干细胞的研究进展

在美国《Ｓｃｉｅｎｃｅ》杂志评选出的１９９９年度１０大科学进展中，干细胞（ｓｔｅｍ ｃｅｌｌ， ＳＣ）的研究工作格外令人瞩目。这不仅因为在过去短短的一年里，科学家们在干细胞的功能研究方面发表了１０余篇具有里程碑意义的论文，更重要的是，这些突破性进展使得生物学家和医学家们更进一步地认识到：ＳＣ作为一类既有自我更新能力、又有多分化潜能的细胞，具有非常重要的理论研究意义和临床应用价值［１］。这些成果一方面揭示了许多有关细胞生长和发育的基础理论难题；另一方面，可望将其用于创伤修复、神经再生和抗衰老等临床医…     

干细胞移植治疗肝脏疾病的研究进展

背景：干细胞移植治疗肝病是近年来众多学者研究的热点,干细胞移植的基本理论和临床应用研究都取得了很大的进展。 目的：对干细胞移植的理论依据、干细胞来源、移植方式、实验与临床研究、存在问题及前景进行简要综述。 方法：应用计算机检索中国学术期刊全文数据库(CNKI)和Pubmed数据库中2001-01/2011-11关于干细胞移植治疗肝病的文章,检索主题词“干细胞,移植,肝脏疾病,肝损伤”或“stem cell,transplantation,hepatic disease, hepatic injury”。初检索到192篇文献,据纳入标准保留31篇进行分析、综述。 结果与结论：干细胞来源充足,容易获取,可以体外增殖培养,干细胞移植操作简单,安全性高,尤其自体干细胞移植可完全避免移植排斥反应。但自体干细胞移植肝脏疾病的安全性和有效性尚无公识,需更长期的观察。     

胚胎神经干细胞移植治疗阿尔茨海默病

BACKGROUND:More recently, stem cell therapy has become an issue of concern. Exogenous neural stem cell transplantation brings new hope for the treatment of nervous system injury by self-replication and differentiation to complement and replace damaged or dead nerve cells. OBJECTIVE:To explore the therapeutic efficacy of neural stem cell transplantation on Alzheimer’s disease. METHODS:Thirty APP/PS1 mice with Alzheimer’s disease were randomly assigned into model group, cell solution transplantation group or cell transplantation group (n=10 per group). Another 10 C57BL/6 mice were selected as controls. Embryos of C57BL/6 mice at 18 embryonic days were taken to make neural stem cell suspension followed by transfection using lentiviral vectors carrying GFP gene at different multiplicities of infection (1, 5, 10, 15, 20). Afterwards, GFP-transfected neural stem cells were implanted into the hippocampus of Alzheimer’s disease mice in the cell transplantation group, while the same volume of complete medium was injected into the hippocampus of mice in the cell solution transplantation group. Morris water maze test was performed at 2 weeks after cell transplantation, and brain tissues of mice was taken and detected histologically at 4 weeks after cell transplantation. RESULTS AND CONCLUSION:Compared with the control group, the escape latency was significantly higher, and the number of crossings over the target quadrant was lower in the other three groups (P < 0.05). Compared with the cell solution transplantation and model groups, in contrast, the escape latency was significantly lower, and the number of crossings over the target quadrant was significantly higher in the cell transplantation group (P < 0.05). Four weeks after transplantation, more intact neurons were found in the cell transplantation group as compared with the model group. These findings indicate that neural stem cell transplantation can improve behavior and morphology performance of mice with Alzheimer’s disease.     

干细胞移植治疗系统性硬化的研究进展

系统性硬化(systemic sclerosis,SSc)的治疗一直是临床上的难题,现有的治疗手段难以满足患者需求。造血干细胞移植(hematopoietic stem cell transplantation,HSCT)在临床上的发展已相对成熟,近年来其在SSc上的临床试验取得了突破进展,但移植相关并发症问题一直有待...     

