单倍体造血干细胞移植治疗儿童重型β-地中海贫血

目的：目前仅有30％左右的重型β-地中海贫血患者能找到HLA全相合的同胞供者,使造血干细胞移植治疗该病受到限制。该研究通过探讨单倍体造血干细胞移植治疗儿童重型β-地中海贫血的疗效,希望能够拓展供者源。方法：采用单倍体脐血或骨髓对10例重型β-地中海贫血患儿进行11例次移植。使用以羟基脲、氟达拉滨、白消安、环磷酰胺、抗胸腺细胞球蛋白为基础的预处理方案。结果：6例患者获长期稳定植入并脱离红细胞输注;2例短暂植入后排斥,其中1例恢复地中海贫血状态,另1例在移植早期死亡;1例行2次移植均未植入并出现移植后再障;1例未植入,出现再障,1年后恢复地中海贫血状态。8例植入者均发生急性移植物抗宿主病,仅1例发展为皮肤局限性慢性移植物抗宿主病。随访57.1（2.5～85.1）月,总体生存率90%,无病生存率为60%。结论：单倍体造血干细胞移植治疗儿童重型β-地中海贫血能长期重建造血,在无HLA相合同胞供体时,可以作为造血干细胞移植治疗的一种选择。［中国当代儿科杂志,2009,11（7）：546-548］     

幼年型粒单核细胞白血病单倍体相合造血干细胞移植1例

目的探讨单倍体相合造血干细胞移植治疗幼年型粒单核细胞白血病(JMML)的可行性。方法 1岁6个月JMML患儿,行单倍体相合造血干细胞移植。采用Bu/Cy+Flu+ALG方案预处理及CSA+MMF+MTX方案预防移植物抗宿主病(GVHD)。结果于移植+10 d粒系植入成功(1.2×109/L),移植+14 d血小板植入成功(260×109/L),造血初步恢复。移植+21 d查植入证据为100%嵌合。患儿移植后反复出现Ⅰ～Ⅱ度GVHD(皮肤型),给予免疫抑制剂治疗后好转。至今已生存14个月,未见复发。结论单倍体相合造血干细胞移植可能是治愈JMML的可行方法。     

造血干细胞移植治疗重型β- 地中海贫血合并肢带型肌营养不良1 例报告并文献复习

目的探讨重型β-地中海贫血合并肢带型肌营养不良(LGMD)的造血干细胞移植治疗效果。方法回顾分析1例重型β-地中海贫血(CD17纯合子突变)合并LGMD2E患儿行亲缘性HLA全相合造血干细胞移植的治疗过程。结果患儿,女,3岁5个月,供者为妹妹。移植预处理方案:氟达拉滨、白消安、环磷酰胺及抗人胸腺细胞免疫球蛋白;预防移植物抗宿主病方案:环孢素、吗替麦考酚酯及短程甲氨蝶呤。经静脉输注供者骨髓血406 mL,单个核细胞数11.3×10~8/kg,术后监测患儿血常规、植入证据及激酶水平。造血干细胞移植后,患儿重建造血及免疫功能。植入证据提示完全供者嵌合,嵌合率100%,但血清酶学无明显下降,血清肌酸激酶维持在20 000～25 000 IU/L,四肢肌力逐渐下降,近期双下肢肌力3～4级,双上肢肌力4级,易摔倒。结论异基因造血干细胞移植可以治愈患儿的地中海贫血,但无法改善肌营养不良症状。     

