Treatment of aplastic anemia in children by bone marrow transplantation (author's transl)]

The course of a successful bone marrow transplantation in a 8 year old boy with severe aplastic anemia is presented. The boy lives now 22 months after bone marrow transplantation with normal bone marrow function and an essentially undisturbed performance; The indication for bone marrow transplantation for severe aplastic anemia in children is discussed. Despite improved intensive supportive care (antibiotics, infectious prophylaxis, substitution of blood components) and the treatment with corticosteroids and/or androgens the mortality of sever aplastic anemia in childhood is still high. The advantages of early bone marrow transplantation in severe cases are stressed.     

Immunotherapy for severe aplastic anemia following orthotopic liver transplantation in children

Severe aplastic anemia is a well-recognized complication of fulminant non-A, non-B, and non-C hepatitis requiring orthotopic liver transplantation. The first line of therapy for cure in the treatment of aplastic anemia is a histocompatible bone marrow transplant. Immunosuppressive therapy is also effective if a histocompatible donor is not available. We describe two children who developed severe aplastic anemia following orthotopic liver transplant who achieved bone marrow recovery with a single course of anti-thymocyte globulin, solumedrol, and adjustments to their immunosuppressive therapy for prevention of liver allograft rejection.     

Successful engraftment of haploidentical bone marrow with post‐transplantation cyclophosphamide in patients with aplastic anemia

Patients with severe aplastic anemia (SAA) may benefit from hematopoietic stem cell transplantation, but many of them lack a matched donor. Haploidentical transplantation is increasingly utilized for the treatment of nonmalignant disease where patients lack a matched donor. We report patients with aplastic anemia who experienced successful engraftments of haploidentical stem cells with post‐transplantation cyclophosphamide (PTCy). Case series and review of the literature. We present two cases of pediatric patients with severe aplastic anemia who experienced successful engraftment of haploidentical related bone marrow. Both patients received conditioning consisting of rabbit ATG, cyclophosphamide, fludarabine, and total body irradiation pretransplant, with PTCy. The conditioning regimen was well tolerated by both patients, and they achieved full donor engraftment and were weaned off all immunosuppressants. Haploidentical stem cell transplantation in patients with severe aplastic anemia may be an effective alternative when fully matched donors are not available. PTCy can facilitate successful engraftment and therefore expand the pool of eligible donors for patients with aplastic anemia.     

Low Expression of Basic Fibroblastic Growth Factor in Mesenchymal Stem Cells and Bone Marrow of Children with Aplastic Anemia

Background: Our previous experiments with gene chip suggested that basic fibroblastic growth factor (FGF2) levels were lower in mesenchymal stem cell (MSC) from aplastic anemia patients. The purpose of this study was to determine the expression of FGF2 in MSC and in bone marrow of children with aplastic anemia to better understand the role of low FGF2 expression in the pathogenesis of aplastic anemia. Procedure: MSCs from the bone marrow of aplastic anemia children and control group were cultured in vitro. Growth curves of primary and passage MSC were plotted. FGF2 gene expression in MSCs was detected using quantitative real-time polymerase chain reaction (RT-PCR). FGF2 protein expression in mononuclear cells and FGF2 protein level in extracellular fluid of bone marrow were also investigated. Result: Decreased growth of MSCs from aplastic anemia children was observed after passage 8 in serial subcultivation, and FGF2 gene expression was downregulated. Within the patients’ bone marrow, low FGF2 expression was validated both in mononuclear cells and in the extracellular fluid. Conclusion: Low FGF2 gene expression in MSCs and low FGF2 protein level in bone marrow of aplastic anemia may involve to pathogenesis of aplastic anemia.     

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??Abstract?? Objective To investigate the characteristics of 99mTcmsulfur collid bone marrow scintigraphy in childhood aplastic anemia ??AA?? and its clinical significance.Methods A total of 45 children were newly diagnosed with AA??including 19 cases of serious aplastic anemia ??SAA?? and 26 cases of chronic aplastic anemia ??CAA??.Bone marrow scintigraphy using 99mTcmsulfur collid 10??15 MBq/kg was performed in 45 patients and 15 controls.The difference of bone marrow scintigraphy was analysed. The relationship between laboratory indices and clinical response was investigated. Results According to the bone marrow imaging results??grade 2 of marrow activities was defined as normal. Totally 33 patients??33/45??73.3%?? had abnormal marrow activities??and in 15 controls only 3??3/15??20%??.Most AA patients showed 99mTcmsulfur collid uptake decrease. CAA patients had higher marrow activities than SAA patients ??P??0.05??.In the 33 patients who had abnromal marrow activities??less then 2 grade????SAA and CAA patients showed different 99mTcmsulfur collid uptake in the peripheral and the center of bone marrow??and CAA had focals whose uptake was increasing.After treatment of 6 months??45 AA patients were investigated the relationship between the grade of marrow activities and the therapeutic effect??including improved??inefficacy??death??.There showed significantly difference??P??0.05?? between them. Conclusion The 99mTcmsulfur collid bone marrow imaging is helpful to the diagnosis and prognosis of AA??but further study is needed to judge its relationship with the curative effect and prognosis.     