神经干细胞移植治疗老年痴呆

BACKGROUND:Neural stem cell transplantation has been used to treat a series of brain injury diseases, such as cerebral palsy, but its effect on Alzheimer’s disease is rarely reported. OBJECTIVE:To observe the effect of neural stem cell transplantation on the behavior and immune regulating system of Alzheimer’s disease rats.  METHODS:Thirty-five Sprague-Dawley rats were enrolled to make a postcerebral incision and given hippocampal injection of amanita phalloides acid to establish rat models of Alzheimer’s disease. Another 10 rats were only given hippocampal injection of normal saline after preparation of postcerebral skin incision as sham operation group. Then 32 successful rat models were randomly divided into two groups (n=16 per group): rats in experimental group were administrated hippocamal injection of 5×109/L allogeneic neural stem cell suspension; those in model group were given no injection. Five-day Morris water maze test was conducted at 4 weeks after transplantation. At 1 week after Morris water maze test, levels of interleukin-1 and interleukin-10 in the cerebral homogenate were detected, as well as pathological changes of brain tissues were observed in the three groups. RESULTS AND CONCLUSION:Compared with the model group, the abilities of cognition and memory were significantly higher in the sham operation group (P < 0.01), and the abilities of spatial learning and memory were significantly higher in the experimental group (P < 0.05, P < 0.01). Levels of interleukin-1 and interleukin-10 in the model group were significantly higher than those in the sham operation group (P < 0.01) but significantly lower than those in the experimental group (P < 0.01). Besides, the number of neurons in the model group was obviously less than that in the experimental and sham operation group. These results indicate that neural stem cell transplantation supplements and protects neurons against Alzheimer's disease in rats, thereby significantly improving the learning and memory ability.     

同基因与异基因胚胎肝干细胞移植治疗小鼠肝硬化

背景：胚胎肝干细胞移植免疫相关研究较少,同基因与异基因胚胎肝干细胞移植对小鼠肝硬化的治疗作用,目前尚不清楚。 目的：观察同种同基因与同种异基因胚胎肝干细胞移植对小鼠肝硬化的治疗作用,以及治疗过程中免疫排斥反应发生情况。 方法：采用Ⅳ型胶原酶消化法分离纯化BALB/c与C57BL/6胚胎肝干细胞。104只健康BALB/c小鼠随机分为4 组：正常对照组不予任何处理;肝硬化组、同种同基因移植组、同种异基因移植组腹腔注射四氯化碳石蜡油溶液复制肝硬化模型,16周后分别经其尾静脉注射生理盐水,等量同种同基因胚胎肝干细胞和同种异基因胚胎肝干细胞。在移植4周后比较各组受体小鼠存活情况、肝功能恢复情况、肝纤维化程度、免疫细胞(CD4⁺T、CD8⁺T、NK、NKT)数目及比值、肝脏病理学变化。 结果与结论：同种同基因移植组和同种异基因移植组生存率均为100%,与肝硬化组小鼠存活率67%相比差异有显著性意义(P < 0.05);各组肝功能和肝纤维化指标差异无显著性意义(P > 0.05)。各组免疫学指标比较差异无显著性意义(P > 0.05)。肝脏组织病理学显示肝组织修复：同种异基因移植组>同种同基因移植组>肝硬化组。因此,经尾静脉移植胚胎肝干细胞能提高肝硬化小鼠的生存率、减轻肝细胞坏死程度;同种同基因与同种异基因胚胎肝干细胞移植未发现免疫排斥,对小鼠肝硬化有一定的治疗作用。     

自体骨髓干细胞移植治疗肝硬化的疗效观察

治疗终末期肝病,原位肝移植是最理想的手段,然而供体短缺、手术损伤大、术后的免疫排斥反应以及费用高昂等问题限制了肝移植技术的发展和临床应用。自体骨髓干细胞移植操作简便、有效、侵入性小且并发症少,具有重要的临床意义。我科2009年9月至2011年1月共收治严重肝硬化失代偿期患者8例,经自体骨髓干细胞移植,治疗效果良好     

干细胞移植治疗心肌坏死的基础与临床研究

干细胞治疗心肌坏死是一种新的很有前景的治疗手段,但其机制尚不十分清楚。我国目前临床研究发现干细胞移植可以明显改善急性心肌梗死及梗死后心衰心脏功能,但由于关于干细胞移植的安全性还没有定论,因此还需慎重对待。     