造血干细胞移植治疗原发性免疫缺陷病进展

异基因造血干细胞移植(HSCT)是根治部分原发性免疫缺陷病(PID)的重要甚至惟一手段。人类白细胞抗原(HLA)全相合的同胞供者移植后PID患者的长期存活率可达90%以上。国际上重症联合免疫缺陷病(SCID)移植后的长期存活率在70%以上,Wiskott-Aldrich综合征患者移植后的总体存活率在80%以上,慢性肉芽肿病患者接受HLA全相合移植后长期存活率可达90%以上。预处理方案是决定HSCT成功与否的重要因素,移植物抗宿主病及巨细胞病毒的复燃严重影响患者干细胞移植后的存活率及生活质量。文章对近年HSCT治疗PID患者在非HLA全相合同胞供者移植、预处理方案、移植物抗宿主病的防治、巨细胞病毒复燃的防治方面的进展进行介绍。     

伴N-RAS及CBL突变的幼年型粒单核细胞白血病快速急变后单倍体移植1例报告并文献复习

目的减少对幼年型粒单核细胞白血病(JMML)的误诊,探讨单倍体造血干细胞移植治疗急变后未获得完全缓解JMML的可行性,并分析JMML快速急变的原因。方法 3岁患儿历经误诊为免疫性血小板减少症(ITP)和传染性单核细胞增多症后确诊为JMML,伴有N-RAS及CBL基因突变,但快速急变为急性髓细胞性白血病AML-M4型,伴有EVI1阳性表达。患儿接受母亲单倍体(HLA 7/10相合)造血干细胞移植,预处理方案为阿糖胞苷+白舒非+猪抗人T细胞免疫球蛋白+环磷酰胺,移植后采用环孢素A+霉酚酸酯(MMF)+短程甲氨蝶呤+甲基强的松龙方案预防移植物抗宿主病(GVHD)。结果移植后+14d白细胞植活,+18d血小板植活,未发生重度GVHD。移植后2个月减停全部免疫抑制剂,随访至2018年8月1日,患儿无病存活。结论 JMML急变后未获得完全缓解行单倍体造血干细胞移植治疗是可行的,同时存在N-RAS及CBL基因突变且有EVI1阳性可能是患儿快速急变的原因。     

单倍体造血干细胞移植治疗幼年型粒单核细胞白血病的临床研究

目的探索单倍体造血干细胞移植(haplo-HSCT)治疗幼年型粒单核细胞白血病(JMML)的效果。方法回顾性分析2013年12月-2017年12月我科收治的12例JMML患儿进行haplo-HSCT的临床资料。男9例,女3例,平均发病年龄3.4(1.1～5.8)岁。采用haplo-HSCT治疗,观察预处理相关毒性、植入、移植物抗宿主病(GVHD)、移植物排斥、复发、感染及生存情况。结果 12例患儿预处理耐受性可;12例患儿全部获造血重建,中性粒细胞植活中位时间19.5(13～25)d,血小板植活中位时间25(12～129)d;移植后28d进行首次骨髓嵌合率检测:8例完全植入,3例混合植入,1例植入失败;aGVHD总发生率92%(11/12),其中Ⅲ～Ⅳ度aGVHD发生率42%(5/12),cGVHD发生率33%(4/12),广泛型cGVHD发生率为0%(0/12);2例并发移植物排斥,其中1例复发,1例经停用免疫抑制处理后再次达完全嵌合;12例患儿中2例复发,复发后1例接受二次移植,1例给予化疗+供者淋巴细胞输注(DLI)后再次达完全缓解。随访至2019年2月,中位随访时间21.5(7～61)个月,2年OS为75%,2年DFS为67%。结论 haplo-HSCT是治疗JMML的有效方法,但植入、GVHD、排斥、复发、感染仍是影响患儿生存的主要因素,优化移植方案及复发后的挽救性治疗方案是提高JMML生存的关键。     

