Marrow transplantation for severe aplastic anemia associated with exposure to quinacrine

Severe aplastic anemia developed in a patient after administration of quinacrine for treatment of discoid lupus erythematosus. Marrow transplantation was performed from an HLA genotypically identical sister after conditioning with cyclophosphamide. Quinacrine which was accumulated in the patient tissues did not interfere with engraftment, suggesting that the drug has no direct cytotoxic effect on hematopoietic stem cells. This study extends our previous observation that severe aplastic anemia acquired after exposure to drugs or toxins can be cured by marrow transplantation.     

Survival and quality of life in 23 patients with severe aplastic anemia treated with bone marrow transplantation (BMT)

Survival and quality of life are reported in 23 pretransfused patients with severe aplastic anemia (SAA) who underwent bone marrow transplantation (BMT). The projected survival is 76% with 18 of 23 patients being alive 332 to 1677 days post graft (median: 842). 5 patients died between day 4 and 416. 12 of 17 patients at risk developed chronic graft versus host disease (GVH-D). 4 of these patients have a diminished quality of life due GVH-D related disabling manifestations. Autologous haemopoietic recovery was excluded in all patients by the demonstration of haemopoietic chimerism. We recommand age-adapted rejection prophylaxis; such strategy may help to diminish disabling graft versus host disease in otherwise haematologically reconstituted survivors.     

单倍体造血干细胞移植对儿童重型再生障碍性贫血治疗的并发症分析

目的分析儿童重型再生障碍性贫血(SAA)单倍体造血干细胞移植和同胞全相合移植并发症发生率。方法回顾性分析2010年1月1日至2018年12月31日于苏州大学附属儿童医院进行治疗的SAA患儿(56例),分为治疗组(单倍体造血干细胞移植,35例),对照组(同胞全相合移植,21例)。其中患儿年龄、诊断距离移植时间、总单个核细胞数、总CD34+细胞数、中位随访时间、粒细胞植入时间、血小板植入时间及等级资料[供受体血型相合程度、急性移植物抗宿主病(aGVHD)分级、广泛性慢性移植物抗宿主病(cGVHD)分级、出血性膀胱炎分级、渗漏综合征分级]采用Mann-Whitney U检验。性别、疾病种类、供体与受体性别、预处理方案、CD20单抗的使用、HLA配型、供体来源、移植物来源、植入综合征、巨细胞病毒(CMV)血症、EB病毒(EBV)血症、死亡人数、植入失败人数和骨髓增殖不良人数使用卡方检验进行组间分析。生存曲线以及累积发生率用Kaplan-Meier法绘制,并使用Log-rank检验分析组间差异。结果与对照组比较,治疗组CD19+B细胞的重建延迟,而CD16+CD56+NK细胞数量移植后6个月开始增加,逐渐达到对照组的水平。与对照组比较,治疗组aGVHD、cGVHD、植入综合征和骨髓增殖不良累积发生率(14.29﹪±7.64﹪比57.14﹪±8.36﹪,11.67﹪±7.75﹪比61.59﹪±9.65﹪,9.53﹪±6.41﹪比74.86﹪±7.43﹪,0.0﹪比14.29﹪±5.91﹪)均升高,差异具有统计学意义(P<0.05),两组CMV与EBV感染,5年总体生存率(OS)、无失败生存率(FFS)、无GVHD失败存活率(GFFS)、Ⅲ-Ⅳ度aGVHD及广泛性cGVHD累积发生率比较差异无统计意义(P>0.05)。结论单倍体移植是治疗儿童SAA的有效治疗方案,但与同胞全合造血干细胞移植比较,其GVHD发生率较高,植入综合征和骨髓增殖不良的发生率较高,优化单倍体移植方案有望降低并发症,提高儿童重型再生障碍性贫血的生活质量。     

T cells and myeloid progenitors in patients with severe aplastic anemia (SAA)

This report summarizes some of our past and present studies on T cells and hemopoietic progenitors obtained from patients with severe aplastic anemia (SAA). Two main issues are discussed: enhancement of colony growth by manipulation of accessory cells, or by the addition of patients' plasma, and the role of suppressor T cells in the pathogenesis of the disease and response to antilymphocyte globulin (ALG). A complex network of interactions exists. The identification of cells and soluble factors capable of enhancing or suppressing colony formation promises to help us better understand the events leading first to the development of aplasia and then eventually to hematologic recovery.     

Bone marrow transplantation in a patient with drug-induced aplastic anemia

A 23-year-old woman gravely ill with Pseudomonas septicemia secondary to presumed drug-induced bone marrow aplasia received marrow transplantation from two male HL-A identical sibling donors. She had a successful engraftment with excellent but temporary clinical improvement. Subsequently she succumbed to graft-versus-host disease manifested by Pseudomonas and Candida albicans septicemia, cytomegalovirus pneumonitis, three phases of dermatitis, nausea, vomiting, dysphagia, diarrhea, fever, edema and bone pain, with gradual but complete graft suppression by the 74th day after the transplantation. A second marrow transplant on the 70th day was unsuccessful.     

