Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy
Genetic identification of patients with AML older than 60 years achieving long-term survival with intensive chemotherapy
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DOI：
10.1182/blood.2021011103
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发表时间：
2021-08-19
期刊：
影响因子：
20.3
通讯作者：
Duployez, Nicolas
中科院分区：
文献类型：
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作者：
Itzykson, Raphael;Fournier, Elise;Duployez, Nicolas
为了设计一个简单且可重复的分类器来预测年龄≥ 60岁的急性髓性白血病（AML）患者接受7+3治疗后的总生存期（OS），我们对来自ALFA 1200（法国急性白血病协会）研究的471名患者（中位年龄68岁）的37个基因进行了测序。84例细胞遗传学风险低的患者与387例细胞遗传学风险高（n = 13）、中等（n = 339）或未测量（n = 35）的患者的突变模式和OS不同。TP 53（风险比[HR]，2.49; P = 0.0003）和KRAS（HR，3.60; P = 0.001）突变独立地恶化了低风险细胞遗传学患者的OS。在那些没有低风险细胞遗传学的人中，NPM 1（HR，0.57; P = .0004），FLT 3内部串联重复，低（HR，1.85; P = .0005）或较高（HR，3.51; P < 10（-4））等位基因比率，DNMT 3A（HR，1.86; P < 10（-4）），NRAS（HR，1.54; P = 0.019）和ASXL 1（HR，1.89; P=.0003）突变独立预测OS。结合细胞遗传学风险和这7个基因的突变，39.1%的患者可以被分配到“去”层，2年OS为66.1%，7.6%的患者被分配到“不去”组（2年OS为2.8%），3.3%的患者被分配到“慢去”组（2年OS为39.1%; P < 10（-5））。在3个独立验证队列中，分别有31.2%-37.7%和11.2%-13.5%的患者被分配至go-go层和no-go层，所有3个试验队列中各层之间的OS存在显著差异（HDF [奥茨-德-法国]，n = 141，P = 0.003; SAL [StudyAlliance Leukemia]，n=46; AMLSG [AML Study Group]，n = 223，均P < 10（-5））。ALFA决策工具是一种简单、稳健和判别性的预后模型，适用于接受强化化疗的≥ 60岁AML患者。该模型可以指导比较7+3标准治疗方案与强度较低方案的试验设计。
To design a simple and reproducible classifier predicting the overall survival (OS) of patients with acute myeloid leukemia (AML) >= 60 years of age treated with 7+3, we sequenced 37 genes in 471patients fromtheALFA1200 (Acute Leukemia FrenchAssociation) study (median age, 68 years). Mutation patterns and OS differed between the 84 patients with poor-risk cytogenetics and the 387 patientswith good (n = 13), intermediate (n = 339), or unmeasured (n = 35) cytogenetic risk. TP53 (hazards ratio [HR], 2.49; P = .0003) and KRAS (HR, 3.60; P = .001) mutations independently worsened the OS of patients with poor-risk cytogenetics. In those without poor-risk cytogenetics, NPM1 (HR, 0.57; P = .0004), FLT3 internal tandem duplications with low (HR, 1.85; P = .0005) or high (HR, 3.51; P < 10(-4)) allelic ratio, DNMT3A (HR, 1.86; P < 10(-4)), NRAS (HR, 1.54; P = .019), and ASXL1 (HR, 1.89; P=.0003) mutations independently predicted OS. Combining cytogenetic risk and mutations in these 7 genes, 39.1% of patients could be assigned to a "go-go" tier with a 2-year OS of 66.1%, 7.6% to the "no-go" group (2-year OS 2.8%), and 3.3% of to the "slow-go" group (2-year OS of 39.1%; P < 10(-5)). Across 3 independent validation cohorts, 31.2% to 37.7% and 11.2% to 13.5% of patients were assigned to the go-go and the no-go tiers, respectively, with significant differences inOS between tiers in all 3 trial cohorts (HDF [Hauts-de-France], n = 141, P = .003; andSAL [StudyAlliance Leukemia], n=46; AMLSG [AML Study Group], n = 223, both P < 10(-5)). The ALFA decision tool is a simple, robust, and discriminant prognostic model for AML patients >= 60 years of age treated with intensive chemotherapy. This model can instruct the design of trials comparing the 7+3 standard of care with less intensive regimens.