异基因造血干细胞移植治疗粘多糖病I型1例报告

目的：粘多糖病I型是一种进行性多器官受累的遗传代谢性疾病,Hurler综合征是粘多糖病I型的最严重类型,常导致进行性的中枢神经系统受损和早期死亡。该研究进行了异基因造血干细胞移植治疗该病的初步尝试,探讨异基因干细胞移植治疗粘多糖病的疗效。方法：1例男性粘多糖病I型Hurler综合征患者,2岁1个月,供者为其胞姐,HLA配型一个HLA-B位点不合。预处理方案为减低预处理剂量的BuCy方案马利兰(BU)每日3.7mg/kg,-9~-6d;环磷酰胺(Cy)每日42.8mg/kg,-5~-2d;抗胸腺细胞球蛋白每日3.5mg/kg,-7,-5,-3,-1d。输入重组人粒细胞集落刺激因子动员的供者CD34+细胞(12.8×106/kg),以环孢素A、骁悉、赛呢哌、抗胸腺细胞球蛋白和氨甲喋呤预防移植物抗宿主病(GVHD)。结果：移植后14d,短串联重复序列结合聚合酶链反应(STR-PCR)检测显示为完全供者型嵌合,中性粒细胞和血小板植活时间分别为+11d和+19d。仅出现肝、胃肠Ⅰ级预处理相关毒性,无严重预处理相关并发症。未发生急、慢性移植物抗宿主病和移植物衰竭,移植后临床症状明显改善,认知能力持续增加。结论：异基因造血干细胞移植治疗粘多糖病I型疗效肯定,减低剂量的预处理方案有利于降低预处理相关毒性;移植前后加强免疫抑制治疗,适当增加供者造血干细胞输注数量,有利于促进植入,减少移植物衰竭以及GVHD的发生。     

Case report of unrelated cord blood transplantation for the treatment of recurrent refractory Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with intestinal perforation and literature review北大核心CSCD

目的探讨非血缘脐带血移植(UCBT)治疗儿童复发难治性EB病毒相关噬血细胞综合征(EBV-HLH)的临床经验及疗效。方法回顾性分析2015年9月郑州大学第一附属医院儿科诊治的1例复发难治性EBV-HLH合并肠穿孔,最终接受UCBT治愈患儿的临床资料,并进行文献复习。结果患儿,男,1岁6个月,因"发热15 d,皮疹9 d"为主诉入院,主要表现为高热,肝、脾、淋巴结大,快速进展的全血细胞减少、肝功能损害,骨髓涂片可见吞噬血细胞,2015年9月确诊为EBV-HLH,按国际组织细胞协会制定的HLH-2004方案化疗,维持期间2次复发,给予挽救性二线方案"培门冬酰胺酶、阿霉素脂质体、依托泊苷、甲泼尼龙"(L-DEP方案)化疗,化疗后评估噬血细胞综合征指标完全缓解,突发肠穿孔,紧急外科手术行小肠造瘘术,病情稳定后,给予"氟达拉滨+白消安+环磷酰胺"方案(Flu+BU+CY方案)预处理后行UCBT,全程静脉营养支持,移植后第13天中性粒细胞植入,第35天血小板植入,嵌合率为100%,植入成功;移植后第15天出现肝小静脉闭塞征,移植后第22天出现真菌性肺炎,移植后第26天出现皮肤移植物抗宿主病(GVHD)Ⅱ度,给予相应治疗好转;移植后第49天行二期肠造瘘关瘘术;现随访至移植后70个月,患儿一般状况良好,病情持续缓解,无慢性GVHD及其他合并症。结论异基因造血干细胞移植可能是治疗儿童复发难治性EBV-HLH的唯一有效手段;无合适同胞或非血缘供者时,非血缘脐带血干细胞可作为移植物来源;肠穿孔术后肠造瘘不是移植禁忌。     

造血干细胞移植治疗重型β地中海贫血

自1982年美国Thomas等首例报道用异基因骨髓移植(allo-BMT)成功治愈一例14月龄的重型β地中海贫血(简称β地贫)患儿以来，目前全世界已有超过1500例重型β地贫患者接受各种造血干细胞移植(HSCT)。供体造血干细胞的来源包括骨髓、动员后的外周血造血干细胞(mPBSC)和脐带血(UCB)。近20年的临床研究经验表明HSCT是目前能根治重型β地贫血的方法，本文将就如何选择合适的患者／供体和预处理方案、移植物抗宿主病(CVHD)预防及移植效果等作一介绍。     

