Comparable survival outcome between transplantation from haploidentical donor and matched related donor or unrelated donor for severe aplastic anemia patients aged 40 years and older: A retrospective multicenter cohort study

This retrospective multicenter cohort study aimed to compare the outcome of haploidentical hematopoietic stem cell transplantation (HID-HSCT) with matched sibling donor (MSD) and unrelated donor (URD) transplantation in severe aplastic anemia (SAA) patients 40 years of age and older. With a median follow-up time of 17.6 months, 85 consecutive patients were enrolled in the study, and the median patient age was 45 years (40, 58). The cumulative engraftment rates of neutrophil and platelet were 98.8 ± 0.0% and 92.9 ± 0.1%. The cumulative incidences of Grade 2-4 acute graft-versus-host disease (aGvHD) and chronic graft-versus-host disease (cGvHD) at 3 years were 14.1 ± 0.1% and 17.3 ± 0.2%. The 3-year estimated overall survival (OS) and failure-free survival (FFS) were 91.2 ± 3.2% and 89.7 ± 3.5%. In multivariate analysis, the only factor associated with inferior survival was an ECOG score ≥2. HID-HSCT was associated with a higher incidence of GvHD, but the difference of 3-year estimated OS between HID group and the other two cohorts was not significant (86.7 ± 6.4% for HID vs 92.1% ± 4.4% for MSD and 100% for URD, P = .481). HID-HSCT might be a feasible alternative option for selected SAA patients aged 40 years and older without a matched donor.     

Engraftment of heavily transfused patients with severe aplastic anemia with a fludarabine‐based regimen

We have developed a practical conditioning regimen without anti‐thymocyte globulin (ATG), irradiation, or other myeloablative alkylating agent for low‐income countries in which patients with severe aplastic anemia (SAA), who usually have heavily transfused and a prolonged disease history. The application of ATG, Busulphan, and/or irradiation to cyclophosphamide (Cy) to avoid graft rejection has many short‐ and long‐term complications. In this study, we focused on evaluating a fludarabine‐based conditioning regimen, among 83 patients with SAA. Patients were treated with fludarabine (40 mg/m²/d; day [?5 to ?2]) and cyclophosphamide (50 mg/kg/d; day [?5 to ?2]). Altogether, 81 patients indicated initial engraftment, whereas two cases showed primary graft failure. And four of the 81 cases indicated graft rejection during follow‐up. Regardless of a high cumulative incidence of acute (55/83; 66.2% grade II–IV; 47/83; 56.6% III–IV) and chronic graft‐versus‐host disease (50/83; 60.2%), in total, 77 patients showed durable engraftment and transfusion independence, and 64 are alive at a median time of 49 months with an overall survival rate of 66%. In conclusion, this conditioning indicated well toleration, mild toxicity, durable engraftment, excellent survival as well as less cost. Its application might shed new light on SAA at high risk of graft rejection in resource‐limited countries.     

亲缘全相合HSCT与强化免疫抑制治疗再生障碍性贫血的疗效比较

目的 对比分析重型再生障碍性贫血(SAA)患者行亲缘全相合造血干细胞移植( HSCT)和强化免疫抑制治疗(IST)的效果.方法 2008年1月至2010年12月新入院并诊断为SAA者41例,其中14例行亲缘全相合HSCT,27例接受以抗胸腺细胞球蛋白(ATG)+环孢素A(CsA)为基础的IST.结果 行亲缘全相合HSCT的14例全部植活,治疗有效率100％,中位随访14个月,患者均无病存活;接受IST的27例中位随访16个月,其中21例治疗有效(77.8％),6例治疗无效,2例死亡,患者脱离输血的中位时间为132 d.接受IST者的治疗有效率、存活率和死亡率与接受亲缘全相合HSCT者相比较,差异有统计学意义(P＜0.01).结论 亲缘全相合HSCT治疗SAA的效果令人满意,优于IST.     

