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微小残留病在高危Ph阴性急性淋巴细胞白血病中的意义

Minimal residual disease in adults with Philadelphia chromosome negative acute lymphoblastic leukemia in high-risk

摘要:

目的 探讨高危Ph阴性急性淋巴细胞白血病(Ph-ALL)中微小残留病(MRD)对预后和治疗策略的影响.方法 回顾性分析2008年1月1日至2017年12月31日收治的初治成人高危Ph-ALL并获得完全缓解(CR)患者的临床资料,通过Cox回归模型和Landmark分析,寻找预后相关因素.结果 177例患者纳入研究,其中男性99例(56%),中位年龄40(16~65)岁,95例(54%)在第1次完全缓解(CR1)后接受异基因造血干细胞移植(移植组).多因素分析显示,巩固治疗1个疗程后MRD阴性(HR=0.52,95%CI 0.30~0.89,P=0.017)、诱导化疗4周达到CR(HR=0.43,95%CI 0.24~0.79,P=0.006)是影响患者无病生存(DFS)的有利因素,CR1移植是影响患者DFS(HR=0.13,95%CI 0.08~0.22,P<0.001)和总生存(OS)(HR=0.24,95%CI 0.15~0.41,P<0.001)的共同有利因素.121例患者进入Landmark分析,在巩固治疗1个疗程后MRD阴性的85例患者中进行多因素分析显示,巩固治疗3个疗程后MRD阴性是影响患者DFS(HR=0.18,95%CI 0.05~0.64,P=0.008)和OS(HR=0.14,95%CI 0.04~0.50,P=0.003)的有利因素.在巩固治疗1个疗程和3个疗程后MRD均阴性的患者中,移植组患者3年DFS率有高于化疗组的趋势(75.2%对51.3%,P=0.082),但3年OS率相近(72.7% 对68.7%,P=0.992).巩固治疗1个疗程和3个疗程后MRD至少1次阳性的患者中,移植组的3年DFS率(64.8%对33.3%,P=0.006)和3年OS率(77.0%对33.3%,P=0.028)均显著高于化疗组,与这两个时间点MRD均阴性的移植患者的预后差异无统计学意义(P>0.05).结论 在高危成人Ph-ALL患者中,巩固治疗1个疗程后MRD阴性是预后良好的独立影响因素.巩固治疗1个疗程和3个疗程MRD均阴性的患者,接受移植或化疗的生存率相似.移植显著改善了巩固治疗1个疗程和3个疗程后MRD至少一次阳性患者的预后.

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abstracts:

Objective To explore the significance of minimal residual disease (MRD) in predicting prognosis and guiding therapy of adults with Philadelphia- chromosome negative acute lymphoblastic leukemia(Ph- ALL)in high-risk. Methods Data of newly diagnosed adults with Ph- ALL in high-risk who achieved CR were reviewed. Variables associated with outcome were identified by COX regression model and Landmark analysis. Results A total of 177 patients, 99(56%)cases male with a median age of 40 years(range, 16-65 years)were included in this study. Of them, 95(54%)patients received allo- HSCT in CR1. Multivariate analyses showed that MRD negativity after the first cycle of consolidation(HR=0.52, 95% CI 0.30-0.89, P=0.017)and achieving CR within 4 weeks(HR=0.43, 95% CI 0.24-0.79, P=0.006)were the factors significantly-associated with longer DFS, and allo-HSCT was associated with both longer DFS(HR=0.13, 95% CI 0.08-0.22, P<0.001)and OS(HR=0.24, 95%CI 0.15- 0.41, P<0.001). Landmark analysis was performed on 121 patients, of 85 patients achieving MRD negativity after the first cycle of consolidation, multivariate analyses showed that MRD negativity after the third cycle of consolidation was significantly-associated with longer DFS(HR=0.18, 95% CI 0.05-0.64, P=0.008)and OS(HR=0.14, 95% CI 0.04-0.50, P=0.003). For the patients achieving MRD negativity after both the first and the third cycles of consolidation, the 3-year DFS rate in the allo-HSCT cohort had a higher trend compared with that in the chemotherapy cohort(75.2% vs 51.3%, P=0.082), however, the 3-year OS rates in the 2 cohorts were similar(72.7% vs 68.7%, P=0.992). In those with MRD positivity after the first and/or the third cycle of consolidation, 3-year DFS(64.8% vs 33.3%, P=0.006)and OS(77.0% vs 33.3%, P=0.028)rates in the allo-HSCT cohort were significantly higher than those in the chemotherapy cohort, and similar to those in the cohort achieving MRD negativity after both the first and the third cycles of consolidation and receiving allo- HSCT. Conclusions MRD negativity after the first cycle of consolidation was a predictor for better outcome in adults with Ph- ALL in high-risk. The survival advantage of the allo- HSCT cohort was not pronounced compared with that in the chemotherapy cohort even in those with high-risk features but achieving MDR negativity after both the first and third cycles of consolidation. However, allo-HSCT could be a good option for the patients with MRD positivity after the first and/or the third cycle of consolidation.

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