免疫抑制治疗儿童再生障碍性贫血疗效分析

目的探讨提高儿童再生障碍性贫血(再障,aplastic anemia,AA)疗效的治疗方法。方法回顾分析56例接受正规治疗且随访≥3个月的再障患儿的临床资料,56例按治疗方案分为2组,一组为单用环胞素A(CsA)治疗(A组),另一组抗胸腺细胞球蛋白(ATG)联合CsA免疫治疗(B组),比较两组患儿的疗效及生存率。结果 31例慢性再障(CAA)患儿中接受A组治疗30例,总体有效率为83.3%(25/30),仅1例CAA患儿接受B组治疗。25例重型再障(SAA)患儿接受B组治疗16例,治疗有效率为50.0%(8/16),较接受A组治疗的9例SAA患儿的有效率(44.4%)高,但差异无统计学意义(P>0.05)。接受B组治疗的16例SAA患儿,12个月生存率为66.7%,2年生存率70.0%。结论 ATG联合CsA免疫治疗是儿童再障,尤其是无合适供体进行造血干细胞移植的SAA患儿首选方案,但应注意足量、持续用药,并努力降低ATG治疗期间感染发生率,这对提高儿童SAA治愈率有重要意义。[临床儿科杂志,2012,30(5):428-430]     

免疫抑制疗法治疗儿童再生障碍性贫血疗效分析

目的：探讨免疫抑制疗法(IST)治疗儿童再生障碍性贫血(AA)的疗效、安全性及影响疗效的主要因素。方法：对2007年1月至2010年12月接受IST治疗的55例重型再生障碍性贫血（SAA）及51例慢性再生障碍性贫血（CAA）患儿的临床资料进行回顾性分析。结果：① 在CAA患儿中,抗胸腺球蛋白（ATG）联合环孢素A（CsA）治疗组总有效率明显高于CsA单独治疗组(80％ vs 44％,P40%、治疗前无重症感染以及有G-CSF早期治疗反应的患儿治疗效果较好,而治疗效果与AA分型、年龄等指标无关。结论：ATG+CsA联合治疗是治疗儿童AA的一种安全有效的方法;病程长短、有无严重感染、骨髓造血面积及G-CSF早期治疗反应是影响疗效的主要因素。     

儿童再生障碍性贫血的分型研究

目的探讨儿童再生障碍性贫血(再障)的分型标准。方法对已经确诊的61例儿童急性再障和45例儿童慢性再障病例进行回顾性分析。结果急性再障患儿有如下特点外周血呈全血细胞减少,淋巴细胞比例明显增高;髂骨及胸骨骨髓呈多部位增生不良,造血细胞明显减少,非造血细胞明显增多,巨核细胞明显减少,小粒细胞面积＜50％,细胞成分以非造血细胞为主;增生活跃患儿的骨髓中,非造血细胞比例明显增多,巨核细胞明显减少。慢性再障患儿的特点是外周血呈血小板减少和(或)白细胞减少和(或)贫血的血象,淋巴细胞比例增高;髂骨骨髓以增生活跃为主,但粒细胞系比例减低,红细胞系比例可正常,非造血细胞比例增高,巨核细胞减少,小粒细胞面积＜50％,细胞成分以非造血细胞为主。结论儿童急性再障的表现与Camitta提出的重型再障的诊断标准相似,而儿童慢性再障的表现与Camitta提出的轻型再障不同,根据本文结果提出儿童再障的分型标准及胸骨骨髓在诊断急、慢性再障中的意义。     

ALG为主的免疫抑制剂治疗儿童重型再生障碍性贫血的疗效及相关因素

目的通过回顾性分析临床资料,探讨重型再生障碍性贫血(SAA)患儿以抗淋巴细胞球蛋白(ALG)为主的免疫抑制治疗(IST)疗效及相关因素。方法54例重型再生障碍性贫血、并接受ALG治疗患儿的临床资料进行分析。结果基本治愈24例(44.4%),缓解12例(22.2%),明显进步4例(7.4%),无效14例(25.9%),总有效率(74.1%)。典型的血清病多在治疗后7~14 d内出现。随访的54例患儿中1例出现骨髓增生异常综合征(MDS)样病态造血。结论ALG作为重要免疫抑制剂治疗SAA疗效肯定,治疗前患者外周血ANC计数、骨髓涂片中淋巴细胞的比例以及检测CsA有效浓度可能对疗效判断有提示意义。IST后出现重度感染多为预后不良的重要因素之一。     

