不同来源造血干细胞移植治疗重型地中海贫血的临床研究
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摘要
研究背景：地中海贫血(简称地贫,thalassemia),也称为海洋性贫血或库勒氏贫血,是世界上最常见的遗传性血液病之一。地中海贫血是其中一组对人类健康影响最大的溶血性血液病,因该病最早发现的病例为地中海沿岸地区的人而得名,其分子基础为珠蛋白基因缺陷导致珠蛋白链合成障碍,使形成血红蛋白四聚体的α-链/非α-链比例失衡,进而引起红细胞破坏而溶血。我国的高发区主要分布于长江以南各省区,人群中α地贫基因携带者检出率约为1-23%,p-地贫为0.5-6%,其中,尤以广西、广东和海南三省(区)为甚。
地中海贫血是一种进展性疾病,虽然可以给予红细胞输注及去铁治疗,但这一疾病最终还是导致病人早期死亡。死因一是慢性贫血及其并发症,二是死于未适当地使用铁鳌合剂而导致的铁沉积病。目前使用的常规治疗方法主要包含二个方面：一是输血。每10-30天1次,以纠正他们所患的严重贫血,使血红蛋白(Hb)维持在90-120g/L,长期连续地输血导致体内大量铁的沉积,特别对身体的器官如心脏、肝脏和内分泌系统带来损伤；二是正确使用铁鳌合剂。在中国,1名重型地中海贫血患者,如果接受正规输血及去铁治疗,每年的费用在5万元以上。尽管没有确切的统计数据,但临床实践表明,在中国大部分的地贫儿童在生命前十年内死亡,其余的儿童在第二个十年内死亡,能够活至20岁以上重型地贫儿童很少,目前这些病人因经济原因绝大多数得不到有效治疗而在15岁前死亡；广东省总病人数现估计在3000人左右。随着生活水平的提高,接受正规或不正规输血替代治疗的病孩逐渐增多,生存期有所提高,全省总病人数也在增加。这种经历十几年的折磨,最终的残酷结局,对每个地贫病人家庭和社会在精神上和经济上都是沉重的打击。即使给予正规的输血加去铁治疗也常于30岁之前夭折。可见,β重型地贫病人给社会和家庭造成严重的危害,对构建和谐社会和提高人口质量构成严重威胁。
自Thomas和他的同事于1982年首先报道了第一例成功的同胞骨髓移植治疗地贫病例以来,异基因造血干细胞移植(HSCT)开始被用于治愈地贫；异基因HSCT是根治重型地贫唯一的治疗模式,这一治疗策略已经被医学界所普遍接受。因为HSCT是通过克服受者免疫屏障,将供者干细胞作为基因载体植入受者体内替代造血,纠正受者基因缺陷,因此HSCT实际上是一种基因治疗。造血干细胞移植治疗后的地中海贫血患者的生活质量明显高于传统输血及去铁治疗的患者。对有HLA相合同胞供者的重型β-地贫患者来说,造血干细胞移植应作为首选治疗。骨髓移植的效果与患者年龄、身体状况、预处理方案、供者来源、HLA相合程度及对并发症的处理等因素密切相关。
目前在造血干细胞移植治疗地贫方面备受研究者关注的是造血干细胞的来源问题。人类白细胞抗原(HLA)全相合同胞供髓骨髓移植治疗重型β地贫,国外已相当成熟,但由于我国实行计划生育政策,HLA全相合的同胞骨髓来源显得异常困难,绝大部分重型β地贫病人无HLA全相合同胞供者。因此,人们不得不尝试应用其他来源的造血干细胞进行移植。
中国地贫移植研究起步晚,移植的病例不多，患者去铁的情况多不正规(港台地区除外),病人的状况较差,而医疗卫生资源相当有限,需要探索出一条符合中国特色的重型地中海贫血造血干细胞移植的可行之路。本课题主要就不同来源造血干细胞移植方法,不同状态儿童移植效果的差异性,移植物抗宿主病防治方案,移植相关并发症如感染、出血性膀胱炎、肝静脉闭塞病的防治等问题进行研究。
我们自90年代末以来,即开始探索造血干细胞移植治疗地中海贫血,近几年来,不断改进治疗方案,进行新的探索,本文将我中心自2005年1月以来至2009年12月共5年所做的地贫93例共97次造血干细胞移植进行回顾性总结,报告如下。
研究对象与方法：地贫患儿93例,男68例,女25例；中位年龄7岁(0.7岁-12岁)；单次移植89例,二次移植4例。
根据国内地贫患儿年龄、肝大情况和铁蛋白水平,将重型地中海贫血分为低危(17例)、中危(46例)、高危(30例),大体相当于Pesaro地贫分度标准的Ⅰ度、Ⅱ度和Ⅲ度。
为了抑制和减轻患儿骨髓高增殖状态,减轻预处理的负担,增加植入的机会和减少移植后排斥,患儿移植前45天(40-60天)开始,给患儿口服羟基脲(hydroxyurea,30mg/kg.d)和硫唑嘌呤(azathioprine,3mg/kg.d)。
预处理方案。环磷酸胺(cyclophosphaminde,CY):剂量100-120mg/kg,分2天静脉滴注(-10d--9d)。白消安(Busulfan,BU):剂量9.6-17.6mg/kg,分3-4天静脉注射(-8d--5d,或-8d--6d)。年龄越小,单位体重使用BU剂量越大。抗人T-淋巴细胞兔免疫球蛋白(Tabbit Anti-Human T-Lymphocyte Immunoglobulin):剂量15-30mg/kg;或兔抗人胸腺细胞免疫球蛋白(商品名即复宁,Thymoglobuline,法国),剂量6mg/kg,分3天静脉滴注(-3d--1d)。氟达拉滨(Fludarabine, FLU),剂量200mg/m2,分5天静脉滴注(-6d--2d)。噻替哌(thiotepa,TT),剂量10mg/kg,1天分2次静脉滴注(-5d)。上述药物联合应用组成预处理方案。期间,按2500ml/m2的补液量进行水化并加用5%的碳酸氢钠进行碱化、止吐和苯妥英钠预防癫痫治疗。
造血干细胞输注与移植类型。在预处理方案完成之后,次日进行造血干细胞移植物输注,输注造血干细胞的当天称为0天。根据造血干细胞来源不同进行造血干细胞输注。54例骨髓移植物骨髓单个核细胞数量为：2.7(1.8-3.9)×108/kg。CD34+细胞数为6.2(1.7-16.1)×106/kg。外周血干细胞移植35例,其输注的造血干细胞数量为：8.1(7.23-11.0)×108/kg。CD34+细胞数为5.5(2.3-15.3)×106/kg。脐血移植物输注13例,输注的脐血干细胞体积约30-280ml。有核细胞数量从5×108至19×108不等。
移植物抗宿主病防治。本组病例移植物抗宿主病预防(Graft versus host disease，GVHD)的预防方案因移植的种类和造血干细胞的来源不同而有差异。所用药物和用法为：环孢霉素A (cyclosporine, Cs-A)移植前1天(-1天)开始1-3mg/kg.d静脉滴注；甲氨喋呤(methotrexate,MTX)移植后第1、3、6天各给予10-15mg/m2静脉注射。霉酚酸酯(mycophenolate mofetil,MMF)移植后第1天开始给予15mg/kg.d连续口服至30天停药。当发生GVHD时,加用甲基强的松龙(2mg/d)治疗。
肝静脉闭塞病防治。肝静脉闭塞病(Veno-occlusive disease,VOD)预防采用肝素钠100-200u/kg. d持续静注,在无出血表现的情况下维持APTT/TT轻度大于正常；前列腺E脂质微球(1-1.5μg/kg·d)。69例应用熊去氧胆酸12mg/kg.d,分两次餐中口服(08年以后患儿)；24例未用熊去氧胆酸作为对照。
出血性膀胱炎防治(HC)。HC的预防：在预处理期间水化(2.5L/m2/天),保证每小时尿量大于60-100ml/m2；同时应用美斯纳：在第一剂环磷酰胺前半小时开始,加入生理盐水中持续静脉滴注超过12小时；每天美斯纳的剂量=1.25×每天CY量。治疗采用水化+血小板输注。