糖原合成酶激酶3β过表达心肌干细胞移植治疗心肌梗死

BACKGROUND:The mechanism and effect of glycogen synthase kinase 3β (GSK-3β) in the differentiation of cardiac stem cells into cardiomyocytes are still unclear, although GSK-3β is closely related to the life activities of cells. OBJECTIVE:To investigate the changes of GSK-3β expression in the treatment of myocardial infarction in rats undergoing cardiac stem cell transplantation. METHODS:The isolation and culture of cardiac stem cells were performed in 10 neonatal rats. Lentivirus overexpressing GSK-3β or LacZ (control) was constructed and transferred into cardiac stem cells. Animal model of myocardial infarction was made in 30 Sprague-Dawley rats. Six weeks after model preparation, rat models were assigned into GSK-3β, LacZ or PBS group. GSK-3β or LacZ overexpressing cardiac stem cell solution or PBS in equal volume was injected into the rat myocardium, respectively. Four weeks after transplantation, the cardiac function and myocardial collagen production in rats were detected and compared. RESULTS AND CONCLUSION:Compared with the other two groups, the left ventricular ejection fraction was significantly higher, and the left ventricular end diastolic diameter was significantly lower in the GSK-3β group (P < 0.05). Hydroxyproline content, type I collagen mRNA, and type III collagen mRNA expression were significantly lower in the GSK-3β group than the other two groups (P < 0.05). Findings from Masson staining showed that the content of blue-stained collagen was significantly lower in the GSK-3β group than the LacZ group. Moreover, lowest myocardial infarction size was found in the GSK-3β group (P < 0.05). All these experimental findings show that GSK-3 overexpression plays a positive role in promoting the therapeutic effect of cardiac stem cell transplantation.     

静脉移植骨髓间充质干细胞对心肌病心力衰竭心功能的影响

BACKGROUND:Bone marrow mesenchymal stem cell transplantation can effectively improve decreased cardiac function caused by heart failure, but there is a lack of research about the effect in bone marrow mesenchymal stem cell transplantation on cardiac function in heart failure induced by cardiomyopathies. OBJECTIVE:To explore the effect of bone marrow mesenchymal stem cell transplantation on cardiac function in patients with cardiomyopathies accompanied by heart failure. METHODS:Totally 40 Sprague-Dawley rats were enrolled, and bone marrow mesenchymal stem cells were isolated from 10 rats, and the remaining rats were equivalently randomized into normal, model and stem cell transplantation groups. Then rats in the model and stem cell transplantation groups were given intraperitoneal injection of hydrochloric acid doxorubicin to prepare cardiomyopathy-induced heart failure models. At 7 days after modeling, the stem cell transplantation group was treated with bone marrow mesenchymal stem cells through intravenous transplantation, and the model group was treated with equal amount of DMEM medium. Four weeks later, cardiac function of each rat was detected, and the cell survival and differentiation were observed by immunofluorescence method. RESULTS AND CONCLUSION:At 4 weeks after transplantation, compared with normal and stem cell transplantation groups, the left ventricular systolic pressure and maximum rise/fall rate of left ventricular pressure were significantly decreased, but the left ventricular end diastolic pressure significantly increased in the model group (P < 0.05). And there was no significant difference between the normal group and the stem cell transplantation group (P > 0.05). High and dense fluorescence intensity was observed in the host myocardium immediately after transplantation. Subsequently, the fluorescence intensity and density decreased at 4 weeks, but the cell migration could be found, and some cells expressed cardiac troponin T. These results show that intravenous transplantation of bone marrow mesenchymal stem cells can improve cardiac function in rats with heart failure due to cardiomyopathies. Besides, the transplanted cells can survive in the host, and differentiate into cardiomyocyte-like cells.     

单倍体相合异基因造血干细胞移植治疗白血病

背景：对于无HLA全相合同胞供者的患者,采用单倍体相合造血干细胞移植面临移植物抗宿主病重、移植相关死亡率高的风险,但通过不同的移植模式,将有可能获取相近的疗效。 目的：观察亲缘HLA单倍体相合异基因造血干细胞移植治疗白血病的疗效,并与亲缘HLA全相合异基因造血干细胞移植相比较。 方法：45例白血病患者分为2组。单倍体组移植方式为外周血或联合骨髓干细胞移植,预处理方案为改良白消安与环磷酰胺或加抗胸腺细胞球蛋白,移植物抗宿主病的预防采用环孢素A+甲氨蝶呤+霉酚酸脂;全相合组移植方式为外周血干细胞移植,预处理方案为BuCY,移植物抗宿主病的预防采用环孢素A+甲氨蝶呤。 结果与结论：两组均获得造血重建时间差异无显著性意义。单倍体及全相合组急性移植物抗宿主病的累积发病率分别为73%对52%(P > 0.05);慢性移植物抗宿主病的累积发病率分别为56%对45%(P > 0.05);移植相关死亡率分别为36%对17%(P > 0.05);单倍体组无复发,全相合组复发2例;两组的预计3年累积无病生存率分别为61%对60%(P > 0.05)。结果提示,亲缘单倍体异基因造血干细胞移植的总体疗效与亲缘全相合异基因造血干细胞移植相似,但中重度急性移植物抗宿主病的发生率较后者为高。     

