Allogeneic hematopoietic stem cell transplantation in the treatment of 24 patients with severe aplastic anemia

doi:10.12307/2022.805

Abstract

Abstract: BACKGROUND: Severe aplastic anemia has severe illness and high mortality, which requires rapid recovery of hematopoietic function. At present, hematopoietic stem cell transplantation is the first-line treatment, human leucocyte antigen-matched sibling donor hematopoietic stem cell transplantation is the first choice, and haploidentical hematopoietic stem cell transplantation has also achieved good results as an alternative treatment.
OBJECTIVE: To investigate the efficacy of allogeneic hematopoietic stem cell transplantation (including matched sibling donor hematopoietic stem cell transplantation and haploidentical hematopoietic stem cell transplantation) in the treatment of severe aplastic anemia.
METHODS: The clinical data of 24 patients with severe aplastic anemia diagnosed from April 2015 to July 2021 undergoing allogeneic hematopoietic stem cell transplantation in Xuzhou Center Hospital were retrospectively analyzed. Among them, 8 patients received matched sibling donor hematopoietic stem cell transplantation and 16 patients received haploidentical hematopoietic stem cell transplantation. The pretreatment regimen of 24 patients with severe aplastic anemia was fludarabine, cyclophosphamide and anti-lymphocytic globulin. The prevention of graft versus host disease was cyclosporine combined with short-range methotrexate in matched sibling donor hematopoietic stem cell transplantation, and in haploid matched hematopoietic stem cell transplantation on the basis of this addition of mycophenolate mofetil.
RESULTS AND CONCLUSION: (1) Among the 24 patients, 2 severe aplastic anemia patients died of severe infection during pretreatment, and the other 22 patients reached hematopoietic reconstitution. The median time of neutrophil implantation was 12.5 (10-18) days, and the median time of platelet implantation was 14.5 (10-26) days. (2) Totally 22 patients with successful implantation developed acute graft versus host disease in 8 patients (36%), grade III/IV acute graft versus host disease in 2 patients, chronic graft versus host disease in 4 patients (18%), and grade III/IV chronic graft versus host disease in 1 patient. (3) Totally 18 patients survived and 6 patients died. The 5-year estimated overall survival rate was 74%. (4) These results indicate that allogeneic hematopoietic stem cell transplantation is an effective treatment for severe aplastic anemia. Human leucocyte antigen-matched sibling donor is the first choice. When human leucocyte antigen-matched sibling donor is not available, related human leucocyte antigen-haplo identical donor will be an alternative method.

Key words: severe aplastic anemia, allogeneic hematopoietic stem cell transplantation, haploid transplantation, human leucocyte antigen-matched sibling, hematopoietic reconstitution, graft versus host disease, outcome

CLC Number:

Fu Chunmei, Zhang Pu, Wang Yang, Li Xiaolin, Xue Yan, Fu Jie, Zhang Cixian, Yang Yujuan, Duan Yaya, Feng Kai. Allogeneic hematopoietic stem cell transplantation in the treatment of 24 patients with severe aplastic anemia[J]. Chinese Journal of Tissue Engineering Research, 2023, 27(1): 15-20.

Figures/Tables 3

2.3 造血植入移植后1，3，6个月采用短串联重复序列多态性连锁分析(STR-PCR)方法进行供受者嵌合体检查。病例1、病例14为混合嵌合型，其余患者均为完全供者嵌合型。ABO血型不合患者异基因造血干细胞移植后两三个月复查ABO血型均转为供者型。 2.4 移植物抗宿主病发生情况 22例植入成功患者发生急性移植物抗宿主病8例(36%)，其中Ⅰ/Ⅱ度急性移植物抗宿主病6例(同胞移植1例，单倍体移植5例)。Ⅲ/Ⅳ度急性移植物抗宿主病2例，均为亲缘半相合造血干细胞移植，病例14死于肠道移植物抗宿主病，病例22经过甲泼尼龙、抗CD25单克隆抗体、间充质干细胞回输等治疗，肠道移植物抗宿主病治愈，目前有皮肤慢性移植物抗宿主病。慢性移植物抗宿主病累计发生4例(18%)，其中Ⅰ/Ⅱ度慢性移植物抗宿主病3例，为半相合移植；Ⅲ/Ⅳ度慢性移植物抗宿主病1例，为同胞全相合移植，该例患者最终死于肠道移植物抗宿主病。 2.5 移植相关并发症 2.5.1 出血性膀胱炎 2例患者在造血干细胞移植后出现出血性膀胱炎，给予充分水化、碱化、持续膀胱冲击对症支持治疗后痊愈。 2.5.2 移植后感染 24例患者中5例发生移植后重度感染，病例15、病例21出现血流感染合并肺部感染给予广谱抗感染、抗真菌治疗，病例9出现肺部感染合并鼻窦部真菌感染给予清除病变组织、鼻窦腔冲洗、抗真菌治疗，病例4在移植过程中出现血流感染及近平滑念珠菌血症给予广谱抗感染、抗真菌治疗，病例10在移植后出现中枢感染给予广谱抗感染、抗真菌治疗。 2.5.3 病毒感染情况移植后发生EB病毒血症患者8例，发生巨细胞病毒血症患者10例，经抗病毒治疗后，病毒拷贝数下降。 2.5.4 出血病例1、病例14移植后出现重度肠道移植物抗宿主病合并消化道出血，给予抗移植物抗宿主病、止血对症治疗。病例21造血重建失败，出现消化道出血，给予输注血小板、止血对症治疗。病例15在造血重建后发生感染，继发血小板减低出现颅内出血，给予输注血小板、止血对症治疗。 2.5.5 其他并发症接受异基因造血干细胞移植的24例患者，在造血干细胞移植期间出现不同程度的口腔溃疡、恶心、呕吐、腹泻等胃肠道反应，经对症支持治疗后好转。口腔溃疡患者予加强口腔护理，于重组人粒细胞巨噬细胞集落刺激因子含漱、重组人表皮生长因子等促进口腔黏膜修复对症治疗后好转。 2.6 患者死亡情况分析至随访截止日期，24例异基因造血干细胞移植患者中，存活18例，死亡6例，包括同胞相合造血干细胞移植死亡2例，单倍体移植死亡4例。2例患者原发性植入失败；2例患者死于移植后肠道Ⅲ/Ⅳ度移植物抗宿主病；1例(例10)患者造血重建后出现低热、尿失禁、感觉及运动进行性上移，综合影像学检查考虑中枢感染，最终死亡；1例(例15)患者造血重建后出现感染继发血小板减少，最终死于颅内出血。 2.7 生存分析 18例患者存活，6例患者死亡。5年预计总生存率为74%，总生存曲线，见图2。"