再生障碍性贫血患儿骨髓间充质干细胞体外生物学特性及其与免疫抑制疗效的关系

目的：探讨再生障碍性贫血（再障）患儿骨髓间充质干细胞（MSC）体外生物学特性及与免疫抑制治疗（IST）疗效的关系,评价MSC异常在再障发生、发展中的作用。方法：对29例再障患儿进行了骨髓MSC培养,其中17例患儿接受IST,观察MSC体外生长特点、表面标志、细胞周期、对PHA刺激的外周血淋巴细胞增殖的抑制作用,并与5例正常儿童骨髓作对照;观察再障患儿MSC异常与IST疗效的关系。结果：55%（16/29）的再障患儿表现为不同程度的MSC生长异常,主要为MSC数量减少及增殖能力下降,其中以重型再障（SAA）、病程较长者或放/化疗后再障为多见。培养成功的再障患儿第3代MSC表面标志、细胞周期、转化生长因子-β1（TGF-β1）分泌水平及对PHA刺激的淋巴细胞增殖的抑制作用与对照组比较,差异均无显著性（P>0.05）。在17例接受IST患儿中,9例MSC生长基本正常的再障患儿经IST后8例达完全缓解,而8例MSC生长异常者仅2例达完全缓解,两组比较差异具有显著性（P<0.01）。结论：多数再障患儿骨髓MSC体外生长存在不同程度的异常,其MSC异常对IST后患儿骨髓造血功能恢复具有一定的负面影响。     

儿童再生障碍性贫血免疫抑制剂治疗疗效及相关因素分析

目的：探讨免疫抑制疗法（IST）对儿童再生障碍性贫血（AA）的疗效及其影响疗效的相关因素。方法：对2003年2月至2009年11月住院接受IST治疗的、可进行疗效评估的110例AA患儿的临床资料进行回顾性分析。110例患儿中,重型AA（SAA）83例,非重型 AA（非SAA）27例。前者采用抗胸腺细胞球蛋白（ATG）联合环孢素（CSA）及泼尼松、雄激素四联治疗,后者采用CSA联合泼尼松、雄激素三联治疗。结果：SAA与非SAA组的总有效率分别为69.9%和70.4%。单因素分析显示病程、骨髓CD34+细胞比例、CD4+CD25+调节性T细胞比例与疾病严重程度相关,但与预后无关。治疗有效组患儿年龄、病程、骨髓CD3+、CD8+细胞比例显著低于治疗无效组（P<0.05）。多因素分析显示年龄＞10岁、骨髓CD8+细胞比例＞25%的患儿治疗失败的风险分别是对应组的3.36倍和3.59倍。结论：IST治疗儿童AA疗效确切。年龄、病程、CD3+、CD8+ T细胞水平与IST的疗效相关。     

环胞菌素A治疗儿童再生障碍性贫血疗效研究

探讨环胞菌素 A(CSA)治疗儿童再生障碍性贫血 (再障 )的方法 ,疗效和疗效相关因素。方法 :应用 CSA对 34例儿童再障行免疫抑制治疗 (IS) ;部分重型再障(SAA)加用抗胸腺细胞球蛋白 (ATG)或大剂量免疫球蛋白 (HDIG) ,均以雄性激素作为辅助治疗。结果 :基本治愈 4例 ,缓解 1 1例 ,明显进步 8例 ,总有效率为 6 7.6 5 % ;其中 2 9例 SAA总有效率为 6 5 .5 2 % ,1 8例慢性重型再障 (SAA- )有效率为5 5 .5 6 % ;1 1例急性再障 (SAA- )总有效率达 81 .82 % ,单项资料对比分析结果显示SAA的年龄 ,性别和治疗前外周血象等因素与 CSA有效率无关 ;但病程较短者 (<1 2个月 )有效率较高 ;CSA与 ATG等行联合 IS则有效率可明显提高。结论 :CSA为治疗儿童再障的有效方法之一 ,SAA拟选用联合 IS,雄性激素为 CSA的有效辅助治疗     

