Objective: To explore prognostic significance of early assessment of minimal residual leukemia (MRD) in adult patients with de novo acute myeloid leukemia (AML) with mutated NPM1. Methods: 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. Results: 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 (OR=0.3, 95% CI 0.1-0.9, P=0.027) and first induction therapy with "IA10" protocol (OR=0.3, 95% CI 0.1-0.8, P=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 (HR=3.2, 95% CI 1.6-6.7, P=0.002) , high MRD level after 2 cycles of consolidation chemotherapy (NPM1 mutation transcript level <3-log reduction from the individual baseline, HR=23.2, 95% CI 7.0-76.6, P<0.001) and chemotherapy or autologous hematopoietic stem cell transplantation (auto-HSCT) rather than allogeneic HSCT (allo-HSCT) (HR=2.6, 95% CI 1.0-6.6, P=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, OR=2.5, 95% CI 1.0-6.1, P=0.040) and after 2 cycles of consolidation chemotherapy (HR=4.5, 95% CI 2.0-10.3, P<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 (HR=3.5, 95% CI 1.6-7.6, P=0.002 and HR=8.9, 95% CI 3.8-20.7, P<0.001) and OS (HR=2.7, 95% CI 1.1-6.9, P=0.036 and HR=3.1, 95% CI 1.2-8.0, P=0.021) ; meanwhile, high MRD level at the time of achieving the first CR associated with shorter OS (HR=3.1, 95% CI 1.2-8.0, P=0.022) . Conclusion: Positive FLT3-ITD mutation and high MRD level after induction or consolidation chemotherapy associated with poor outcomes in AML patients with mutated NPM1.
目的：探讨NPM1突变阳性急性髓系白血病（AML）患者化疗后早期微小残留病（MRD）水平与预后的关系。 方法：回顾性分析137例初治成人伴NPM1基因主要突变（A、B、D突变）AML患者的治疗结果，以及化疗后早期时间点MRD（NPM1突变转录本）水平对预后的影响。 结果：在137例患者中，男67例（48.9%），中位年龄49（16~67）岁，染色体正常核型107例（78.1%），FLT3-ITD突变阳性57例（41.6%），初诊时NPM1基因突变转录本中位水平84.1%（4.1%~509.9%）。在134例可评估的患者中，115例（85.8%）最终获完全缓解（CR）。多因素分析显示，WBC<100×10(9)/L（OR=0.3，95% CI 0.1~0.9，P=0.027）和初始诱导治疗为"IA10"方案（OR=0.3，95% CI 0.1~0.8，P=0.015）是获得CR的有利因素。在108例可评估的CR患者中，存活患者中位随访24（2~91）个月，3年无病生存（DFS）和总生存（OS）率分别为48.0%和63.9%。多因素分析显示，FLT3-ITD突变阳性（HR=3.2，95% CI 1.6~6.7，P=0.002）、巩固治疗2个疗程后MRD高水平（NPM1突变转录本水平较治疗前下降<3个对数级，HR=23.2，95% CI 7.0~76.6，P<0.001）、未接受异基因造血干细胞移植（allo-HSCT）（HR=2.6，95% CI 1.0~6.6，P=0.045）是影响患者DFS的不利因素；MRD在首次获得CR时高水平（NPM1突变转录本水平下降<2个对数级，HR=2.5，95% CI 1.0~6.1，P=0.040）和巩固治疗2个疗程后高水平（HR=4.5，95% CI 2.0~10.3，P<0.001）是影响患者OS的不利因素。进一步分析78例接受化疗（或自体移植）的CR患者，3年DFS和OS率分别为39.7%和59.1%，FLT3-ITD突变阳性和巩固治疗2个疗程后MRD高水平是独立影响患者DFS（HR=3.5，95% CI 1.6~7.6，P=0.002和HR=8.9，95% CI 3.8~20.7，P<0.001）和OS（HR=2.7，95% CI 1.1~6.9，P=0.036和HR=3.1，95% CI 1.2~8.0，P=0.021）的共同不利因素，此外，首次获得CR时MRD高水平（HR=3.1，95% CI 1.2~8.0，P=0.022）也是影响患者OS的不利因素。 结论：在NPM1突变阳性AML患者中，伴有FLT3-ITD突变和化疗后早期MRD高水平预示不良预后。.
Keywords: Gene, NPM1; Leukemia, myeloid, acute; Minimal residual disease; Prognosis.