The use of a fludarabine‐based conditioning regimen in patients with severe aplastic anemia – a retrospective analysis from three Indian centers

Between 2001 and 2009, 121 patients with severe aplastic anemia (SAA) underwent hematopoietic stem cell transplantation (HSCT) using a conditioning protocol of fludarabine and cyclophosphamide at three Indian hospitals. Donors were HLA‐identical sibling or family donors. Seventy‐six patients were considered “high risk” as per criteria. The graft source included peripheral blood stem cells in 109 and G‐CSF‐stimulated bone marrow in 12. GVHD prophylaxis consisted of cyclosporine and mini‐methotrexate. Engraftment occurred in 117 (96.6%) while two had graft failure and two expired in the first two wk. Neutrophil engraftment was seen at 12.3 d (range: 9–19) while platelet engraftment occurred at 12.4 d (range: 8–32). Grade II–IV acute GVHD was seen in 26.7% and grade IV GVHD in 8.6%. Chronic GVHD occurred in 44% and was extensive in 10%. The five‐yr overall survival for the entire cohort is 75.8 ± 3.9% with a survival of 95.6 ± 3.1% in the low‐risk group (n = 45) and 64.0 ± 5.6% in the high‐risk group (n = 76). Conditioning with fludarabine and cyclophosphamide is associated with very good long‐term survival in patients undergoing HSCT for SAA.     

重型再生障碍性贫血治疗进展

重型再生障碍性贫血（SAA）是一类少见的骨髓造血功能衰竭性疾病,与患者体内毒性T淋巴细胞为主的免疫功能紊乱、造血微环境的异常和造血干细胞的损伤相关。SAA起病急、进展快、病情重且致死率高,需快速并稳定地恢复患者造血功能。本文就免疫抑制剂疗法（IST）治疗SAA、同胞人类白细胞抗原（HLA）全相合异基因造血干细胞移植（allo-HSCT）治疗SAA、替代供者造血干细胞移植治疗SAA、非血缘脐血造血干细胞移植治疗SAA等方面的治疗进展进行综述。     

亲缘单倍体相合外周血造血干细胞移植治疗重症再生障碍性贫血

【摘要】目的探讨改良白消安／环磷酰胺＋抗胸腺细胞球蛋白（Bu／Cy＋ATG）预处理方案在亲缘单倍体造血干细胞移植治疗重症再生障碍性贫血（SAA）临床应用中的有效性和安全性。方法回顾分析河北唐山钢铁集团有限责任公司医院血液肿瘤科自2009年10月至2011年5月间采用亲缘单倍体外周血干细胞移植治疗的3例SAA患者资料。供者均为母亲,1例HLA3／6位点相合,2例HLA4／6位点相合。预处理方案均为改良Bu／Cy＋ATG,具体为白消安0．8m∥kg,每天4次,连用2d;环磷酰胺50mg·kg-1·d-1,连用4d;抗胸腺细胞球蛋白2．5mg·kg-1·d-1,连用4d。环孢素＋短程甲氨蝶呤＋吗替麦考酚酯预防排斥反应。结果3例患者均达完全供者植入,2例合并Ⅱ-Ⅲ度急性移植物抗宿主病（GVHD）,1例患者合并局限型慢性GVHD。3例患者均发生血CMV感染,经抗病毒治疗均得以控制。随访5～25个月,3例患者至今均无病存活。结论初步经验Bu／Cy＋ATG预处理方案经改良用于亲缘单倍体外周血造血干细胞移植治疗SAA安全、有效。     

重型再生障碍性贫血的治疗与造血干细胞移植

重型再生障碍性贫血（SAA）是由多种病因导致的重度骨髓造血功能衰竭综合征,临床以严重的贫血、感染、出血为主要特征。SAA发病机制复杂,至今尚未完全明了。SAA起病急,病情重,病情进展快,目前随着对SAA的深入研究以及诊疗水平的提高,对于其治疗策略也发生了改变。从经典的免疫抑制治疗,即主要以抗胸腺细胞球蛋白和环孢素为基础的治疗方案,到血小板生成素受体激动剂的应用及以异基因造血干细胞移植等为基础的联合治疗方案,均不同程度促进SAA患者的造血功能重建,极大改善其生存及预后,成为当下SAA治疗的研究热点。本文结合国内外文献对SAA治疗的新进展进行综述。     

Pre‐existing anti‐HLA antibodies negatively impact survival of pediatric aplastic anemia patients undergoing HSCT