感染防治。清除龋齿、肛屡等感染病灶,移植前肠道消毒,移植后无菌饮食,全环境保护性隔离,无菌操作及护理,药物预防(静脉应用抗生素、更昔洛韦/阿昔洛韦和口服复方新诺明)等。出现发热等感染症状时,根据经验及早选择有效足量的广谱抗生素。真菌的预防：采用伊曲康唑(4-6mg/kg.d)、从+5天开始至粒细胞大于0.5×109/L后3天停药。抗真菌治疗选用脂质体两性霉素B (3mg/kg.d)、科赛斯(1-2mg/kg.d)、伏立康唑(14mg/kg.d)。
心功能检测。对19例地贫移植患儿进行了N端脑利钠肽前体的动态观察,以评价N端脑利钠肽前体与急性心力衰竭的关系。从预处理开始每隔3-4 d抽外周血检测血浆NT-ProBNP、心肌酶、肌钙蛋白、肌红蛋白,直至植入稳定出院或者植入失败自身造血恢复出院。
移植后植活指标检测。(1)、间接指标：移植后临床存活超过21天；各系统造血恢复正常,包括红系、粒系、淋巴系、巨核系等；临床上发生GVHD。肿大的肝脾回缩至正常大小；乳酸脱氢酶(LDH)降至正常水平。(2)、直接指标：红细胞抗原(ABO和Rh血型改变成供者型)、细胞遗传学标记(外周血或骨髓性染色体转变成供者型)、HLA抗原(在HLA配型不全相合的病例中,HLA抗原改变为供者型)、分子遗传学证据(应用PCR扩增短串联重复序列分析移植后病例外周血中,供者的遗传学标记及所占的比例)。
结果：造血重建。不同类型移植造血重建时间不同,骨髓加脐血恢复较快、外周干细胞移植次之,骨髓移植相对较慢,NEU>0.5×109/L、PLT＞20×109/L、HGB>90g/L在骨髓供者移植所需时间分别是19、24、32天,在骨髓+脐血供者所需时间分别是14、23、27天,在外周血干细胞移植所需时间分别是17、22、28天。骨髓+脐血供者的粒细胞与血小板恢复较单纯骨髓供者移植快,两者相比有显著差异(P<0.05),有统计学意义；外周血干细胞移植与骨髓移植相比,粒细胞恢复较快,差异有统计学意义,而血小板与血红蛋白的恢复的差异无统计学意义
生存情况。93例地贫患儿,移植后成功植入83例,植入率89.2%,随访时间0.4-5年。中位随访时间24月。存活75例,无病存活68例(73.1%),总生存率为80.6%,死亡18例(19.4%)：4例地贫患儿进行了2次移植,2例为同胞移植,只有1例2次移植时采用非亲缘外周干细胞移植获得植入,植入后存在慢性GVHD。1例同胞移植未植入,予非亲缘脐血移植亦未植入,恢复地贫状态,1例同胞移植被排斥后改用同胞外周干细胞移植因慢性GVHD死亡。1例非亲缘外周干细胞移植再次采用非亲缘外周干细胞移植因感染死亡。
对89例病人的移植结果进行分析,亲缘相关HSCT(同胞和单倍体)的植入率、无病存活率、死亡率分别为89.5%、73.7%、18.4%,非亲缘相关HSCT的植入率、无病存活率、总生存率、死亡率分别为90.2%、76.5%、80.9%、17.6%。结果显示亲缘移植与非亲缘移植供者植入及生存情况差异无显著性意义(P>0.05)。比较非亲缘移植中造血干细胞移植中骨髓移植与外周血干细胞移植的治疗结果,显示外周血干细胞移植植入率高、排斥率低、无病存活率高,但统计学显示尚无意义(P>0.05)。
移植相关并发症。93例地贫移植病例,发生各类并发症至少17种,发生率超过40%的并发症有血清病(54.8%)、口腔炎(49.5%)、呼吸道感染(44.1%)、急性GVHD (43.1%),其他并发症包括植入综合征、胃肠道感染、败血症、CMV感染、出血性膀胱炎、VOD、慢性GVHD、癫痫、糖尿病、自身免疫性溶血、肝功能损害等。大多数可以控制,不影响治疗效果,但部分病人死于并发症,或留下后遗症。正确防治各种并发症,是保证移植成功的关键。病例的选择和HLA配型的相合、以及预处理方案、GVHD的预防是预防并发症的关键措施。本组病例中,感染及GVHD是患儿移植死亡的最常见的致死并发症,其他死亡原因包括ARDS、VOD、心衰、颅内出血等。
结论：
1.造血干细胞移植治疗重型地中海贫血,无病生存率在70%以上,但移植存在一定的风险,部分病人可因移植并发症而死亡。
2.不同类型移植造血重建时间不同,骨髓加脐血恢复较快、外周干细胞移植次之,骨髓移植相对较慢。
3.同胞骨髓移植仍是治疗地中海贫血的重要手段,动员后的同胞骨髓加脐血混合移植治疗儿童重型β-地中海贫血植入时间早、排斥反应不重,疗效安全可靠,具有良好的应用前景。Ⅰ-Ⅱ度地贫比Ⅲ度地贫移植效果好,提示重型地贫患儿应及早移植。
4.非亲缘移植治疗效果已达到同胞移植的疗效水平,非亲缘外周干细胞较非亲缘骨髓移植的植入率更高、无病存活率更高,疗效更好。非亲缘移植发生急性GVHD较同胞骨髓移植高。
5.熊去氧胆酸联合肝素及前列腺素E脂质微球预防重型β地中海贫血造血干细胞移植后肝静脉闭塞病疗效显著。
6.重型β-地中海贫血病人allo-HSCT后血浆NT-ProBNP的浓度与AHF发生有相关性,而心肌酶、肌钙蛋白、肌红蛋白的变化与AHF无明显相关性,血浆NT-ProBNP可作为重型地贫病人异基因造血干细胞中急性心衰的一个早期实验室预测指标。
7.移植并发症较多,包括个GVHD、VOD、HC、感染等,多数并发症可控制。部分引起死亡。感染及GVHD是患儿移植死亡的最常见的致死并发症,其他死亡原因包括ARDS、VOD、心衰、颅内出血等。
8.儿童Allo-HSCT后侵袭性真菌感染(IFI)较常见,真菌感染发生率呈上升趋势,发病时间多在移植后1月内。有口腔粘膜炎的患儿发生真菌感染机会大；真菌感染症状体征无特异性,感染部位以肺部为主。IFI的死亡率较高,是Allo-HSCT后因感染而死亡的重要原因。
Background:Thalassemia, also known as Mediterranean anemia or Cooley's anemia, is one of the commonest inherited hematopathy. Thalassemia is one of hemolytic hematopathies affecting human health profoundly, and gets its name from earliest patients located along Mediterranean coast. Its molecular basis is defect of globin gene which hinder synthesizing of globin, then cause imbalance of hemoglobin tetramer'sα-chain/nonα-chain ratio, and lead to red blood cells' breaking down--hemolysis. In our country, provinces of southern Yangzi river, especially Guangxi, Guangdong and Hainan provinces have high prevalence. Detectable ration of a thalassemia gene among population is 1-23%,βthalassemia is 0.5-6%.
