Chinese Journal of Tissue Engineering Research ›› 2020, Vol. 24 ›› Issue (19): 3093-3100.doi: 10.3969/j.issn.2095-4344.2073
Previous Articles Next Articles
Wei Yuanfeng, Huang Dongping
Received:
2019-09-11
Revised:
2019-09-11
Accepted:
2019-10-31
Online:
2020-07-08
Published:
2020-04-09
Contact:
Huang Dongping, Master’s supervisor, Chief physician, Department of Hematopathology, Yijishan Hospital of Wannan Medical College, Wuhu 241000, Anhui Province, China
About author:
Wei Yuanfeng, Master candidate, Department of Hematopathology, Yijishan Hospital of Wannan Medical College, Wuhu 241000, Anhui Province, China
Supported by:
CLC Number:
Wei Yuanfeng, Huang Dongping. Current status of hematopoietic stem cell transplantation in the treatment of aplastic anemia[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(19): 3093-3100.
2.1 同胞全相合造血干细胞移植 随着移植失败及重度急慢性移植物抗宿主病发生率的减少,MSD-HSCT疗效有了显著提高,成人长期生存率可达80%,儿童高达90%以上[2-4]。YOSHIDA等[5]回顾性分析了日本1992至2009年期间599例年龄<17岁的重型再生障碍性贫血患儿接受免疫抑制治疗(n=386)或MSD-HSCT治疗(n=213)的数据,结果显示:两组之间的总体生存率无显著差异[免疫抑制治疗(88%) vs. MSD-HSCT(92%)],但免疫抑制治疗组无失败生存率明显低于MSD-HSCT组[免疫抑制治疗(56%) vs. MSD-HSCT(87%)]。GALLO等[6]报告其中心对21例重型再生障碍性贫血患者(包括儿童和成人)行MSD-HSCT,所有患者均未发生移植排斥,获得持续稳定植入,4年总体生存率达到100%。目前国内外指南推荐对于年龄≤35岁的有同胞全相合供者的重型再生障碍性贫血患者一线治疗选择MSD-HSCT[7-8]。 2.1.1 年龄 既往研究表明年龄是影响移植疗效的重要因素,> 40岁的患者植入失败、移植物抗宿主病及移植相关死亡率均显著增加[9-10]。意大利最新的一项大型研究再次证实了这一观点,该研究纳入2001至2009年、2010至2015年2个时间段768例40岁以上行造血干细胞移植的重型再生障碍性贫血患者。研究表明15年来年龄超过40岁的重型再生障碍性贫血患者造血干细胞移植的疗效没有提高,40岁以上重型再生障碍性贫血患者行异基因造血干细胞移植仍然存在显著的死亡风险[11]。近期韩国的一项研究结果与此相反,研究纳入2002至2014年117例行MSD-HSCT的重型再生障碍性贫血患者,结果显示:年龄> 40岁的患者总体生存率、无失败生存率与< 40岁的患者之间无统计学差异[12]。RICE等[13]研究50岁以上的重型再生障碍性贫血患者行异基因造血干细胞移植的疗效,该研究中499例患者的中位年龄57.8岁,16%的患者年龄在65-77岁之间。研究显示:年龄和生存无关,但是年龄> 65岁的患者Ⅱ-Ⅳ度急性移植物抗宿主病的发生率较高。目前国内指南将移植年龄上限调至50岁[7]。 2.1.2 移植物 由粒细胞集落刺激因子动员的外周血造血干细胞具有易采集、对供者创伤小、造血及免疫重建快、移植早期感染率低的优点,但是SCHREZENMEIER等[14]回顾性分析了1995至2003年在EBMT和CIBMTR进行MSD-HSCT的692例重型再生障碍性贫血患者,结果显示:对于年龄> 20岁的患者,外周血造血干细胞组和骨髓造血干细胞组慢性移植物抗宿主病的发生率、总体死亡率相似。然而对于< 20岁的患者,外周血造血干细胞组慢性移植物抗宿主病的发生率、总体死亡率显著高于骨髓造血干细胞组。2012年发表在《Haematologica》上的一篇文章,其认为不论对于< 20岁或> 20岁的患者来说,外周血造血干细胞组移植物抗宿主病的发生率均高于骨髓造血干细胞组,总体生存率均低于骨髓造血干细胞组[15]。欧洲血液和骨髓移植学会的一项纳入1 448例重型再生障碍性贫血患者的大型研究再次证实了外周血造血干细胞是影响移植后生存的不利因素,5年总体生存率在骨髓造血干细胞组和外周血造血干细胞组分别为83%和70%,由移植物抗宿主病和感染引起的死亡率在骨髓造血干细胞组及外周血造血干细胞组中分别为7%和17%[16]。2017年中国专家共识中推荐使用含骨髓的移植物进行移植[7]。 2.1.3 预处理 年轻患者的标准预处理方案为总剂量200 mg/kg环磷酰胺+抗淋巴细胞球蛋白[17-18]。 200 mg/kg的环磷酰胺对于高龄患者来说毒性太大,其引起的移植相关死亡让人不得不改变高龄患者的预处理方案。根据EBMT的一组最新数据显示:对于40岁以上的患者,使用以氟达拉滨、环磷酰胺、抗淋巴细胞球蛋白或阿仑珠单抗的减低剂量的预处理方案,不仅可以避免高剂量环磷酰胺引起的毒性反应,而且能获得与21-40岁年龄组相似的总体生存率[19]。2016年英国血液学协会制定的指南:对于年龄超过30岁计划行MSD-HSCT的重型再生障碍性贫血患者,推荐使用氟达拉滨、环磷酰胺、抗淋巴细胞球蛋白或阿仑单抗的预处理方案[8]。近期巴基斯坦一项纳入147例高危再生障碍性贫血患者的研究中探索了以氟达拉滨为基础的预处理方案中氟达拉滨及环磷酰胺的剂量,该研究分为2组,组1:氟达拉滨120-150 mg/m2,环磷酰胺120- 200 mg/kg,抗淋巴细胞球蛋白20 mg/kg;组2:氟达拉滨120 mg/m2,环磷酰胺300 mg/m2,抗淋巴细胞球蛋白20 mg/kg。研究发现18例患者植入失败,多数病例来自组2,且组2的总体生存率较组1低,因此研究认为氟达拉滨联合小剂量的环磷酰胺更有利于患者的生存[20]。尽管目前在每个移植中心的预处理中使用的环磷酰胺的量是不同的,但通常认为剂量在40-120 mg/kg之间较为合适。 2.1.4 移植物抗宿主病的预防 移植后移植物抗宿主病标准预防方案为甲氨蝶呤联合环孢素[18]。巴基斯坦一项纳入147例高危再生障碍性贫血患者的研究中,110例患者单独使用环孢素预防移植物抗宿主病,37例患者使用环孢素+甲氨蝶呤预防移植物抗宿主病。147例患者中共17例发生Ⅰ-Ⅳ度急性移植物抗宿主病,19例发生慢性移植物抗宿主病。单独采用环孢素组的总体生存率、无失败生存率与环孢素+甲氨蝶呤组无统计学差异,而且无复发、移植物抗宿主病生存高于环孢素+甲氨蝶呤组,研究认为可以单独使用环孢素预防移植物抗宿主病[20]。目前推荐移植后应用以环孢素为基础的免疫抑制剂来预防移植物抗宿主病。 2.2 无关供者造血干细胞移植 指南推荐无全相合亲缘供者的儿童重型再生障碍性贫血患者可以选择MUD-HSCT作为一线治疗方案;有全相合无关供者且年龄<50岁(年龄在50-60岁之间者,需要一般状况良好)的成年重型再生障碍性贫血患者,在至少经过1个疗程的免疫抑制治疗无效后可以选择MUD-HSCT作为二线或三线治疗[7]。