Schnittger Susanne, Schoch Claudia, Kern Wolfgang, Mecucci Cristina, Tschulik Claudia, Martelli Massimo F, Haferlach Torsten, Hiddemann Wolfgang, Falini Brunangelo
Department of Internal Medicine III, University Hospital Grosshadern, Ludwig Maximilian's University, Munich, Germany.
Blood. 2005 Dec 1;106(12):3733-9. doi: 10.1182/blood-2005-06-2248. Epub 2005 Aug 2.
Nucleophosmin (NPM1) exon-12 gene mutations are the hallmark of a large acute myelogenous leukemia (AML) subgroup with normal karyotype, but their prognostic value in this AML subset has not yet been determined. We screened 401 AML patients with normal karyotype treated within the German AML Cooperative Group Protocol 99 (AMLCG99) study for NPM1 mutations. Results were related with partial tandem duplications within the MLL gene (MLL-PTD), Fms-like tyrosine kinase 3-length mutations (FLT3-LM), the tyrosine kinase domain of FLT3 (FLT3-TKD), NRAS, KIT, and CEBPA mutations and with clinical characteristics and outcome. NPM1 mutations were detected in 212 (52.9%) of 401 patients. Fourteen mutations, including 8 new variants, were identified. NPM1-mutated cases associated frequently with FLT3 mutations but rarely with other mutations. The NPM1-mutated group had a higher complete remission (CR) rate (70.5% vs 54.7%, P = .003), a trend to a longer overall survival (OS; median 1012 vs 549 days, P = .076), and significantly longer event-free survival (EFS; median 428 vs 336 days; P = .012). The favorable impact of NPM1 mutations on OS and EFS clearly emerged in the large group (264 [66.8%] of 395 cases) of normal-karyotype AML without FLT3-LM. This positive effect was lost in the presence of a concomitant FLT3-LM, since survival of the NPM1+/FLT3-LM+ double positive was similar to NPM1-/FLT3-LM+ cases. In conclusion, this study demonstrates that NPM1+/FLT3-LM- mutations are an independent predictor for a favorable outcome in AML with normal karyotype.
核磷蛋白（NPM1）外显子12基因突变是核型正常的一大类急性髓系白血病（AML）亚组的标志，但它们在该AML亚组中的预后价值尚未确定。我们在德国AML协作组方案99（AMLCG99）研究中，对401例核型正常的AML患者进行了NPM1突变筛查。结果与混合系白血病基因（MLL）内的部分串联重复（MLL-PTD）、Fms样酪氨酸激酶3长度突变（FLT3-LM）、FLT3的酪氨酸激酶结构域（FLT3-TKD）、NRAS、KIT和CEBPA突变以及临床特征和预后相关。401例患者中有212例（52.9%）检测到NPM1突变。鉴定出14种突变，包括8种新变体。NPM1突变病例常与FLT3突变相关，但很少与其他突变相关。NPM1突变组的完全缓解（CR）率较高（70.5%对54.7%，P = 0.003），总生存期（OS）有延长趋势（中位数1012天对549天，P = 0.076），无事件生存期（EFS）显著延长（中位数428天对336天；P = 0.012）。在核型正常且无FLT3-LM的AML大组（395例中的264例[66.8%]）中，NPM1突变对OS和EFS的有利影响明显显现。在存在伴随的FLT3-LM时，这种积极作用消失，因为NPM1+/FLT3-LM+双阳性患者的生存期与NPM1-/FLT3-LM+病例相似。总之，本研究表明NPM1+/FLT3-LM-突变是核型正常的AML预后良好的独立预测因素。