Allogeneic Hematopoietic Stem Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen

Allogeneic hematopoietic stem cell transplantation (HSCT) reverses the bone marrow failure syndrome due to GATA2 deficiency. The intensity of conditioning required to achieve reliable engraftment and prevent relapse remains unclear. Here, we describe the results of a prospective study of HSCT in 22 patients with GATA2 deficiency using a busulfan-based conditioning regimen. The study included 2 matched related donor (MRD) recipients, 13 matched unrelated donor (URD) recipients, and 7 haploidentical related donor (HRD) recipients. MRD and URD recipients received 4 days of busulfan and 4 days of fludarabine. HRD recipients received low-dose cyclophosphamide for 2 days, fludarabine for 5 days, 2 to 3 days of busulfan depending on cytogenetics, and 200 cGy total body irradiation. MRD and URD recipients received tacrolimus and short-course methotrexate for graft-versus-host disease (GVHD) prophylaxis. HRD recipients received high-dose post-transplant cyclophosphamide (PTCy) followed by tacrolimus and mycophenolate mofetil. At a median follow-up of 24 months (range, 9 to 50), 19 of 22 patients were alive with reversal of the disease phenotype and correction of the myelodysplastic syndrome, including eradication of cytogenetic abnormalities. Three patients died: 1 from refractory acute myelogenous leukemia, 1 from GVHD, and 1 from sepsis. There was a 26% incidence of grades III to IV acute GVHD in the MRD and URD groups and no grades III to IV acute GVHD in the HRD cohort. Similarly, there was a 46% incidence of chronic GVHD in the MRD and URD cohorts, whereas only 28% of HRD recipients developed chronic GVHD. Despite excellent overall disease-free survival (86%), GVHD remains a limitation using standard prophylaxis for GVHD. We are currently extending the use of PTCy to the MRD and URD cohorts to reduce GVHD.     

HLA单倍体与全相合异基因造血干细胞移植治疗恶性血液病

背景：异基因造血干细胞移植是治疗恶性血液病的一种非常有效的方法。单倍体相合的造血干细胞移植扩大了移植的应用范围,是无HLA相合供者患者的一种重要选择。 目的：比较HLA单倍体相合与全相合异基因造血干细胞移植治疗恶性血液病的临床疗效。 方法：回顾性分析接受异基因造血干细胞移植79例恶性血液病患者的临床资料,其中HLA单倍体相合组26例、全相合组53例,对比两组受者移植物抗宿主病的发生率、复发率、2年生存率等。 结果与结论：78例受者获得完全、持久供者干细胞植入;1例受者在移植后28 d尚未植入,后因感染死亡。两组慢性移植物抗宿主病发生率、复发率和2年无病生存率差异无显著性意义(P > 0.05)。单倍体相合组急性移植物抗宿主病发生率高于全相合组(P < 0.05);2年总生存率低于全相合组(P < 0.05)。提示血缘HLA单倍体相合移植治疗恶性血液病的安全性及疗效接近于全相合移植,在缺乏HLA相合供者的情况下,行HLA单倍体相合造血干细胞移植治疗恶性血液病是切实可行的选择。     

Treosulfan-Thiotepa-Fludarabine–Based Conditioning Regimen for Allogeneic Transplantation in Patients with Thalassemia Major: A Single-Center Experience from North India

