异基因造血干细胞移植治疗复发/难治性急性白血病患者的疗效及预后影响因素分析

Analysis of efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory acute leukemia

目的探讨异基因造血干细胞移植(allo-HSCT)治疗复发/难治性急性白血病(R/R AL)患者的疗效及预后影响因素。方法选择2008年1月至2020年11月于西安交通大学第一附属医院接受allo-HSCT治疗的34例R/R AL患者为研究对象。根据患者移植前疾病状态将其分为未缓解状态(NR)组(n=10)和完全缓解(CR)组(n=24)。2组患者的中位年龄分别为29.0岁(14.8,46.5岁)和34.0岁(26.5,43.8岁),男性患者分别为7和15例,女性分别为3和9例,急性髓细胞白血病(AML)分别为6和15例,急性淋巴细胞白血病(ALL)分别为4和9例。2组患者的一般临床资料比较,差异均无统计学意义(均P>0.05)。2组患者接受移植前均接受以改良BuCy2(白消安+环磷酰胺+司莫司汀)方案为基础的清髓性预处理,移植后定期随访至2020年11月30日。采用回顾性研究方法,收集患者的年龄、初诊时白细胞计数、中性粒细胞植入时间、移植相关并发症发生率等临床资料,2组比较采用Fisher确切概率法、成组t检验或Mann-Whitney U检验。采用Kaplan-Meier法绘制总体生存(OS)、无进展生存(PFS)曲线,2组患者生存曲线比较采用log-rank检验。采用Cox比例风险回归模型对可能影响患者预后的影响因素进行单因素和多因素分析。本研究遵循的程序符合2013年修订版《世界医学协会赫尔辛基宣言》要求,并且与所有受试者签署临床研究知情同意书。结果①本研究34例患者接受移植后,均获得造血功能重建,NR组患者的血小板植入时间较CR组缩短,并且差异有统计学意义[(11.6±2.2)d比(14.5±3.2)d;t=2.622,P=0.013]。②34例患者的移植后100 d移植相关死亡率(TRM)为17.6%(6/34),NR组患者的100 d TRM高于CR组,并且差异有统计学意义[40.0%(4/10)比8.3%(2/24),P=0.048];NR组和CR组患者的急性移植物抗宿主病(aGVHD)发生率[70.0%(7/10)比54.2%(13/24)]和慢性GVHD(cGVHD)发生率[16.7%(1/6)比38.1%(8/21)]分别比较,差异均无统计学意义(P=0.467、0.628)。③本研究中位随访时间51.9个月(32.3,71.5个月)时,34例患者的中位OS期、中位PFS期,2年OS率、2年PFS率分别为27.9个月(12.5,156.0个月),未达到(14.2个月,未达到),55.7%和70.1%。与CR组患者相比,NR组患者的中位OS期[9.8个月(9.4,30.6个月)比34.9个月(14.5,156.0个月)]和中位PFS期[14.2个月(9.0个月,未达到)比未达到(28.2个月,未达到)]缩短,2年累积复发率升高(60.0%比18.4%),并且差异均有统计学意义(χ^(2)=5.622、5.526、5.526,P=0.018、0.019、0.019)。④单因素和多因素Cox比例风险回归模型分析结果显示,初诊时高白细胞计数(HR=1.006,95%CI:1.000~1.012,P=0.049)为影响患者OS的独立危险因素,移植前处于NR为影响患者PFS的独立危险因素(HR=3.588,95%CI:1.001~12.866,P=0.049)。结论allo-HSCT是治疗R/R AL患者的有效治疗手段,而初诊时高白细胞计数和移植前NR者的预后较差。

ObjectiveTo investigate efficacy and prognostic factors of allogeneic hematopoietic stem cell transplantation(allo-HSCT)for patients with relapsed or refractory acute leukemia(R/R AL).MethodsFrom January 2008 to November 2020,a total of 34 patients with R/R AL who underwent allo-HSCT at the First Affiliated Hospital of Xi′an Jiaotong University were selected as research subjects in this study.According to patients′pre-transplant disease status,all patients were divided into no remission(NR)group(n=10)and complete remission(CR)group(n=24).The median age of patients was 29.0 years(14.8,46.5 years)in NR group,including 7 males and 3 females,and 6 acute myeloid leukemia(AML)and 4 acute lymphoblastic leukemia(ALL)patients.In CR group,median age of patients was 34.0 years(26.5,43.8 years),including 15 males and 9 females,and 15 AML and 9 ALL patients.There were no statistical differences in clinical characteristics between two groups(all P>0.05).All patients received a modified BuCy2(busulfan+cyclophosphamide+semustine)-based regimen as conditioning.All patients were followed up until November 2020.The retrospective study method was used to collect clinical data such as the patients′age,white blood cell count at initial diagnosis,time of neutrophil implantation,and incidence of transplant-related complications.The comparison between two groups was conducted using Fisher exact probabilities,group t-test,or Mann-Whitney U test.The overall survival(OS)and progression-free survival(PFS)curves were plotted by Kaplan-Meier method,and the log-rank test was used to compare the survival curves of the two groups.The Cox proportional hazards regression model was used to perform univariate and multivariate analysis of the influencing factors that may affect the prognosis of patients.This study was in line with World Medical Association Declaration of Helsinki revised in 2013 and informed contents were obtained from the subjects.Results①In this study,all 34 patients who underwent allo-HSCT achieved hematopoietic function reconstruction.The patients in NR group had a shorter time for platelet engraftment compared to CR group,and the difference was statistically significant[(11.6±2.2)d vs(14.5±3.2)d;t=2.622,P=0.013].②The transplant-related mortality(TRM)within 100 d after transplantation in all 34 patients was 17.6%(6/34).The patients in NR group had a higher 100 d TRM compared to CR group,and the difference was statistically significant[40.0%(4/10)vs 8.3%(2/24),P=0.048].The incidence of acute graft-versus-host disease(aGVHD)and chronic GVHD(cGVHD)of patients in NR group were 70.0%(7/10)and 16.7%(1/6),and which were 54.2%(13/24)and 38.1%(8/21)in CR group respectively,and there were not statistically significant between two groups(P=0.467,0.628).③At the median follow-up of 51.9 months(32.3,71.5 months)in this study,the median OS time,median PFS time,2-year OS rate and 2-year PFS rate of all 34 patients were 27.9 months(12.5,156.0 months),not reached(14.2 months,not reached),55.7%and 70.1%,respectively.Compared with CR group,the median OS time[9.8 months(9.4,30.6 months)vs 34.9 months(14.5,156.0 months)]and median PFS time[14.2 months(9.0 months,not reached)vs not reached(28.2 months,not reached)]were shortened in NR group,and 2-year cumulative recurrence rate was increased(60.0%vs 18.4%),and the differences were statistically significant(χ^(2)=5.622,5.526,5.526;P=0.018,0.019,0.019).④The results of univariate and multivariate Cox proportional hazards regression model analysis showed that high white blood cell count at initial diagnosis(HR=1.006,95%CI:1.000-1.012,P=0.049)was an independent risk factor affecting the patients′OS,and NR before transplantation was an independent risk factor affecting PFS(HR=3.588,95%CI:1.001-12.866,P=0.049).ConclusionsAllo-HSCT is an effective treatment for patients with R/R AL.Patients with high white blood cell count at initial diagnosis,or NR before allo-HSCT have poor prognosis.