Infusion of haploidentical hematopoietic stem cells combined with mesenchymal stem cells for treatment of severe aplastic anemia in adult patients yields curative effects

Background aimsDespite the great advances in immunosuppressive therapy for severe aplastic anemia (SAA), most patients are not completely cured. Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has been recommended as an alternative treatment in adult SAA patients. However, haplo-HSCT presents a higher incidence of graft failure and graft-versus-host disease (GVHD). The authors designed a combination of haplo-HSCT and umbilical cord-derived mesenchymal stem cells (UC-MSCs) for treatment of SAA in adult patients and evaluated its effects.MethodsAdult patients (≥18 years) with SAA (N = 25) were given HLA-haploidentical hematopoietic stem cells (HSCs) combined with UC-MSCs after a conditioning regimen consisting of busulfan, cyclophosphamide, fludarabine and anti-thymocyte globulin and intensive GVHD prophylaxis, including cyclosporine, basiliximab, mycophenolate mofetil and short-term methotrexate. Additionally, the effects of the protocol in adult SSA patients were compared with those observed in juvenile SAA patients (N = 75).ResultsAll patients achieved myeloid engraftment after haplo-HSCT at a median of 16.12 days (range, 11–26). The median time of platelet engraftment was 28.30 days (range, 13–143). The cumulative incidence of grade II acute GVHD (aGVHD) at day +100 was 32.00 ± 0.91%. No one had grade III–IV aGVHD at day +100. The cumulative incidence of total chronic GVHD was 28.00 ± 0.85%. The overall survival was 71.78 ± 9.05% at a median follow-up of 42.08 months (range, 2.67–104). Promisingly, the protocol yielded a similar curative effect in both young and adult SAA patients.ConclusionsThe authors’ data suggest that co-transplantation of HLA-haploidentical HSCs and UC-MSCs may provide an effective and safe treatment for adult SAA.     

Improvement of anemia by recombinant erythropoietin in patients with myelodysplastic syndromes and aplastic anemia

Eight patients with myelodysplastic syndromes (MDS) and four patients with aplastic anemia (AA) were treated with recombinant erythropoietin (rEpo) to investigate its effect on the anemia of these patients. rEpo was administered by i.v. injection three times a week for at least four weeks. The doses were 3,000, 6,000, or 12,000 U/day. Despite an elevated "endogenous" Epo level, a greater than 1.5 g/dl increase in hemoglobin (Hb) concentration was observed in one patient with refractory anemia (RA), one patient with refractory anemia with excess of blasts (RAEB), and one patient with AA. A greater than 50% decrease in red cell transfusion requirement was observed in one patient with RA and one patient with AA. One RA patient and one AA patient have received rEpo as maintenance therapy for more than 64 and 100 weeks, respectively. They no longer need red cell transfusions and have had a normal Hb concentration and normal ferrokinetics. No side effect was seen. These results indicate that rEpo may benefit some patients with MDS and AA who are dependent on red cell transfusions while further studies will be necessary to elucidate the mechanism by which rEpo stimulates erythropoiesis and improves anemia in patients with these diseases.     

Analysis of cytotoxic effector cell function in patients with leukemia or aplastic anemia before and after marrow transplantation

Cytotoxic effector cells mediating natural killing (NK), antibody-dependent cellular cytotoxicity (ADCC), and lectin-dependent cellular cytotoxicity (LDCC) were studied in patients with leukemia or aplastic anemia before and/or after marrow transplantation. Before transplantation, about one-third to one-half of the patients were deficient in cytotoxic activity. In patients with leukemia, this was most likely due to large numbers of circulating blast cells diluting or replacing the effector cells. In patients with aplastic anemia there was an apparent absence of the effector cells in a proportion of the patients. After marrow transplantation, cytotoxic activity in all three systems returned to normal rapidly, by 30 days, and remained so through 100 days. However, about 20% of patients studied beyond 1 year were deficient in these functions. There were no significant associations between cytotoxic activity and important clinical parameters including infections, graft-vs-host disease, and recurrence of leukemia. Our findings do not support an immunosurveillance role for NK against leukemia after marrow transplantation. Furthermore, they point out the need for new in vitro approaches for meaningful monitoring of marrow transplant patients. Finally, our results showed a significant discordance between NK, ADCC, and LDCC activities in these immunologically perturbed individuals, indicating that either different cell populations or different cellular mechanisms are involved in these cytotoxic functions.     

