无关脐血移植治疗儿童高危急性白血病临床研究

目的　探讨无关脐血移植 (UD UCBT)治疗儿童高危急性白血病的疗效及合并症。方法　采用UD UCBT治疗儿童高危急性白血病 5例 ,其中急性淋巴细胞白血病 (ALL) 2例 ,急性混合性白血病 (HAL) 1例 ,慢性粒细胞白血病 (CML)急淋变 1例 ,非霍奇金淋巴瘤 (Ⅳ期 )第 2次完全缓解 (CR2 ) 1例。人类白细胞相关抗原(HLA) 5 / 6个位点相合 3例 ,6 / 6个位点相合 2例。输入脐血 (UCB)有核细胞数为 (4 9～ 11 78)× 10 7/kg。结果　 5例患儿中 4例获得造血重建。白细胞恢复至 1 0× 10 9/L以上所需时间为 13～ 18d ,与异基因骨髓移植无明显差别 ;但血小板恢复延迟 ,恢复至 2 0× 10 9/L以上所需时间为 4 5～ 6 0d。 4例获得造血重建患儿中 ,2例发生Ⅰ度急性移植物抗宿主病 (aGVHD) ,Ⅱ度和Ⅲ度aGVHD各 1例。aGVHD出现较早 (在脐血输注后 4～ 10d)。但增加环孢素A(CsA)剂量 ,加用甲基泼尼松龙治疗 ,aGVHD容易控制。结论　UD UCBT可有效重建造血 ,但血小板恢复延迟。严重aGVHD的发生与HLA不相合位点数目无关。在疾病的恢复稳定状态进行移植治疗 ,可望获得更好的远期疗效。     

非血缘相关脐血移植治疗儿童高危白血病的临床观察

目的：非血缘脐血具有快速寻求、容易得到和HLA配型不严格的特点，该文进行了非血缘相关脐血移植（UD-UCBT）治疗儿童恶性白血病的研究并探讨其疗效问题。方法：对6例难治性白血病患儿，包括3例急性淋巴细胞白血病（2例高危CR1，1例标危CR2），2例幼年慢性粒单细胞白血病（1例缓解期，1例加速期）和1例急性髓系白血病（AML- M5，CR1）进行了非血缘相关脐血移植，HLA高分辨1例全相合，1例5个位点相合，1例4个位点相合，3例3个位点相合。预处理选用白消安/环磷酰胺/ATG或全身放疗/环磷酰胺/ATG为主方案。于 0 d 回输脐血，有核细胞中位数为8.51×107/kg，CD34+细胞中位数为1.81×105/kg。预防移植物抗宿主病（GVHD）采用环孢霉素A、甲基泼尼松龙和骁悉或CD25单抗。结果：中性粒细胞绝对值（ANC）≥0.5×109/L和PLT≥20×109/L的中位天数分别是+13 d、+30 d，移植证据均为供者型。4例出现Ⅰ~Ⅲ度GVHD，均控制。随访中位时间12个月，未发生慢性GVHD，现存活4例血型均转为供者型，无复发。结论：脐血提供快速有效的造血干细胞，为治疗儿童白血病提供良好时机，非血缘相关脐血移植能耐受HLA多个位点不相合。急性GVHD发生率也较高，存在移植物抗白血病作用。     