亲缘单倍体造血干细胞移植治疗22例儿童高危血液肿瘤的安全性及疗效分析

目的评估亲缘单倍体造血干细胞移植在儿童高危血液肿瘤治疗中的安全性及疗效。方法回顾性分析22例14岁及以下的高危恶性血液病患儿在接受亲缘单倍体造血干细胞移植后的并发症及疗效。结果全部患儿移植后造血干细胞植入成功。I～Ⅱ度急性移植物抗宿主病（GVHD）发生率为64％（14／22）,Ⅲ-Ⅳ度为14％（3／22）;慢性广泛型GVHD发生率为23％（5／22）;6例无GVHD发生。至随访期末,移植早期（〈100d）相关死亡率为O,总生存率为86％（19／22）,多因素分析提示移植后原发病的复发为影响总生存率的高危因素（P〈0．05）,移植后未出现复发或者复发倾向、出现复发或者复发倾向的两组患儿总生存率分别为94％和60％（P=0．017）。结论亲缘单倍体因造血干细胞移植在高危儿童血液肿瘤的治疗中是安全有效的,亲缘单倍体供者为合适的供者选择。     

Three consecutive related bone marrow transplants for juvenile myelomonocytic leukaemia

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only cure for juvenile myelomonocytic leukaemia (JMML), but relapse remains the major cause of failure. A second transplant may be considered a way to induce the graft vs. leukaemia effect in patients who relapse after their first HSCT. We describe a 7-month-old girl with JMML who relapsed after a first, related allo-HSCT, and who again relapsed 8 months after the second transplant, despite discontinuation of immusuppressive therapy. She underwent a third allogeneic transplant from another related donor. At the time of this report the patient is in complete remission 26 months after the third transplant. We suggest that a third allo-HSCT may be taken into consideration for JMML patients who experience relapse, even after two previous transplants.     

A conditioning regimen of busulfan, fludarabine, and melphalan for allogeneic stem cell transplantation in children with juvenile myelomonocytic leukemia

A pilot study was undertaken using a myeloablative conditioning with fludarabine, busulfan, and melphalan to improve the outcome of HSCT in 10 children, aged six months to six yr, with JMML. All patients were conditioned with oral busulfan (560 mg/m(2)), fludarabine (120 mg/m(2)), and melphalan (180-210 mg/m(2)) prior to HSCT, and received stem cells from bone marrow in seven cases, and from cord blood in three cases. Engraftment was documented in eight patients, whereas graft failure occurred in two, one of whom had received HLA-mismatched cord blood and other had received bone marrow from HLA-mismatched mother. Three patients, including two in who graft failure had occurred, relapsed. Five patients developed acute GVHD and two developed chronic GVHD. Seven patients are alive and in remission 27-69 months after transplantation. Thus, our study showed that HSCT following conditioning with fludarabine, busulfan, and melphalan was well tolerated and appeared to be effective for JMML.     

Treatment of refractory CMV-infection following hematopoietic stem cell transplantation with the combination of foscarnet and leflunomide