既往研究表明重型再生障碍性贫血患儿一线治疗选择MUD-HSCT的疗效优于免疫抑制治疗及免疫抑制治疗失败后的MUD-HSCT[21-22]。巴西的学者比较了重型再生障碍性贫血患儿行MRD-HSCT(n=69)和MUD-HSCT(n=37)的疗效,中位随访4.5年,81例患者存活,两组间4年总体生存率、移植后6个月急性移植物抗宿主病、移植后2年慢性移植物抗宿主病发生率无统计学差异[23]。目前MUD-HSCT治疗成人重型再生障碍性贫血缺乏一线治疗数据。瑞典的一项全国性的队列研究以MUD-HSCT作为二线治疗方案与MSD-HSCT的疗效比较,不论是儿童还是成人的MUD-HSCT均可以获得与MSD-HSCT类似的高总体生存率及无复发、移植物抗宿主病生存[24]。 2.2.1 移植物 由于国内相关政策法规,对无关供者只允许采集外周血造血干细胞,这限制了再生障碍性贫血患者移植疗效。间充质干细胞构成骨髓造血微环境,可促进移植后的快速植入、诱导免疫耐受、预防及治疗移植物抗宿主病,部分移植中心在移植时试验性地加入间充质干细胞,均获得可喜的结果。国内学者王玲等[25]为19例重型再生障碍性贫血患儿使用MUD-HSCT和间充质干细胞共移植,证实间充质干细胞的输注是安全的,所有患儿不仅能获得迅速的造血重建,而且急性移植物抗宿主病及慢性移植物抗宿主病发生率低且程度较轻。 2.2.2 预处理 MUD-HSCT目前无统一标准的预处理方案,近年来有报道且疗效尚可的预处理方案有:氟达拉滨+环磷酰胺+抗淋巴细胞球蛋白±2 Gy全身照射(FCATG±2 Gy全身照射方案)[26],氟达拉滨+环磷酰胺+阿仑单抗(FCC方案)[21,27]。编码为NCT00326417的多中心临床试验中探讨了FCATG+2 Gy全身照射方案中环磷酰胺的最佳剂量。所有患者均采用马抗淋巴细胞球蛋白[30 mg/(kg·d),-4 d至-2 d]或者兔抗淋巴细胞球蛋白[3 mg/(kg·d),-4 d至-2 d];氟达拉滨30 mg/(m2·d) (-5 d至-2 d);全身照射2 Gy(-1 d);环磷酰胺的剂量从150 mg/kg开始,每组剂量递减50 mg/kg(分别为 100 mg/kg,50 mg/kg,0 mg/kg)。研究结果示:移植后100 d,环磷酰胺50 mg/kg组3例(8%)植入失败,35例(92%)存活;100 mg/kg组6例(15%)植入失败,35例(85%)存活,研究认为环磷酰胺的总剂量在50- 100 mg/kg较为合适[26]。2016年国外指南推荐FCATG+ 2 Gy全身照射或者FCC方案作为成人MUD-HSCT的预处理方案[8]。有研究显示阿仑单抗在减低移植物抗宿主病发生率的同时会增加移植后病毒感染的概率[28]。中国2017年专家共识:年轻患者推荐使用环磷酰胺 300 mg/(m2·d)×4 d;氟达拉滨30 mg/(m2·d)×4 d;兔源抗淋巴细胞球蛋白;环孢素。共识中指出年轻的患者应避免使用全身照射,尽管低剂量全身照射可能降低老年患者的排斥反应[7]。 2.2.3 移植物抗宿主病的预防 改进的预处理方案不仅可以促进植入,而且可以减低移植物抗宿主病的发生率[27]。大多数移植中心在优化的预处理方案移植后常辅以环孢素为基础的免疫抑制剂来预防移植物抗宿主病的发生。英国骨髓移植工作组在FCC预处理方案MUD-HSCT后单独使用环孢素预防移植物抗宿主病,获得与MSD-HSCT相似的2年无病生存率[21]。 2.3 单倍体造血干细胞移植 既往推荐在无全相合供者且免疫抑制治疗失败的情况下,重型再生障碍性贫血患者可以选择Haplo-HSCT作为二线或三线治疗。随着移植方案与技术的改进,目前Haplo-HSCT的疗效有着明显提高。近期国内一项多中心研究比较了免疫抑制治疗和Haplo-HSCT治疗成人重型再生障碍性贫血的疗效。研究共纳入了113例成人重型再生障碍性贫血患者,分为免疫抑制治疗组(n=37)和Haplo-HSCT组(n=76)。研究发现两组之间8年总体生存率无统计学差异,但免疫抑制治疗组无失败生存率明显低于Haplo-HSCT组[29]。儿童及青少年患者Haplo-HSCT的疗效同样优于免疫抑制治疗[30-31]。北大人民医院等多移植中心比较了89例一线治疗为Haplo-HSCT和同期68例一线治疗为MSD-HSCT的重型再生障碍性贫血患者相关临床数据,结果显示:两组间1年累计Ⅱ-Ⅳ度急性移植物抗宿主病、Ⅲ-Ⅳ度急性移植物抗宿主病及慢性移植物抗宿主病发生率有统计学差异,中位粒系植入时间、累积粒系植入率、广泛性慢性移植物抗宿主病及3年总体生存率均无统计学差异[32]。 2.3.1 移植物 (1)体外去T细胞的移植物:体外去T细胞分为间接去T细胞及直接去T细胞,间接去T细胞即选择CD34+移植物,直接去T细胞即去CD3+细胞或αβT细胞。KIM等[33]采用体外去T细胞单倍体移植治疗32例重型再生障碍性贫血患者,其中12例采用去CD3+T细胞移植物,4例采用去CD3+和CD19+T细胞移植物,16例采用去αβT细胞移植物,将其分为去CD3+T细胞组(16例)及去αβT细胞组(16例),中位随访2.4年,去CD3+T细胞组有6例发生植入失败,而去αβT细胞组没有患者发生植入失败。两组间Ⅲ-Ⅳ度急性移植物抗宿主病的发生率无统计学差异;共3例发生慢性移植物抗宿主病,其中2例为去CD3+T细胞组,1例为去αβT细胞组。两组5年总体生存率相似,但5年无失败生存率去αβT细胞组明显优于去CD3+T细胞组。 (2)非体外T细胞清除的粒细胞集落刺激因子动员外周血干细胞联合骨髓移植物:国内以北大人民医院为首的多移植中心均采用粒细胞集落刺激因子动员的骨髓和外周血干细胞。具体为供者从-3 d开始皮下注射 5 μg/(kg·d)粒细胞集落刺激因子直到干细胞采集最后 1 d。第1天采集骨髓,第2天采集外周血干细胞。若前 2 d采集的总单核细胞计数小于(6-8)×108/kg,第3天继续采集外周血干细胞[32,34-35]。 (3)亲缘供者干细胞联合第三方的间充质干细胞:为增加Haplo-HSCT的疗效国内多个中心在移植时加入间充质干细胞。国内一项多中心试验用供者来源的骨髓间充质干细胞联合单倍体造血干细胞移植治疗35例重型再生障碍性贫血患儿。35例患者均实现造血重建,并显示持续的供体嵌合;粒系植入中位时间为14 d(10-22 d),血小板植入中位时间为18 d(9-36 d);Ⅱ-Ⅳ度急性移植物抗宿主病和慢性移植物抗宿主病的发生率分别为25.71%和22.86%;中位随访22个月(3.5-37个月),总生存率为85.71%[36]。另一项国内的多中心Ⅱ期临床试验纳入44例重型再生障碍性贫血患者,44例患者中有3例在造血移植前死亡,没有进行评估;剩余41例患者实现造血重建,维持供体完全嵌合;Ⅱ-Ⅳ度急性移植物抗宿主病的发生率为29.3%,慢性移植物抗宿主病的发生率为14.6%;中位随访时间为12个月(0.9-30.8个月),总生存率为77.3%[37]。骨髓间充质干细胞的联合移植可以降低重型再生障碍性贫血患者移植失败和严重移植物抗宿主病的风险[38-39]。 2.3.2 预处理 目前对于单倍体移植无统一的预处理方案,KIM等[33]采用兔抗胸腺球蛋白+氟达拉滨+环磷酰胺+全身照射的预处理方案,给药剂量及时间具体如下:氟达拉滨150 mg/m2,环磷酰胺120 mg/kg,兔抗胸腺球蛋白2.5 mg/(kg·d)(-8 d至-6 d),全身照射200 cGy/d (-3 d至-2 d)。结果显示:与同期行MSD-HSCT、MUD-HSCT的患者相比,不仅粒系植入快,而且+30 d粒系累积植入率高。约翰·霍普金斯大学医学院采用移植后环磷酰胺非清髓性预处理方案治疗16例重型再生障碍性贫血,包括兔抗胸腺球蛋白+氟达拉滨+低剂量环磷酰胺+全身照射。