Ph染色体阳性急性淋巴细胞白血病行异基因造血干细胞移植的临床分析
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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。
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.
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.
引文
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