单倍体相合异基因造血干细胞移植治疗肾上腺脑白质营养不良

doi:10.19723/j.issn.1671-167X.2019.03.006

北京大学学报（医学版） ›› 2019, Vol. 51 ›› Issue (3): 409-413. doi: 10.19723/j.issn.1671-167X.2019.03.006

单倍体相合异基因造血干细胞移植治疗肾上腺脑白质营养不良

陈瑶^1,²,张晓辉^1,²,许兰平^1,²,刘开彦^1,²,秦炯³,杨艳玲⁴,黄晓军^1,^2△()

^1. 北京大学人民医院血液病研究所,北京　100044
^2. 造血干细胞移植治疗血液病北京市重点实验室,北京　100044
^3. 北京大学人民医院儿科,北京　100044
^4. 北京大学第一医院儿科,北京　100034

收稿日期:2019-03-11 出版日期:2019-06-18 发布日期:2019-06-26
作者简介:黄晓军,教授,博士生导师,北京大学人民医院血液病研究所所长,血液病专家。国家血液系统疾病临床医学研究中心负责人,国家自然科学基金创新研究群体项目负责人,科技部创新团队及教育部创新团队带头人,国家重点学科、国家临床重点专科负责人;兼任亚太血液联盟常委会主任、第四届中国医师协会血液科医师分会会长、第九届中华医学会血液学分会主任委员、美国血液学会国际常委会委员、国际白血病比较研究组织全球委员会委员。
主持国家高技术研究发展计划(863计划)、国家重点研发计划、国家自然科学基金重点项目、国家杰出青年科学基金等国家课题;以通信或第一作者发表SCI 论文320余篇,包括New England Journal of Medicine、 Lancet Oncology、 Journal of Clinical Oncology、 Blood、 Leukemia、 Biology of Blood and Marrow和Bone Marrow Transplantation等,入选2014—2018年中国高被引学者榜单(医学);移植领域的相关成果被美国、英国骨髓移植协会、美国国家癌症研究所等共28项国际指南或共识引用;荣获国家科学技术进步奖二等奖2项,省部级一等奖4项,何梁何利科学技术与进步奖,吴阶平医药创新奖。
任《中华血液学杂志》总编辑,British Journal of Haematology副主编,Journal of Hematology and Oncology副主编, Chinese Medical Journal (English)副主编, Annals of Hematology高级编委,以及Blood、Bone Marrow Transplantation、Blood Reviews编委。牵头制定17项指南/共识,培养博士后6名,博士生58名,硕士生10名,北京市拔尖人才2名,科技新星1名。
基金资助:
国家自然科学基金(81621001)

Haploidentical allogenetic hematopoietic stem cell transplantation for X-linked adrenoleukodystrophy

Yao Chen^1,²,Xiao-hui ZHANG^1,²,Lan-ping XU^1,²,Kai-yan LIU^1,²,Jiong QIN³,Yan-ling YANG⁴,Xiao-jun HUANG^1,^2△()

^1. Peking University People’s Hospital, Peking University Institute of Hematology,Beijing 100044, China
^2. Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, Beijing 100044, China
^3. Department of Pediatrics, Peking University People’s Hospital, Beijing 100044, China
^4. Department of Pediatrics, Peking University First Hospital, Beijing 100034, China

Received:2019-03-11 Online:2019-06-18 Published:2019-06-26
Supported by:
Supported by National Natural Science Foundation(81621001)