药品剂量及使用方法如下:兔抗胸腺球蛋白0.5 mg/kg(-9 d)、2 mg/kg(-8 d至-7 d);氟达拉滨:30 mg/(m2·d)(-6 d至-2 d)(总剂量为150 mg/m2);环磷酰胺:14.5 mg/(kg·d) (-6 d至-5 d);-1 d以200 cGy的单剂量给予全身照射;环磷酰胺50 mg/kg(+3 d至 +4 d)。结果显示:16例患者全部植入成功,仅2例患者发生Ⅰ-Ⅱ度皮肤急性移植物抗宿主病,中位随访21个月(3-64个月),所有患者全部存活,且不依赖输血也无克隆性演化[40]。北京方案采用白消安+环磷酰胺+兔抗胸腺球蛋白方案,剂量和使用方法如下:白消安 3.2 mg/(kg·d)×2 d(-7 d至-6 d),环磷酰胺 50 mg/(kg·d)×4 d(-5 d至-2 d),兔抗胸腺球蛋白 2.5 mg/(kg·d)×4 d(-5 d至-2 d)。该方案植入好,移植相关毒性小[32,34-35]。 2.3.3 急性移植物抗宿主病的预防 北京方案采用环孢素+霉酚酸酯+甲氨蝶呤预防急性移植物抗宿主病,具体用药方案如下:环孢素在-9 d开始每12 h给药1次,剂量为1.5 mg/kg,维持血药浓度在150-250 μg/L,患者胃肠功能恢复以后改为口服给药。霉酚酸酯在-9 d开始每12 h口服给药0.5 g (儿童的剂量减少一半),移植后1个月剂量减半至移植后2个月停药。甲氨蝶呤从+1 d开始15 mg/m2,+3 d、+6 d、+11 d剂量为10 mg/m2。急性移植物抗宿主病和慢性移植物抗宿主病发生率低且程度轻[32,34-35]。约翰·霍普金斯大学医学院采用移植后大剂量环磷酰胺预处理方案及霉酚酸酯联合他克莫司的免疫抑制剂预防移植物抗宿主病的发生,其中霉酚酸酯+5 d开始使用至+35 d停用,他克莫司治疗+5 d开始至移植后1年停用。中位随访时间为21个月(范围为3-64个月),2例患者发生Ⅰ-Ⅱ度单纯皮肤型急性移植物抗宿主病,也只有这2例患者发生了轻微的皮肤/口腔慢性移植物抗宿主病,这2例患者分别在移植后15个月和17个月停用免疫抑制剂,其他患者在移植后1年停止免疫抑制剂[40]。国内学者比较了北京方案及移植后大剂量环磷酰胺方案,研究分为移植后大剂量环磷酰胺组及北京方案组:移植后大剂量环磷酰胺组20例,北京方案组80例。移植后大剂量环磷酰胺组移植物抗宿主病预防方案为环磷酰胺60 mg/(kg·d)(+3 d至+4d)+环孢素+甲氨蝶呤+霉酚酸酯(其中17例用了霉酚酸酯,3例未使用霉酚酸酯);北京方案组移植物抗宿主病预防方案为环孢素+甲氨蝶呤+霉酚酸酯;两组间总体生存率、无失败生存率、移植失败、移植相关死亡率、移植物抗宿主病发生率均无统计学差异,但移植后大剂量环磷酰胺组粒系植入较北京方案组延迟[41]。 2.4 脐血移植 脐血移植凭借其易及时获得、免疫原性低可耐受1到2个人类白细胞抗原位点不合、移植后移植物抗宿主病的发生率低且程度轻、移植后患者生存质量高等优点,在造血干细胞移植中占比逐渐增加。近期PAGLIUCA等[42]报道了1988至2014年在欧洲骨髓移植中心进行同胞供者脐血移植的117例骨髓衰竭综合征患者的移植疗效。82例患者输注单份脐血,35例患者输注来自同一供者的脐血和骨髓混合移植物。中性粒细胞累积植入率为88.8%,移植后100 d内急性移植物抗宿主病积累发病率为15.2%,7年慢性移植物抗宿主病累积发病率14.5%,7年总体生存率为87.9%。日本学者进行UCBT和非血缘骨髓移植的疗效比较[43],实验分为UCBT组、无关供者HLA位点8/8相合组、HLA位点7/8相合组以及HLA位点6/8相合组。结果显示:8/8相合非血缘骨髓移植的死亡率低于UCBT;7/8相合及6/8相合非血缘骨髓移植死亡率与UCBT没有显著性差异;重度的急性和慢性移植物抗宿主病在4组间没有显著性差异;UCBT和6/8相合非血缘骨髓移植最常见的死亡原因是移植失败,而8/8相合和7/8相合非血缘骨髓移植的最常见死亡原因是移植后感染;在40岁以下的患者中,UCBT的生存率与非血缘骨髓移植相似。日本学者ONISHI等[44]对22例年龄≥16岁的再生障碍性贫血患者在首次造血干细胞移植失败后进行挽救性UCBT治疗结果进行了回顾性分析。患者中位年龄36岁(16-72岁),第1次至第2次移植中位时间77 d(29-1 061 d);移植后第60天粒系植入的累积发生率为45.5%;中位随访50个月,4年总生存率(总体生存率)为38.5%。 2.4.1 移植物 脐血移植的主要缺点仍然是干细胞数量有限,尤其是在成年人及大体质量儿童中,这可能导致较高的植入失败和造血恢复延迟,导致移植相关死亡率或移植后的总死亡率更高。2016年英国血液和骨髓移植协会脐血工作组更新了UCBT指南,指南中指出对于非恶性血液病,冻存时细胞数≥(3-5)×107/kg,解冻后细胞数≥3.0×107/kg。对于再生障碍性贫血等骨髓衰竭性疾病,冻存时总的有核细胞≥5×107/kg,CD34+细胞数不管在冻存还是复苏后细胞数均要≥1.7×105/kg[45]。目前多采用双份脐血扩增干细胞数量,虽然成人双份脐血移植(dUCBT)成功率高,但造血功能恢复通常仅仅来自其中1个脐血单位(脐血单位)。一项研究观察到双份脐血移植后血液中CD4+T细胞数量迅速增加,而且可以通过早期CD4+T细胞嵌合状态预测哪一份是优势脐血。双份脐血移植中常有HLA Ⅱ类等位基因不相合,文中推测优势脐血单位的HLAⅡ类特异性CD4+T细胞不仅能快速排斥“劣势”脐血单位,还可能识别白血病细胞导致移植物抗白血病[46]。国外学者使用细胞因子和铜螯合剂四乙戊胺对选定的部分脐血单位(20%-50%)进行体外扩增,并在清髓性预处理后后输注扩增后的脐血。该项研究的实验组共纳入了101例患者,与同期双份脐血移植组(n=295)进行比较。结果显示:实验组100 d总体生存率为84.2%,而双份脐血移植组为74.6% (P=0.035);两组患者180 d总体生存率相似;急性移植物抗宿主病和慢性移植物抗宿主病发生率相似。在这项研究中,与行双份脐血移植相比,体外扩增脐血干细胞不仅促进骨髓和血小板移植,而且提高了患者100 d的总体生存率[47]。目前扩增脐血中干细胞数量的方法还包括:脐血联合同一供者骨髓干细胞、脐血联合第三方单倍体干细胞或者间充质干细胞,但多为单中心小样本的临床研究,需要扩大病例数进一步研究。 2.4.2 预处理 日本学者为12例行UCBT的重型再生障碍性贫血患者采用氟达拉滨+美法仑+全身照射非清髓性预处理方案[48],具体为:氟达拉滨125 mg/m2,美法仑80 mg/m2,4 Gy全身照射。1例原发性植入失败,1例继发性植入失败;中位随访36个月,10例患者存活,获得完全供者嵌合及完全造血重建。法国多中心UCBT治疗难治性重型再生障碍性贫血患者的预处理方案 为[49]:氟达拉滨+环磷酰胺+抗淋巴细胞球蛋白+全身照射,其中氟达拉滨 30 mg/m2(-6 d至-3 d),环磷酰胺 30 mg/kg(-6 d至-3 d),抗淋巴细胞球蛋白2.5 mg/kg (-3 d至-2 d);全身照射2 Gy(-2 d)。中位随访38.8个月,23例患者(88%)植入;Ⅱ-Ⅳ级急性移植物抗宿主病和慢性移植物抗宿主病的累积发生率分别为45.8%和36%,23例患者1年生存率为88.5%。KUDO等[50]通过回顾性分析27例重型再生障碍性贫血患者临床资料,研究抗淋巴细胞球蛋白在UCBT的预处理方案中是否是必需的,实验组采用氟达拉滨+环磷酰胺/美法仑+全身照射方案(不加抗淋巴细胞球蛋白组),对照组采用其他预处理方案。研究结果显示实验组全部植入成功,5年无失败生存率和5年总体生存率均为100%,疗效远远超过对照组。研究认为氟达拉滨+环磷酰胺/美法仑+全身照射(不加抗淋巴细胞球蛋白组)可能是一个最佳的预处理方案。 2.4.3 移植物抗宿主病的预防 脐血移植后移植物抗宿主病的发生率较低,研究表明系因脐血中富含白细胞介素10调节B细胞,这种细胞可以降低移植物抗宿主病的发生率[51]。法国多中心单独使用环孢素预防移植物抗宿主病,移植后的前3个月浓度维持在200-300 μg/L,随后逐渐减量,至移植后1年停用。结果显示:10例发生急性移植物抗宿主病,100 d内急性移植物抗宿主病的累积发生率为45.8%;9例发生慢性移植物抗宿主病,1年内慢性移植物抗宿主病的累积发生率为36%,中位随访18个月,存活的22例患者中有18例已停用免疫抑制剂[50]。目前认为脐血移植后单用环孢素可以有效预防移植物抗宿主病,移植后环孢素应持续6个月至1年[52-53]。 "