BACKGROUND: Treatment of cytomegalovirus (CMV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is limited by toxicities of current antiviral drugs and the occurrence of drug resistant strains. Leflunomide, an immunosuppressive agent used for treatment of rheumatoid arthritis, also has activity against CMV by impairing viral assembly. Here we report the control of refractory CMV disease by the combined use of foscarnet and leflunomide. PATIENTS AND RESULTS: A 1S-year-old boy with juvenile myelo-monocytic leukemia (JMML) received an allogeneic HSCT with bone marrow stem cells from a mismatched, unrelated donor (MMUD, recipient and donor CMV-positive). CMV-reactivation two months post transplantation (Tx) could only be controlled by the use of cidofovir. Because of secondary graft failure, the boy received a second HSCT with peripheral blood stem cells (PBSC) of the same donor after overall 6 months. CMV-infection was noticed three weeks later, associated with a considerable rise of both CMV-copy number and pp65-antigen. Since reinduction with cidofovir was ineffective and ganciclovir not warranted due to the history of graft failure, the child then received a combination of foscarnet/leflunomide, leading to a rapid decline of his CMV-copy number and to an afebrile state. Hematological, hepatic or renal toxicities were not observed. CONCLUSION: This case report suggests that leflunomide may be of use in the management of transplant recipients with CMV-infection refractory or intolerant to conventional antiviral therapy.     

Differentiating juvenile myelomonocytic leukemia from chronic myeloid leukemia in childhood

Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disease of early childhood. To determine the diagnostic features, appropriate treatment, and overall patient survival pertaining to JMML for children, the authors reviewed the clinical data of 16 children with JMML admitted to the National Taiwan University Hospital between 1978 and 2001. Median age at diagnosis was 2.5 years. Fever was the most common symptom at diagnosis. At initial presentation, the mean white blood count and absolute monocyte count were 30 x 10(9)/L and 4.5 x 10(9)/L, respectively. Cytogenetic analysis was performed in 14 patients, and 2 patients (14%) had monosomy 7. Another patient, with normal karyotype at diagnosis, had deletion of 7q22 at the follow-up chromosome study. Forty-seven chronic myeloid leukemia (CML) patients were also diagnosed and followed at the same hospital during the same interval period. The age, leukocyte counts, platelet counts, basophil counts, monocyte percentages on peripheral blood smears, and median survival rate showed significant differences between JMML and CML patients (P < 0.05). The median survival was 10 months and the probability of 10-month survival was 0.38 by Kaplan-Meier analysis for 12 of the 16 JMML patients who did not receive hematopoietic stem cell transplantation (HSCT). Among three patients receiving HSCT, one patient relapsed 9 months after the first HSCT and was treated successfully by a second HSCT from the same sibling donor.     

Outcome of allogeneic hematopoietic stem cell transplantation for children with acute myelogenous leukemia in second complete remission: Single center experience

Abstract: We reviewed 26 consecutive patients with AML who were transplanted in second CR2 between 1994 and 2005. The most common conditioning regimen was CY and TBI. Median age at transplant was 8.9 yr (range 2.2–18.2). Nine patients received related donor, 16 patients received unrelated donors, and one patient received unrelated cord stem cells. Acute grade III–IV and chronic extensive GVHD occurred in eight (30%) and nine (35%) patients, respectively. Six patients (23%) relapsed, four of them died. Six patients (23%) died from TRM. Estimate of three‐yr EFS was 0.53 (95% CI; 0.34–0.72). Including the two relapsed patients who were salvaged by DLI and second transplantation, three‐yr OS was 0.61 (95% CI; 0.41–0.78) with a median follow‐up of three and a half yr (range 1.5–11.2 yr). When entering remission, children with relapsed AML have a reasonable survival with HSCT, but relapse and TRM remain a concern.     

Successful unrelated mismatched cord blood transplantation in a child with malignant infantile osteopetrosis

Allogeneic hematopoietic stem cell transplantation represents the only curative option for malignant infantile osteopetrosis (MIOP), a rare disease of infants and young children, characterized by excessive accumulation of mineralized bone and abnormal hematopoiesis. We report a case of successful engraftment and stable full-donor chimerism in a patient with MIOP who underwent unrelated donor cord blood transplantation (CBT). The donor was 2-loci human leukocyte antigen (HLA)-mismatch. After a conditioning regimen based on the combination of busulfan, cyclophosphamide, total body irradiation, and antithymocyte globulin, the patient received a dose of 3.85 x 10(7)/kg of nucleated cells. Neutrophil and platelet engraftment had been achieved by day +33 and +82, respectively, and the patient was discharged home on day +89. A successful engraftment of donor hematopoiesis was demonstrated and the child experienced grade II acute graft-vs.-host disease (GVHD) involving the skin only. A remarkable but non-progressive decrease in lumbar spine bone mineral density was observed in the first nine months post-transplant. This case suggests that unrelated donor CBT may be a feasible option in case of unavailability of a fully HLA-matched related or unrelated donor.     