Results of splenectomy in patients with hypoplastic and aplastic anemia]

The results of spleen exstirpation in 129 patients with hypoplastic and aplastic anaemia are presented. For this purpose the role of splenectomy in connection with blood formation is dealt with on the basis of analysing morphological blood findings. The impact of the duration of the disease, of sex, age, and the dosage of corticosteroids on the postoperative development of the disease is demonstrated. The following observations of the patients which were made within 3 to 14 years after the operation revealed that 63 patients from 129 survived, namely 21 patients up to 5 years, 26 patients up to 10 years, 16 patients up to 14 years. 66 patients died, the highest lethality being observed during the first year after the operation (47 patients).     

First-line matched related donor hematopoietic stem cell transplantation compared to immunosuppressive therapy in acquired severe aplastic anemia

Introduction

Acquired severe aplastic anemia (SAA) is a rare and progressive disease characterized by an immune-mediated functional impairment of hematopoietic stem cells. Transplantation of these cells is a first-line treatment option if HLA-matched related donors are available. First-line immunosuppressive therapy may be offered as alternative. The aim was to compare the outcome of these patients in controlled trials.

Methods

A systematic search was performed in the bibliographic databases MEDLINE, EMBASE, and The Cochrane Library. To show an overview of various outcomes by treatment group we conducted a meta-analysis on overall survival. We evaluated whether studies reported statistically significant factors for improved survival.

Results

26 non-randomized controlled trials (7,955 patients enrolled from 1970 to 2001) were identified. We did not identify any RCTs. Risk of bias was high except in 4 studies. Young age and recent year of treatment were identified as factors for improved survival in the HSCT group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the IST group. In 19 studies (4,855 patients), summary statistics were sufficient to be included in meta-analysis. Considerable heterogeneity did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies.

Conclusions

Young age and recent year of treatment were identified as factors for improved survival in the transplant group. Advanced age, SAA without very severe aplastic anemia, and combination of anti-lymphocyte globulin with cyclosporine A were factors for improved survival in the immunosuppressive group. Considerable heterogeneity of non-randomized controlled studies did not justify a pooled estimate. Adverse events were inconsistently reported and varied significantly across studies.     

Pregnancy and delivery after bone marrow transplantation (BMT) for severe aplastic anemia (SAA). A case report

A 23 years old multiple pretransfused female with severe aplastic anemia (SAA) underwent bone marrow transplantation (BMT). Cyclophosphamide (200 mg/kg) was used for conditioning, donor buffy coat cells were given as rejection prophylaxis. Seven months after BMT regular menses started in the absence of exogenous hormonal manipulation and 21 months after BMT the patient became pregnant. Pregnancy was complicated by mumps in the 14th week. It was terminated at term by cesarean section. The normally developed newborn girl (3,450 gm) presented with a "persistent fetal circulation syndrome". After surgical correction of the patent ductus arteriosus Botalli the girl baby recovered quickly.     

T-lymphocyte subpopulations in the peripheral blood and bone marrow of patients with aplastic anemia

A decrease in the absolute number of total lymphocytes, OKT3+ and OKT4+ lymphocytes, and a normal number of OKT8+ lymphocytes were found in the peripheral blood of patients with aplastic anemia. The OKT4:OKT8 ratio was decreased in patients due to a reduction in the percentage of OKT4+ cells and 3 out of 18 patients had a ratio less than 1. The values of the OKT4:OKT8 ratio were not associated either with the severity of the disease or with treatment with androgens. There was no correlation between the OKT4:OKT8 ratio and the number of transfusions received by patients. On the other hand, studies performed with bone marrow lymphocytes showed that the OKT4:OKT8 ratio for both patients and controls was lower than that of the peripheral blood. Since the ratio of OKT4:OKT8 cells in aplastic and control bone marrow was similar no direct pathogenic role can be assigned to the marrow for the imbalance detected in the peripheral blood.     

Prognosis in acquired aplastic anemia. An approach in the selection of patients for allogeneic bone marrow transplantation.

In a retrospective study, factors influencing the eventual course and outcome of patients suffering from aplastic anaemia were analysed. Of the 62 patients with pancytopenia concomitant with an aplastic or hypoplastic bone marrow, 36 have died during the first 24 months following diagnosis, 27 of these 36 cases within the first six months. 26 patients survived more than two years after presentation, but a further six of these cases succumbed during the following months. Of the 62 cases, 46 had neutrophil counts under 1 X 10(9)/l and platelet counts under 20 X 10(9)/l. These cases were subdivided according to their reticulocyte levels. In the age group of patients between 10 and 35 years, all those patients having more than 10,000/mul reticulocytes survived more than two years with only one exception, whereas only one of the 11 patients having reticulocyte counts below 10,000/mul has survived. In our series, the initial neutrophil and platelet counts were not of predictive value in identifying poor prognosis patients. The initial reticulocyte counts, however, appear to be a valid parameter for selecting patients in two groups, one with a favorable, and the other with an extremely unfavorable prognosis on conservative treatment. Young individuals with a poor predicted prognosis could thus be defined as possible candidates for bone marrow transplantation.     