[1] 杨崇礼,张晓波.全国再生障碍性贫血发病情况调查[J].中国医学科学院学报,1992,14(1):6-11. [2] DUFOUR C, PILLON M, SOCIÈ G, et al. Outcome of aplastic anaemia in children. A study by the severe aplastic anaemia and paediatric disease working parties of the European group blood and bone marrow transplant. Br J Haematol. 2015;169(4):565-573. [3] DUFOUR C, PILLON M, PASSWEG J, et al. Outcome of aplastic anemia in adolescence: a survey of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation. Haematologica. 2014;99(10):1574-1581. [4] EBENS CL, DEFOR TE, TRYON R, et al. Comparable Outcomes after HLA-Matched Sibling and Alternative Donor Hematopoietic Cell Transplantation for Children with Fanconi Anemia and Severe Aplastic Anemia. Biol Blood Marrow Transplant. 2018;24(4):765-771. [5] YOSHIDA N, KOBAYASHI R, YABE H, et al. First-line treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy. Haematologica. 2014;99(12):1784-1791. [6] GALLO S, WOOLFREY AE, BURROUGHS LM, et al. Marrow grafts from HLA-identical siblings for severe aplastic anemia: does limiting the number of transplanted marrow cells reduce the risk of chronic GvHD? Bone Marrow Transplant. 2016;51(12):1573-1578. [7] 付蓉.再生障碍性贫血诊断与治疗中国专家共识(2017年版)[J].中华血液学杂志,2017,38(1):1-5. [8] KILLICK SB, BOWN N, CAVENAGH J, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016;172(2):187-207. [9] GUPTA V, EAPEN M, BRAZAUSKAS R, et al. Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. Haematologica. 2010; 95(12):2119-2125. [10] PASSWEG JR, MARSH JC. Aplastic anemia: first-line treatment by immunosuppression and sibling marrow transplantation. Hematology Am Soc Hematol Educ Program. 2010;2010:36-42. [11] GIAMMARCO S, PEFFAULT DE LATOUR R, SICA S, et al. Transplant outcome for patients with acquired aplastic anemia over the age of 40: has the outcome improved? Blood. 2018;131(17):1989-1992. [12] SHIN SH, JEON YW, YOON JH, et al. Comparable outcomes between younger (⩽40 years) and older (>40 years) adult patients with severe aplastic anemia after HLA-matched sibling stem cell transplantation using fludarabine-based conditioning. Bone Marrow Transplant. 2016; 51(11):1456-1463. [13] RICE C, EIKEMA DJ, MARSH JCW, et al. Allogeneic Hematopoietic Cell Transplantation in Patients Aged 50Years or Older with Severe Aplastic Anemia. Biol Blood Marrow Transplant. 2019;25(3):488-495. [14] SCHREZENMEIER H, PASSWEG JR, MARSH JC, et al. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia. Blood. 2007; 110(4):1397-1400. [15] BACIGALUPO A, SOCIÉ G, SCHREZENMEIER H, et al. Bone marrow versus peripheral blood as the stem cell source for sibling transplants in acquired aplastic anemia: survival advantage for bone marrow in all age groups. Haematologica. 2012;97(8):1142-1148. [16] BACIGALUPO A, SOCIÉ G, HAMLADJI RM, et al. Current outcome of HLA identical sibling versus unrelated donor transplants in severe aplastic anemia: an EBMT analysis. Haematologica. 2015;100(5): 696-702. [17] STORB R, ETZIONI R, ANASETTI C, et al. Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia. Blood. 1994; 84(3):941-949. [18] KAHL C, LEISENRING W, DEEG HJ, et al. Cyclophosphamide and antithymocyte globulin as a conditioning regimen for allogeneic marrow transplantation in patients with aplastic anaemia: a long-term follow-up. Br J Haematol. 2005;130(5):747-751. [19] BACIGALUPO A. How I treat acquired aplastic anemia. Blood. 2017; 129(11):1428-1436. [20] CHAUDHRY QUN, IFTIKHAR R, SATTI TM, et al. Outcome of Fludarabine-Based Conditioning in High-Risk Aplastic Anemia Patients Undergoing Matched Related Donor Transplantation: A Single-Center Study from Pakistan. Biol Blood Marrow Transplant. 2019;25(12): 2375-2382. [21] DUFOUR C, VEYS P, CARRARO E, et al. Similar outcome of upfront-unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party, Paediatric Diseases Working Party and Severe Aplastic Anaemia Working Party of EBMT. Br J Haematol. 2015; 171(4):585-594. [22] CHOI YB, YI ES, LEE JW, et al. Immunosuppressive therapy versus alternative donor hematopoietic stem cell transplantation for children with severe aplastic anemia who lack an HLA-matched familial donor. Bone Marrow Transplant. 2017;52(1):47-52. [23] DARRIGO LG JR, COLTURATO V, DE SOUZA MP, et al. Allogeneic Bone Marrow Transplants for Pediatric Severe Aplastic Anemia: Real-world Data comparing Matched Related and Unrelated Donors in a Developing Country. Retrospective study on behalf of the Pediatric Hematopoietic Stem Cell Transplant Working Group of the Brazilian Bone Marrow Transplantation Society (SBTMO) and the Brazil-Seattle Consortium (Gedeco). Pediatr Transplant. 2019;23(7):e13552. [24] VAHT K, GÖRANSSON M, CARLSON K, et al. High Graft-versus-Host Disease-Free, Relapse/Rejection-Free Survival and Similar Outcome of Related and Unrelated Allogeneic Stem Cell Transplantation for Aplastic Anemia: A Nationwide Swedish Cohort Study. Biol Blood Marrow Transplant. 2019;25(10):1970-1974. [25] 王玲,王恒湘,朱玲.HLA相合无关供者造血干细胞移植联合脐带间充质干细胞输注治疗儿童重型再生障碍性贫血19例疗效及安全性研究[J].中华血液学杂志,2016,37(6):453-457. [26] ANDERLINI P, WU J, GERSTEN I, et al. Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study. Lancet Haematol. 2015;2(9):e367-375. [27] HAMAD N, DEL BEL R, MESSNER HA, et al. Outcomes of hematopoietic cell transplantation in adult patients with acquired aplastic anemia using intermediate-dose alemtuzumab-based conditioning. Biol Blood Marrow Transplant. 2014;20(11):1722-1728. [28] MARSH JC, PEARCE RM, KOH MB, et al. Retrospective study of alemtuzumab vs ATG-based conditioning without irradiation for unrelated and matched sibling donor transplants in acquired severe aplastic anemia: a study from the British Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2014;49(1):42-48. [29] XU ZL, ZHOU M, JIA JS, et al. Immunosuppressive therapy versus haploidentical transplantation in adults with acquired severe aplastic anemia. Bone Marrow Transplant. 2019;54(8):1319-1326. [30] YANG S, YUAN X, MA R, et al. Comparison of Outcomes of Frontline Immunosuppressive Therapy and Frontline Haploidentical Hematopoietic Stem Cell Transplantation for Children with Severe Aplastic Anemia Who Lack an HLA-Matched Sibling Donor. Biol Blood Marrow Transplant. 2019;25(5):975-980. [31] 唐湘凤,井远方,卢伟.单倍型造血干细胞移植治疗儿童获得性重型再生障碍性贫血的临床研究[J].