Thalassemia is a developing disease, in spite of red blood cell transfusion and desferrioxamine therapy, it causes patients' early death eventually. The commonest reason of death is chronic anemia and its complications, and the second is iron deposition because of improper using of iron chelating agent. Presently, standard therapy includes two methods:one is transfusion, once every 10-30 days, to improve patients' severe anemia, keeps Hb level around 90-120 g/L. Long time and consecutive transfusion can cause high quantity of iron deposition in patients' bodies, and damage different organs such as heart, liver and endocrine system; the other one method is using iron chelating agent properly.In China, the cost of treatment of one thalassemia major patient, if he or she goes through standard blood transfusion and iron chelating agent treatment, is more than 50,000 Yuan annually. Although without accurate statistical data, according clinical experience, most of pediatric thalassemia major patients died at the first decade of their lives, rest of them died at their second decade, very few of them survived over 20 years old. Most of these patients don't have access to proper treatment because of economic reason and died before they were 15 years old. The number of these patients in Guangdong province is about 3000. Along with improving of economic situation, more and more pediatric patients accept standard or irregular blood transfusion, their life time is prolonged, and the patients'number also increased. Suffering over decades, brutal ending, are heavy burdens on patients' families and community both psychologically and economically. Even with standard blood transfusion and iron chelating agent treatment, patients often died before 30 years old. Therefore,βthalassemia major causes severe damages on patients' families and community, and is threatening constructing of harmonious community and quality of the population's improving.
Since Thomas and his colleagues reported the first case of sibling's bone marrow transplantation treating thalassemia at 1982, allo-HSCT has been used to treat thalassemia world widely; Allo-HSCT is the ultimate cure for thalassemia major, that is the strategy acknowledged by medical workers commonly. HSCT overcomes patient's immune barrier, plants donor's stem cells as gene carrier into patient's body to replace patient's hemopoiesis, corrects patient's gene defects, therefore, HSCT is a gene therapy. Thalassemia major patients'life quality after HSCT is obviously higher than patients accepting traditional blood transfusion and iron chelating agent therapy. For B thalassemia major patients who have HLA compatible siblings, HSCT should be the first choice. Effect of HSCT is highly related with patients' age, general condition, conditioning regimen, donor resource, HLA compatibility and treatment for complications.
The most concerned problem at the present time is the resource of HSC. Treatingβthalassemia major with a perfect matched sibling BMT is already a highly matured technology abroad, but in our country, because of the population control policy, there hardly is the chance to find a perfect matched sibling as BM donor, most ofβthalassemia major patients don't have a HLA matched sibling. So people have to find other source to provide HSC for transplantation.
Researching work about HSCT for thalassemia in China began rather late, there are not many transplantation cases, iron chelating agent therapy was often not carried out properly (except Hongkong, Taiwan area). Patients' situation is generally poor, medical resource is limited, there is urgent need to find a feasible way to treatβthalassemia major patients with HSCT that also fit in China's situation. Our research discusses questions about HSCT with various stem cell resources, difference of effect among pediatric patients of various ages, preventing and treatment of GVHD, complication of HSCT such as infection, hemorrhagic cystitis, hepatic veno-occlusive disease, etc.
Since late 1990, we began to explore treating thalassemia major with HSCT, and we have been improving therapeutic regimen at recent years. Here we summarize information of 97 HSCT of 93 patients in our centre from Jan.2005 to Dec.2009:
Objects and Methods:total 93 patients, male 68, female 25, mean age 7 (0.7-12 years old), single HSCT 89 cases, twice HSCT 4 cases.
According patients' age, hepatomegaly and ferritin level, we graded native pediatric thalassemia major patients into low risk(17cases), middle risk(46cases) and high risk groups(30cases), equally to Pesaro gradesⅠ,Ⅱ,Ⅲ..
Inorder to depress and alleviate high multiplication level in patient's bone marrow as well as to lower the burden of conditioning regimen, improve opportunity of engraftment and reduce rejection reaction after transplantation, patients were given hydroxyurea,30 mg/kg.d and azathioprine 3 mg/kg.d average 45 days(40-60) before transplantation.
Preconditioning regimen:Cyclophosphamide (CY), dosage 100-120mg/kg, intravenous dripping for 2 days(-10d---9d). Busulfan (BU), dosage 9.6-17.6mg/kg, intravenous injection for 3-4 days (-8d---5d,或-8d---5d), the younger the age, the larger dosage per body weight. Tabbit anti-human T lymphocyte immunoglobulin (ATG-Fresenius s, German):dosage 15-30mg/kg, or Thymoglobuline (French) dosage 6mg/kg, intravenous dripping for 3 days(-3d---1d). Fludarabine (FLU), dosage 200mg/m2, intravenous dripping for 5 days(-6d---2d). Thiotepa (TT) dosage 10 mg/kg, intravenous dripping in one day for two times (-4d). The above medications combined together consists the preconditioning regimen and a dose of 2500ml/m2 is used as fluid replacement for hydration; 5% sodium bicarbonate is added for alkalinization and vomiting prevention and Phenytoin for epilepsy treatment.
Infusion of HSC and transplantation categories:After preconditioning, we infused HSC in the second day, calling it zero-day. The infusion was based on the resources of HSC. The quantity of bone marrow mononuclear Cells in the infusion was 1.8-3.9(2.7)×108/kg and CD34+was1.7-16.1(6.2)×106/kg. Of the 35 cases of PBSCT, the quantity of bone marrow mononuclear Cells was 7.23-11.0 (8.1)×108/kg and CD34+is 2.3-15.3 (5.5)×106/kg. Of the 13 cases of UCBSCT, the volume was 30-280ml and the quantity of nuclear Cells varied from 5×108 to 19×108 or so.
Prevention of GVHD:Prevention regimens are different according different HSC resources and transplantation methods. Drugs and administration methods are: Cyclosporine (Cs-A) was given 1 day before (-1 day) HSCT, dosage 1-3 mg/kg.d intravenous dripping; Methotrexate (MTX) was given at 1st,3rd,6th day after HSCT, dosage 10-15mg/m2 intravenous injection. Mycophenolate mofetil (MMF) was given 1 day after HSCT, dosage 15 mg/kg.d oral taken consecutively for 30days.When GVHD occurred, we added methylprednisolone (2mg/d) for treatment.
Prevention of VOD:Heparin sodium 100-200u/kg.d, sustained dripping, keep APTT/TT higher than normal mildly as long as without hemorrhagic symptom. Patients treated were given prostaglandin E (1-1.5ug/(kg·d)。In 69 cases,ursodeoxycholic acid were used about 12 mg/kg.d, divided into 2 doses, oral taken along with meal.In other 24 cases, ursodeoxycholic acid were not used.