Graft failure and survival are the major problems for patients with aplastic anemia undergoing hematopoietic stem cell transplantation (HSCT). Previous studies showed that anti‐HLA antibodies negatively impact engraftment in HSCT. This retrospective study of 51 pediatric patients with acquired aplastic anemia who underwent allogeneic HSCT at a single institution between 2006 and 2012 investigated the influence of anti‐HLA antibodies on the outcome of HSCT. Serum samples collected before HSCT were tested for the presence of anti‐HLA antibodies. Pre‐existing anti‐HLA antibodies were detected in 54.9% (28/51) of patients, among whom 39.2% (20/51) had anti‐HLA class I antibodies. Anti‐HLA antibodies were associated with worse five‐yr survival (78.6% vs. 100%, p = 0.021) and higher treatment‐related mortality (21.4% vs. 0%, p = 0.028) compared with antibody‐negative patients. Anti‐HLA class I antibody‐positive patients had poorer five‐yr survival (75.0%) than anti‐HLA class I&II antibody‐positive and antibody‐negative patients (87.5% and 100.0%, respectively, p = 0.039). Presence of anti‐HLA class I antibodies (p = 0.024) and older age (10 yr or more; p = 0.027) significantly increased the risk of post‐HSCT mortality. Pre‐existing anti‐HLA antibodies negatively affect the outcome of HSCT in pediatric patients with aplastic anemia. Routine testing for anti‐HLA antibodies concurrent with efficient treatment should be conducted prior to HSCT.     

不同预处理方案对重型再生障碍性贫血患者单倍体造血干细胞移植的疗效分析

目的分析氟达拉滨＋环磷酰胺＋抗胸腺细胞球蛋白(FC/ATG)预处理方案联合环孢素延迟口服方案对重型再生障碍性贫血(SAA)患者行单倍体造血干细胞移植(HSCT)的疗效与预后的影响。 方法回顾性分析2011年12月至2021年9月在山西白求恩医院行单倍体HSCT治疗的106例SAA患者。对比FC/ATG与白消安＋环磷酰胺＋抗胸腺细胞球蛋白(Bucy/ATG)预处理方案、环孢素延迟口服与正常口服方案的疗效,评价指标包括预处理相关不良反应、造血重建、供受者干细胞嵌合情况、环孢素血药浓度监测和移植物抗宿主病(GVHD)发生率,并进行生存预后分析。正态分布计量资料采用成组t检验比较,非正态分布计量资料采用Mann-Whitney U检验比较;计数资料采用Fisher确切概率法比较;急性与慢性GVHD累积发病率应用Gray检验进行计算;采用Kaplan-Meier法计算总生存率,并用log-rank检验进行比较;用Cox比例风险模型分析SAA患者HSCT后发生急性GVHD的危险因素。P<0.05为差异有统计学意义。 结果Bucy/ATG预处理组34例受者,FC/ATG预处理组72例受者;36例选择环孢素正常口服方案(消化道症状消失后口服),62例选择环孢素延迟口服方案(维持静脉输注到＋50 d再改为口服)。两种预处理方案均获得中性粒细胞与血小板成功植入。Bucy/ATG组受者Ⅲ～Ⅳ度口腔溃疡和腹泻发生率(61.8%和44.1%)均高于FC/ATG组(16.7%和18.1%),差异均有统计学意义(P均<0.05)。Bucy/ATG组和FC/ATG组受者预处理期间分别因合并重度感染导致死亡5(14.7%)、3例(4.2%),病死率差异有统计学意义(P<0.05)。在＋30、＋40和＋50 d不同时间段时,环孢素正常口服组受者环孢素血药浓度均低于延迟口服组,差异均有统计学意义(t＝－4.322、－5.751和－9.773,P均<0.05)。环孢素正常口服组受者急性GVHD累积发病率(52.8%)和中重度慢性GVHD累积发病率(55.6%)均高于环孢素延迟口服组(24.2%和22.6%),差异均有统计学意义(P均<0.05)。HLA配型不相合(RR＝0.476,95%可信区间：0.932～1.679,P<0.05)、环孢素正常口服方案(RR＝0.329,95%可信区间：1.331～1.843,P<0.05)是发生急性GVHD的危险因素。随访至2021年9月,106例受者中位随访时间为37.6个月(11～93个月),共死亡21例。Bucy/ATG组和FC/ATG组受者HSCT后2年生存率分别为66.3%、87.9%,差异有统计学意义(χ²＝7.355,P<0.05)。 结论FC/ATG预处理联合环孢素延迟口服方案可能是单倍体HSCT治疗SAA安全、有效的方案。     