中华血液学杂志, 2019,40(4):301-305. [32] XU LP, JIN S, WANG SQ, et al. Upfront haploidentical transplant for acquired severe aplastic anemia: registry-based comparison with matched related transplant. J Hematol Oncol. 2017;10(1):25. [33] KIM H, IM HJ, KOH KN, et al. Comparable Outcome with a Faster Engraftment of Optimized Haploidentical Hematopoietic Stem Cell Transplantation Compared with Transplantations from Other Donor Types in Pediatric Acquired Aplastic Anemia. Biol Blood Marrow Transplant. 2019;25(5):965-974. [34] XU LP, WANG SQ, WU DP, et al. Haplo-identical transplantation for acquired severe aplastic anaemia in a multicentre prospective study. Br J Haematol. 2016;175(2):265-274. [35] 许兰平,左扬杨.《Upfront haploidentical transplant for acquired severe aplastic anemia:registry-based comparison with matched related transplant》解读[J].临床血液学杂志, 2017,30(6):834-838. [36] WANG Z, YU H, CAO F, et al. Donor-derived marrow mesenchymal stromal cell co-transplantation following a haploidentical hematopoietic stem cell transplantation trail to treat severe aplastic anemia in children. Ann Hematol. 2019;98(2):473-479. [37] LIU Z, ZHANG Y, XIAO H, et al. Cotransplantation of bone marrow-derived mesenchymal stem cells in haploidentical hematopoietic stem cell transplantation in patients with severe aplastic anemia: an interim summary for a multicenter phase II trial results. Bone Marrow Transplant. 2017;52(5):704-710. [38] XU L, LIU Z, WU Y, et al. Clinical evaluation of haploidentical hematopoietic combined with human umbilical cord-derived mesenchymal stem cells in severe aplastic anemia. Eur J Med Res. 2018;23(1):12. [39] YUE C, DING Y, GAO Y, et al. Cotransplantation of haploidentical hematopoietic stem cells and allogeneic bone marrow-derived mesenchymal stromal cells as a first-line treatment in very severe aplastic anemia patients with refractory infections. Eur J Haematol. 2018;100(6):624-629. [40] DEZERN AE, ZAHURAK M, SYMONS H, et al. Alternative Donor Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Refractory Severe Aplastic Anemia. Biol Blood Marrow Transplant. 2017;23(3):498-504. [41] XU L, FU B, WANG W, et al. Haploidentical hematopoietic cell transplantation for severe acquired aplastic anemia: a case-control study of post-transplant cyclophosphamide included regimen vs. anti-thymocyte globulin & colony-stimulating factor-based regimen. Sci China Life Sci. 2019 Aug 14. doi: 10.1007/s11427-019-9585-x. [Epub ahead of print] [42] PAGLIUCA S, PEFFAULT DE LATOUR R, VOLT F, et al. Long-Term Outcomes of Cord Blood Transplantation from an HLA-Identical Sibling for Patients with Bone Marrow Failure Syndromes: A Report From Eurocord, Cord Blood Committee and Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2017;23(11):1939-1948. [43] KUWATSUKA Y, KANDA J, YAMAZAKI H, et al. A Comparison of Outcomes for Cord Blood Transplantation and Unrelated Bone Marrow Transplantation in Adult Aplastic Anemia. Biol Blood Marrow Transplant. 2016;22(10):1836-1843. [44] ONISHI Y, MORI T, KAKO S, et al. Outcome of Second Transplantation Using Umbilical Cord Blood for Graft Failure after Allogeneic Hematopoietic Stem Cell Transplantation for Aplastic Anemia. Biol Blood Marrow Transplant. 2017;23(12):2137-2142. [45] HOUGH R, DANBY R, RUSSELL N, et al. Recommendations for a standard UK approach to incorporating umbilical cord blood into clinical transplantation practice: an update on cord blood unit selection, donor selection algorithms and conditioning protocols. Br J Haematol. 