脐带造血干细胞移植治疗儿童恶性或非恶性疾病死亡分析

目的 探讨脐带造血干细胞移植治疗儿童恶性或非恶性疾病后患儿的常见死亡原因.方法 对本院采用脐带造血干细胞移植治疗的28例儿童恶性疾病或非恶性疾病患儿的临床资料进行回顾性分析,包括24例恶性疾病和4例非恶性疾病.3例行同胞脐血干细胞移植,25例行异基因脐带造血干细胞移植,其中HLA高分辨全相合、5个位点相合各10例,4个位点相合5例,3个位点相合3例.预处理均采用清髓性方案,7例ALL采用全身放疗/环磷酰胺/抗胸腺Ig,余21例采用白消安/环磷酰胺/抗胸腺Ig.于0 d回输脐血有核细胞中位数为8.51(4.27～12.2)×107/kg,CD34+细胞的中位数为1.81(1.27～2.31)×105/kg.预防急性移植物抗宿主病均采用环孢素和小剂量甲泼尼龙,其中3例另加霉酚酸酯,1例加CD20单抗. 随访4～86个月.结果 28例行脐血造血干细胞移植的恶性或非恶性疾病儿童,存活16例(57.1%),死亡12例(42.9%).死于感染7例(25.0%),其中间质性肺炎、真菌感染性肺炎各3例,病毒性肺炎1例;死于复发3例(10.7%);死于急性移植物抗宿主病2例(7.1%).结论 儿童恶性疾病的原发病复发是脐带造血干细胞移植后常见的死亡原因之一,感染是儿童恶性疾病和非恶性疾病行脐血造血干细胞移植后另一常见死亡原因.     

异基因造血干细胞移植治疗儿童血液病的临床研究

目的评估异基因造血干细胞移植治疗儿童血液病的疗效及合并症.方法脐血移植(UCBT)治疗9例重症β地中海贫血(β-thal)、1例慢性特发性溶血性贫血(CIHA)、3例急性髓性白血病(AML-M3b、M2a、M5)及1例急性淋巴细胞白血病(ALL)合并中枢神经系统白血病;异基因外周血干细胞移植(allo-PBSCT)治疗5例β-thal及1例慢性粒细胞性白血病慢性期(CML-CP)患儿.同胞UCBT8例中5例HLA相合(6/6),5/6为1例,3/6为2例.6例非血缘相关脐血移植(UD-UCBT)中4例为6/6,1例5/6,双份脐血混合者为5/6和6/6.allo-PBSCT中5例均为血缘相关,HLA相合同胞及1例5/6父亲供者.输入脐血(UCB)有核细胞数(NC)为7.5(3.4～19.4)×107/kg,外周血NC为9.39(2.5～14.4)×108/kg.结果血缘相关脐血移植(RD-UCBT)8例中植入6例,其中排斥1例,死于肝静脉闭塞病(HVOD)1例,恢复地中海贫血状态2例;UD-UCBT中2例β-thal及2例AML均植入,1例AML-M5复发,AML-M3b自体恢复造血并完全缓解,1例AML-M2a死于巨细胞病毒间质性肺炎,1例ALL未植入,死于败血症.急性移植物抗宿主病(aGVHD)8例(80%),III度以上2例,广泛慢性移植物抗宿主病(cGVHD2)例.β-thal总生存率为90%,无病存活率(EFS)为60%,平均生存时间为21个月(2～42个月).allo-PBSCT病例全部植入,cGVHD5例,III°以上者2例,广泛cGVHD3例,死于HVOD1例.EFS5例,中位生存时间10个月(3～26个月).结论UCBT及allo-PBSCT是治疗儿童血液病的有效方法,UD-UCBT首次成功治疗β-thal.     

脐血移植治疗儿童恶性血液病的临床研究

目的观察脐血移植(CBT)治疗儿童血液系统恶性疾病的植入率、移植相关并发症和生存情况。方法血液系统恶性疾病患儿19例,其中无关供者16例,同胞供者3例。脐血与患儿HLA6个位点全相合6例,1个位点错配10例,2个位点错配3例。移植时疾病状态,高危10例,标危9例。预处理主要采用Bu/Cy或Cy/TBI方案,同时应用抗胸腺球蛋白(ATG)。GVHD预防主要采用环孢菌素A(CsA)、骁悉(MMF)及甲基泼尼松龙(MP)三联方案,3例同胞供者移植则单用CsA预防GVHD。移植脐血的细胞数量是,有核细胞(TNC)5.96×107/kg(2.57～12.20),CD34+细胞2.20×105/kg(0.31～5.80)。结果18例成功重建粒系造血,中位重建时间17(11～35)天;15例血小板植入,中位重建时间38(25～112)天。发生急性GVHD9例,其中Ⅰ度～Ⅱ度7例,Ⅲ度～Ⅳ度aGVHD2例;慢性GVHD3例。移植后随访4～86个月,复发3例,死亡8例,其中移植相关死亡6例,移植相关死亡率(TRM)31.6%。因CMV感染导致间质性肺炎死亡4例,占移植相关死亡的66.7%(4/6)。2年总生存率(OS)和无事件生存率(EFS)分别为62.54%(±11.24%)、44.53%(±12.22%);标危移植组与高危移植组病人2年OS分别为88.89%(±10.48%)、40.00%(±15.49%)。结论本组儿童血液系统恶性疾病脐血移植的植入率、移植相关并发症和生存情况与国外文献报道相似,移植时疾病状态为标危时治疗效果较好,CMV感染所致间质性肺炎是移植相关死亡的主要原因。     