摘要/Abstract

摘要： 目的 X-连锁肾上腺脑白质营养不良(X-linked adrenoleukodystrophy,ALD)是一种严重的遗传性疾病,导致神经系统迅速恶化和过早死亡,异基因造血干细胞移植(hematopoietic stem cell transplantation,HSCT)仍然是唯一能阻止该疾病神经症状的治疗方法。然而,许多患者缺乏合适的人类白细胞抗原(human leukocyte antigen,HLA)匹配相关供体,必须依赖替代供体作为干细胞来源,故本研究探讨采用单倍体相合异基因造血干细胞移植治疗肾上腺脑白质营养不良患儿。方法 2014年12月至2018年12月, 8例无HLA完全相合供体的ALD儿童接受了单倍体异基因造血干细胞移植治疗。预处理方案主要用药为马利兰(9.6 mg/kg)、环磷酰胺(200 mg/kg)和氟达拉滨(90 mg/m ²),预防移植物抗宿主病的药物包括抗人胸腺细胞免疫球蛋白、环孢菌素A、霉酚酸酯和短疗程甲氨蝶呤。结果 8例患儿均接受父亲来源的单倍体异基因造血干细胞移植治疗。患儿中位年龄为8岁(范围5~12岁),供者中位年龄为36(32~40)岁。干细胞来源采用粒细胞集落刺激因子(granulocyte colony-stimulating factor,G-CSF)动员的骨髓联合动员后的外周血采集物,总有核细胞中位数为10.89 (9.40~12.16)×10 ⁸/kg, CD34 ⁺细胞中位数为7.06(0.74~7.80)×10 ⁶/kg。中性粒细胞植入发生在移植后11 d(范围8~13 d),血小板植入中位时间为移植后10 d(范围8~12 d), 所有患儿在植入时均获得完全的供体细胞嵌合。4例患儿患有Ⅱ~Ⅳ级急性移植物抗宿主病,1例患儿患有慢性移植物抗宿主病,均无重度慢性移植物抗宿主病(graft-versus-host disease GVHD)发生。所有患儿中发生2例巨细胞病毒(cytomegalovirus,CMV)血症,2例EB病毒(Epstein-Barr virus,EBV)血症。总体来看,7例患儿无严重相关移植合并症发生且均生存,1例患儿移植后125 d癫痫后脑疝死亡。结论初步观察表明,采用这种新方案的单倍体异基因干细胞移植能成功地实现ALD患者的完全供体嵌合;根据我们的经验,单倍体相合异基因造血干细胞移植治疗肾上腺脑白质营养不良是安全可行的。

关键词: 单倍体相合, 异基因造血干细胞移植, 肾上腺脑白质营养不良, 移植物抗宿主病

Abstract: Objective: X-linked adrenoleukodystrophy (ALD) is a severe inherited disorder leading to rapid neurological deterioration and premature death. Allogeneic hematopoietic stem cell transplantation (HSCT) is still the only treatment that halts the neurologic symptoms in ALD. However, many patients lack suitable human leukocyte antigen (HLA) matched related donors and must rely on alternative donors for a source of stem cells. The purpose of this study was to explore the outcomes of haploidentical allogeneic stem cell transplantation for ALD patients.Methods: Between December 2014 and December 2018, eight children with ALD lacking HLA matched related or unrelated donors were treated with haploidentical allogeneic hematopoietic stem cell transplantation. The patients received conditioning regimen with busulfan 9.6 mg/kg, cyclophosphamide 200 mg/kg and fludarabine 90 mg/m ². Graft-versus-host disease (GVHD) prophylaxis consisted of anti-human thymocyte globulin, cyclosporine A, mycophenolate mofetil and short course of methotrexate. Results: All the 8 children received allogeneic stem cell transplants from their fathers. The median age of the recipients was 8 (range: 5-12) years. The median age of the donors was 36 (range: 32-40) years. All the recipients received granulocyte colony-stimulating factor (G-CSF) mobilized bone marrow and peripheral blood-derived stem cells. The median number of total mononuclear cells dose and CD34 ⁺ dose was 10.89 (range: 9.40-12.16)×10 ⁸/kg and 7.06 (range: 0.74-7.80)×10 ⁶/kg, respectively. Neutrophil engraftment occurred a median of 11 days (range:8-13 days) after transplantation. Platelet engraftment occurred a median of 10 days (range:8-12 days) after transplantation. All the patients achieved complete donor chimerism at the time of engraftment. Four patients had grades Ⅱ-Ⅳ acute GVHD and 1 had chronic graft-versus-host disease. No severe chronic GVHD occurred. Among all the children, 2 had cytomegalovirus (CMV) DNAemia and 2 Epstein-Barr virus (EBV) DNAemia. Overall, seven of them survived and had no major complications related to transplantation. One died of cerebral hernia after epilepsy 125 days after transplantation. Conclusion: The preliminary observation demonstrates that haploidentical allogeneic stem cell transplantation with this novel regimen could successfully achieve full donor chimerism in ALD patients. According to our experience, haploidentical allogeneic hematopoietic stem cell transplantation is safe and feasible in the treatment of X-linked adrenoleukodystrophy.

