多变量分析中，ASXL1和RUNX1突变作为单一变量对预后没有显著影响。然而，我们观察到这些突变之间存在显著的相互作用（P=0.04），即与无该基因型的患者相比，ASXL1（突变型）/RUNX1（突变型）基因型的患者死亡风险更高（风险比1.8）。ASXL1突变，特别是在同时存在RUNX1突变的情况下，是急性髓系白血病的一个强烈不良预后因素。