2016;172(3):360-370. [46] LAMERS CH, WIJERS R, VAN BERGEN CA, et al. CD4+ T-cell alloreactivity toward mismatched HLA class II alleles early after double umbilical cord blood transplantation. Blood. 2016;128(17):2165-2174. [47] STIFF PJ, MONTESINOS P, PELED T, et al. Cohort-Controlled Comparison of Umbilical Cord Blood Transplantation Using Carlecortemcel-L, a Single Progenitor-Enriched Cord Blood, to Double Cord Blood Unit Transplantation. Biol Blood Marrow Transplant. 2018; 24(7):1463-1470. [48] YAMAMOTO H, KATO D, UCHIDA N, et al. Successful sustained engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with severe aplastic anemia. Blood. 2011;117(11):3240-3242. [49] PEFFAULT DE LATOUR R, CHEVRET S, JUBERT C, et al. Unrelated cord blood transplantation in patients with idiopathic refractory severe aplastic anemia: a nationwide phase 2 study. Blood. 2018;132(7): 750-754. [50] KUDO K, MURAMATSU H, NARITA A, et al. Unrelated cord blood transplantation in aplastic anemia: is anti-thymocyte globulin indispensable for conditioning? Bone Marrow Transplant. 2017;52(12): 1659-1661. [51] SARVARIA A, BASAR R, MEHTA RS, et al. IL-10+ regulatory B cells are enriched in cord blood and may protect against cGVHD after cord blood transplantation. Blood. 2016;128(10):1346-1361. [52] GEORGIA A, CHRISTINA O, AIKATERINI K, et al. Successful long-term hematological and immunological reconstitution by autologous cord blood transplantation combined with post-transplant immunosuppression in two children with severe aplastic anemia. Pediatr Transplant. 2019;23(1):e13320. [53] SUN Y, LIU Z, XIAO J, et al. Autologous cord blood transplantation in children with acquired severe aplastic anemia. Pediatr Transplant. 2019;23(1):e13325. [54] 杨世伟,马荣军,赵娟娟,等.不同方式异基因造血干细胞移植一线治疗儿童及青少年重型再生障碍性贫血的比较[J].中华血液学杂志,2018,39(3): 184-189. [55] GEORGES GE, DONEY K, STORB R. Severe aplastic anemia: allogeneic bone marrow transplantation as first-line treatment. Blood Adv. 2018;2(15):2020-2028. |
[1] | Chen Xiao, Guo Zhi, Chen Lina, Liu Xuanyong, Zhang Yihuizhi, Li Xumian, Wang Yueqiao, Wei Liya, Xie Jing, Lin Li. Factors affecting the mobilization and collection of autologous peripheral blood hematopoietic stem cells [J]. Chinese Journal of Tissue Engineering Research, 2021, 25(19): 2958-2962. |
[2] | Cao Linlin, Ding Kaiyang, Song Hao, Wu Guolin, Hu Maogui, Fan Dandan, Zhou Chenyang, Wang Cuicui, Feng Yuanyuan. Efficacy and influencing factors of autologous hematopoietic stem cell transplantation in the treatment of malignant lymphoma [J]. Chinese Journal of Tissue Engineering Research, 2021, 25(13): 1993-1998. |
[3] | Wei Zhongling, Jiang Yizhi, Huang Laiquan, Yan Jiawei, Yu Zhengzhi, Wang Nana, Huang Chen, Wang Ran, Huang Dongping. Severe aplastic anemia treated with unrelated cord blood combined with matched sibling allogeneic hematopoietic stem cell transplantation [J]. Chinese Journal of Tissue Engineering Research, 2021, 25(13): 2049-2054. |
[4] | Zhang Suping, Sun Ling, Wan Dingming, Cao Weijie, Li Li, Liu Changfeng, Liu Yufeng, Wang Dao, Guo Rong, Jiang Zhongxing, Xie Xinsheng. Effectiveness of unrelated peripheral blood stem cell transplantation in the treatment of severe aplastic anemia [J]. Chinese Journal of Tissue Engineering Research, 2020, 24(31): 4994-5001. |