Prevention of HC:During preconditioning, hydration was applied (2.5L/m2/d) to maintain a higher 60-100ml/m2urinary volume. At the same time, half an hour before using the first dose of Cyclophosphamide, mesna in sodium chloride was intravenously dripped for 12 hours. Dosage of mesna every day=1.25×CY dosage every day. The treatment is hydration+platelet infusion.
Prevention of infection:To wipe off dental necrosis and anus residue, we sterilized the intestinal tract of the patients before the transplantation,asked them to keep a steriled diet and provided them with an isolated clean enviroment. All the manipulations and nursing in the ward was out of bacteria. Mediactions prevention: (antibiotic and Ganciclovir/Aciclovir intravenously, and trimethoprim-sulfamethoxazole orally ect.).According to experience, when infection occurred, we used sufficient antibiotics. Prevention of fungus:used itraconazole (4-6mg/kg.d) from the fifth day until the third day after granulocyte rose up to 0.5×109/L. Anti-fungus treatment:Amphotericin B (3mg/kg.d), Cancidas (1-2mg/kg.d),Vorionazole (14mg/kg.d)
Cardiac function tests:19 caese of P-thalassemia major patients received dynamic observation of the N terminal pro-brain natriuretic peptide, as to evaluate the relation of the N terminal pro-brain natriuretic peptide and acute heart failure. Every 3-4d during the preconditioning, patients should let peripheral Blood for testing NT-ProBNP, cardiac muscle enzymes, cardiac troponin and myoglobin. They should not be disachrged until engraftment get stable or hematopoietic function recover itself after engraftment failure,
Engraftment index test after HSCT:a, indirect index:patients are alive more than 21 days after HSCT; hematopoiesis recover and values of erythrocyte, granulocyte, lymphocyte and megacaryocyte are normal; presentation of clinical GVHD. Hepatomegaly and splenomegaly shrink to normal; lactate dehydrogenase (LDH) level lower to normal. b, direct index:red cell antigen (ABO and Rh type changed into donor's type), genetic mark of cell (DNA of peripheral blood or bone marrow changed into donor's), HLA antigen (mismatch cases, HLA antigen changed into donor's), Molecular genetic evidence (PCR proliferation technology was used to analyze patient's peripheral blood after HSCT, calculate donor's genetic mark's ration).
Results:
Hematopoietic reconstitution:The time of hematopoietic reconstitution is different according to various resources hematopoietic stem cell transplantation. Hematopoietic reconstitution in BMT plus CBT group is most fast, followed by PBSCT. Hematopoietic reconstitution in BMT group is relatively slow. The required mean times of NEU>0.5×109/L,PLT>20×109/L and HGB>90g/L in BMT group are 19,24 and 32 days, respectively. The times in BMT plus CBT group are 14,23 and 27 days, respectively and in BMT group are 17,22 and 28 days. The granulocyte and platelet of BMT plus CBT donors recovered faster than bone marrow alone donor, and the difference had statistical significance (P<0.05); compared with the granulocyte of bone marrow transplantation, that of peripheral blood stem cell transplantation recover faster, and the difference was statistically significant, but the recovery of platelets and hemoglobin had no significant differences.
Survival:Out of the 93 pediatricβthalassemia major patients,83 were engrafted successfully, with engraftment rate in 89.3% and follow-up time of 0.4-5 years.75 patients survived and 68 survived disease-freely (73.1%) and the overall survival rate was 80.6%.18 died; 4 patients went through HSCT twice,2 of whom accepted HSC from their siblings, only 1 accepted un-related donor's HSC twice, and this patient developed chronic GVHD after engraftment.1 patient didn't achieve engraftment with sibling as donor, and failed again after transfusing un-related donor's cord blood, remaining thalassemia status.1 patient's first time HSCT failed by transfusing sibling's bone marrow, and followed by sibling's peripheral blood stem cells at second time, but the patient died of chronic GVHD eventually.1 patient used un-related donor's peripheral blood stem cells again and died of infection after second transplantation.
The transplantation results of 89 patients were analyzed. The engraftment rate, disease-free survival rate and death rate of related donor HSCT (compatriots and haploid) were 89.5%,73.7% and 18.4%, respectively, and those of un-related donor were 90.2,76.5% and 17.6%, with the total survival rate of 80.9%. The result showed that the differences of both engraftment and survival situations of related donor and unrelated donor transplantation had no statistical significance (P>0.05). Through the comparison of treatment results of bone marrow transplantation and peripheral blood stem cell transplantation in unrelated HSCT, we can see that the peripheral blood stem cell transplantation had higher engraftment rate, lower rejection rate and higher disease-free survival rate, but the difference had no statistical significance (P>0.05).
HSCT related complication:93βthalassemia major patients recieved HSCT, and at least 17 kinds of complication occurred. Complications' morbidity was higher than 40% including serum disease (54.8%), stomatitis (49.5%), respiratory infection (44.1%), acute GVHD (43.1%), and other complications such as engraftment syndrome, gastroenteritis, sepsis, CMV infection, hemorrhagic cystitis, VOD, chronic GVHD, epilepsy, diabetes mellitus, auto-immune hemolysis, liver function damage, etc. Most of the complications are controllable, they-do not affect prognosis of HSCT, but some of the patients died of complications, or developed sequelae. Preventing complications properly is the key to guarantee the successful engraftment. Patients' choosing, HLA matching, conditioning regimen, GVHD preventing are crucial strategies to prevent complications. Among our patients, Infection and GVHD are the commonest lethal complications in pediatric HSCT, other causes of death include ARDS, VOD, heart failure, and intracranial hemorrhage.
Conclusion:
1, HSCT can cureβthalassemia major, with disease-free survival rate at over 70%. Anyhow, HSCT has great risk at the same time. Some patients could be died of severe complications.
2, The hematopoietic reconstitution time of different transplantations are different, with the most rapid recovery of bone marrow combined with cord blood, followed by peripheral stem cell transplantation and bone marrow transplantation is relatively slow.
3, Sibling as donor still plays important part in HSCT. Using primed sibling's bone marrow combined with same sibling's umbilical cord blood as HSC resource to treatβthalassemia major patients can achieve earlier engraftment, milder rejection, more countable effect, so it has a promising future application.ⅠandⅡgrade thalassemia can achieve better engraftment thanⅢgrade thalassemia, which suggests that pediatricβthalassemia major patients should accept HSCT as early as possible.
4, Un-related donor's HSCT has nearly achieved the same prognosis of sibling's HSCT; un-related peripheral stem cell transplantation can get higher engraftment rate than un-related bone marrow transplantation, as well as higher disease-free survival rate and better efficacy. Un-related HSCT has higher morbidity of acute GVHD than sibling HSCT.
5, Ursodeoxycholic acid with low-dose heparin and PGE1 is-more effective than low-dose heparin and PGE1 only (control group) for the prevention of VOD after allo-SCT for children withβ-thalassemia major.
6,βthalassemia major patients' plasma NT-ProBNP concentration after allo-HSCT is correlated with occurrence of AHF, and variation of cardiac enzymes, troponin, myoglobin has no obvious relation with AHF, so NT-ProBNP can be used as early predictive lab index to find acute heart failure during HSCT.
7, There are many transplantation complications, including GVHD, VOD, HC, infection and so on. Most of them could be controlled but parts may cause death. Infection and GVHD are the commonest lethal complications in pediatric HSCT, other causes of death include ARDS, VOD, heart failure, and intracranial hemorrhage.
