Severe aplastic anemia treated with unrelated cord blood combined with matched sibling allogeneic hematopoietic stem cell transplantation

doi:10.3969/j.issn.2095-4344.3516

Abstract

Abstract: BACKGROUND: Sibling matched allogeneic hematopoietic stem cell transplantation is still the first-line treatment for severe aplastic anemia. However, with the increase of patients’ age, the effect of transplantation decreases significantly.
OBJECTIVE: To explore the efficacy and safety of unrelated cord blood combined with matched sibling hematopoietic stem cell transplantation in the treatment of severe aplastic anemia.
METHODS: A total of four severe aplastic anemia patients who underwent unrelated cord blood combined with matched sibling hematopoietic stem cell transplantation in First Affiliated Hospital (Yijishan Hospital) of Wannan Medical College from July 2017 to February 2018 were enrolled and their clinical data were used for retrospective analysis.
RESULTS AND CONCLUSION: (1) All the four patients were male. The median age was 40 years old and the median time from diagnosis to transplantation was 2.5 months. Bone marrow and peripheral blood stem cells from a sibling donor as well as a unit of unrelated cord blood with HLA matching ≥ 4/6 were applied. (2) The median stem cells of total nucleated cells and CD34+ were 13.67×108/kg and 2.7×106/kg of the sibling donor, 2.1×107/kg and 1.21×105/kg of the unrelated cord blood, respectively. (3) The median implantation time of neutrophils and platelets was +10 days and +20 days, respectively. (4) After transplantation, one patient was sibling donor chimerism while that of another three patients was double donors. At the follow-up date, among the three cases of mixed chimerism from two donors, one was completely implanted with unrelated cord blood; one was completely implanted with sibling donor; the third case had mixed chimerism with sibling donor and recipient giving up treatment because of infection. (5) Only one patient developed grade II acute graft versus host disease. The incidence of III-IV acute graft versus host disease and chronic graft versus host disease was 0%. (6) Two-year post-transplant disease free survival and overall survival rates were both 75% and graft versus host disease-free and relapse-free survival was 100%. (7) The results show that sibling allogeneic hematopoietic stem cell transplantation combined with unrelated cord blood transfusion for the treatment of older patients with severe aplastic anemia has a low incidence of graft versus host disease and a positive effect, but the dynamics for the implantation of two kinds of donor stem cells is worthy of further study.

Key words: stem cells, bone marrow, peripheral blood, cord blood, aplastic anemia, siblings, transplantation, chimerism

CLC Number:

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.

Figures/Tables 4

2.5 干细胞植入情况所有患者在移植后1个月均获得干细胞稳定植入，造血重建。中性粒细胞中位植入时间为+10 d (9-18 d)，血小板中位植入时间为+20 d(12-24 d)，红系中位植入时间为19.5 d(15-27 d)，见表3。 2.6 短串联重复序列(STR)监测嵌合状态移植后1例患者(病例2)为同胞供者嵌合；其余3例患者为2种供者干细胞混合嵌合，总的供者嵌合率>95%。移植后4例患者检测短串联重复序列嵌合变化如图2所示。病例1在移植后3个月开始出现非血缘脐血成分，并逐渐取代同胞供者成为优势植入。病例3在移植后6个月以内一直存在2种供者的混合植入，至移植后8个月逐渐转为同胞供者完全植入；病例4在移植后8个月出现供者嵌合明显下降，脐血干细胞丢失，供受者混合嵌合状态，给予输注同胞供者动员后外周血干细胞2次，回输后同胞供者嵌合率增加。 2.7 染色体监测所有同胞供者均为女性，输注的非血缘脐血均为男性；在移植后监测性染色体核型转变如图3所示，病例2为完全同胞供者核型；其余3例患者存在2种供者混合染色体核型，病例1逐渐转为脐血染色体核型，病例3和4转为同胞供者核型。 2.8 移植物抗宿主病及其他并发症发生情况 4例患者中，病例2出现上消化道Ⅰ级急性移植物抗宿主病，给予小剂量甲强龙治疗后症状消失；其余患者未发生任何级别的急性移植物抗宿主病或慢性移植物抗宿主病。在移植过程中，均发生肺部感染，病例1合并出现肛周脓肿；病例4出现败血症和双侧踝关节腔感染，关节腔穿刺病理提示阿萨西毛孢子菌感染，给予关节腔局部注射两性霉素B及全身静脉使用两性霉素B脂质体和伏立康唑治疗，感染部分控制，但患者放弃治疗自动出院；病例1，2，3经过积极抗感染治疗，感染均治愈。有3例患者发生巨细胞病毒感染，均为巨细胞病毒血症，经过更昔洛韦和/或膦甲酸钠治疗后巨细胞病毒转阴；EB病毒感染发生率为100%，病例1同时出现肝脾肿大，临床上疑诊移植后淋巴组织增殖性疾病，所有患者经过减撤免疫抑制剂、应用免疫球蛋白及利妥昔单抗，获得临床治愈，见表3。 2.9 随访与生存分析随访至2020-02-28，中位随访21(15-30)个月，病例4患者由于反复肺部和关节腔感染，于移植后15个月放弃治疗后自动出院；其余3例患者均无病生存。生存时间见表3。 2.10 不良反应发生情况所有患者输注同胞供者骨髓和外周血干细胞以及非血缘脐血过程顺利，未发生输注相关死亡。"