[5] | Ding Yubin, Tang Yufeng, Tang Xudong. Application and research advances in stem cell transplantation for severe aplastic anemia [J]. Chinese Journal of Tissue Engineering Research, 2020, 24(19): 3084-3092. |
[6] | Qin Yang, Wan Dingming, Cao Weijie, Zhang Suping, Li Li, Zhang Ran, Song Yongping, Zhang Yanli, Wang Dao. Matched-sibling donor versus unrelated umbilical cord blood transplantation for treating hematological malignancies in children [J]. Chinese Journal of Tissue Engineering Research, 2020, 24(13): 1969-1975. |
[7] | Zhang Ling, Sun Yanling, Wang Xiaozhen, Long Bing , Liu Jiajun. Umbilical cord mesenchymal stem cells for the treatment of refractory chronic graft-versus-host disease [J]. Chinese Journal of Tissue Engineering Research, 2020, 24(13): 2034-2038. |
[8] | Zhong Ping, Cui Xing. Mechanism of angelica polysaccharide regulating mitochondrial apoptosis for improving bone marrow failure [J]. Chinese Journal of Tissue Engineering Research, 2020, 24(13): 2074-2079. |
[9] | Xue Hui, Feng Shuqing, Hu Yongchao, Liu Zhibin, Li Xiaoyu, Gao Feng. Stratification therapy for cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation [J]. Chinese Journal of Tissue Engineering Research, 2019, 23(5): 756-760. |
[10] | Chen Xiaoling, Deng Huilan, Lu Quanyi, Hong Xiuli, Hu Jiasheng. Pure red cell aplasia follows allogeneic hematopoietic stem cell transplantation: a two-case report and literature review [J]. Chinese Journal of Tissue Engineering Research, 2019, 23(5): 761-766. |
[11] | Guo Zhi, Ren Hua, Ji Yong, Chen Liping, Chen Lina, Liu Xuanyong, Zheng Shanshan, Liu Xiaodong, Chen Huiren. Thrombopoietin improves platelet recovery after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia: an assessment of safety and efficacy [J]. Chinese Journal of Tissue Engineering Research, 2019, 23(33): 5269-5274. |
[12] | Liu Jiao, Wang Daming, An Taixue, Hu Xuesong, Li Nankai, Wang Hongfu, Ma Wen, Nie-He Zhongrong, Xiao Lijia, Zhou Yiwen, Zheng Lei. Expression profile analysis of miRNAs in serumal exosomes as sensitive biomarkers in patients with graft-versus-host disease following allogeneic hematopoietic stem cell transplantation [J]. Chinese Journal of Tissue Engineering Research, 2019, 23(21): 3418-3425. |
[13] | Wang Xiaoning, Chen Ying, Zhu Huachao, Zhang Mei, He Pengcheng. Protective effect of human umbilical cord mesenchymal stem cells on acute drug-induced liver injury after conditioning in haploidentical hematopoietic stem cell transplantation [J]. Chinese Journal of Tissue Engineering Research, 2019, 23(17): 2690-2695. |
[14] | Wei Yuanfeng, Wei Zhongling, Yang Yuqiong, Qi Jing, Yan Jiawei, Huang Dongping. Allogeneic hematopoietic stem cell transplantation for severe aplastic anemia in 10 cases [J]. Chinese Journal of Tissue Engineering Research, 2019, 23(13): 2042-2048. |
[15] | Wan Ding-ming, Sun Lin-lin, Xie Xin-sheng, Guo Rong, Cao Wei-jie, Zhang Su-ping, Li Li, Chen Xiao-na, Liu Yu-ye. Peripheral blood haploidentical hematopoietic stem cell transplantation for treatment of acute lymphoblastic leukemia in adults: monitoring minimal residual diseases to intervene recurrence [J]. Chinese Journal of Tissue Engineering Research, 2018, 22(9): 1413-1418. |
Viewed | ||||||
Full text |
|
|||||
Abstract |
|
|||||