Complement-dependent hematopoietic inhibitors in the sera of patients with aplastic anemia and paroxysmal nocturnal hemoglobinuria

The sera of 14 out of 48 patients with aplastic anemia and four out of nine patients with paroxysmal nocturnal hemoglobinuria (PNH) contained complement-dependent hematopoietic inhibitory activity against allogeneic marrow progenitor cells. Some sera with hematopoietic inhibitory activity, however, demonstrated no effect on autologous marrow progenitor cells. Hematopoietic inhibitory activity was absorbed by pooled, packed platelets. Serum hematopoietic inhibitory activity was present in both IgM and IgG fractions. These data suggested that serum hematopoietic inhibitors are alloantibodies and might be associated with graft rejection in the transplanted marrow of patients with aplastic anemia and PNH.     

单倍体相合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的临床观察及安全性分析

目的观察单倍体相合造血干细胞移植（hi-HSCT）联合脐带间充质干细胞（hUC-MSC）输注治疗儿童重型再生障碍性贫血（SAA）的临床效果及安全性。 方法整理海军总医院儿科2010年2月至2014年1月收治的11例接受hi-HSCT联合hUC-MSC输注治疗的SAA患儿的临床资料,进行回顾性分析。对其治疗情况、并发症发生情况及生存情况进行观察,总结该治疗方案的临床效果与安全性,以及治疗体会。 结果患儿全部获得造血重建,移植后1个月复查嵌合体均为70% ~ 100%供者嵌合。白细胞植入时间8 ~ 21 d,中位时间为12 d;血小板植入时间10 ~ 24 d,中位时间为15 d。11例患儿中,2例发生Ⅰ度急性移植物抗宿主病（GVHD）,1例发生Ⅲ度急性GVHD,均经相关治疗后好转;1例发生局限性慢性GVHD,经相关治疗后好转;2例发生广泛性慢性GVHD,发生率为18.18%。患儿移植期间均发生不同程度的恶心、呕吐、纳差和发热等症状,给予对症支持治疗后好转。8例（72.73%）发生口腔黏膜炎,2例（18.18%）发生肺部感染,9例（81.82%）发生病毒感染,2例（18.18%）发生腹泻,均经综合治疗后好转。11例患儿随访时间12 ~ 29个月,中位随访时间16个月,截止末次随访时1例因广泛性慢性GVHD接受持续治疗,2例接受免疫抑制剂减量治疗,其余4例均停用免疫抑制剂;1例患儿因家属自行停用环孢素A发生排异死亡。 结论hi-HSCT联合hUC-MSC输注治疗儿童SAA具有良好临床疗效,值得进一步关注。     

儿童获得性再生障碍性贫血造血干细胞移植后Epstein-Barr病毒血症危险因素及预后分析

目的分析儿童获得性再生障碍性贫血(AA)异基因造血干细胞移植(allo-HSCT)后Epstein-Barr病毒(EBV)血症的危险因素、利妥昔单抗的干预效果及EBV相关疾病的临床转归。方法回顾性分析2010年4月至2018年3月于上海儿童医学中心完成allo-HSCT的257例AA患儿,根据是否发生EBV血症分为:EBV血症组(141例,单纯EBV血症组125例和EBV相关疾病组16例)和非EBV血症组(116例)。采用Cox回归分析危险因素,采用Kaplan-Meier法分析累积生存率,定性资料的组间比较采用卡方检验。结果(1)257例患儿行allo-HSCT后发生EBV血症为141例,发生率为54.86﹪(141/257),其中原发感染为5.67﹪(8/257),再激活为94.33﹪(133/141)。EBV血症的中位发生时间为移植后44 d(13~568 d),单纯EBV血症的移植相关死亡率为6.40﹪(8/125);EBV相关疾病的病死率为56.25﹪(9/16)。(2)利妥昔单抗抢先治疗EBV血症的有效率为88.73﹪(63/71)。(3)与单纯EBV血症组比较,EBV相关疾病组患儿生存率降低,差异有统计学意义(Log-rank P<0.001)。(4)多因素分析结果显示,使用全身照射治疗(TBI)预处理的患儿,发生EBV感染的风险是不使用TBI预处理的患儿1.717倍(95﹪的CI:1.160~2.542);患儿移植物中CD34阳性细胞≥3×10^6个/kg是<3×10^6个/kg患儿的1.775倍(95﹪的CI:1.089~2.894)。结论移植后EBV血症的发生和TBI的应用、输注CD34阳性细胞数大于3×10^6个/kg密切相关,EBV血症进展为EBV疾病后移植相关死亡率升高,对高危患儿应积极予以利妥昔单抗抢先治疗改善预后。