Bone marrow transplantation for severe aplastic anemia in children

For young adults and children who have a bone marrow donor who is a genotypic or phenotypic sibling match, bone marrow transplantation is now the preferred treatment for severe aplastic anemia. For those who lack such a matched donor, use of matched unrelated donors and family member donors who are mismatched for a single HLA antigen have been successful and appear to be the treatment of choice. Patients lacking either of these alternatives should receive antilymphocyte globulin, either alone or combined with cyclosporine as a first step. Although the success rate of marrow transplants in our series using mismatched family donors is similar to that following treatment with antilymphocyte globulin, several caveats must be kept in mind. First, the results reported with use of alternative donors must be confirmed with study of larger numbers of patients and longer follow-up. Second, the preparative regimen given prior to bone marrow transplantation destroys the patient's residual bone marrow, whereas antilymphocyte globulin cyclosporine A and androgens do not. The sequence of immunosuppression followed by transplantation with alternative donor marrow should produce greater long-term hematopoietic improvement. Unfortunately, when marrow transplant follows one or more courses of immunosuppressive therapy, nonengraftment is then a problem because of sensitization to blood cell antigens. It should also be kept in mind that studies done in children, especially in those younger than 6 years old, show that these patients respond better to transplantation than to treatment regimens not including marrow transplantation. Therefore, for the child with severe aplastic anemia, every effort should be made to identify a suitable bone marrow donor. Finally, we need to determine the specific components of the conditioning regimen and the constitution of the donor marrow necessary for engraftment and to minimize potential long-term complications, and there should be only a tolerable degree of graft-versus-host disease. Many of the transplant-related problems that plagued us in the 1970s have still not been fully resolved, but many have shown improvement. As we enter the 1990s, increasing the pool of marrow donors for patients with severe aplastic anemia who lack an HLA-matched sibling will continue to be a top priority for research.     

Drug-induced aplastic anemia: pathogenesis and clinical aspects

Drug-induced aplastic anemia is one of the few life-threatening reactions to drugs. Although the majority of reported cases have been associated with chloramphenicol, many drugs have the potential to be toxic to the bone marrow. There are two distinct types of toxicity with differing pathogenic mechanisms--a dose-related reversible marrow aplasia and a dose-independent idiosyncratic aplasia with a high mortality. These two forms of marrow suppression may be difficult to distinguish. The pathogenesis of idiosyncratic marrow aplasia is not well understood. Various studies have demonstrated biochemical, immune, pharmacokinetic, and genetic defects that could affect hematopoietic stem cells. The clinical significance of the reported experimental findings is not established. The prognosis of drug-induced aplastic anemia is similar to that of idiopathic aplastic anemia. Patients with this condition respond to bone marrow transplantation or immunosuppressive therapy in a manner similar to patients with idiopathic marrow aplasia. Many questions regarding drug-induced aplastic anemia remain to be answered; little progress has been made in the last decade.     

Comparison between bone marrow transplantation and antithymocyte globulin in treatment of young patients with severe aplastic anemia

Fifty-seven patients younger than 25 years with severe aplastic anemia underwent either bone marrow transplantation or antithymocyte globulin therapy (ATG) to ascertain which approach should be used in young patients. Thirty-five patients who had an HLA-identical sibling donor underwent bone marrow transplantation after conditioning with cyclophosphamide and low-dose total-body radiation. Twenty-two patients who did not have an HLA-identical donor received ATG. The 2-year actuarial survival of patients after transplant is 72% (95%, CI 64% to 80%), versus 45% (95%, CI 29% to 61%) in those given ATG therapy (P = 0.18). In those patients surviving 6 months after treatment, return of peripheral blood counts to normal values was more common in patients who received marrow transplant compared with those given ATG therapy (P less than 0.001). Furthermore, 24 of 26 transplant survivors had Karnofsky performance scores greater than 90%, compared with only five of 13 ATG survivors. These data suggest that bone marrow transplantation is the preferred therapy for severe aplastic anemia in young patients who have an HLA-identical sibling donor. ATG should be reversed for those young patients with severe aplastic anemia who do not have a histocompatible marrow donor.     