儿童获得性再生障碍性贫血的免疫抑制治疗

再生障碍性贫血(再障)包括获得性及先天性2种类型,是儿童常见的难治性血液病之一,尤其重型再障(SAA),病情严重,死亡率高。80年代初,HLA配型全相合的骨髓移植被认为是根治SAA的唯一方法,近20余年,随着有关免疫介导致病机制的深入研究及临床免疫抑制治疗经验的不断总结,认为儿童获得性再障大多存在免疫功能紊乱,应用免疫抑制治疗(immunosuppressive therapy,IST)使SAA的治疗缓解率已由20世纪80年代10%以下提高到60%~80%,长期存活率及生存质量与骨髓移植相当[1~3],目前在我国因造血干细胞来源困难和昂贵经费等问题限制其广泛应用情况下,…     

免疫抑制治疗对儿童重型再生障碍性贫血细胞因子表达的影响

目的探讨重型再生障碍性贫血(AA)患儿经免疫抑制治疗(IST)后外周血相关细胞因子表达水平的变化。方法纳入2017年10月至2018年12月在首都医科大学附属北京儿童医院(我院)住院初诊为获得性重型AA(SAA)/极重型AA(VSAA)且应用IST治疗的患儿为SAA/VSAA组,同期在我院住院初诊为获得性非重型AA(MAA)并给予环孢素A(CsA)口服治疗的患儿为MAA组。采用流式细胞术检测两组患儿初诊时、SAA/VSAA组治疗6个月和12个月、MAA组治疗6个月外周血中IFN-γ、TNF-α、IL-2、IL-4、IL-6和IL-10的表达水平。结果 SAA/VSAA组25例,MAA组37例。①初诊时SAA/VSAA组IFN-γ和IL-6表达较MAA组增加(P0.05)。②SAA/VSAA组经IST治疗1年后,IFN-γ和IL-6较治疗前明显降低,差异均有统计学意义(P0.05)。③截至末次随访,SAA/VSAA组除3例失访外,余22例全部生存,无复发。结论 SAA/VSAA患儿血清细胞因子水平异常,IST可显著改善初治患儿相关造血负向调控因子的表达。     

儿童获得性非重型再生障碍性贫血中西医结合诊疗专家共识

正再生障碍性贫血(aplastic anemia,AA,简称再障)是一组以骨髓造血细胞增生减低和外周血细胞减少为特征的骨髓衰竭性疾病~([1-5])。中华医学会儿科分会血液学组曾于2014年和2019年分别推荐《儿童获得性再生障碍性贫血诊疗建议》和《儿童再生障碍性贫血诊疗规范》~([3,6]),对于重型再障(severe aplastic anemia,SAA)的诊治原则已达成共识,但对儿童非重型再障(non-severe aplastic anemia,NSAA)的重视程度远不及SAA,尚无相应共识。祖国医学遵循整体观和辨证论治理论,对儿童AA尤其是NSAA,积累了丰富的实践经验。     

Upfront eltrombopag monotherapy induces stable hematologic remission in pediatric patients with nonsevere idiopathic aplastic anemia

Aplastic anemia (AA) is characterized by multilineage cytopenias and bone marrow hypocellularity. Severe AA can be treated with immunosuppressive therapy (IST) and/or allogeneic hematopoietic stem cell transplantation. The thrombopoietin agonist eltrombopag has been shown to induce hematopoietic recovery and transfusion independence in adults with refractory and relapsed AA. Recently, upfront eltrombopag therapy in patients with AA in combination with IST has shown efficacy. Data for its use without concurrent IST in pediatric patients with AA remain sparse. Here we report two pediatric patients with AA not meeting severe criteria who achieved hematologic response with upfront eltrombopag monotherapy.     