8, Invasive fungus infection (IFI) is relatively common after pediatric allo-HSCT, its morbidity shows the tendency of increasing, and it occurs usually within 1 month after HSCT. Patients with stomatitis have higher risk of fungus infection; fungus infection usually has no significant menifestation, most of the infection happened in lung. Mortality of IFI is high. IFI is a major cause of death after HSCT.
地中海贫血是一种进展性疾病,虽然可以给予红细胞输注及去铁治疗,但这一疾病最终还是导致病人早期死亡。死因一是慢性贫血及其并发症,二是死于未适当地使用铁鳌合剂而导致的铁沉积病。目前使用的常规治疗方法主要包含二个方面：一是输血。每10-30天1次,以纠正他们所患的严重贫血,使血红蛋白(Hb)维持在90-120g/L,长期连续地输血导致体内大量铁的沉积,特别对身体的器官如心脏、肝脏和内分泌系统带来损伤；二是正确使用铁鳌合剂。在中国,1名重型地中海贫血患者,如果接受正规输血及去铁治疗,每年的费用在5万元以上。尽管没有确切的统计数据,但临床实践表明,在中国大部分的地贫儿童在生命前十年内死亡,其余的儿童在第二个十年内死亡,能够活至20岁以上重型地贫儿童很少,目前这些病人因经济原因绝大多数得不到有效治疗而在15岁前死亡；广东省总病人数现估计在3000人左右。随着生活水平的提高,接受正规或不正规输血替代治疗的病孩逐渐增多,生存期有所提高,全省总病人数也在增加。这种经历十几年的折磨,最终的残酷结局,对每个地贫病人家庭和社会在精神上和经济上都是沉重的打击。即使给予正规的输血加去铁治疗也常于30岁之前夭折。可见,β重型地贫病人给社会和家庭造成严重的危害,对构建和谐社会和提高人口质量构成严重威胁。
自Thomas和他的同事于1982年首先报道了第一例成功的同胞骨髓移植治疗地贫病例以来,异基因造血干细胞移植(HSCT)开始被用于治愈地贫；异基因HSCT是根治重型地贫唯一的治疗模式,这一治疗策略已经被医学界所普遍接受。因为HSCT是通过克服受者免疫屏障,将供者干细胞作为基因载体植入受者体内替代造血,纠正受者基因缺陷,因此HSCT实际上是一种基因治疗。造血干细胞移植治疗后的地中海贫血患者的生活质量明显高于传统输血及去铁治疗的患者。对有HLA相合同胞供者的重型β-地贫患者来说,造血干细胞移植应作为首选治疗。骨髓移植的效果与患者年龄、身体状况、预处理方案、供者来源、HLA相合程度及对并发症的处理等因素密切相关。
目前在造血干细胞移植治疗地贫方面备受研究者关注的是造血干细胞的来源问题。人类白细胞抗原(HLA)全相合同胞供髓骨髓移植治疗重型β地贫,国外已相当成熟,但由于我国实行计划生育政策,HLA全相合的同胞骨髓来源显得异常困难,绝大部分重型β地贫病人无HLA全相合同胞供者。因此,人们不得不尝试应用其他来源的造血干细胞进行移植。
中国地贫移植研究起步晚,移植的病例不多，患者去铁的情况多不正规(港台地区除外),病人的状况较差,而医疗卫生资源相当有限,需要探索出一条符合中国特色的重型地中海贫血造血干细胞移植的可行之路。本课题主要就不同来源造血干细胞移植方法,不同状态儿童移植效果的差异性,移植物抗宿主病防治方案,移植相关并发症如感染、出血性膀胱炎、肝静脉闭塞病的防治等问题进行研究。
我们自90年代末以来,即开始探索造血干细胞移植治疗地中海贫血,近几年来,不断改进治疗方案,进行新的探索,本文将我中心自2005年1月以来至2009年12月共5年所做的地贫93例共97次造血干细胞移植进行回顾性总结,报告如下。
研究对象与方法：地贫患儿93例,男68例,女25例；中位年龄7岁(0.7岁-12岁)；单次移植89例,二次移植4例。
根据国内地贫患儿年龄、肝大情况和铁蛋白水平,将重型地中海贫血分为低危(17例)、中危(46例)、高危(30例),大体相当于Pesaro地贫分度标准的Ⅰ度、Ⅱ度和Ⅲ度。
为了抑制和减轻患儿骨髓高增殖状态,减轻预处理的负担,增加植入的机会和减少移植后排斥,患儿移植前45天(40-60天)开始,给患儿口服羟基脲(hydroxyurea,30mg/kg.d)和硫唑嘌呤(azathioprine,3mg/kg.d)。
预处理方案。环磷酸胺(cyclophosphaminde,CY):剂量100-120mg/kg,分2天静脉滴注(-10d--9d)。白消安(Busulfan,BU):剂量9.6-17.6mg/kg,分3-4天静脉注射(-8d--5d,或-8d--6d)。年龄越小,单位体重使用BU剂量越大。抗人T-淋巴细胞兔免疫球蛋白(Tabbit Anti-Human T-Lymphocyte Immunoglobulin):剂量15-30mg/kg;或兔抗人胸腺细胞免疫球蛋白(商品名即复宁,Thymoglobuline,法国),剂量6mg/kg,分3天静脉滴注(-3d--1d)。氟达拉滨(Fludarabine, FLU),剂量200mg/m2,分5天静脉滴注(-6d--2d)。噻替哌(thiotepa,TT),剂量10mg/kg,1天分2次静脉滴注(-5d)。上述药物联合应用组成预处理方案。期间,按2500ml/m2的补液量进行水化并加用5%的碳酸氢钠进行碱化、止吐和苯妥英钠预防癫痫治疗。
造血干细胞输注与移植类型。在预处理方案完成之后,次日进行造血干细胞移植物输注,输注造血干细胞的当天称为0天。根据造血干细胞来源不同进行造血干细胞输注。54例骨髓移植物骨髓单个核细胞数量为：2.7(1.8-3.9)×108/kg。CD34+细胞数为6.2(1.7-16.1)×106/kg。外周血干细胞移植35例,其输注的造血干细胞数量为：8.1(7.23-11.0)×108/kg。CD34+细胞数为5.5(2.3-15.3)×106/kg。脐血移植物输注13例,输注的脐血干细胞体积约30-280ml。有核细胞数量从5×108至19×108不等。
移植物抗宿主病防治。本组病例移植物抗宿主病预防(Graft versus host disease，GVHD)的预防方案因移植的种类和造血干细胞的来源不同而有差异。所用药物和用法为：环孢霉素A (cyclosporine, Cs-A)移植前1天(-1天)开始1-3mg/kg.d静脉滴注；甲氨喋呤(methotrexate,MTX)移植后第1、3、6天各给予10-15mg/m2静脉注射。霉酚酸酯(mycophenolate mofetil,MMF)移植后第1天开始给予15mg/kg.d连续口服至30天停药。当发生GVHD时,加用甲基强的松龙(2mg/d)治疗。
肝静脉闭塞病防治。肝静脉闭塞病(Veno-occlusive disease,VOD)预防采用肝素钠100-200u/kg. d持续静注,在无出血表现的情况下维持APTT/TT轻度大于正常；前列腺E脂质微球(1-1.5μg/kg·d)。69例应用熊去氧胆酸12mg/kg.d,分两次餐中口服(08年以后患儿)；24例未用熊去氧胆酸作为对照。