Haploidentical stem cell transplantation as a salvage therapy for cord blood engraftment failure in a patient with Fanconi anemia

A 7‐year‐old male with Fanconi Anemia who developed primary graft failure following one antigen‐mismatched unrelated cord blood transplantation and a nonradiation‐based conditioning, underwent a second hematopoietic stem cell transplantation (HSCT) from his 2‐loci mismatched haploidentical father, using a nonradiation‐based regimen, 79 days after the first HSCT. A sustained hematological engraftment was achieved at 9 days post‐second HSCT. At 15 months post‐second HSCT; the patient demonstrated normal blood counts, sustained donor chimerism, and no evidence of GVHD. Haploidentical HSCTs as primary or secondary sources of stem cells, with appropriate T‐cell depletion, may be a readily available option in the absence of HLA‐matched related or unrelated donors. Pediatr Blood Cancer. 2010;55:580–582. © 2010 Wiley‐Liss, Inc.     

Successful hematopoietic stem cell transplantation from an HLA‐mismatched parent for engraftment failure after unrelated cord blood transplantation in patients with juvenile myelomonocytic leukemia: Report of two cases

JMML is an aggressive hematopoietic malignancy of early childhood, and allogeneic HSCT is the only curative treatment for this disease. Umbilical cord blood is one of donor sources for HSCT in JMML patients who do not have an HLA‐compatible relative, but engraftment failure remains a major problem. Here, we report two cases of JMML who were successfully rescued by HSCT from an HLA‐mismatched parent after development of primary engraftment failure following unrelated CBT. Both patients had severe splenomegaly and underwent unrelated CBT from an HLA‐mismatched donor. Immediately after diagnosis of engraftment failure, both patients underwent HSCT from their parent. For the second HSCT, we used RIC regimens consisting of FLU, CY, and a low dose of rabbit ATG with or without TBI and additionally administered ETP considering their persistent severe splenomegaly. Both patients achieved engraftment without severe treatment‐related adverse effects. After engraftment of second HSCT, their splenomegaly was rapidly regressed, and both patients showed no sign of relapse for over 4 years. These observations demonstrate that HSCT from an HLA‐mismatched parent could be a feasible salvage treatment for primary engraftment failure in JMML patients.     

Second allogeneic hematopoietic stem cell transplantation for juvenile myelomonocytic leukemia: case report and literature review

Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disease in young childhood. Hematopoietic stem cell transplantation (HSCT) is the only way to cure the disease, but relapse after HSCT remains a major cause of treatment failure. A 5-year-old girl with JMML, who had experienced a relapse after the first transplant, did not respond to donor lymphocyte infusion and withdrawal of immune-suppressing agents. She was successfully treated using a second transplant. Detailed reports from the English literature since 1988 relating to a total of 13 JMML patients undergoing a second transplant were reviewed. Seven of the 13 JMML patients (54%) were alive and disease-free, with a median follow-up of 53 months after the second transplant. Within the first 6 months following the initial transplant, 10 JMML patients suffered either autologous recovery (n = 6) or early relapse (n = 4). Seven of the 10 (70%) were alive, with a median survival period of 53 months after the second transplant. Six JMML patients underwent retransplantation within 6 months of the first transplant, with three of these (50%) alive at follow-ups of 24, 57, and 90 months after the second procedure. The authors conclude that a second transplant within 6 months may be worth considering for JMML patients who experience autologous recovery or earlier relapse after the first transplant.     

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。