NPM1高突变负荷是NPM1阳性急性髓系白血病患者的预后不良因素
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摘要
目的:探讨NPM1基因突变阳性成人急性髓系白血病(NPM1+AML)患者的临床特征、伴随基因突变特征及影响预后的因素。方法:收集并应用第二代测序法测定22种AML常见的基因突变中NPM1基因突变阳性初诊成人AML患者73例,用实时荧光定量PCR法测定43种AML常见的融合基因,应用Kaplan-Meier生存曲线和Cox多因素回归分析影响预后的因素。结果:73例NPM1+AML患者中,共检测到74个NPM1基因位点突变,其发生率分别为L287fs(92.0%)、Q289fs和W288fs(2.7%)、L258fs和Q289H(1.4%),其中1例患者存在2个NPM1突变位点;不同突变位点对NPM1+AML的预后无影响。NPM1变异等位基因频率(VAF)的中位值为35.4(1.8-56.6)%,以四分位数上间距38.4%为界,NPM1 VAF>38.4%的AML患者(NPM1highAML)与NPM1VAF≤38.4%的患者(NPM1lowAML)相比,早期死亡率显著增加(33.3%vs 7.3%,P<0.05)、中位EFS(148 d,95%CI 58-238 vs 372 d,95%CI 264-480 d)(P<0.01)及中位OS(179 d,95%CI 6-352 d vs 444 d,P<0.01)均显著缩短。在87.7%的NPM1+AML患者中共检测到126个伴随基因突变;NPM1伴随NRAS基因突变的患者完全缓解率高(100%vs 58%)(P<0.05),且中位OS时间显著延长(未达到vs 320 d,95%CI 150-490 d)(P<0.05)。73例NPM1+AML患者中65例完善了43种融合基因检查,所有患者融合基因检查结果均为阴性。多因素分析显示,NPM1 VAF>38.4%是EFS(HR=3.1,95%CI 1.6-6.4,P<0.01)及OS(HR=3.0,95%CI 1.4-6.2,P<0.01)的独立预后不良因素。结论:AML患者NPM1基因突变常伴随其它基因突变,但罕有融合基因并存;NPM1高突变负荷是NPM1阳性成人AML患者的独立预后不良因素。
Objective: To investigate the clinical features, accompanying gene mutation characteristics and prognostic factors of adult patients with acute myeloid leukemia with mutated NPM1(NPM1+AML). Methods: Seventy-three patients with newly diagnosed adult NPM1+AML were selected. The mutations of 22 genes were detected by second generation sequencing and 43 fusion genes of AML were detected by real-time fluorescent quantitative PCR. The KaplanMeier survival curve and Cox multivariate regression analysis were used to study the prognostic factors. Results: A total of 74 NPM1 site mutations were detected in 73 patients with NPM1+AML. The incidence rates were 92.0% L287 fs, 2.7%Q289 fs and W288 fs, 1.4% L258 fs and Q289 H, among which 1 patient had 2 NPM1 mutations; the different mutation sites had no effect on the prognosis of NPM1+AML. The median value of NPM1 variant allele frequency(VAF) was35.4%(1.8%-56.6%). Based on the uppermost quartile of 38.4%, the patients were classified as NPM1 VAF>38.4%(NPM1 highAML) and NPM1 VAF≤38.4%(NPM1 lowAML). Compared with NPM1 lowAML, the early mortality rate was statistically significantly higher(33.3% vs 7.3%, P<0.05), and median EFS(148 d,95%CI 58-238 d vs 372 d,95%CI264-480 d)(P<0.01) and median OS(179 d 95%CI 6-352 d vs 444 d)(P<0.01) were significantly shorter in NPM1 high AML. A total of 126 accompanying gene mutation sites were detected in 87.7% of patients with NPM1+AML. The patients with NRAS gene mutation displayed a higher rate of complete remission(100% vs 58%)(P<0.05) and longer median OS(not reached to 320 d, 95%CI 150-490 d)(P<0.05). The 43 fusion genes were examined in 65 out of 73 cases of NPM1+AML, and in all the patients the fusion gene test was negative. Multivariate analysis showed that NPM1 VAF>38.4% was an independent prognostic factor for EFS(HR=3.1, 95% CI 1.6-6.4, P<0.01) and OS(HR=3.0,95% CI 1.4-6.2, P<0.01). Conclusion: The NPM1 gene mutation in AML patients often is accompanied by other gene mutations, while the coexistence of fusion genes is rare; high NPM1 mutant allele burden is an independent prognostic factor for adult AML patients with mutated NPM1.
Objective: To investigate the clinical features, accompanying gene mutation characteristics and prognostic factors of adult patients with acute myeloid leukemia with mutated NPM1(NPM1+AML). Methods: Seventy-three patients with newly diagnosed adult NPM1+AML were selected. The mutations of 22 genes were detected by second generation sequencing and 43 fusion genes of AML were detected by real-time fluorescent quantitative PCR. The KaplanMeier survival curve and Cox multivariate regression analysis were used to study the prognostic factors. Results: A total of 74 NPM1 site mutations were detected in 73 patients with NPM1+AML. The incidence rates were 92.0% L287 fs, 2.7%Q289 fs and W288 fs, 1.4% L258 fs and Q289 H, among which 1 patient had 2 NPM1 mutations; the different mutation sites had no effect on the prognosis of NPM1+AML. The median value of NPM1 variant allele frequency(VAF) was35.4%(1.8%-56.6%). Based on the uppermost quartile of 38.4%, the patients were classified as NPM1 VAF>38.4%(NPM1 highAML) and NPM1 VAF≤38.4%(NPM1 lowAML). Compared with NPM1 lowAML, the early mortality rate was statistically significantly higher(33.3% vs 7.3%, P<0.05), and median EFS(148 d,95%CI 58-238 d vs 372 d,95%CI264-480 d)(P<0.01) and median OS(179 d 95%CI 6-352 d vs 444 d)(P<0.01) were significantly shorter in NPM1 high AML. A total of 126 accompanying gene mutation sites were detected in 87.7% of patients with NPM1+AML. The patients with NRAS gene mutation displayed a higher rate of complete remission(100% vs 58%)(P<0.05) and longer median OS(not reached to 320 d, 95%CI 150-490 d)(P<0.05). The 43 fusion genes were examined in 65 out of 73 cases of NPM1+AML, and in all the patients the fusion gene test was negative. Multivariate analysis showed that NPM1 VAF>38.4% was an independent prognostic factor for EFS(HR=3.1, 95% CI 1.6-6.4, P<0.01) and OS(HR=3.0,95% CI 1.4-6.2, P<0.01). Conclusion: The NPM1 gene mutation in AML patients often is accompanied by other gene mutations, while the coexistence of fusion genes is rare; high NPM1 mutant allele burden is an independent prognostic factor for adult AML patients with mutated NPM1.
