自体和异基因造血干细胞移植治疗自然杀伤/T细胞淋巴瘤患者的多中心临床研究

Multi-center clinical analysis on autologous and allogeneic hematopoietic stem cell transplantation in treatment of patients with natural killer/T cell lymphoma

目的探讨自体造血干细胞移植(auto-HSCT)和异基因造血干细胞移植(allo-HSCT)治疗自然杀伤/T细胞淋巴瘤(NKTL)患者的疗效及预后差异。方法选择2007年6月至2017年6月,于国内8家三级甲等教学医院住院并接受auto-HSCT或allo-HSCT治疗的37例NKTL患者为研究对象。根据患者接受的造血干细胞移植(HSCT)类型,将其分为auto-HSCT组(n=17)和allo-HSCT组(n=20)。auto-HSCT和allo-HSCT组患者的中位年龄分别为34.0岁(27.5~43.5岁)和33.0岁(25.8~41.3岁);男性患者分别为10和17例;女性分别为7和3例。采用回顾性队列研究方法,收集2组患者的临床病例资料,并且分析其疗效及预后。对2组患者的随访截至2017年12月31日。2组NKTL患者的临床分期、受累部位及移植前化疗方案种类构成比等计数资料比较,采用χ^(2)检验或Fisher确切概率法;对于呈偏态分布的计量资料,如患者年龄、单个核细胞(MNC)及CD34+细胞输注量等,2组比较采用Mann-Whitney U检验。采用Kaplan-Meier法绘制2组NKTL患者的累积复发、累积移植相关死亡率(TRM)、总体生存(OS)和疾病无进展生存(PFS)曲线,并且对2组上述指标采用log-rank检验进行比较。采用Cox比例风险回归模型,对NKTL患者OS率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①auto-HSCT组17例NKTL患者中,移植前处于完全缓解(CR)、部分缓解(PR)、疾病稳定(SD)和疾病进展(PD)的患者分别为12、4、1例及0;allo-HSCT组分别为4、11、1及4例。2组患者骨髓受累、移植前疾病状态、预处理方案种类的构成比分别比较,差异均有统计学意义(P=0.001,χ^(2)=12.087、P=0.016,χ^(2)=23.632、P<0.001)。②auto-HSCT组NKTL患者的中性粒细胞和血小板均植入成功,中位植入时间分别为11.0 d(9.5~11.0 d)和11.0 d(9.5~14.0 d);allo-HSCT组患者中,中性粒细胞和血小板植入成功者均为18例,中位植入时间分别为15.0 d(13.0~16.0 d)和16.0 d(13.0~20.3 d)。2组患者的3年累积TRM比较,差异无统计学意义(6.2%比23.7%,χ^(2)=1.658,P=0.198)。③allo-HSCT组NKTL患者中,发生移植物抗宿主病(GVHD)、急性GVHD(aGVHD)、慢性GVHD(cGVHD)者分别为13、6和9例;GVHD患者经治疗后,其GVHD相关临床症状均获得有效控制并好转。④auto-HSCT组与allo-HSCT组NKTL患者的3年累积复发率、2年PFS率分别比较,差异均无统计学意义(35.5%比48.1%,χ^(2)=0.796,P=0.372;64.8%和43.1%,χ^(2)=2.765,P=0.096);auto-HSCT组患者的2年OS率较allo-HSCT组显著升高,并且差异有统计学意义(82.0%比41.3%,χ^(2)=4.697,P=0.03)。⑤多因素Cox风险比例回归模型分析结果显示,allo-HSCT并非影响NKTL患者OS率的独立危险因素(HR=4.618,95%CI:0.992~21.497,P=0.051)。结论auto-HSCT和allo-HSCT均为治疗NKTL的有效方法。移植前获得CR的NKTL患者接受auto-HSCT后,其OS率获得明显改善。部分复发/难治性NKTL患者接受allo-HSCT后,病情得到有效控制。但是由于本研究为回顾性研究,并且纳入样本量较少,auto-HSCT和allo-HSCT治疗NKTL患者的疗效及预后差异,尚需前瞻性、大样本量的多中心随机对照临床试验进一步研究及证实。