非血缘脐血干细胞移植治疗X连锁慢性肉芽肿7例

目的探讨非血缘脐血干细胞移植(UR-UCBT)治疗X连锁慢性肉芽肿(X-CGD)的疗效。方法回顾性分析2007年5月至2015年5月海军总医院收治7例X-CGD患儿进行UR-UCBT的临床资料并复习相关文献。给7例X-CGD患儿进行UR-UCBT,6例为单份脐血,1例为双份脐血。HLA配型4例全相合,2例5个位点相合,1例4个位点相合。预处理选用白消安/环磷酰胺/兔抗人T-淋巴细胞免疫球蛋白(ATG),其中6例在其基础上加氟达拉滨(Flu)。于0 d回输脐血,有核细胞中位数为8.51×10~7/kg,CD34~+细胞中位数为3.81×10~5/kg。预防移植物抗宿主病(GVHD)采用环孢霉素A/吗替麦考酚酯,其中1例在其基础上加甲基泼尼松龙。结果 ANC≥0.5×10~9/L和PLT≥20×10~9/L的中位天数分别是+14 d和+30 d。4例出现Ⅰ~Ⅲ度急性GVHD,给予激素后均控制。在+30 d所有患儿通过PCR-SSO/FISH检测均为供者型完全嵌合。ECGD酶活力均于+1个月恢复正常。CYBB基因异常者+2个月未检测出突变基因。随访中位时间10(5~101)个月,未发生慢性GVHD,1例+3个月死于心功能衰竭,现存活6例酶活力均恢复正常,为无病存活。结论非血缘脐血能快速有效的提供造血干细胞,能耐受HLA多个位点不相合,UR-UCBT可对X-CGD起到根治性治疗作用。     

含氟达拉滨的预处理方案在脐血移植治疗重型β地中海贫血的疗效观察

目的　观察在“Bu+Cy+ATG”典型预处理中加入氟达拉滨 (Flu)对脐血造血干细胞移植 (UCBT)治疗重型β地中海贫血(地贫)的植入和移植物抗宿主病(GVHD)的影响。方法　2000年 6月至 2004年 6月中山大学附属二院儿科对 22例行脐血干细胞移植的地贫患儿,按预处理方案是否含Flu分为无Flu组 (8例 )和Flu组(14例)。无Flu组:Bu,Cy和马抗人胸腺细胞球蛋白 (ATG);Flu组在此基础上加Flu。观察两组植入率,急、慢性GVHD(aGVHD、cGVHD)的发生率及其程度。结果　无Flu组 8例患儿HLA全相合 5例,不全相合 3例,接受单个核细胞(MNC)为 7 03×107 /kg[ (4 7 ~12 7 )×107 /kg],其中CD34+数为 4 0×105 /kg[ ( 0 6 ~11 7 )×105 /kg], 6例植入,中性粒细胞绝对计数 (ANC)≥0 5×109 /L时间平均为 18d,血小板 (BPC)≥20×109 /L时间平均为 36 5d, 4例发生aGVHD, 1例发生cGVHD;Flu组 14例,HLA全相合 6例,不全相合 8例,平均输入供者MNC为 7 53×107 /kg[ (3 4~10)×107 /kg],其中CD34+数为 5 01×105 /kg[ (0 6~11 7)×105 /kg], 4例植入,ANC≥0 5×109 /L时间平均为 16d,BPC≥20×109 /L时间平均为 72d, 2例发生aGVHD, 3例发生cGVHD;两组植入率、aGVHD及cGVHD发生率无明显差异。Flu组的HLA不全相合病例多于非Flu组。结论　allo H     