Hematopoietic stem cell transplantation (HSCT) is the definite treatment for patients with thalassemia major. A busulfan (Bu) and cyclophosphamide (Cy)–based regimen has been the standard myeloablative chemotherapy, but it is associated with higher treatment-related toxicity, particularly in patients classified as high risk by the Pesaro criteria. Treosulfan-based conditioning regimens have been found to be equally effective and less toxic. Consequently, we analyzed the safety and efficacy of treosulfan/thiotepa/fludarabine (treo/thio/flu)-based conditioning regimens for allogeneic HSCT in patients with thalassemia major between February 2010 and September 2012. We compared those results retrospectively with results in patients who underwent previous HSCT with a Bu/Cy/antithymocyte globulin (ATG)–based conditioning regimen. A treo/thio/flu-based conditioning regimen was used in 28 consecutive patients with thalassemia major. The median patient age was 9.7 years (range, 2-18 years), and the mean CD34⁺ stem cell dose was 6.18 × 10⁶/kg. Neutrophil and platelet engraftment occurred at a median of 15 days (range, 12-23 days) and 21 days (range, 14-34 days), respectively. Three patients developed veno-occlusive disease, 4 patients developed acute graft-versus-host disease (GVHD), and 2 patients had chronic GVHD. Treatment-related mortality (TRM) was 21.4%. Two patients experienced secondary graft rejection. We compared these results with results in patients who underwent previous HSCT using a Bu/Cy/ATG-based conditioning regimen. Twelve patients were treated with this protocol, at a median age of 7.2 years (range, 2-11 years). One patient had moderate veno-occlusive disease, 2 patients developed acute GVHD, 2 patients had chronic GVHD, and 2 patients experienced graft rejection. There was no TRM in this group. We found no significant differences between the 2 groups (treo/thio/flu vs Bu/Cy/ATG) in terms of the incidence of acute GVHD, chronic GVHD, TRM, and graft failure, although a trend toward higher TRM was seen with the treo/thio/flu regimen.     

Prospective Study of Allogeneic Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide and Antithymocyte Globulin from HLA-Mismatched Related Donors for Nonmalignant Diseases

Allogeneic hematopoietic stem cell transplantation (HSCT) is performed as a curative treatment for children with nonmalignant diseases, such as bone marrow failure syndromes and primary immunodeficiencies. Because graft-versus-host-disease (GVHD) is a major factor affecting survival probability and quality of life after HSCT, the availability of HLA-matched donors restricts the application of HSCT. Recently, HSCT with post-transplantation cyclophosphamide (PTCy) has emerged as a potent method to prevent GVHD after HSCT from HLA-haploidentical donors, and some studies have suggested the safety of PTCy-HSCT for nonmalignant diseases. We conducted a prospective clinical trial aiming to help confirm the safety of HSCT and further reduction of GVHD using a combination of PTCy and low-dose antithymocyte globulin (ATG) from HLA-mismatched related donors for children with nonmalignant diseases. Six patients underwent HSCT and achieved engraftment at a median of 14.5 days, and no patient developed severe acute GVHD. All patients had sustained donor chimerism without developing chronic GVHD at the last follow-up. In conclusion, HSCT with PTCy and low-dose ATG from an HLA-mismatched related donor were feasible to control GVHD for nonmalignant diseases in the children involved in our study.© 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.     

Conditioning Regimen of 5-Day Decitabine Administration for Allogeneic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome and Myeloproliferative Neoplasms

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). However, post-HSCT relapse remains a major cause of treatment failure. Here we assessed the efficacy of a new conditioning regimen comprising decitabine (Dec), busulfan (Bu), cyclophosphamide (Cy), fludarabine (Flu), and cytarabine (Ara-c) for allo-HSCT in patients with MDS and MDS/MPN. A total of 48 patients were enrolled, including 44 with MDS and 4 with chronic myelomonocytic leukemia (CMML). Patients received Dec 20 mg/m²/day on days -9 to -5, combined with a Bu/Cy/Flu/Ara-c-modified preparative regimen. At a median follow-up of 522 days (range, 15 to 1313 days), the overall survival (OS) was 86%, relapse incidence was 12%, and nonrelapse mortality was 12%. The incidence of severe acute (grade III-IV) graft-versus-host disease (GVHD) was 23% and that of chronic GVHD was 15%. At 2 years, OS was 74% and 86%, respectively for high-risk and very-high-risk patients with MDS. Survival was promising in patients with poor-risk gene mutations, such as TP53 and ASXL1 (88%), and in those with ≥3 gene mutations (79%). Results of immunomonitoring studies revealed that proper natural killer cells made essential contributions to these favorable clinical outcomes. Overall, this new regimen was associated with a low relapse rate, low incidence and severity of GVHD, and satisfactory survival in allo-HSCT recipients with MDS and MDS/MPN.     

