【作者】 杜凯利；

【导师】 黄河；

【作者基本信息】 浙江大学 ， 血液病学（专业学位）， 2013， 博士

【摘要】 成人急性淋巴细胞白血病(ALL)中约20-25%的患者为Ph染色体阳性,Ph染色体阳性急性淋巴细胞白血病(Ph+ALL)属于高危亚型,预后较差。尽管酪氨酸激酶抑制剂的引入使得Ph+ALL在完全缓解率和总生存率得到很大提高,但异基因造血干细胞移植(allo-HSCT)仍是当前Ph+ALL最重要的根治手段,对于年轻患者更是缓解后治疗中的一线方案。本文对自2006年8月至2012年12月在我中心行allo-HSCT的Ph+ALL患者进行了回顾性研究,旨在评估Ph+ALL患者的移植预后,并对影响预后的因素进行分析,尤其是对采用实时定量PCR测定的BCR/ABL融合基因及流式细胞仪测定的微小残留病灶的预后意义进行分析。共45名Ph+ALL患者纳入本研究,其中41名患者移植时处于完全缓解(Complete Remission,CR),4名患者移植时未缓解行挽救性移植。所有患者均接受以BUCY为基础的清髓预处理方案；干细胞均通过经动员后的供者外周血采集；24.4%的患者行亲缘全相合移植,46.7%行非亲缘移植,28.9%行半相合移植；77.8%的患者移植前使用伊马替尼联合化疗进行治疗。预后变量有：总生存率(Overall Survival, OS)、无复发生存率(Relapse Free Survival, RFS)、复发率(Relapse Incidence, RI)、非复发死亡率(Non-Relapse Mortality, NRM)。结果显示：总体的3年OS率为48.5%,3年RFS率为39.1%；累积NRM率为39.9%。其中,41例处于CR行allo-HSCT的患者,3年OS率为53.5%,3年RFS率为47.6%；累积RI率为24.0%,累积NRM率为28.4%。对移植时处于CR的患者的预后因素进行单因素及多因素分析,结果发现：移植时BCR/ABL定量水平高(RR1=1.191,P=0.004；RR2=1.217,P=0.002)与Ⅲ-Ⅳ度aGVHD的发生(RR1=6.81,P=0.006；RR2=1.981,P=0.019)是影响移植后OS、RFS的主要危险因素。移植后复发与移植时BCR/ABL定量水平高(RR=1.358,P=0.001),诊断至移植间隔时间短(RR=1.021,P=0.006)相关。Ⅲ-Ⅳ度aGVHD是移植后非复发死亡的独立危险因素(RR=6.262,P=0.023)。我们未发现移植前伊马替尼使用,供者来源,BCR/ABL融合基因阴性/阳性,流式细胞仪测定的MRD水平对移植预后有显著影响,但对此仍需要更多设计良好的临床试验结果来证实。总之,本研究结果强调了移植时BCR/ABL定量水平在判断移植预后中的重要作用,并证实Ⅲ-Ⅳ度aGVHD的发生显著增加了非复发死亡率,并对生存预后有损害作用。在伊马替尼时代,BCR/ABL的动态监测对移植疗效的预后意义仍有待进一步研究。更多还原

【Abstract】 Around20-25%of adult acute lymphoblastic leukemia (ALL) patients are philadelphia chromosome positive (Ph+) and these Ph+ALL patients are classified as high risk and are related to a poor prognosis. Although the introduction of tyrosine kinase inhibitors has revolutionized therapy for Ph+ALL and greatly improved prognosis, allogenic hematopoietic stem cell transplantation (allo-HSCT) remains an indispensable and curable treatment. A retrospective analysis was conducted on Ph+ALL patients who received allo-HSCT in our center between2005and2012, aiming to evaluate their prognosis after allo-HSCT and find out factors related to the prognosis. A total of45patients were enrolled in our study,41patients were in complete remission (CR) before allo-HSCT, and4patients were in active disease. Thirty-five (77.8%) patients received imatinib with induction and consolidation therapy before allo-HSCT. All patients received BUCY based conditioning and mobilized peripheral stem cell from matched related (24.4%), matched unrelated (46.7%), or haploidentical (28.9%) donors. Endpoint variables included Overall Survival (OS), Relapse Free Survival (RFS), Relapse Incidence (RI) and Non-Relapse Mortality (NRM). Our results showed that3-year OS was48.5%,3-year RFS was39.1%, cumulative incidence of NRM was39.9%in the whole population. Among patients in CR at the time of allo-HSCT (n=41),3-year OS was53.5%,3-year RFS was47.6%, cumulative incidence of relapse was24%, and cumulative incidence of NRM was28.4%. Further prognostic factor analysis revealed that a high quantification of BCR/ABL transcript at the time of allo-HSCT (RR1=1.191, P=0.004; RR2=1.217, P=0.002) and Ⅲ-Ⅳ aGVHD (RR1=6.81, P=0.006; RR2=1.981, P=0.019) were unfavorable predictors for OS and RFS by both univariate and multivariate analyses. Relapse after allo-HSCT was associated with a high quantification of BCR/ABL transcript at allo-HSCT (RR=1.358, P=0.001) and a short duration between diagnosis and allo-HSCT (RR=1.021,P=0.006).Ⅲ-Ⅳ aGVHD was an independent prognostic factor of NRM (RR=6.262, P=0.023). We didn’t find a prognostic significance of pretransplant imatinib use, donor source, positivity of BCR/ABL and minimal residual disease detected by flow cytometry in predicting survival outcomes. Although a limited patients was a major drawback in our study, our results emphasized qualitative measuring of BCR/ABL transcripts was a strong predictor of survival and relapse post transplantation, and we also confirmed Ⅲ-Ⅳ aGVHD was related to a high NRM and a survival impairment. In imatinib era, further studies focusing on the kinetics of BCR/ABL transcripts before and after allo-HSCT were needed to find out the predictive value of BCR/ABL quantification.更多还原