Objective To explore difference of clinical effects and prognosis of autologous hematopoietic stem cell transplantation(auto-HSCT)and allogeneic hematopoietic stem cell transplantation(allo-HSCT)in treatment of patients with natural killer/T cell lymphoma(NKTL).Methods From June 2007 and June 2017,a total of 37 patients underwent auto-HSCT or allo-HSCT from 8 Chinese GradeⅢclass A teaching hospitals were selected as research subjects.The median ages of patients in auto-HSCT group and allo-HSCT group were 34.0 years(27.5-43.5 years)and 33.0 years(25.8-41.3 years),respectively.There were 10 male and 7 female patients in auto-HSCT group,and 17 male and 3 female patients in allo-HSCT group,respectively.According to hematopoietic stem cell transplantation(HSCT)types of patients underwent,all subjects were divided into auto-HSCT group(n=17)and allo-HSCT group(n=20).Then clinical data of NKTL patients in auto-HSCT group and allo-HSCT group were collected,and clinical effect and prognosis of patients in two groups were analyzed by retrospectively cohort method.Patients in both groups were followed up until December 31,2017.Chi-square test or Fisher probabilities were used to compare categorical data between two groups,including composition ratios of clinical stages,marrow metastases,types of chemotherapy regimen and so on.Mann-Whitney U test was used to compare measurement data with skewed distribution,including age,transfusion amount of mononuclear cells(MNC)and CD34+cells etc..Kaplan-Meier method was used to draw survival curve of cumulative relapse,cumulative transplant-related mortality(TRM),overall survival(OS)and progression-free survival(PFS)of two groups,which were compared by log-rank test.Cox proportional hazards regression model was performed for univariate and multivariate analysis of OS rates between two groups.This study was in line with World Medical Association Declaration of Helsinki revised in 2013,and informed contents were obtained from all subjects.Results①In auto-HSCT group,there were 12,4,1 and 0 patients evaluated as complete remission(CR),partial remission(PR),stable disease(SD)and progressive disease(PD)before HSCT,respectively.There were 4,11,1 and 4 cases in allo-HSCT group,respectively.There were significant differences among composition ratios of bone marrow metastase,disease states before HSCT and types of conditioning regimen(P=0.001;χ^(2)=12.087,P=0.016;χ^(2)=23.632,P<0.001)between two groups.②In auto-HSCT group,all 17 NKTL patients had successful neutrophil and platelet engraftment,and median engraftment time were 11.0 d(9.5-11.0 d)and 11.0 d(9.5-14.0 d),respectively.In allo-HSCT group,there were 18 NKTL patients with sucsessful neutrophil and platelet engraftment,and median engraftment time were 15.0 d(13.0-16.0 d)and 16.0 d(13.0-20.3 d),respectively.There was no significant difference in 3-year cumulative TRM(6.2%vs 23.7%;χ^(2)=1.658,P=0.198)between two groups.③There were 13,6 and 9 patients with graft versus host disease(GVHD),acute GVHD(aGVHD)and chronic GVHD(cGVHD),respectively.Patients with GVHD acquired effective control and improved of GVHD-related clinical symptoms after therapy.④There were no significant differences in 3-year cumulative relapsed rates(35.5%vs 48.1%;χ^(2)=0.796,P=0.372)and 2-year PFS rates(64.8%vs 43.1%;χ^(2)=2.765,P=0.096)between two groups,but 2-year OS rate in auto-HSCT group was significantly higher than that of allo-HSCT group(82.0%vs 41.3%;χ^(2)=4.697,P=0.03).⑤The results of multivariate Cox proportional hazard regression analysis showed that underwent allo-HSCT was not an independent risk factor influencing OS rate of NKTL patients(HR=4.618,95%CI:0.992-21.497,P=0.051).Conclusions Auto-HSCT and allo-HSCT are both effective therapeutic methods for NKTL patients.OS rate of NKTL patients who acquire CR before HSCT could be improved by auto-HSCT,and disease state of patients who are relapsed or refractory can be controlled by allo-HSCT.However,this study is analysis by retrospective mothod,and sample size is limited,so the differences in efficacy and prognosis between auto-HSCT and allo-HSCT in treatment of NKTL patients needs to be further confirmed by prospective,large sample size and clinical randomized controlled studies.