二次互补性移植联合地西他滨治疗幼年型粒单核细胞白血病1例

目的探讨单倍体+无关不全相合脐血互补性移植联合地西他滨治疗幼年型粒单细胞白血病(JMML)的安全性和有效性。方法 4岁患儿采用单纯地西他滨治疗后[20mg/(m~2·d)×5d为1个疗程,共2疗程,间隔4周]桥接第一次母亲单倍体(5/10)+无关脐血(7/10)互补移植,植入失败后50d改用第二次同胞单倍体(5/10)+第二份无关脐血(7/10)互补移植进行挽救;移植预处理方案以Cy+Flu+BU为基础,使用PT-Cy并序贯MMF、FK506、CsA组合的预防GVHD方案;移植后继续使用地西他滨[5～10mg/(m~2·d)×5d]4个疗程(疗程间间隔4～6周)作为维持治疗,以清除"免疫逃逸"之白血病瘤细胞。结果随访时间15个月,第一次移植后+45d发生原发性植入失败;二次移植为独立脐血植入,粒细胞植入时间为二次移植后的+71d,血小板植入时间为+105d,第二次移植后20天并发重度aGVHD(肠道3级,皮肤2级),给予静脉FK506+MMF+MP抗GVHD治疗后均得到控制,未发生慢性GVHD。移植后使用地西他滨期间未见明显肝肾毒性,未发生严重骨髓抑制(粒细胞大于0.5G/L)。6个月后逐渐停服免疫抑制剂,无病存活至今。结论单倍体+无关不全相合脐血互补移植联合地西他滨治疗JMML是安全有效的,移植前适当的化疗对于HLA不全相合的移植而言可能是必要的。     

脐血移植治疗重型β地中海贫血的临床研究

目的探讨脐血移植(UCBT)治疗重型β-地中海贫血(简称β-地贫)的疗效.方法用人类白细胞抗原(HLA) 全相合或不全相合UCBT治疗重型β-地贫患儿12例.供受者的有核细胞(3.63～16.0)×107/kg,CD34+细胞(0.11～1.03)×106/kg,粒-巨噬细胞集落形成单位(0.17～1.18)×105/kg.移植的预处理方案HLA全相合的患儿采用马利兰+环磷酰胺+抗胸腺细胞球蛋白方案;HLA 2个位点不全相合者采用高剂量输血+连续静脉滴注去铁胺+羟基脲+氟达拉宾+马利兰+环磷酰胺+抗胸腺细胞球蛋白方案.结果 10例患儿获得植入,其中7例为长期稳定植入,3例植入后发生排斥;2例未能植入.获得植入的10例患儿均发生急性移植物抗宿主病(aGVHD),其中Ⅰ度aGVHD 7例,Ⅱ度aGVHD 3例.脱离地贫状态生存7例,血红蛋白始终维持正常.3例恢复地贫状态.2例未获植入的患儿1例发生移植后再生障碍性贫血,1例死于严重感染.结论 UCBT是目前β-地贫最有效的治疗手段.     

幼年粒单细胞白血病造血干细胞移植疗效初探

目的探讨造血干细胞移植治疗幼年粒单细胞白血病(JMML)的疗效。方法 5例JMML患儿接受无关供者脐血造血干细胞移植治疗。预处理均采用Bu/Cy+Mel+ATG方案:马利兰(0.8～1.0)mg/kg,每6小时1次共用16次(-8d～-5d);环磷酰胺60mg/(kg·d)用2d(-4～-3d);马法兰140mg/m2用1次(-2d):抗胸腺细胞球蛋白2.5mg/(kg·d)连用4d(-4～-1d)。GVHD预防采用CsA+MP±MMF。结果 5例成功植入,3例复发,1例复发后死于卡氏肺囊虫肺炎,1例死于CMV感染相关间质性肺炎,1例长期无病存活。结论 5例JMML移植初步治疗结果不满意,移植失败主要原因为白血病复发。为减少复发,今后需进一步改进移植方法 ,包括选择其他供体、改进GVHD预防方案。     