出血性膀胱炎防治(HC)。HC的预防：在预处理期间水化(2.5L/m2/天),保证每小时尿量大于60-100ml/m2；同时应用美斯纳：在第一剂环磷酰胺前半小时开始,加入生理盐水中持续静脉滴注超过12小时；每天美斯纳的剂量=1.25×每天CY量。治疗采用水化+血小板输注。
感染防治。清除龋齿、肛屡等感染病灶,移植前肠道消毒,移植后无菌饮食,全环境保护性隔离,无菌操作及护理,药物预防(静脉应用抗生素、更昔洛韦/阿昔洛韦和口服复方新诺明)等。出现发热等感染症状时,根据经验及早选择有效足量的广谱抗生素。真菌的预防：采用伊曲康唑(4-6mg/kg.d)、从+5天开始至粒细胞大于0.5×109/L后3天停药。抗真菌治疗选用脂质体两性霉素B (3mg/kg.d)、科赛斯(1-2mg/kg.d)、伏立康唑(14mg/kg.d)。
心功能检测。对19例地贫移植患儿进行了N端脑利钠肽前体的动态观察,以评价N端脑利钠肽前体与急性心力衰竭的关系。从预处理开始每隔3-4 d抽外周血检测血浆NT-ProBNP、心肌酶、肌钙蛋白、肌红蛋白,直至植入稳定出院或者植入失败自身造血恢复出院。
移植后植活指标检测。(1)、间接指标：移植后临床存活超过21天；各系统造血恢复正常,包括红系、粒系、淋巴系、巨核系等；临床上发生GVHD。肿大的肝脾回缩至正常大小；乳酸脱氢酶(LDH)降至正常水平。(2)、直接指标：红细胞抗原(ABO和Rh血型改变成供者型)、细胞遗传学标记(外周血或骨髓性染色体转变成供者型)、HLA抗原(在HLA配型不全相合的病例中,HLA抗原改变为供者型)、分子遗传学证据(应用PCR扩增短串联重复序列
结果：造血重建。不同类型移植造血重建时间不同,骨髓加脐血恢复较快、外周干细胞移植次之,骨髓移植相对较慢,NEU>0.5×109/L、PLT＞20×109/L、HGB>90g/L在骨髓供者移植所需时间分别是19、24、32天,在骨髓+脐血供者所需时间分别是14、23、27天,在外周血干细胞移植所需时间分别是17、22、28天。骨髓+脐血供者的粒细胞与血小板恢复较单纯骨髓供者移植快,两者相比有显著差异(P<0.05),有统计学意义；外周血干细胞移植与骨髓移植相比,粒细胞恢复较快,差异有统计学意义,而血小板与血红蛋白的恢复的差异无统计学意义
生存情况。93例地贫患儿,移植后成功植入83例,植入率89.2%,随访时间0.4-5年。中位随访时间24月。存活75例,无病存活68例(73.1%),总生存率为80.6%,死亡18例(19.4%)：4例地贫患儿进行了2次移植,2例为同胞移植,只有1例2次移植时采用非亲缘外周干细胞移植获得植入,植入后存在慢性GVHD。1例同胞移植未植入,予非亲缘脐血移植亦未植入,恢复地贫状态,1例同胞移植被排斥后改用同胞外周干细胞移植因慢性GVHD死亡。1例非亲缘外周干细胞移植再次采用非亲缘外周干细胞移植因感染死亡。
对89例病人的移植结果进行分析,亲缘相关HSCT(同胞和单倍体)的植入率、无病存活率、死亡率分别为89.5%、73.7%、18.4%,非亲缘相关HSCT的植入率、无病存活率、总生存率、死亡率分别为90.2%、76.5%、80.9%、17.6%。结果显示亲缘移植与非亲缘移植供者植入及生存情况差异无显著性意义(P>0.05)。比较非亲缘移植中造血干细胞移植中骨髓移植与外周血干细胞移植的治疗结果,显示外周血干细胞移植植入率高、排斥率低、无病存活率高,但统计学显示尚无意义(P>0.05)。
移植相关并发症。93例地贫移植病例,发生各类并发症至少17种,发生率超过40%的并发症有血清病(54.8%)、口腔炎(49.5%)、呼吸道感染(44.1%)、急性GVHD (43.1%),其他并发症包括植入综合征、胃肠道感染、败血症、CMV感染、出血性膀胱炎、VOD、慢性GVHD、癫痫、糖尿病、自身免疫性溶血、肝功能损害等。大多数可以控制,不影响治疗效果,但部分病人死于并发症,或留下后遗症。正确防治各种并发症,是保证移植成功的关键。病例的选择和HLA配型的相合、以及预处理方案、GVHD的预防是预防并发症的关键措施。本组病例中,感染及GVHD是患儿移植死亡的最常见的致死并发症,其他死亡原因包括ARDS、VOD、心衰、颅内出血等。
结论：
1.造血干细胞移植治疗重型地中海贫血,无病生存率在70%以上,但移植存在一定的风险,部分病人可因移植并发症而死亡。
2.不同类型移植造血重建时间不同,骨髓加脐血恢复较快、外周干细胞移植次之,骨髓移植相对较慢。
3.同胞骨髓移植仍是治疗地中海贫血的重要手段,动员后的同胞骨髓加脐血混合移植治疗儿童重型β-地中海贫血植入时间早、排斥反应不重,疗效安全可靠,具有良好的应用前景。Ⅰ-Ⅱ度地贫比Ⅲ度地贫移植效果好,提示重型地贫患儿应及早移植。
4.非亲缘移植治疗效果已达到同胞移植的疗效水平,非亲缘外周干细胞较非亲缘骨髓移植的植入率更高、无病存活率更高,疗效更好。非亲缘移植发生急性GVHD较同胞骨髓移植高。
5.熊去氧胆酸联合肝素及前列腺素E脂质微球预防重型β地中海贫血造血干细胞移植后肝静脉闭塞病疗效显著。
6.重型β-地中海贫血病人allo-HSCT后血浆NT-ProBNP的浓度与AHF发生有相关性,而心肌酶、肌钙蛋白、肌红蛋白的变化与AHF无明显相关性,血浆NT-ProBNP可作为重型地贫病人异基因造血干细胞中急性心衰的一个早期实验室预测指标。
7.移植并发症较多,包括个GVHD、VOD、HC、感染等,多数并发症可控制。部分引起死亡。感染及GVHD是患儿移植死亡的最常见的致死并发症,其他死亡原因包括ARDS、VOD、心衰、颅内出血等。
8.儿童Allo-HSCT后侵袭性真菌感染(IFI)较常见,真菌感染发生率呈上升趋势,发病时间多在移植后1月内。有口腔粘膜炎的患儿发生真菌感染机会大；真菌感染症状体征无特异性,感染部位以肺部为主。IFI的死亡率较高,是Allo-HSCT后因感染而死亡的重要原因。
Background:Thalassemia, also known as Mediterranean anemia or Cooley's anemia, is one of the commonest inherited hematopathy. Thalassemia is one of hemolytic hematopathies affecting human health profoundly, and gets its name from earliest patients located along Mediterranean coast. Its molecular basis is defect of globin gene which hinder synthesizing of globin, then cause imbalance of hemoglobin tetramer'sα-chain/nonα-chain ratio, and lead to red blood cells' breaking down--hemolysis. In our country, provinces of southern Yangzi river, especially Guangxi, Guangdong and Hainan provinces have high prevalence. Detectable ration of a thalassemia gene among population is 1-23%,βthalassemia is 0.5-6%.