A Comparison of the Myeloablative Conditioning Regimen Fludarabine/Busulfan with Cyclophosphamide/Total Body Irradiation,for Allogeneic Stem Cell Transplantation in the Modern Era: A Cohort Analysis

With improvement in transplantation practices in the modern era, nonrelapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (HSCT) has improved, while disease relapse rates have remained unchanged. Survival outcomes are therefore driven by NRM in the modern era. Myeloablative conditioning (MAC) regimens are used to maximize disease control and facilitate engraftment; however, their use is often limited by toxicity. The commonly used MAC regimens incorporate either chemotherapy plus total body irradiation (TBI) or combination chemotherapy. Furthermore, reduced-toxicity myeloablative (RTM) regimens, such as fludarabine/busulfan (FluBu), have emerged as alternatives to traditional MAC and their impact on outcomes in the current era have not been fully investigated. In this study, we compare outcomes following HSCT, using the chemotherapy only RTM MAC regimens FluBu with the chemoradiotherapy regimen cyclophosphamide/TBI (CyTBI), for patients with hematologic malignancies who underwent MAC HSCT at the Dana-Farber Cancer Institute. We hypothesized that the chemotherapy-only regimen would fare better, primarily due to improved NRM. A retrospective cohort analysis was performed on 387 patients with myeloid or lymphoid hematologic malignancies who underwent HLA-matched related (8/8), matched unrelated (8/8), or single-antigen mismatched unrelated (7/8) HSCT following myeloablative conditioning. Patients received FluBu (n?=?158) or CyTBI (n?=?229). The primary outcome was overall survival (OS) and all other outcomes were regarded as secondary. A subset analysis was performed for patients <55 years of age and for acute myelogenous leukemia/myelodysplastic syndrome patients of age?<55 years. For the whole cohort, 3-year OS was similar for FluBu compared with CyTBI in unadjusted analysis. However, in multivariable analysis, FluBu resulted in superior OS compared with CyTBI (3-year adjusted estimate: 65% versus 55%, respectively; HR for death, .62; 95% CI, .40 to .97; P?=?.036). While relapse rates were similar between the 2 regimens, NRM and acute graft-versus-host disease (GVHD) (grade II to IV) were significantly worse with CyTBI compared with FluBu. Rates of chronic GVHD were similar between 2 regimens. These results were consistent in a subset of patients <55 years of age and in acute myelogenous leukemia/myelodysplastic syndrome patients below 55 years of age. The RTM chemotherapy-only regimen FluBu appears to be as effective and more tolerable than the chemoradiotherapy regimen CyTBI, leading to better OS driven by better NRM. The improvement in NRM was attributable chiefly to lower rates of grade II to IV acute GVHD. Relapse rates were not increased with FluBu. In the absence of randomized data, FluBu appears to be the optimal regimen for myeloablative HSCT in patients of all age groups.     

αβ T Cell-Depleted Haploidentical Hematopoietic Stem Cell Transplantation without Antithymocyte Globulin in Children with Chemorefractory Acute Myelogenous Leukemia

We evaluated the outcome of αβ T cell-depleted haploidentical hematopoietic stem cell transplantation (HSCT) in a cohort of children with chemorefractory acute myelogenous leukemia (AML). Twenty-two patients with either primary refractory (n = 10) or relapsed refractory (n = 12) AML in active disease status received a transplant from haploidentical donors. The preparative regimen included cytoreduction with fludarabine and cytarabine and subsequent myeloablative conditioning with treosulfan and thiotepa. Antithymocyte globulin was substituted with tocilizumab in all patients and also with abatacept in 10 patients. Grafts were peripheral blood stem cells engineered by αβ T cell and CD19 depletion. Post-transplantation prophylactic therapy included infusion of donor lymphocytes, composed of a CD45RA-depleted fraction with or without a hypomethylating agent. Complete remission was achieved in 21 patients (95%). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 18%, and the cumulative incidence of chronic GVHD was 23%. At 2 years, transplantation-related mortality was 9%, relapse rate was 42%, event-free survival was 49%, and overall survival was 53%. Our data suggest that αβ T cell-depleted haploidentical HSCT provides a reasonable chance of long-term survival in a cohort of children with chemorefractory AML and creates a solid basis for further improvement.     