抗胸腺细胞球蛋白联合环孢菌素A治疗儿童再生障碍性贫血疗效及相关因素分析

目的探索采用抗胸腺细胞球蛋白(ATG)联合环孢菌素A(CSA)的免疫抑制疗法(IST)治疗儿童再生障碍性贫血(再障)的疗效及其相关影响因素,为进一步提高临床疗效提供参考依据。方法共40例再障患儿(重型再障28例,依赖成分输血的慢性再障12例)接受ATG联合CSA治疗。统计分析治疗前病程和外周血三系下降程度;ATG治疗后外周血淋巴细胞绝对计数(ALC)下降程度、血清病发生率及不同制剂ATG治疗等临床因素与远期疗效的相关性。结果中位随访时间19(9～44)个月,总有效率和显效率分别为78%和45%。疗效相关统计分析显示:(1)ATG治疗后2周内,ALC下降幅度≥2×109/L者的有效率明显高于下降幅度<2×109/L者,两组总有效率分别为89%和54%(P<0.05)。(2)从确诊再障到接受ATG治疗,病程≤6个月者有效率明显高于病程>6个月者,两组总有效率分别为92%和53%(P<0.05)。(3)采用两种ATG制剂(美国Genzyme或德国Fresenius)各治疗18例和22例,两组疗效差异无显著性(P>0.05)。结论 ATG联合CSA的免疫抑制治疗是儿童再障的有效疗法,目前常用的两种ATG制剂,均能获得显著疗效。再障确诊后早期治疗有助于提高疗效。治疗期间密切观察ALC下降程度,对于ALC下降不明显者,是否需要适当增加ATG剂量,有待进一步研究论证。     

Immunosuppressive treatment of aplastic anemia in Chinese children with antithymocyte globulin and cyclosporine

Fifty-one children with aplastic anemia (AA) from 1993 to 2004 in the authors' institution were treated by 3 therapies: 11 patients in group 1 received the SSL-6 protocol; 16 patients in group 2 had CsA alone, where the dose of CsA began from 9-12 mg/kg in the initial 2 weeks and tapered off to 5 mg/kg later; 24 patients in group 3 were treated combining rabbit ATG (Pasteur, Merieux) 2.5 mg/kg for 5 days with CsA, which was the same dose as in group 2. The response was 27, 50, and 79%, respectively. The statistical analysis showed that the protocol of intensive immunosuppressive treatment (IST) was the most effective one and CsA was better than that of SSL-6. None of our patients developed clone diseases although the follow-up was as long as more than to 9 years. The data suggest that children with AA should receive IST as first-line therapy in developing countries.

Hematopoietic stem cell transplantation (HSCT) is effective treatment for patients with aplastic anemia (AA). However, HSCT is not widely used in China for economic reasons and lack of donors. Immunosuppressive therapy (IST) is now the mainstay treatment for AA. To evaluate the effect of immunosuppressive therapy, combining antithymocyte globulin (ATG) with cyclosporine (CsA), a retrospective study on 51 children with AA from January 1993 to December 2004 treated in the authors' department was performed.     

Diagnosis and management of childhood aplastic anaemia

Aplastic anaemia (AA) is a rare and heterogeneous disorder. AA results in pancytopenia and a hypocellular bone marrow in the absence of an abnormal infiltrate, major dysplasia or marrow fibrosis. In children, most cases are idiopathic and caused by T lymphocyte-mediated destruction of haemopoietic stem and progenitor cells (HSPC's). Inherited bone marrow failure syndromes (IBMFS) account for around 20% of cases and have to be excluded. This can be challenging but has specific implications for management. Haemopoietic stem cell transplantation (HSCT) is the only definitive curative treatment for AA. For patients less than 35 years old with severe aplastic anaemia (SAA), a matched sibling donor (MSD) haematopoietic stem cell transplant is the treatment of choice. For those lacking such a donor, immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin has historically been initial treatment. Improved outcomes following matched unrelated donors (MUD) transplantation has led to UK guidelines recommending upfront MUD HSCT in children and young adults where a suitable donor can be quickly identified. Recent advances in the treatment of patients with AA have shown that horse ATG with cyclosporine remains the current standard IST. The thrombopoietin receptor agonist eltrombopag has significant activity as a single agent and in combination with IST as initial treatment and in refractory patients. For patients with IBMFS, transplantation remains the only curative procedure.     

儿童血细胞减少伴骨髓增生减低100例临床特征分析

目的：总结中日两国100例儿童血细胞减少伴骨髓增生减低病例临床特征,探讨儿童骨髓增生异常综合征（MDS）有效治疗方案。方法：非随机选取中日两国2006~2011年血细胞减少伴骨髓增生减低病例100例,回顾性分析其临床特点并对我国患者进行预后分析。结果：中日两国病例MDS及获得性再生障碍性贫血（AA）构成比差异无统计学意义。100例患儿中,AA、难治性血细胞减少（RCC）、难治性血细胞减少伴多系发育异常(RCMD) 病例数分别为29、58、13。3组病例网织红细胞绝对值及骨髓增生程度的差异具有统计学意义（P＜0.05）。对我国患儿进行随访,中位随访时间41（16~70）个月。环孢素A(CSA)联合康力龙治疗者,AA、RCC及RCMD 3组病例3个月有效率分别为25%、47%、60%,其6个月的有效率分别为75%、82%、60%。结论：RCC、RCMD、AA 3组外周血网织红细胞绝对值及骨髓增生程度具有显著性差别。CSA联合康力龙治疗儿童获得性AA和低增生性MDS疗效确切,但由于病例数少,随访时间短,仍需扩大病例长期观察。     