Thalassemia is a developing disease, in spite of red blood cell transfusion and desferrioxamine therapy, it causes patients' early death eventually. The commonest reason of death is chronic anemia and its complications, and the second is iron deposition because of improper using of iron chelating agent. Presently, standard therapy includes two methods:one is transfusion, once every 10-30 days, to improve patients' severe anemia, keeps Hb level around 90-120 g/L. Long time and consecutive transfusion can cause high quantity of iron deposition in patients' bodies, and damage different organs such as heart, liver and endocrine system; the other one method is using iron chelating agent properly.In China, the cost of treatment of one thalassemia major patient, if he or she goes through standard blood transfusion and iron chelating agent treatment, is more than 50,000 Yuan annually. Although without accurate statistical data, according clinical experience, most of pediatric thalassemia major patients died at the first decade of their lives, rest of them died at their second decade, very few of them survived over 20 years old. Most of these patients don't have access to proper treatment because of economic reason and died before they were 15 years old. The number of these patients in Guangdong province is about 3000. Along with improving of economic situation, more and more pediatric patients accept standard or irregular blood transfusion, their life time is prolonged, and the patients'number also increased. Suffering over decades, brutal ending, are heavy burdens on patients' families and community both psychologically and economically. Even with standard blood transfusion and iron chelating agent treatment, patients often died before 30 years old. Therefore,βthalassemia major causes severe damages on patients' families and community, and is threatening constructing of harmonious community and quality of the population's improving.
Since Thomas and his colleagues reported the first case of sibling's bone marrow transplantation treating thalassemia at 1982, allo-HSCT has been used to treat thalassemia world widely; Allo-HSCT is the ultimate cure for thalassemia major, that is the strategy acknowledged by medical workers commonly. HSCT overcomes patient's immune barrier, plants donor's stem cells as gene carrier into patient's body to replace patient's hemopoiesis, corrects patient's gene defects, therefore, HSCT is a gene therapy. Thalassemia major patients'life quality after HSCT is obviously higher than patients accepting traditional blood transfusion and iron chelating agent therapy. For B thalassemia major patients who have HLA compatible siblings, HSCT should be the first choice. Effect of HSCT is highly related with patients' age, general condition, conditioning regimen, donor resource, HLA compatibility and treatment for complications.
The most concerned problem at the present time is the resource of HSC. Treatingβthalassemia major with a perfect matched sibling BMT is already a highly matured technology abroad, but in our country, because of the population control policy, there hardly is the chance to find a perfect matched sibling as BM donor, most ofβthalassemia major patients don't have a HLA matched sibling. So people have to find other source to provide HSC for transplantation.
Researching work about HSCT for thalassemia in China began rather late, there are not many transplantation cases, iron chelating agent therapy was often not carried out properly (except Hongkong, Taiwan area). Patients' situation is generally poor, medical resource is limited, there is urgent need to find a feasible way to treatβthalassemia major patients with HSCT that also fit in China's situation. Our research discusses questions about HSCT with various stem cell resources, difference of effect among pediatric patients of various ages, preventing and treatment of GVHD, complication of HSCT such as infection, hemorrhagic cystitis, hepatic veno-occlusive disease, etc.
Since late 1990, we began to explore treating thalassemia major with HSCT, and we have been improving therapeutic regimen at recent years. Here we summarize information of 97 HSCT of 93 patients in our centre from Jan.2005 to Dec.2009:
Objects and Methods:total 93 patients, male 68, female 25, mean age 7 (0.7-12 years old), single HSCT 89 cases, twice HSCT 4 cases.
According patients' age, hepatomegaly and ferritin level, we graded native pediatric thalassemia major patients into low risk(17cases), middle risk(46cases) and high risk groups(30cases), equally to Pesaro gradesⅠ,Ⅱ,Ⅲ..
Inorder to depress and alleviate high multiplication level in patient's bone marrow as well as to lower the burden of conditioning regimen, improve opportunity of engraftment and reduce rejection reaction after transplantation, patients were given hydroxyurea,30 mg/kg.d and azathioprine 3 mg/kg.d average 45 days(40-60) before transplantation.
Preconditioning regimen:Cyclophosphamide (CY), dosage 100-120mg/kg, intravenous dripping for 2 days(-10d---9d). Busulfan (BU), dosage 9.6-17.6mg/kg, intravenous injection for 3-4 days (-8d---5d,或-8d---5d), the younger the age, the larger dosage per body weight. Tabbit anti-human T lymphocyte immunoglobulin (ATG-Fresenius s, German):dosage 15-30mg/kg, or Thymoglobuline (French) dosage 6mg/kg, intravenous dripping for 3 days(-3d---1d). Fludarabine (FLU), dosage 200mg/m2, intravenous dripping for 5 days(-6d---2d). Thiotepa (TT) dosage 10 mg/kg, intravenous dripping in one day for two times (-4d). The above medications combined together consists the preconditioning regimen and a dose of 2500ml/m2 is used as fluid replacement for hydration; 5% sodium bicarbonate is added for alkalinization and vomiting prevention and Phenytoin for epilepsy treatment.
Infusion of HSC and transplantation categories:After preconditioning, we infused HSC in the second day, calling it zero-day. The infusion was based on the resources of HSC. The quantity of bone marrow mononuclear Cells in the infusion was 1.8-3.9(2.7)×108/kg and CD34+was1.7-16.1(6.2)×106/kg. Of the 35 cases of PBSCT, the quantity of bone marrow mononuclear Cells was 7.23-11.0 (8.1)×108/kg and CD34+is 2.3-15.3 (5.5)×106/kg. Of the 13 cases of UCBSCT, the volume was 30-280ml and the quantity of nuclear Cells varied from 5×108 to 19×108 or so.
Prevention of GVHD:Prevention regimens are different according different HSC resources and transplantation methods. Drugs and administration methods are: Cyclosporine (Cs-A) was given 1 day before (-1 day) HSCT, dosage 1-3 mg/kg.d intravenous dripping; Methotrexate (MTX) was given at 1st,3rd,6th day after HSCT, dosage 10-15mg/m2 intravenous injection. Mycophenolate mofetil (MMF) was given 1 day after HSCT, dosage 15 mg/kg.d oral taken consecutively for 30days.When GVHD occurred, we added methylprednisolone (2mg/d) for treatment.
Prevention of VOD:Heparin sodium 100-200u/kg.d, sustained dripping, keep APTT/TT higher than normal mildly as long as without hemorrhagic symptom. Patients treated were given prostaglandin E (1-1.5ug/(kg·d)。In 69 cases,ursodeoxycholic acid were used about 12 mg/kg.d, divided into 2 doses, oral taken along with meal.In other 24 cases, ursodeoxycholic acid were not used.
Prevention of HC:During preconditioning, hydration was applied (2.5L/m2/d) to maintain a higher 60-100ml/m2urinary volume. At the same time, half an hour before using the first dose of Cyclophosphamide, mesna in sodium chloride was intravenously dripped for 12 hours. Dosage of mesna every day=1.25×CY dosage every day. The treatment is hydration+platelet infusion.
