Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.
Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.
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DOI：
10.1056/nejmoa1112304
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发表时间：
2012-03-22
期刊：
影响因子：
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通讯作者：
Levine RL
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文献类型：
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作者：
Patel JP;Gönen M;Figueroa ME;Fernandez H;Sun Z;Racevskis J;Van Vlierberghe P;Dolgalev I;Thomas S;Aminova O;Huberman K;Cheng J;Viale A;Socci ND;Heguy A;Cherry A;Vance G;Higgins RR;Ketterling RP;Gallagher RE;Litzow M;van den Brink MR;Lazarus HM;Rowe JM;Luger S;Ferrando A;Paietta E;Tallman MS;Melnick A;Abdel-Wahab O;Levine RL
急性髓细胞白血病（AML）是一种异质性疾病的表现和临床结果。最近发现的体细胞突变的预后价值尚未在AML治疗的3期试验中进行系统评价。我们对398例年龄小于60岁的AML患者的18个基因进行了突变分析，这些患者被随机分配接受高剂量或标准剂量柔红霉素的诱导治疗。我们在一组104例患者中验证了我们的预后结果。我们在97.3%的患者中确定了至少一个体细胞改变。我们发现FLT 3中的内部串联重复FLT 3-ITD、MLL部分串联重复（MLL-PTD）以及ASXL 1和PHF 6突变与总生存率降低相关（FLT3-ITD P = 0.001，MLL-PTD P = 0.009，ASXL1 P = 0.05，PHF6 P = 0.006）; CEBPA和IDH 2突变与总生存率改善相关（CEBPA为P = 0.05，IDH 2为P = 0.01）。NPM 1突变的有利作用仅限于同时存在NPM 1和IDH 1或IDH 2突变的患者。我们确定了与年龄、白细胞计数、诱导剂量和缓解后治疗无关的改善AML患者风险分层的遗传预测因子，并在一个独立队列中验证了这些预测因子的意义。与标准剂量柔红霉素相比，高剂量柔红霉素提高了DNMT 3A或NPM 1突变或MLL易位患者的生存率（P = 0.001），但在野生型DNMT 3A，NPM 1和MLL患者中没有（P = 0.67）。我们发现，在AML患者中，DNMT 3A和NPM 1突变和MLL易位预测了高剂量诱导化疗的改善结果。这些发现表明，突变谱可能用于风险分层，并为AML患者的预后和治疗决策提供信息。（由国家癌症研究所和其他机构资助。
Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML. We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients. We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P = 0.001 for FLT3-ITD, P = 0.009 for MLL-PTD, P = 0.05 for ASXL1, and P = 0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P = 0.05 for CEBPA and P = 0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P = 0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P = 0.67). We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.)