Key words: Haploidentical, Allogeneic hematopoietic stem cell transplantation, X-linked adrenoleukodystrophy, Graft-versus-host disease

中图分类号:

R551.3

陈瑶,张晓辉,许兰平,刘开彦,秦炯,杨艳玲,黄晓军. 单倍体相合异基因造血干细胞移植治疗肾上腺脑白质营养不良[J]. 北京大学学报（医学版）, 2019, 51(3): 409-413.

Yao Chen,Xiao-hui ZHANG,Lan-ping XU,Kai-yan LIU,Jiong QIN,Yan-ling YANG,Xiao-jun HUANG. Haploidentical allogenetic hematopoietic stem cell transplantation for X-linked adrenoleukodystrophy[J]. Journal of Peking University(Health Sciences), 2019, 51(3): 409-413.

参考文献 18

[1]	Igarashi M, Schaumburg HH, Powers J , et al. Fatty acid abnormality inadrenoleukodystrophy[J]. J Neurochem, 1976,26(4):851-860. doi: 10.1111/jnc.1976.26.issue-4
[2]	Mahmood A, Dubey P, Moser HW , et al. X-linked adrenoleukodystrophy: therapeutic approaches to distinct phenotypes[J]. Pediatr Transplant, 2005,9(Suppl 7):55-62. doi: 10.1111/ptr.2005.9.issue-s7
[3]	Aubourg P, Blanche S, Jambaque I , et al. Reversal of early neurologic and neuroradiologic manifestations of X-linked adrenoleukodystrophy by bone marrow transplantation[J]. N Engl J Med, 1990,322(26):1860-1866. doi: 10.1056/NEJM199006283222607
[4]	Mahmood A, Raymond GV, Dubey P , et al. Survival analysis of haematopoietic cell transplantation for childhood cerebral X-linked adrenoleukodystrophy: a comparison study[J]. Lancet Neurol, 2007,6(8):687-692. doi: 10.1016/S1474-4422(07)70177-1
[5]	Wang Y, Chang YJ, Xu LP , et al. Who is the best donor for a related HLA haplotype-mismatched transplant?[J]. Blood, 2014,124(6):843-850. doi: 10.1182/blood-2014-03-563130
[6]	Xu LP, Xu ZL, Wang FR , et al. Unmanipulated haploidentical transplantation conditioning with busulfan, cyclophosphamide and anti-thymoglobulin for adult severe aplastic anaemia[J]. Bone Marrow Transplant, 2018,53(2):188-192 doi: 10.1038/bmt.2017.237
[7]	Bashey A, Zhang X, Sizemore CA , et al. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched rela-ted and unrelated donor transplantation[J]. J Clin Oncol, 2013,31(10):1310-1316. doi: 10.1200/JCO.2012.44.3523
[8]	Kühl JS, Kupper J, Baqué H , et al. Potential risks to stable long-term outcome of allogeneic hematopoietic stem cell transplantation for children with cerebral X-linked adrenoleukodystrophy[J]. JAMA Netw Open, 2018,1(3):e180769. doi: 10.1001/jamanetworkopen.2018.0769
[9]	Chen Y, Xu LP, Zhang XH , et al. Busulfan, fludarabine, and cyclophosphamide (BFC) conditioning allowed stable engraftment after haplo-identical allogeneic stem cell transplantation in children with adrenoleukodystrophy and mucopolysaccharidosis[J]. Bone Marrow Transplant, 2018,53(6):770-773. doi: 10.1038/s41409-018-0175-8
[10]	Przepiorka D, Weisdorf D, Martin P , et al. 1994 consensus conference on acute GVHD grading[J]. Bone Marrow Transplant, 1995,15(6):825-828.
[11]	Martin PJ, Lee SJ, Przepiorka D , et al. National institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: Ⅵ. The 2014 Clinical Trial Design Working Group Report[J]. Biol Blood Marrow Transplant, 2015,21(8):1343-1359. doi: 10.1016/j.bbmt.2015.05.004
[12]	赵晓甦, 刘代红, 许兰平 , 等. 异基因造血干细胞移植后巨细胞病毒肺炎临床特点分析[J]. 北京大学学报(医学版), 2009,41(5):548-553.
[13]	许兰平, 刘代红, 刘开彦 , 等. 利妥昔单抗治疗异基因造血干细胞移植后EB病毒病的疗效和安全性[J]. 中华内科杂志, 2012,51(12):966-970. doi: 10.3760/cma.j.issn.0578-1426.2012.12.010
[14]	Peters C, Shapiro EG, Anderson J , et al. Hurler syndrome: Ⅱ. Outcome of HLA-genotypically identical sibling and HLA-haploidentical related donor bone marrow transplantation in fifty-four children. The Storage Disease Collaborative Study Group[J]. Blood, 1998,91(7):2601-2608.
[15]	Fernandes JF, Bonfim C, Kerbauy FR , et al. Haploidentical bone marrow transplantation with post transplant cyclophosphamide for patients with X-linked adrenoleukodystrophy: a suitable choice in an urgent situation[J]. Bone Marrow Transplant, 2018,53(4):392-399. doi: 10.1038/s41409-017-0015-2
[16]	Souillet G, Guffon N, Maire I , et al. Outcome of 27 patients with Hurler’s syndrome transplanted from either related or unrelated haematopoietic stem cell sources[J]. Bone Marrow Transplant, 2003,31(12):1105-1117. doi: 10.1038/sj.bmt.1704105
[17]	Chun HG, Leyland-Jones B, Cheson BD . Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies[J]. J Clin Oncol, 1991,9(1):175-188. doi: 10.1200/JCO.1991.9.1.175
[18]	Keating MJ , O’Brien S, Lerner S, et al. Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receivingfludarabine regimens as initial therapy[J]. Blood, 1998,92(4):1165-1171.