小儿恶性病患者血液唾液酸检测意义探讨

为了观察儿童良性、恶性病血唾液酸 (SA)浓度水平 ,用快速测定法试剂盒 ,测定了 34例急性白血病 ,2例慢性粒细胞白血病 ,1 3例其它恶性病 (淋巴瘤、恶性组织细胞病、神经母细胞瘤、骨髓增生异常综合征 ) ,2 0例良性病病人 ,5 0例正常对照。结果 :88%的急性白血病、1 0 0 %的其它恶性病SA明显增高 (P <0 .0 0 1 ) .仅有1 0 %的良性病人SA增高。结果表明 :SA检测可作为鉴别小儿恶性病的过筛试验。     

H1N1 infection in children with haematological and oncological diseases in Norway

Aim: To describe the impact of H1N1 infections in children with haematological and oncological diseases during the 2009 H1N1 pandemics. Methods: A short questionnaire was e‐mailed to all paediatric departments taking care of patients with oncological and chronic haematological diseases, asking for known cases of H1N1 infections in this patient group. Results: Nine children treated for cancer and seven children with haematological diseases were registered. No death occurred, but two patients treated for cancer (acute lymphoblastic leukaemia at diagnosis, acute myeloid leukaemia in chemotherapy‐induced bone marrow aplasia) experienced life‐threatening respiratory complications. Conclusion: In all patients with haematological disease and most cases of oncological diseases, the infections ran a mild course. However, life‐threatening complications occurred in severely immunosuppressed and neutropenic patients. Delay of anticancer treatment is a concern even in mild cases.     

Evidence for BCR/ABL1‐positive T‐cell acute lymphoblastic leukemia arising in an early lymphoid progenitor cell

BCR‐ABL1‐positive leukemias have historically been classified as either chronic myelogenous leukemia or Ph+ acute lymphoblastic leukemia. Recent analyses suggest there may be a wider range of subtypes. We report a patient with BCR‐ABL1 fusion positive T‐cell ALL with a previously undescribed cell distribution of the fusion gene. The examination of sorted cells by fluorescence in situ hybridization showed the BCR‐ABL1 fusion in the malignant T cells and a subpopulation of the nonmalignant B cells, but not nonmalignant T cells or myeloid or CD34+ progenitor cells providing evidence that the fusion may have occurred in an early lymphoid progenitor.     

Serum ferritin level in infants and children with anaemia and malignant disease

Serum ferritin was determined by immunoradiometry in children aged 6 months to 3 years, immediately before leaving hospital where they had been treated for various acute, non-haematological diseases. A low value was found in 13% of them. Serum ferritin concentration is a sensitive method in differentiating between iron deficiency and infectious anaemia. A significantly higher mean value was found in children affected by malignant disease (acute lymphoid or myeloid leukaemia, various solid tumours).     

EXPRESSION OF PTEN AND SHP1, INVESTIGATED FROM TISSUE MICROARRAYS IN PEDIATRIC ACUTE LYMPHOBLASTIC,LEUKEMIA

PTEN and SHP1 are tumor suppressor genes involved in the regulation of cell cycle control and apoptosis. The authors investigated the protein expression of PTEN and SHP1, by immunohistochemistry in tissue microarrays from bone marrow samples in children, diagnosed with acute lymphoblastic leukaemia and nonmalignant controls. PTEN was overexpressed in diagnostic ALL samples, while SHP1 showed a low expression. Both proteins showed a significant difference in expression compared to nonmalignant controls. The roles of PTEN and SHP1 are not well investigated in pediatric leukemia and could in the future play a role as prognostic factors.     