Use of hematopoietic growth factors for treatment of aplastic anemia

The recent discovery and manufacture of recombinant human hematopoietic growth factors offers a novel approach to treating patients with aplastic anemia. There are ongoing preclinical trials of a number of recombinant proteins that demonstrate remarkable hematopoietic activity in a variety of bone marrow failure states. Moreover, there are preliminary results of phase I/II trials of the administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with aplastic anemia. It appears that this factor, the first to reach the stage of actual clinical trials, effectively increases proliferation of myeloid cellular elements of the peripheral blood and bone marrow, particularly in patients with milder forms of aplastic anemia. The side effects of GM-CSF at low to moderate doses of the growth factor (less than 16 micrograms/kg/day) appear tolerable. These results suggest that GM-CSF holds promise as a therapeutic option for patients with aplastic anemia. Long-term clinical trials will be needed to assess accurately the role that GM-CSF and other promising hematopoietic growth factors can play in the treatment of this disease, relative to other therapies such as antithymocyte globulin and bone marrow transplantation.     

儿童获得性低巨核细胞性血小板减少性紫癜临床特点分析

目的通过分析儿童获得性低巨核细胞性血小板减少性紫癜(acquired amegakaryocytic thrombocytopenic purpura,AATP)的临床资料,疏理其临床特点,为临床准确诊断治疗提供帮助。方法回顾性分析北京儿童医院血液病中心2005年至2006年收治的9例AATP病人的临床资料。结果男女性别发病比例无明显差异,临床均以出血为主要症状和体征;患儿骨髓髂后0~5个/片活检未见巨核细胞。入院前院外诊断"特发血小板减少性紫癜"均治疗无效。入院后达到完全治疗反应者3例,部分有效2例,基本无效1例,无效1例,总有效率71·4%(5/7);2例失访;3例转为再生障碍性贫血。结论儿童AATP临床仅表现与血小板减少相关的出血症状,骨髓穿刺及活检提示巨核细胞极度减少,而粒、红系统不受影响;大剂量丙种球蛋白和糖皮质激素无效,需要选择环孢菌素或抗胸腺球蛋白等T细胞免疫抑制剂治疗或骨髓移植;有42·9%(3/7)进展为再生障碍性贫血     

Bone marrow failure in children with acute liver failure

BACKGROUND: Aplastic anemia is a rare but well-recognized complication of acute hepatitis and acute liver failure. The cause is unknown, and the condition is fatal without bone marrow recovery. Treatment includes immunosuppression regimens or bone marrow transplantation. The purpose of this study was to investigate the incidence, cause, treatment, and outcomes of this disorder in children. METHODS: Retrospective chart review of 75 patients with acute liver failure in a major pediatric liver center. RESULTS: Eight patients had evidence of bone marrow failure. Of those, six had aplastic anemia, and two had transient bone marrow suppression. There were five boys, median age 57 months (range, 36-132 months). Two had parvovirus B19, six had non-A, non-B, non-C hepatitis. Five underwent liver transplantation: auxiliary in one, orthotopic in four. The interval between initial symptoms and development of aplastic anemia and/or bone marrow suppression was 21 to 99 days (median, 39 days). Four patients with aplastic anemia received intravenous antithymocyte globulin (ATG) or antilymphocyte globulin (ALG). Median recovery period of granulopoiesis was 62 days (range, 27-115 days). Two made a full recovery, one had myelodysplasia, and one with unresponsive disease died of septic complications. Four did not receive ATG/ALG, two had aplastic anemia, and two had bone marrow suppression. Three underwent liver transplantation, and all four resumed granulopoiesis. One child who underwent liver transplantation died of sepsis with chronic rejection. Median recovery of granulopoiesis was 99 days (range, 20-153 days). CONCLUSIONS: Bone marrow failure occurs in 10.7% of children with acute liver failure. It sometimes occurs in association with non-A, non-B, non-C hepatitis and parvovirus B19 infection. Treatment with ATG/ALG is successful and is well tolerated in most cases.     