非清髓性无关供者脐血移植与同胞供者骨髓移植治疗再生障碍性贫血的比较

目的 对非清髓性无关供者脐血移植与同胞供者骨髓移植治疗重型再生障碍性贫血(SAA)的临床效果进行评价和比较.方法 回顾性分析15例SAA患者进行非清髓性造血干细胞移植的临床资料,根据造血干细胞(HSC)来源的不同,将患者分为骨髓移植组(BMT组;6例)和脐血移植组(UCBT组;9例).对两组患者术后的外周血象、骨髓象、细胞嵌合体状态、移植物抗宿主病(GVHD)以及存活率等长期随访结果进行了统计学分析.结果 BMT组和UCBT组造血干细胞植入率分别为100%和66.7%,两组比较,差异有统计学意义(P＜0.05).UCBT组移植后大多数形成了供、受者型细胞混合嵌合体,BMT组大多数形成了供者型完全嵌合体.BMT组血象恢复正常的中位时间为25 d、UCBT组为120 d,BMT组骨髓象恢复正常的中位时间为25 d,UCBT组为150 d.BMT组慢性GVHD的表现以肝功能异常为主,而UCBT组则以皮疹为主.UCBT组术后早期感染率为33.3%,BMT组为16.7%.结论 非清髓性无关供者脐血移植和同胞供者骨髓移植均可成功治疗SAA;但与BMT比较,UCBT的造血功能恢复较慢、血型转变少而延迟、早期感染率较高、而慢性GVHD的程度却较轻.     

Fludarabine-based reduced intensity conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with aplastic anemia and fungal infections

Abstract:  Eighteen patients (12 men and 6 women) with aplastic anemia and active fungal infections (10 proven/probable; 8 possible) underwent stem cell transplantation using fludarabine combined with cyclophosphamide or total body irradiation. Peripheral blood stem cells (PBSC) were the main graft source and a combination of cyclosporine with either methotrexate or methylprednisolone was used for graft versus host disease prophylaxis. Fourteen patients (77.8%) achieved neutrophil engraftment after a median time of 11 d, while four died of fungal sepsis. Resolution of fungal infection occurred in 60% of patients with proven/probable infections and in 100% with possible fungal infections. At a median follow up of 30 months, 11 patients (61.1%) were alive and well. Fludarabine-based conditioning regimens with PBSC transplantation can be used successfully in patients with aplastic anemia and fungal infections.     

Experience with a Novel Efalizumab‐Based Immunosuppressive Regimen to Facilitate Single Donor Islet Cell Transplantation

Islet transplantation is an experimental therapy for selected patients with type 1 diabetes (T1DM). It remains limited by immunosuppressive drug toxicity, progressive loss of insulin independence, allosensitization and the need for multiple islet donors. We describe our experience with an efalizumab‐based immunosuppressive regimen as compared to the prevailing standard regimen, the Edmonton protocol. Twelve patients with T1DM received islet transplants: eight were treated with the Edmonton protocol; four were treated with daclizumab induction, a 6‐month course of tacrolimus, and maintenance with efalizumab and mycophenolate mofetil. The primary endpoint was insulin independence after one islet infusion. Only two Edmonton protocol treated patients achieved the primary endpoint; six required islets from multiple donors, and all experienced leukopenia, mouth ulcers, anemia, diarrhea and hypertransaminasemia. Four became allosensitized. All patients treated with the efalizumab‐based regimen achieved insulin independence with normal hemoglobin A1c after a single islet cell infusion and remained insulin independent while on efalizumab. These patients experienced significantly fewer side effects and none became allosensitized. Trial continuation was terminated by withdrawal of efalizumab from the market. These data suggest that this efalizumab‐based regimen prevents islet rejection, is well tolerated, and allows for single donor islet transplantation.     