Metrics

Viewed

Full text

Abstract

Cited

Shared

Discussed

单倍体相合异基因造血干细胞移植治疗肾上腺脑白质营养不良

Haploidentical allogenetic hematopoietic stem cell transplantation for X-linked adrenoleukodystrophy

RICH HTML

PDF (PC)

摘要/Abstract

引用本文

使用本文

参考文献 18

相关文章 9

Metrics

本文评价

推荐阅读 10

[1]	高峰，冯术青，李晓宇，胡永超，薛慧，姚艳红. 同期同胞人类白细胞抗原全相合与亲缘间单倍体相合外周血造血干细胞移植后慢性移植物抗宿主病的对比观察[J]. 北京大学学报(医学版), 2017, 49(4): 745-封三.
[2]	代琛贤, 孙晓云, 苏茵, 栗占国. 慢性移植物抗宿主病狼疮小鼠模型免疫学特征分析[J]. 北京大学学报（医学版）, 2008, 40(4): 419-424.
[3]	陆敏, 邹万忠, 张燕, 王盛兰, 王薇. 移植相关性血栓性微血管病的肾损害[J]. 北京大学学报（医学版）, 2008, 40(4): 392-394.
[4]	平莉莉, 包新华, 王爱花, 潘虹, 吴晔, 熊晖, 张月华, 秦炯, 吴希如. 40例X连锁肾上腺脑白质营养不良患者的基因型与表型[J]. 北京大学学报（医学版）, 2006, 38(1): 66-70.
[5]	刘代红, 黄晓军, 郭乃榄, 许兰平, 陈欢, 韩伟, 江倩, 刘开彦, 陆道培. 异基因造血干细胞移植后肺炎的病因分析[J]. 北京大学学报（医学版）, 2005, 37(2): 130-133.
[6]	齐焕英, 付越, 金江, 张建中. 硬皮病样慢性移植物抗宿主病2例[J]. 北京大学学报（医学版）, 2004, 36(5): 559-560.
[7]	黄晓军, 韩伟, 许兰平, 陈欢, 刘代红, 陈育红, 江倩, 路瑾, 刘开彦, 任汉云, 陆道培. HLA配型不合情况下造血干细胞移植的新方法[J]. 北京大学学报（医学版）, 2004, 36(3): 229-233.
[8]	陈育红, 黄晓军, 许兰平, 张耀臣, 任汉云, 高志勇, 郭乃榄, 陆道培. 异基因造血干细胞移植中甲氨蝶呤3次与4次给药的比较[J]. 北京大学学报（医学版）, 2003, 35(2): 215-216.
[9]	黄晓军, 陈育红, 韩伟, 陈瑶, 洪虹, 陆道培. 人类白细胞抗原不相合造血干细胞移植治疗白血病的临床研究[J]. 北京大学学报（医学版）, 2003, 35(2): 115-118.