Severe acquired aplastic anemia in children: 11-year experience with bone marrow transplantation and immunosuppressive therapy

We reviewed the management and outcome of severe acquired aplastic anemia in 36 patients younger than 18 years old between March 1977 and June 1987. In most patients, no cause could be found. The best therapeutic results were achieved with allogeneic bone marrow transplantation from histocompatible related donors (14 patients), with a cure rate of 79%. Bone marrow transplantation from mismatched related donors was attempted in two patients and failed in both. Immunosuppression using antithymocyte globulin and/or high-dose methylprednisolone represented an alternative treatment in the absence of a suitable bone marrow donor (12 patients) and induced complete remission in 25% of the patients. Children treated with supportive care only (eight patients) had a 75% mortality with a very short survival time. These data confirm the superiority of allogeneic bone marrow transplantation over immunosuppressive therapy in children with severe aplastic anemia.     

再生障碍性贫血患儿骨髓核素显像特点及其临床意义分析

目的 应用99mTc-硫胶体全身骨髓显像检测再生障碍性贫血（再障）患儿全身骨髓显影特点,探讨其在再障诊治中的价值。方法　对2009年1月至2012年1月青岛大学医学院附属医院小儿血液科收治的45例再障患儿（再障组）及15名对照组进行99mTc-硫胶体全身骨髓显像。99mTc-硫胶体注射放射剂量10～15 MBq/kg,分析骨髓核素显像的特异性、敏感性及不同类型再障患儿骨髓显像特点和临床转归的相关性。结果　再障组45例骨髓显像中活性减低33例（73.3%,包括0级11例、1级22例）,表现为全身骨髓显像有不同程度受抑,其特点是全身骨髓显影不良、显影骨髓总量减少;2级12例（26.7%）,骨髓活性正常。45例再障组临床诊断为急性再障（SAA）组19例、慢性再障（CAA）组26例,其中SAA组骨髓显像表现为中央＋外周骨髓均抑制者15例,仅中央骨髓抑制2例;CAA组中央＋外周骨髓均抑制6例,仅中央周骨髓抑制6例,仅外周抑制4例;两组骨髓显像抑制部位差异有统计学意义（χ2= 10.37,P＜0.05）;提示慢性再障骨髓显像受抑程度较轻,可仅有中央或外周骨髓的抑制并多存在灶状增生。对再障患儿骨髓显像与早期治疗反应进行统计分析,结果示不同骨髓显像分级间疗效差异有统计学意义（χ2=12.49,P＜0.05）,骨髓显像0级组有效率为36.3%,较1级组、2级组（77.3%、83.4%）疗效差。结论　全身骨髓显影不良、显影骨髓总量减少及显像特点有助于对儿童再障的诊断、分型及预后判断。骨髓显像与临床转归和预后关系仍需进一步扩大病例研究。     

Diagnosis and treatment of aplastic anemia

Severe aplastic anemia is a rare disorder in childhood. Among various therapeutical strategies bone marrow transplantation (BMT) and immunosuppressive treatment with antithymocyte globulin (ATG) have proven to be most successful. Priority should be given to BMT over ATG treatment for patients with HLA-identical donors. Patients with Fanconi's anemia require a reduced conditioning program with cyclophosphamide and irradiation for BMT. Own experiences indicate that cooperative studies are highly needed to improve medical care for patients with severe aplastic anemia.     

Etiologic mechanisms of hematopoietic failure

Our understanding of the pathophysiology of aplastic anemia has lagged behind advances in treatment of the disease. The data available indicate that the heterogeneous assortment of drugs, as well as the array of chemical, physical, and infectious agents that are clinically associated with aplastic anemia, probably exert their action through restricted pathways. Based on certain clinical features of aplastic anemia, animal models of hematopoietic failure, and considerations of the organization of the hematopoietic system, we propose two general types of aplastic anemia as a conceptual framework for further studies: type I aplastic anemia, representing a congenital or acquired stem cell defect that can only be cured by bone marrow transplantation, and type II aplastic anemia, which is caused by reversible suppression of normal stem cells by external agents and is amenable to immunosuppressive therapy.     

Parvovirus B19 infection presenting as pre-B-cell acute lymphoblastic leukemia: a transient and progressive course in two children

Parvovirus B19 is the causative agent of various forms of hematologic diseases such as aplastic crisis in patients with hemolytic anemia, aplastic anemia, hypoplastic anemia, and idiopathic thrombocytopenic purpura. In addition, parvovirus B19 infection may precede or be associated with acute lymphoblastic leukemia (ALL). The authors present two cases of parvovirus B19 infection and bone marrow infiltration with pre-B-cell lymphoblasts; one patients was diagnosed as having ALL, and the other patient, with neurologic findings, showed total resolution of the blastic morphology and phenotype.     