Outcome of children with aplastic anemia treated with immunosuppressive therapy

Background

Immunosuppressive therapy (IST) is the alternative treatment in children with aplastic anemia (AA) who do not have an HLA‐matched sibling. The aim of this study is to evaluate the outcome of children with AA treated with IST.

Methods

We retrospectively reviewed the hospital records of children with AA from 1984 to 2004, treated at our institution with antithymocyte globulin (ATG), cyclosporine (CS), and short course of prednisone.

Result

Forty‐two patients were treated with IST (24 boys, 18 girls); of whom 26% received G‐CSF. The median age at diagnosis was 8.5 years. Sixty‐nine, 19, and 12% were diagnosed with severe, very severe, and moderate AA, respectively. Twenty‐one percent had hepatitis‐associated AA. Median follow‐up time was 53.3 months. Sixty‐two percent had complete response; 19% had partial response. Two patients relapsed and received a second course of ATG; both had a partial response. The actuarial 5 years survival rate was 67.5%. Two patients developed myelodysplastic syndrome (MDS); both received long‐term G‐CSF and had partial response after two courses of IST. Fifteen percent of survivors had significant hypertension which persisted after CS was discontinued.

Conclusions

This study shows promising response in children with AA treated with IST; however, the outcome was inferior to our institutional results with hematopoietic stem cell transplantation from a sibling donor. Hypertension and MDS are late complications. Longer follow‐up, larger cohorts, and prospective studies are warranted to evaluate late complications and risk factors. Pediatr Blood Cancer 2008;50:52–57. © 2007 Wiley‐Liss, Inc.     

两种免疫抑制疗法治疗儿童严重型再生障碍性贫血的比较

目的 探讨提高儿童严重型再生障碍性贫血（ＳＡＡ）疗效的方法。方法 结合骨髓基质液体培养法及针对性应用重组人粒－巨噬细胞集落刺激因子,比较联合免疫抑制疗法（ＣＩＳＴ）与强化免疫抑制疗法（ⅡＳＴ）治疗ＳＡＡ（分别为１１例和１６例）的疗效。结果在适当应用ｒｈｕＧＭ＿ＣＳＦ的基础上,ＣＩＳＴ及ⅡＳＴ方案治疗儿童ＳＡＡＵ职效差异无显著性（有效率分别为８２％及８１％）。结论 采用ＣＩＳＴ及ⅡＳＴ方案联合适当     

Outcome of Pediatric Acquired Aplastic Anemia: A Developing World Experience

Introduction: Outcome data of children with acquired aplastic anemia (AA) are lacking from the developing world. Here, we describe the same from a centre in North India. Methods: Retrospective data regarding medical history, physical examination, complete blood count, bone marrow aspirate, and biopsy were retrieved for all children <18 years, with acquired AA admitted between January 2005 and June 2012. In addition, the outcome data after immunosuppressive therapy (IST) or bone marrow transplant (BMT) was obtained. Results: A total of 61 children were diagnosed with AA (Inherited-18 and acquired-43). Among 43 children with acquired AA, 3 had nonsevere and 40 had severe. One patient with nonsevere AA died of sepsis and 2 recovered spontaneously. Of the 40 remaining children with severe AA, 10 refused therapy and 3 died due to severe sepsis prior to any therapy. Five underwent upfront matched sibling donor BMT and one post-IST failure. Four year overall survival (OS) and event free survival (EFS) for children undergoing BMT was 100% and 80 ± 17.9, respectively. Out of 22 treated with IST, 20 were evaluable for response. Seventeen received one course and 3 received two course of IST. The overall response to IST was seen in 14/20 (70%). Only two achieved complete response while remaining 12 had partial response. The 4-year estimated OS and EFS for children treated with IST was 74.4 ± 12.1% and 65.6 ± 12.2. Conclusion: Outcomes for children with AA are encouraging in the developing world although barriers like sepsis and treatment abandonment remain. BMT offers faster and complete recovery.