Prevention of infection:To wipe off dental necrosis and anus residue, we sterilized the intestinal tract of the patients before the transplantation,asked them to keep a steriled diet and provided them with an isolated clean enviroment. All the manipulations and nursing in the ward was out of bacteria. Mediactions prevention: (antibiotic and Ganciclovir/Aciclovir intravenously, and trimethoprim-sulfamethoxazole orally ect.).According to experience, when infection occurred, we used sufficient antibiotics. Prevention of fungus:used itraconazole (4-6mg/kg.d) from the fifth day until the third day after granulocyte rose up to 0.5×109/L. Anti-fungus treatment:Amphotericin B (3mg/kg.d), Cancidas (1-2mg/kg.d),Vorionazole (14mg/kg.d)
Cardiac function tests:19 caese of P-thalassemia major patients received dynamic observation of the N terminal pro-brain natriuretic peptide, as to evaluate the relation of the N terminal pro-brain natriuretic peptide and acute heart failure. Every 3-4d during the preconditioning, patients should let peripheral Blood for testing NT-ProBNP, cardiac muscle enzymes, cardiac troponin and myoglobin. They should not be disachrged until engraftment get stable or hematopoietic function recover itself after engraftment failure,
Engraftment index test after HSCT:a, indirect index:patients are alive more than 21 days after HSCT; hematopoiesis recover and values of erythrocyte, granulocyte, lymphocyte and megacaryocyte are normal; presentation of clinical GVHD. Hepatomegaly and splenomegaly shrink to normal; lactate dehydrogenase (LDH) level lower to normal. b, direct index:red cell antigen (ABO and Rh type changed into donor's type), genetic mark of cell (DNA of peripheral blood or bone marrow changed into donor's), HLA antigen (mismatch cases, HLA antigen changed into donor's), Molecular genetic evidence (PCR proliferation technology was used to analyze patient's peripheral blood after HSCT, calculate donor's genetic mark's ration).
Results:
Hematopoietic reconstitution:The time of hematopoietic reconstitution is different according to various resources hematopoietic stem cell transplantation. Hematopoietic reconstitution in BMT plus CBT group is most fast, followed by PBSCT. Hematopoietic reconstitution in BMT group is relatively slow. The required mean times of NEU>0.5×109/L,PLT>20×109/L and HGB>90g/L in BMT group are 19,24 and 32 days, respectively. The times in BMT plus CBT group are 14,23 and 27 days, respectively and in BMT group are 17,22 and 28 days. The granulocyte and platelet of BMT plus CBT donors recovered faster than bone marrow alone donor, and the difference had statistical significance (P<0.05); compared with the granulocyte of bone marrow transplantation, that of peripheral blood stem cell transplantation recover faster, and the difference was statistically significant, but the recovery of platelets and hemoglobin had no significant differences.
Survival:Out of the 93 pediatricβthalassemia major patients,83 were engrafted successfully, with engraftment rate in 89.3% and follow-up time of 0.4-5 years.75 patients survived and 68 survived disease-freely (73.1%) and the overall survival rate was 80.6%.18 died; 4 patients went through HSCT twice,2 of whom accepted HSC from their siblings, only 1 accepted un-related donor's HSC twice, and this patient developed chronic GVHD after engraftment.1 patient didn't achieve engraftment with sibling as donor, and failed again after transfusing un-related donor's cord blood, remaining thalassemia status.1 patient's first time HSCT failed by transfusing sibling's bone marrow, and followed by sibling's peripheral blood stem cells at second time, but the patient died of chronic GVHD eventually.1 patient used un-related donor's peripheral blood stem cells again and died of infection after second transplantation.
The transplantation results of 89 patients were analyzed. The engraftment rate, disease-free survival rate and death rate of related donor HSCT (compatriots and haploid) were 89.5%,73.7% and 18.4%, respectively, and those of un-related donor were 90.2,76.5% and 17.6%, with the total survival rate of 80.9%. The result showed that the differences of both engraftment and survival situations of related donor and unrelated donor transplantation had no statistical significance (P>0.05). Through the comparison of treatment results of bone marrow transplantation and peripheral blood stem cell transplantation in unrelated HSCT, we can see that the peripheral blood stem cell transplantation had higher engraftment rate, lower rejection rate and higher disease-free survival rate, but the difference had no statistical significance (P>0.05).
HSCT related complication:93βthalassemia major patients recieved HSCT, and at least 17 kinds of complication occurred. Complications' morbidity was higher than 40% including serum disease (54.8%), stomatitis (49.5%), respiratory infection (44.1%), acute GVHD (43.1%), and other complications such as engraftment syndrome, gastroenteritis, sepsis, CMV infection, hemorrhagic cystitis, VOD, chronic GVHD, epilepsy, diabetes mellitus, auto-immune hemolysis, liver function damage, etc. Most of the complications are controllable, they-do not affect prognosis of HSCT, but some of the patients died of complications, or developed sequelae. Preventing complications properly is the key to guarantee the successful engraftment. Patients' choosing, HLA matching, conditioning regimen, GVHD preventing are crucial strategies to prevent complications. Among our patients, Infection and GVHD are the commonest lethal complications in pediatric HSCT, other causes of death include ARDS, VOD, heart failure, and intracranial hemorrhage.
Conclusion:
1, HSCT can cureβthalassemia major, with disease-free survival rate at over 70%. Anyhow, HSCT has great risk at the same time. Some patients could be died of severe complications.
2, The hematopoietic reconstitution time of different transplantations are different, with the most rapid recovery of bone marrow combined with cord blood, followed by peripheral stem cell transplantation and bone marrow transplantation is relatively slow.
3, Sibling as donor still plays important part in HSCT. Using primed sibling's bone marrow combined with same sibling's umbilical cord blood as HSC resource to treatβthalassemia major patients can achieve earlier engraftment, milder rejection, more countable effect, so it has a promising future application.ⅠandⅡgrade thalassemia can achieve better engraftment thanⅢgrade thalassemia, which suggests that pediatricβthalassemia major patients should accept HSCT as early as possible.
4, Un-related donor's HSCT has nearly achieved the same prognosis of sibling's HSCT; un-related peripheral stem cell transplantation can get higher engraftment rate than un-related bone marrow transplantation, as well as higher disease-free survival rate and better efficacy. Un-related HSCT has higher morbidity of acute GVHD than sibling HSCT.
5, Ursodeoxycholic acid with low-dose heparin and PGE1 is-more effective than low-dose heparin and PGE1 only (control group) for the prevention of VOD after allo-SCT for children withβ-thalassemia major.
6,βthalassemia major patients' plasma NT-ProBNP concentration after allo-HSCT is correlated with occurrence of AHF, and variation of cardiac enzymes, troponin, myoglobin has no obvious relation with AHF, so NT-ProBNP can be used as early predictive lab index to find acute heart failure during HSCT.
7, There are many transplantation complications, including GVHD, VOD, HC, infection and so on. Most of them could be controlled but parts may cause death. Infection and GVHD are the commonest lethal complications in pediatric HSCT, other causes of death include ARDS, VOD, heart failure, and intracranial hemorrhage.
8, Invasive fungus infection (IFI) is relatively common after pediatric allo-HSCT, its morbidity shows the tendency of increasing, and it occurs usually within 1 month after HSCT. Patients with stomatitis have higher risk of fungus infection; fungus infection usually has no significant menifestation, most of the infection happened in lung. Mortality of IFI is high. IFI is a major cause of death after HSCT.
引文
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