Successful cytokine treatment of aplastic anemia following living-related orthotopic liver transplantation for non-A, non-B, non-C hepatitis

The relationship between aplastic anemia and viral hepatitis is well recognized, and such patients usually have a high mortality. We successfully treated a case of aplastic anemia following living-related orthotopic liver transplantation (LROLT) for non-A, non-B, non-C hepatitis.A 2-yr-old boy with fulminant hepatic failure from non-A, non-B, non-C hepatitis received LROLT. Before transplantation, he had pancytopenia which was probably hepatitis associated, and viral suppression was suspected after bone marrow (BM) biopsy. After the transplantation, he developed progressive pancytopenia and a diagnosis of aplastic anemia was made via BM biopsy. With immunosuppressant agents (cyclosporine, methylprednisolone), cytokine therapy (granulocyte-colony stimulating factor (G-CSF), macrophage-colony stimulating factor (M-CSF), recombinant human erythropoietin (rhEPO)) was effectual and the patient recovered from pancytopenia. He was discharged from the hospital 57 d after the liver transplantation and remains well 1 yr after LROLT. Combined cytokine therapy with high doses of G-CSF, M-CSF and rhEPO appeared to be effective in the treatment of aplastic anemia following liver transplantation for non-A, non-B, non-C hepatitis. Since M-CSF activates macrophages, it may have contributed to the graft rejection. Careful consideration should be given to the use of high-dose M-CSF in liver transplant patients.     

Modified donor lymphocyte infusion‐associated acute graft‐versus‐host disease after haploidentical T‐cell‐replete hematopoietic stem cell transplantation: incidence and risk factors

We performed a study to investigate the profile of donor lymphocyte infusion (DLI)‐associated acute graft‐versus‐host disease (GVHD) in haploidentical T‐cell‐replete hematopoietic stem cell transplantation (HSCT). A total of 124 patients receiving modified DLI after haploidentical T‐cell‐replete HSCT were enrolled. The cumulative incidence of DLI‐associated acute GVHD was 53.2% for grades II–IV and 28.4% for grades III–IV. The duration of GVHD prophylaxis after DLI was the only risk factor for DLI‐associated grades III–IV acute GVHD (p < 0.05). The cumulative incidence of grades III–IV acute GVHD in patients with prophylaxis more than six, four to six, two to four, and <2 wk were 9.3%, 14.4%, 31.6%, and 49.5%, respectively (p = 0.018). Furthermore, DLI‐associated grades III–IV acute GVHD was the only risk factor for overall survival (p = 0.038, OR   = 2.869) and transplant‐related mortality (p = 0.018, OR = 3.296) but not a risk factor for relapse after DLI (p = 0.840). This study confirms for the first time that the duration of GVHD prophylaxis after DLI is the only risk factor for the development of grades III–IV acute GVHD. Donor lymphocyte infusion with prophylaxis more than six wk was associated with a lower incidence of grades III–IV acute GVHD.     

Parvovirus B19‐induced severe anemia in heart transplant recipients: Case report and review of the literature

We report a case of a 64‐year‐old woman who developed transfusion‐dependent anemia after cardiac transplantation, the etiology of which was unknown after initial comprehensive evaluation. At the suggestion of the Transplant Infectious Diseases consultant, microbial agents with red blood cell tropism pertinent to this patient such as Parvovirus B 19 (B19V) were investigated. The B19V viral load by PCR in peripheral blood was >100 000 000 copies/ml and after treatment with intravenous immunoglobulin (IVIG), her anemia resolved. Here, we summarize the clinical and virologic characteristics, treatment, and outcome of fifteen cases of B19V‐induced anemia in heart transplant recipients. Spontaneous recovery from anemia secondary to B19V has also been reported in some heart transplant recipients, possibly due to an absence of their B19V P‐antigen receptor and/or reduction in their immunosuppression. Therefore, in heart transplant patients, B19V should be suspected early as a cause of severe anemia of unknown etiology. The extent that B19V‐induced anemia is underdiagnosed in heart transplant recipients is unknown.