引文
1Cazzola M. Introduction to a review series:the 2016 revision of the WHO classification of tumors of hematopoietic and lymphoid tissues. Blood, 2016; 127(20):2361-2364.
2 陈华英.急性髓系白血病NPM1基因突变研究.中国实验血液学杂志, 2013; 21(1):258-262.
3 Gale RE, Green C, Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood, 2008; 111(5):2776-2784.
4 Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med, 2016; 374(23):2209-2221.
5 Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization(WHO)classification of myeloid neoplasms and acute leukemia:rationale and important changes.Blood, 2009; 114(5):937-951.
6 Patel SS, Kuo FC, Gibson CJ, et al. High NPM1-mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML.Blood, 2018; 131(25):2816-2825.
7 吴克复,郑国光,马小彤,等.白血病的克隆性演化.中国实验血液学杂志, 2015; 23(1):1-5.
8 魏辉,张轶群,林冬,等.初诊急性髓系白血病NPM1突变患者临床特征的研究.中国实验血液学杂志, 2014; 22(1):11-15.
9 主鸿鹄,江滨,卢锡京,等.初诊急性髓系白血病患者NPM1基因突变与临床特征的关系.中华血液学杂志, 2010; 31(5):315-318.
10 Schlenk RF, D?hner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med, 2008; 358(18):1909-1918.
11 Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood, 2014; 124(23):3441-3449.
12 马亮,姜永玮,王少婷,等.高通量测序在FLT3-ITD阳性急性髓细胞白血病患者中的应用.中国实验血液学杂志, 2016;24(2):381-387.
13 陈芳,江雪杰,阴常欣,等. FLT3-ITD基因突变及其碱基重排长度对急性髓系白血病的预后影响.中国实验血液学杂志,2018; 26(3):678-683.
14 丁莎莎,沈宏杰,陈子兴,等. FLT3-ITD突变数量、长度及水平对急性髓系白血病患者预后的影响.中华血液学杂志,2015; 36(6):449-454.
15 邱少伟,万玉玲,王敏,等. NPM1基因表达对急性髓系白血病细胞系的影响及其机制探讨.中华血液学杂志, 2017; 38(11):940-944.
16 Wong JC, Hasan MR, Rahman M, et al. Nucleophosmin 1,upregulated in adenomas and cancers of the colon, inhibits p53-mediated cellular senescence. Int J Cancer, 2013; 133(7):1567-1577.
2 陈华英.急性髓系白血病NPM1基因突变研究.中国实验血液学杂志, 2013; 21(1):258-262.
3 Gale RE, Green C, Allen C, et al. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood, 2008; 111(5):2776-2784.
4 Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med, 2016; 374(23):2209-2221.
5 Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization(WHO)classification of myeloid neoplasms and acute leukemia:rationale and important changes.Blood, 2009; 114(5):937-951.
6 Patel SS, Kuo FC, Gibson CJ, et al. High NPM1-mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML.Blood, 2018; 131(25):2816-2825.
7 吴克复,郑国光,马小彤,等.白血病的克隆性演化.中国实验血液学杂志, 2015; 23(1):1-5.
8 魏辉,张轶群,林冬,等.初诊急性髓系白血病NPM1突变患者临床特征的研究.中国实验血液学杂志, 2014; 22(1):11-15.
9 主鸿鹄,江滨,卢锡京,等.初诊急性髓系白血病患者NPM1基因突变与临床特征的关系.中华血液学杂志, 2010; 31(5):315-318.
10 Schlenk RF, D?hner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med, 2008; 358(18):1909-1918.
11 Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation. Blood, 2014; 124(23):3441-3449.
12 马亮,姜永玮,王少婷,等.高通量测序在FLT3-ITD阳性急性髓细胞白血病患者中的应用.中国实验血液学杂志, 2016;24(2):381-387.
13 陈芳,江雪杰,阴常欣,等. FLT3-ITD基因突变及其碱基重排长度对急性髓系白血病的预后影响.中国实验血液学杂志,2018; 26(3):678-683.
14 丁莎莎,沈宏杰,陈子兴,等. FLT3-ITD突变数量、长度及水平对急性髓系白血病患者预后的影响.中华血液学杂志,2015; 36(6):449-454.
15 邱少伟,万玉玲,王敏,等. NPM1基因表达对急性髓系白血病细胞系的影响及其机制探讨.中华血液学杂志, 2017; 38(11):940-944.
16 Wong JC, Hasan MR, Rahman M, et al. Nucleophosmin 1,upregulated in adenomas and cancers of the colon, inhibits p53-mediated cellular senescence. Int J Cancer, 2013; 133(7):1567-1577.