Calcineurin Inhibitors Replacement by Ruxolitinib as Graft-versus-Host Disease Prophylaxis for Patients after Allogeneic Stem Cell Transplantation

Graft-versus-host disease (GVHD) is a common complication of allogeneic stem cell transplantation (allo-SCT) that carries a high mortality. Although calcineurin inhibitors (CNIs) have been widely used in GVHD prophylaxis, the incidence of acute GVHD (aGVHD) remains at roughly 30% to 50%. Moreover, some allo-SCT recipients cannot tolerate CNI. Thus, improved GVHD prevention methods are needed. Our study aimed to determine the prophylactic value of ruxolitinib for GVHD in CNI-intolerant patients after allo-SCT. Between September 2017 and March 2019, 10 patients with hematopoietic malignancies after allo-SCT who were intolerant to CNI at our center were enrolled in this study. The regimens were based on a myeloablative busulfan and cyclophosphamide regimen. Antithymocyte globulin was administered to patients with an HLA-haploidentical related donor (HRD) at a dosage of 6 mg/kg. All received ruxolitinib to replace CNI as GVHD prophylaxis. Ruxolitinib was initiated at 5 to 10 mg twice daily until 2 to 3 months post-transplantation and then tapered gradually, and in the absence of GVHD, discontinued by day +180. Eight patients had acute leukemia, 1 patient had myeloproliferative neoplasm, and 1 patient had natural killer T cell (NK/T) lymphoma. The donor type was a matched sibling donor in 3 patients and an HLA-haploidentical related donor (HRD) in 7 patients. All patients received CNI plus short-course of methotrexate as GVHD prophylaxis, but showed intolerance to CNI within 45 days post-transplantation. After ruxolitinib replacement, only 1 patient (10%) developed grade II skin aGVHD within 100 days, and only 1 patient developed severe aGVHD after 100 days. Two patients developed moderate/severe chronic GVHD (cGVHD) after tapering or stopping ruxolitinib, resulting in a 1-year cumulative incidence of moderate/severe cGVHD of 21.4%. Cytomegalovirus (CMV) reactivation occurred in 4 patients (40%), and Epstein-Barr virus (EBV) reactivation occurred in 3 patients (30%). None of the patients developed CMV disease or EBV post-transplantation lymphoproliferative disorder. After a median follow-up of 11 months (range, 2 to 15.5 months), 2 patients (20%) relapsed and 7 (70%) were alive, of whom 6 (60%) were negative for minimal residual disease and 4 were off immunosuppressant therapy. The prophylactic application of ruxolitinib for CNI-intolerant patients after allo-SCT appears to be safe and effective in preventing GVHD, but this awaits further study in larger cohorts.     

Survival after second hematopoietic stem cell transplantation for recurrent pediatric acute myeloid leukemia.

Recurrent acute myeloid leukemia (AML) after hematopoietic stem cell transplantation (HSCT) predicts a dismal prognosis. We sought to determine whether a second HSCT would result in long-term disease-free survival with acceptable toxicity. We evaluated the outcome of a second HSCT with a preparative regimen of cyclophosphamide and total body irradiation in pediatric patients with AML who relapsed after an initial HSCT with a busulfan and cyclophosphamide preparative regimen. Twenty-five patients aged 1.1 to 17.2 years (median, 4.1 years) with AML received a second HSCT for recurrent disease. All patients were conditioned with busulfan and cyclophosphamide for the first HSCT and with cyclophosphamide and total body irradiation for the second HSCT. Donor sources for the first HSCT were autologous (n = 11) or allogeneic (n = 14), whereas all donors for the second HSCT were allogeneic (12 matched related, 9 mismatched related, and 4 unrelated). Engraftment after the second HSCT occurred in all patients at median of 19.0 days (range, 11-32 days). The cumulative incidence of grade II to IV graft-versus-host disease was 76% after the second HSCT. Three patients died from regimen-related toxicity before day 100, 9 relapsed at a median of 5.4 months (range, 1.8-34.0 months), and 12 survived a median of 9.1 years (range, 7.0-14.4 years) after the second HSCT. The Kaplan-Meier estimates of survival at 100 days, 1 year, and 10 years were 88%, 56%, and 48%, respectively. The disease-free survival rate at 10 years was 44%. Multivariate Cox regression analysis suggested that patients who received a second HSCT in relapse had a relative risk of relapse of 7.8 (P =.02) compared with patients who underwent transplantation in remission. In addition, patients who received their second HSCT 相似文献