References

[1] BURROUGHS LM, WOOLFREY AE, STORER BE, et al. Success of allogeneic marrow transplantation for children with severe aplastic anaemia. Br J Haematol. 2012; 158(1):120-128.
[2] 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.
[3] 刘立民,张彦明,周惠,等.单倍型造血干细胞联合第三方脐血干细胞移植治疗重型再生障碍性贫血127例临床观察[J]. 中华血液学杂志,2018,39(8): 624-628.
[4] 中华医学会血液学分会红细胞疾病(贫血)学组. 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.
[5] SCHEINBERG P, RIOS O, SCHEINBERG P, et al. Prolonged cyclosporine administration after antithymocyte globulin delays but does not prevent relapse in severe aplastic anemia. Am J Hematol. 2014;89(6):571-574.
[6] PEZESHKI A, PODDER S, KAMEL R, et al. Monosomy 7/del (7q) in inherited bone marrow failure syndromes: A systematic review. Pediatr Blood Cancer. 2017; 64(12):10.
[7] KUM CD, LEE MJ, PARK JE. Successful engraftment after infusion of multiple low doses of CD34+ cells from a poorly matched sibling donor in a patient with severe aplastic anemia. Yeungnam Univ J Med. 2019;36(2):148-151.
[8] 吴德沛,陈佳.改善移植预后的新方向：双重造血干细胞移植[J].中华医学杂志, 2014,94(40):3121-3123.
[9] SANZ J, KWON M, BAUTISTA G, et al. Single umbilical cord blood with or without CD34+ cells from a third-party donor in adults with leukemia. Blood Adv. 2017; 1(15):1047-1055.
[10] 杜振兰,陈鹏,罗荣牡,等.第三方脐血辅助输注的单倍型造血干细胞移植36 例疗效分析[J].中华临床医师杂志(电子版),2014,8(6):1200-1203.
[11] BARKER JN, SCARADAVOU A, STEVENS CE. Combined effect of total nucleated cell dose and HLA match on transplantation outcome in 1061 cord blood recipients with hematologic malignancies. Blood. 2010;115(9):1843-1849.
[12] 孙自敏. 非血缘脐血移植是GVHD 与GVL 分离的最佳移植类型[J].中国科学技术大学学报, 2018,48(10):791-796.
[13] ROCHA V, GLUCKMAN E; EUROCORD-NETCORD REGISTRY AND EUROPEAN BLOOD AND MARROW TRANSPLANT GROUP. Improving outcomes of cord blood transplantation: HLA matching, cell dose and other graft- and transplantation-related factors. Br J Haematol. 2009;147(2):262-274.
[14] YANG D, YANG J, HU X, et al. Aplastic Anemia Preconditioned with Fludarabine, Cyclophosphamide, and Anti-Thymocyte Globulin. Ann Transplant. 2019;24: 461-471.
[15] 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.
[16] SHETH VS, POTTER V, GANDHI SA, et al. Similar outcomes of alemtuzumab-based hematopoietic cell transplantation for SAA patients older or younger than 50 years. Blood Adv. 2019;3(20):3070-3079.
[17] 卢静,吴德沛,胡绍,等.不同方式异基因造血干细胞移植治疗63例重型再生障碍性贫血患者的预后比较[J].中华血液学杂志,2015,36(8):633-636.
[18] KAKO S, KANDA Y, ONIZUKA M, et al. Allogeneic hematopoietic stem cell transplantation for aplastic anemia with pre-transplant conditioning using fludarabine, reduced-dose cyclophosphamide, and low-dose thymoglobulin: A KSGCT prospective study. Am J Hematol. 2020;95(3):251-257.
[19] 张钦,邹秉含,楼晓,等.异基因造血干细胞移植后EB病毒感染的危险因素及预后分析[J].中华内科杂志,2016,55(8):619-623.
[20] UHLIN M, WIKELL H, SUNDIN M, et al. Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation. Haematologica. 2014;99(2):346-352.
[21] LIU L, ZHANG X, FENG S. Epstein-Barr Virus-Related Post-Transplantation Lymphoproliferative Disorders After Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant. 2018;24(7):1341-1349.