Normal neurodevelopment in four young children treated with bone marrow transplantation for acute leukemia or aplastic anemia

Longitudinal neurodevelopmental studies of four consecutive young children treated by bone marrow transplantation for acute leukemia or aplastic anemia are presented. The children, the only four children less than 2 years of age who have received bone marrow transplants for these diseases at UCLA Medical Center, ranged in age from 36 weeks to 24 months at the time of transplantation. Conditioning involved high-dose cyclophosphamide treatment; three also had total body irradiation prior to bone marrow transplantation. Their respective outcomes after follow-up times of 28 months to 71 months posttransplantation are remarkable for normal somatic growth and normal development of intelligence, language, perception, and motor coordination. These findings indicate that future therapeutic studies of infants and young children with acute leukemia or aplastic anemia using total body irradiation, cyclophosphamide, and bone marrow transplantation are not contraindicated by risks of debilitating neurodevelopmental sequelae.     

再生障碍性贫血发病机制的研究进展

再生障碍性贫血是一种获得性骨髓造血功能衰竭综合征.主要表现为骨髓造血功能低下、全血细胞减少以及贫血、出血、感染综合征.其发病机制尚未完全明确,主要涉及造血干/祖细胞缺陷、免疫功能紊乱、骨髓造血微环境异常三个方面.近年来各国学者对再生障碍性贫血进行了大量的临床以及实验研究,对其发病机制有了更进一步的认识,该文对此方面的研究进展做简要综述.     

Screening for paroxysmal nocturnal hemoglobinuria (PNH) clone in Egyptian children with aplastic anemia

Aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH) are clinically related. In addition to their concurrent or sequential appearance in individual patients, PNH and aplastic anemia share several pathophysiologic features. The aim of the present study was to screen for PNH clone in Egyptian aplastic anemia pediatric patients before the initiation of any specific therapy and to evaluate the clinical status of studied patients 3-6 months after initiation of immunosuppressive therapy. We studied 11 pediatric patients with newly diagnosed acquired aplastic anemia and followed them up clinically for 3-6 months after initiation of immunosuppressive therapy. In addition to routine clinical and laboratory evaluation, sucrose lysis test and staining of bone marrow for CD59 were performed in all subjects. All studies cases had severe aplastic anemia (SAA) except one case which had very severe aplastic anemia (VSAA). Sucrose lysis test was negative in all studied cases. Presence of PNH clone (as evident by loss of normal staining of hematopoietic cells for CD59 = CD59 negative cells) was evident in four subjects. All cases with PNH clone were >6 years old and one of them developed splenic vein thrombosis. As regards the laboratory data WBC < or = 2.8 x 10(3)/mm3 and reticulocytes > or = 0.6 per cent were the most frequent factors associated with PNH clone found in all PNH subjects, but only in 28.6 per cent and 14.3 per cent respectively, of non-PNH subjects. Mortality rate was higher in non-PNH subjects (28.5 per cent) compared to 25 per cent of PNH subjects. We conclude that immunohistochemical staining of bone marrow sections is a sensitive tool to detect the emergence of PNH clone in aplastic anemia patients. Thrombotic complications should be anticipated in cases with aplastic anemia having a PNH clone.     

儿童肝炎相关再生障碍性贫血的临床特征

目的：探讨儿童肝炎相关再生障碍性贫血(HAAA)临床特征。方法：回顾性地研究2007年1月至2008年12月该院诊治的HAAA患儿的临床资料,包括临床表现、血常规、骨髓象、病毒血清学、免疫功能指标及治疗和预后。结果：共收治HAAA患儿8例,占同期获得性再生障碍性贫血（再障）的4.9%;男7例、女1例;平均7.5岁（4.4～10.3岁）。肝炎病因不明。患肝炎后至血细胞减少的间隔时间中位数为6周。3例为重症再障（SAA）,5例极重型再障（VSAA）。全部病例均有严重T细胞免疫紊乱,Ts细胞明显升高、Th细胞明显下降。4例免疫治疗有效,3例起病1个月内死亡, 1例放弃治疗。结论：儿童HAAA发病率男性高于女性,学龄期多见。HAAA儿童存在严重T细胞免疫紊乱,早期死亡率高,免疫抑制治疗有效。［中国当代儿科杂志,2010,12（8）：609-612］