Zhao T, Zhu H H, Wang J, Jia J S, Yang S M, Jiang H, Lu J, Chen H, Xu L P, Zhang X H, Jiang B, Ruan G R, Wang D B, Huang X J, Jiang Q
Peking University People's Hospital, Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing 100044, China.
Zhonghua Xue Ye Xue Za Zhi. 2017 Jan 14;38(1):10-16. doi: 10.3760/cma.j.issn.0253-2727.2017.01.003.
To explore prognostic significance of early assessment of minimal residual leukemia (MRD) in adult patients with acute myeloid leukemia (AML) with mutated NPM1. The response, NPM1 mutated transcript level after induction chemotherapy and the first 2 cycles of consolidation chemotherapy, disease-free survival (DFS) and overall survival (OS) in 137 patients with AML with NPM1 mutations of A, B and D were retrospectively analyzed. Data of 137 patients were collected, 67 were male, the median age was 49 years (16-67 years) , 107 (78.1%) had normal karyotype, 57 (41.6%) had positive FLT3-ITD mutation, the median NPM1 mutated transcript level at diagnosis was 84.1%. Among the 134 evaluable patients, 115 (85.8%) achieved a complete remission (CR) . Multivariate analyses revealed that WBC<100×10(9)/L (=0.3, 95% 0.1-0.9, =0.027) and first induction therapy with "IA10" protocol (=0.3, 95% 0.1-0.8, =0.015) were factors associated with achieving a CR. With a median follow-up period of 24 months (range, 2 to 91 months) in 77 survived CR patients, the probabilities of DFS and OS at 3 years were 48.0% and 63.9%, respectively. Multivariate analyses showed that positive FLT3-ITD (=3.2, 95% 1.6-6.7, =0.002) , high MRD level after 2 cycles of consolidation chemotherapy (NPM1 mutation transcript level <3-log reduction from the individual baseline, =23.2, 95% 7.0-76.6, <0.001) and chemotherapy or autologous hematopoietic stem cell transplantation (auto-HSCT) rather than allogeneic HSCT (allo-HSCT) (=2.6, 95% 1.0-6.6, =0.045) were the unfavorable factors affecting DFS, high MRD level at the time of achieving the first CR (NPM1 mutation transcript level <2-log reduction from the individual baseline, =2.5, 95% 1.0-6.1, =0.040) and after 2 cycles of consolidation chemotherapy (=4.5, 95% 2.0-10.3, <0.001) were the unfavorable factors affecting OS. Furthermore, DFS and OS rates at 3 years in those receiving chemotherapy or auto-HSCT were 39.7% and 59.1%, respectively; positive FLT3-ITD and high MRD level after 2 cycles of consolidation chemotherapy were independent factors associated with both shorter DFS (=3.5, 95% 1.6-7.6, =0.002 and =8.9, 95% 3.8-20.7, <0.001) and OS (=2.7, 95% 1.1-6.9, =0.036 and =3.1, 95% 1.2-8.0, =0.021) ; meanwhile, high MRD level at the time of achieving the first CR associated with shorter OS (=3.1, 95% 1.2-8.0, =0.022) . Positive FLT3-ITD mutation and high MRD level after induction or consolidation chemotherapy associated with poor outcomes in AML patients with mutated NPM1.
探讨成人急性髓系白血病（AML）伴NPM1突变患者早期微小残留白血病（MRD）评估的预后意义。回顾性分析137例A、B和D型NPM1突变的AML患者的缓解情况、诱导化疗及巩固化疗前2个周期后的NPM1突变转录水平、无病生存期（DFS）和总生存期（OS）。收集137例患者的数据，男性67例，中位年龄49岁（16 - 67岁），107例（78.1%）核型正常，57例（41.6%）FLT3-ITD突变阳性，诊断时NPM1突变转录水平中位数为84.1%。在134例可评估患者中，115例（85.8%）达到完全缓解（CR）。多因素分析显示，白细胞计数<100×10⁹/L（P = 0.3，95%可信区间0.1 - 0.9，P = 0.027）和采用“IA10”方案进行首次诱导治疗（P = 0.3，95%可信区间0.1 - 0.8，P = 0.015）是与达到CR相关的因素。7起例CR后存活患者的中位随访期为24个月（范围2至91个月），3年时DFS和OS的概率分别为48.0%和63.9%。多因素分析表明，FLT3-ITD阳性（P = 3.2，95%可信区间1.6 - 6.7，P = 0.002）、巩固化疗2个周期后MRD水平高（NPM1突变转录水平较个体基线降低<3对数，P = 23.2，95%可信区间7.0 - 76.6，P<0.001）以及接受化疗或自体造血干细胞移植（auto-HSCT）而非异基因造血干细胞移植（allo-HSCT）（P = 2.6，95%可信区间1.0 - 6.6，P = 0.045）是影响DFS的不利因素，首次CR时MRD水平高（NPM1突变转录水平较个体基线降低<2对数，P = 2.5，95%可信区间1.0 - 6.1，P = 0.040）和巩固化疗2个周期后（P = 4.5，95%可信区间2.0 - 10.3，P<0.001）是影响OS的不利因素。此外，接受化疗或auto-HSCT患者的3年DFS和OS率分别为39.7%和59.1%；FLT3-ITD阳性和巩固化疗2个周期后MRD水平高是与较短DFS（P = 3.5，95%可信区间1.6 - 7.6，P = 0.002和P = 8.9，95%可信区间3.8 - 20.7，P<0.001）和OS（P = 2.7，95%可信区间1.1 - 6.9，P = 0.036和P = 3.1，95%可信区间1.2 - 8.0，P = 0.021）均相关的独立因素；同时，首次CR时MRD水平高与较短OS相关（P = 3.1，95%可信区间1.2 - 8.0，P = 0.022）。FLT3-ITD阳性突变以及诱导或巩固化疗后MRD水平高与NPM1突变的AML患者预后不良相关。
