Prognostic Significance of CEBPA Mutations in a Large Cohort of Younger Adult Patients With Acute Myeloid Leukemia: Impact of Double CEBPA Mutations and the Interaction With FLT3 and NPM1 Mutations
Prognostic Significance of CEBPA Mutations in a Large Cohort of Younger Adult Patients With Acute Myeloid Leukemia: Impact of Double CEBPA Mutations and the Interaction With FLT3 and NPM1 Mutations
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DOI：
10.1200/jco.2009.26.2501
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发表时间：
2010-06-01
影响因子：
45.3
通讯作者：
Gale, Rosemary E.
中科院分区：
文献类型：
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作者：
Green, Claire L.;Koo, Kenneth K.;Gale, Rosemary E.
目的探讨CCAAT/增强子结合蛋白α(CEBPA)基因突变在急性髓系白血病(AML)中的临床意义及影响预后的因素。方法采用变性高效液相色谱法和直接测序法对1,427例青年AML患者进行CEBPA基因全序列筛查。CEBPA-Double患者在具有和不具有正常核型的中等细胞遗传学风险患者中的发生率相似(分别为6%和5%)。CEBPA-Double患者有证据表明与Flt3/ITDS的符合率较低(P=.04)，并且极不可能有NPM1突变(P<；.0001)。CEBPA-Double而不是CEBPA-Single患者8年的总体生存率(OS)显著高于CEBPA-野生型、CEBPA-Single和CEBPA-Double患者(分别为34%、31%和54%，P=0.004)。如果存在Flt3/ITD(CEBPA-WT、CEBPA-Single和CEBPA-Double Flt3/ITD阴性患者的OS分别为36%、35%和59%，P=.002；CEBPA-WT、CEBPA-Single和CEBPA-Double Flt3/ITD阳性患者的OS分别为26%、21%和14%，P=.05)，这一好处就消失了。对于NPM1阳性/CEBPA-WT、NPM1阳性/CEBPA-Single和NPM1阴性/CEBPA-Double患者，分别为45%、44%和56%(OS，分别为45%、44%和56%，P=.2)。结论CEBPA突变筛查可仅限于缺乏FLT3/ITD或NPM1突变的中等风险细胞遗传学患者。只有CEBPA-双突变的存在才能用于治疗风险分层。J Clin Oncol28：2739-2747。(C)2010年美国临床肿瘤学会
PurposeTo determine the clinical relevance of mutations in the CCAAT/enhancer binding protein alpha (CEBPA) gene in acute myeloid leukemia (AML) and to examine factors that might modify prognostic impact.Patients and MethodsThe entire CEBPA coding sequence was screened in 1,427 young adult patients with AML, excluding acute promyelocytic leukemia, using denaturing high-performance liquid chromatography and direct sequencing.ResultsOf 107 patients (7%) with CEBPA mutations, 48 patients (45%) had one mutation (CEBPA-single), and 59 patients (55%) had two mutations (CEBPA-double). The incidence of CEBPA-double patients was similar in intermediate cytogenetic risk patients with and without a normal karyotype (6% and 5%, respectively). CEBPA-double patients had evidence of a lower coincidence with FLT3/ITDs (P = .04) and were highly unlikely to have an NPM1 mutation (P < .0001). CEBPA-double but not CEBPA-single patients had a significantly better overall survival ( OS) at 8 years (34%, 31%, and 54% for CEBPA-wild-type [WT], CEBPA-single, and CEBPA-double, respectively, P = .004). This benefit was lost in the presence of a FLT3/ITD ( OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-negative patients: 36%, 35%, 59%, respectively, P = .002; OS for CEBPA-WT, CEBPA-single, and CEBPA-double FLT3/ITD-positive patients: 26%, 21%, 14%, respectively, P = .05). There was no evidence of any additional favorable benefit for a CEBPA-single mutation in the presence of an NPM1 mutation ( OS, 45%, 44%, and 56%, P = .2, for NPM1-positive/CEBPA-WT, NPM1-positive/CEBPA-single, and NPM1-negative/CEBPA-double patients, respectively).ConclusionScreening for CEBPA mutations can be restricted to patients with intermediate-risk cytogenetics lacking an FLT3/ITD or NPM1 mutation. Only the presence of a CEBPA-double mutation should be used for therapy risk stratification. J Clin Oncol 28:2739-2747. (C) 2010 by American Society of Clinical Oncology