Schnittger Susanne, Kern Wolfgang, Tschulik Claudia, Weiss Tamara, Dicker Frank, Falini Brunangelo, Haferlach Claudia, Haferlach Torsten
MLL Munich Leukemia Laboratory, Munich, Germany.
Blood. 2009 Sep 10;114(11):2220-31. doi: 10.1182/blood-2009-03-213389. Epub 2009 Jul 8.
Nucleophosmin (NPM1)-mutated acute myeloid leukemia (AML), which is recognized as a provisional entity in the World Health Organization 2008 classification of myeloid neoplasms, accounts for 30% of AML. We analyzed 1227 diagnostic and follow-up samples in 252 NPM1-mutated AML patients with 17 different NPM1 mutation-specific real-time quantitative polymerase chain reaction (RQ-PCR) assays. Paired diagnostic/relapse samples of 84 patients revealed stable NPM1 mutations in all cases, suggesting that they are pathogenetically early events and thus applicable for minimal residual disease detection. A total of 47 relapses were predictable because of an NPM1 mutation level (%NPM1/ABL1) increase of at least 1 log or in 15 cases because of NPM1 mutation levels not decreasing less than 3 log ranges. A high prognostic value of NPM1 levels was shown for 4 different intervals after therapy was initiated. Furthermore, thresholds of 0.1 and 0.01%NPM1/ABL1 during/after treatment discriminated between prognostic subgroups. Univariate analyses, including age, white blood cell count, blast count, CD34 positivity, FLT3 mutations status, FAB type, karyotype, NPM1 mutation type, and pretreatment NPM1 mutational level, showed that, besides NPM1 mutation level, only age and FLT3-LM mutation status were prognostically significant for EFS. Multivariate analysis, including age, FLT3-LM status, and NPM1 mutation level at different time points, demonstrated that NPM1 level was the most relevant prognostic factor during first-line treatment. Similar results were obtained in patients undergoing second-line chemotherapy or allogeneic stem cell transplantation.
核磷蛋白（NPM1）突变的急性髓系白血病（AML）在世界卫生组织2008年髓系肿瘤分类中被视为一个暂定实体，占AML的30%。我们使用17种不同的NPM1突变特异性实时定量聚合酶链反应（RQ-PCR）检测方法，对252例NPM1突变的AML患者的1227份诊断和随访样本进行了分析。84例患者的配对诊断/复发样本显示，所有病例中的NPM1突变均稳定，这表明它们是发病早期事件，因此适用于微小残留病检测。由于NPM1突变水平（%NPM1/ABL1）至少增加1个对数，共有47例复发是可预测的，或在15例中，由于NPM1突变水平下降不超过3个对数范围。在开始治疗后的4个不同时间段，NPM1水平显示出较高的预后价值。此外，治疗期间/治疗后的NPM1/ABL1阈值为0.1%和0.01%可区分预后亚组。单因素分析包括年龄、白细胞计数、原始细胞计数、CD34阳性、FLT3突变状态、FAB类型、核型、NPM1突变类型和预处理NPM1突变水平，结果显示，除了NPM1突变水平外，只有年龄和FLT3-LM突变状态对无事件生存期具有预后意义。多因素分析包括年龄、FLT3-LM状态和不同时间点的NPM1突变水平，结果表明，NPM1水平是一线治疗期间最相关的预后因素。在接受二线化疗或异基因干细胞移植的患者中也获得了类似的结果。