Bone marrow transplantation. I. Use in neoplastic diseases

Over the last decade, bone marrow transplantation has been employed with increasing frequency in an attempt to treat a variety of malignant processes--including acute and chronic leukemia, lymphomas, and a variety of solid tumors. This review attempts to summarize the progress that has been made over the last 10 years in applying bone marrow transplantation to the treatment of these diseases. Some of the limitations of the procedure will be discussed, as well as some of the possible techniques for overcoming these limitations. Future sections will deal with the application of bone marrow transplantation to nonmalignant disorders and to a general discussion of the complications of the procedure as it applies to both malignant and nonmalignant diseases. Some of the recent advances in marrow transplantation technology will also be reviewed.     

Leukaemia in children in Papua New Guinea: an unusual pattern

We report data on 110 children aged <15 years diagnosed with leukaemia during two periods covering 13.25 years. The data sets were consistent. The reported incidence of leukaemia was low. Only 34 (31%) of the children were diagnosed with acute lymphoblastic leukaemia (ALL) compared with 54 (49%) children with acute myeloid leukaemia (AML). The overall mean (SD) age was 6.6 (3.5) years, 6.1 (3.5) for ALL and 6.9 (3.5) for AML. There was no evidence of an early childhood peak of ALL. The male : female ratio was 1.2 : 1 for all leukaemias, 1.3 for ALL and 1.25 for AML. Only eight (22%) of those diagnosed with ALL were classified as type L1. Our figures reflect a relative absence of the common (cALL) cell type in early childhood leukaemia and support the role of infection and its effect on the immune system in the aetiology of childhood leukaemia. Our data also revealed an unusually high proportion of chronic myeloid leukaemia (CML).     

Acute lymphoblastic leukemia

Acute leukemia is the most common childhood malignancy, representing 30% of all cancer in American children under the age of 15 years and 12% of cancer cases in those ages 15 to 19 years old. In the United States, approximately 2500 new cases are diagnosed annually; 80% of these are acute lymphoblastic leukemia, 15% are acute myelogenous leukemia, and 5% belong to the chronic leukemia category.(1) The survival rates of children with acute leukemia have increased dramatically in the last 40 years.(2-5) The most success in outcome has occurred in acute lymphoblastic leukemia, although improvement is also being reported in acute myelogenous leukemia in the past few years. Progress comes from treatment strategy modifications on the basis of observations made in sequential large-scale therapeutic trials, an approach that serves as a paradigm for research in other malignant diseases.     

Haematological disorders in Down syndrome

Haematological abnormalities are common in children with Down syndrome. These are mostly benign. Neonatal changes include polycythaemia, neutrophilia and thrombocytopenia. In later childhood changes include secondary polycythaemia, red-cell macrocytosis, increased red-cell distribution width, leukopenia, and immune dysfunction. Transient myeloproliferative disorder occurs in about 5% and indicates a group at particularly high risk of subsequent leukaemia. A full blood count should be checked in all neonates with Down syndrome. Those with transient myeloproliferative disorder should be discussed with a paediatric haematologist. Of all children with Down syndrome, 1–2% will develop acute leukaemia. Children with Down syndrome and acute myeloid leukaemia usually respond well to chemotherapy. Acute lymphoblastic leukaemia responds less well, and particular care must be taken to minimize risk of infection. There is a paucity of data for both benign and malignant haematological disease, and this needs to be addressed.     

Acute leukemia after cytotoxic treatment for nonmalignant disease in childhood

The case history of an 11-year-old boy is reported. The child developed the nephrotic syndrome at the age of 17 months. He was treated with prednisolone, cyclophosphamide, cytosine-arabinoside and chlorambucil for the following three and a half years. Three and a half years after cessation of any medical treatment he developed anemia, thrombocytopenia and a diagnosis of acute lymphocytic leukemia (ALL) was made. Subsequently he responded to the West Berlin Protocol. Reviewing the literature, another eight cases of acute leukemia after cytotoxic treatment for nonmalignant disease in childhood have been reported. Most often the myeloblastic form of acute leukemia was diagnosed. Even though the pathogenic mechanism of acute leukemia after cytotoxic treatment is not known, the possibility must be considered that the incidence of this malignant disease is increased after cytotoxic treatment for nonmalignant diseases.