References

[1] CHEN M, LIU C, ZHUANG J, et al. Long-term follow-up study of porcine anti-human thymocyte immunoglobulin therapy combined with cyclosporine for severe aplastic anemia. Eur J Haematol. 2016; 96(3):291-296.
[2] ALASHKAR F, OELMÜLLER M, HERICH-TERHÜRNE D, et al. Immunosuppressive therapy (IST) in adult patients with acquired aplastic anemia (AA): A single-center experience over the past 15 years. Eur J Haematol. 2019;103(1):18-25.
[3] VIOLLIER R, PASSWEG J, GREGOR M, et al. Quality-adjusted survival analysis shows differences in outcome after immunosuppression or bone marrow transplantation in aplastic anemia. Ann Hematol. 2005; 84(1):47-55.
[4] GEORGES GE, DONEY K, STORB R. Severe aplastic anemia: allogeneic bone marrow transplantation as first-line treatment. Blood Adv. 2018; 2(15):2020-2028.
[5] BACIGALUPO A. How I treat acquired aplastic anemia. Blood. 2017;129(11): 1428-1436.
[6] BACIGALUPO A. Alternative donor transplants for severe aplastic anemia. Hematology Am Soc Hematol Educ Program. 2018;2018(1): 467-473.
[7] 张之南,沈悌.血液病诊断及疗效标准[M].3版.北京:科学出版社,2007.
[8] 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.
[9] 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.
[10] 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.
[11] XU L, CHEN H, CHEN J, et al. The consensus on indications, conditioning regimen, and donor selection of allogeneic hematopoietic cell transplantation for hematological diseases in China-recommendations from the Chinese Society of Hematology. J Hematol Oncol. 2018;11(1): 33.
[12] Pierri F, Dufour C. Management of aplastic anemia after failure of frontline immunosuppression. Expert Rev Hematol. 2019;12(10):809-819.
[13] 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.
[14] LU Y, SUN RJ, ZHAO YL, et al. Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation Achieved Outcomes Comparable With Matched Unrelated Donor Transplantation in Young Acquired Severe Aplastic Anemia. Biol Blood Marrow Transplant. 2018; 24(9):1881-1887.
[15] 肖方,刘强,范丹,等.一线与挽救性单倍体相合造血干细胞移植治疗重型再生障碍性贫血患者的疗效比较[J].中国实验血液学杂志,2020,28(5):1683-1688.
[16] 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.
[17] GENG C, LIU X, CHEN M, et al. Comparison of frontline treatment with intensive immunosuppression therapy and HLA-haploidentical hematopoietic stem cell transplantation for young patients with severe aplastic anemia - A meta analysis. Leuk Res. 2020;88:106266.
[18] KUMAR R, KIMURA F, AHN KW, et al. Comparing Outcomes with Bone Marrow or Peripheral Blood Stem Cells as Graft Source for Matched Sibling Transplants in Severe Aplastic Anemia across Different Economic Regions. Biol Blood Marrow Transplant. 2016;22(5):932-940.
[19] 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.
[20] KIM H, LEE KH, SOHN SK, et al. Effect of Stem Cell Source and Dose on Allogeneic Hematopoietic Stem Cell Transplantation in Adult Patients with Idiopathic Aplastic Anemia: Data from the Korean Aplastic Anemia Trials. Acta Haematol. 2020;143(3):232-243.
[21] 危薇,丁丽,郑晓丽,等.移植物成分对单倍体相合造血干细胞移植治疗再生障碍性贫血后急性移植物抗宿主病的影响[J].中国实验血液学杂,2018,26(5):1442-1446.
[22] 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.
[23] BAI LY, CHIOU TJ, LIU JH, et al. Hematopoietic stem cell transplantation for severe aplastic anemia--experience of an institute in Taiwan. Ann Hematol. 2004;83(1):38-43.
[24] YaNG D, YANG J, HU X, et al. Aplastic Anemia Preconditioned with Fludarabine, Cyclophosphamide, and Anti-Thymocyte Globulin. Ann Transplant. 2019;24:461-471.
[25] 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.
[26] 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.
[27] MARSH JC, GUPTA V, LIM Z, et al. Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia. Blood. 2011;118(8):2351-2357.
[28] 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.
[29] YE L, ZHANG F, KOJIMA S. Current insights into the treatments of severe aplastic anemia in China. Int J Hematol. 2020;112(3):292-299.