原发性免疫缺陷病造血干细胞移植和基因治疗

原发性免疫缺陷病(primary immunodeficiency disease,PID)是一组以先天免疫缺陷为特点的遗传性疾病,中性粒细胞、巨噬细胞、树突状细胞、T淋巴细胞、B淋巴细胞、补体等免疫细胞缺陷可导致患儿严重感染而早期死亡。随着基础免疫学不断发展,PID所包含的疾病数量不断增长,目前已明确100多种疾病由120余种基因突变所致,且仍以每年新发现3～4种病种的速度增长[1]。国外PID发病率为1/万～2/万。我国PID患儿多数不能得到及时诊断,获得分子生物学、基因诊断的病例更是寥寥无几。普通变异型免     

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??Allogeneic-hematopoietic stem cell transplantation??HSCT?? is the most important or even the only radical cure for some primary immunodeficiency diseases. The long-term survival is 90% or even higher with HLA matched sibling donor transplantation. In total??the overall survival for the patients with severe combined immunodeficiency disease??Wiskott-Aldrich sydrome and chronic granulomatous disease is 70%??80% and 90%??respectively. Proper conditioning regimen promotes the success of transplantation??while severe graft versus host disease and reactivation of cytomegalovirus in patients negetively affect the overall survival and life quality after transplantation. This review summerized the rencent advances in allogeneic-HSCT for primary immunodeficiency patients with respect to alternative donor transplantation??conditiong regimen consideration??prevention and treatment of graft versus host disease and reactivation of cytomegalovirus.     

Hematopoietic stem cell transplantation in CD40 ligand deficiency: A single‐center experience

Deficiency of the CD40L, expressed on the surface of T lymphocytes, is caused by mutations in the glycoprotein CD40L (CD154) gene. Resulting defective humoral and cellular responses cause a clinical presentation that includes recurrent sinopulmonary bacterial infections, opportunistic infections, sclerosing cholangitis, neutropenia, and autoimmune manifestations. HSCT represents the only curative treatment modality. However, the therapeutic decision to use HSCT proves challenging in many cases, mainly due to the lack of a phenotype‐genotype correlation. We retrospectively reviewed patients with CD40L deficiency who were transplanted in Antalya and Göztepe MedicalPark Pediatric HSCT units from 2014 to 2019 and followed by Akdeniz University School of Medicine Department of Pediatric Immunology. The records of eight male cases, including one set of twins, were evaluated retrospectively. As two transplants each were performed on the twins, a total of ten transplants were evaluated. Conditioning regimens were predominantly based on myeloablative protocols, except for the twins, who received a non‐myeloablative regimen for their first transplantation. Median neutrophil and platelet engraftment days were 13 (range 10‐19) and 14 (range 10‐42) days, respectively. In seven of ten transplants, a CMV reactivation was developed without morbidity. None of the patients developed GVHD, except for one mild case of acute GVHD. All patients survived, and the median follow‐up was 852 days. Our data show that HSCT for patients with CD40 ligand deficiency is a potentially effective treatment for long‐term disease control.     

Hematopoietic stem cell transplantation for children with thalassemia major in China

Thalassemia is the most common single-gene disorder worldwide that is considered a major public health issue. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for thalassemia major, the form of the disease reflecting homozygosity for a mutant allele. In China, many patients with thalassemia major cannot financially afford life-long regular supportive care with blood transfusions and iron chelation. Although HSCT is expensive, it is a one-time treatment that is possible in some patients. Disease-free survival rates have been 52-82% after HSCT in China. Graft rejection is the main cause of failure following HSCT. Humoral immune activity may play an important role in engraftment of donor cells. This article reviews the current status of HSCT for children with thalassemia major in China.     

Hematopoietic stem cell transplantation in children with sickle cell anemia: The parents’ experience

Genoidentical HSCT is currently the only curative treatment for SCA, preventing further vascular complications in high‐risk children. Studies on the psychological implications of HSCT for recipient, sibling donor, and the rest of the family have been limited in SCA. This study enrolled ten families and used semi‐structured interviews to explore the parents' experience at three time points: first before transplantation, then 3 months later, and 1 year later. Three themes emerged from the results: (a) the presence of anxiety, experienced throughout the process, and alleviated by coping strategies (positive thinking, family support, praying); (b) the ability to remain parents to recipient and other family members, despite apprehension and feelings of helplessness, reinforced by the mobilization of important resources at the individual/family levels; (c) the ability to acknowledge the opportunity for their child to be cured of the disease, despite feelings of guilt toward families without a donor, or their own families back home. Overall, the parental experience with HSCT is complex, involving intra‐psychic, familial, cultural, religious, and existential factors. Thus, it is important for medical teams to be cognizant of these issues in order to provide the best support to families during the HSCT process.     

Hematopoietic stem cell transplantation without in vivo T‐cell depletion for pediatric aplastic anemia: A single‐center experience

For young patients, HLA‐MRD HSCT is the first‐line treatment of SAA. However, due to China's birth control policy, few patients could find suitable sibling donors and HLA‐MUD. More and more transplantation centers have used Haplo‐D as the donor source for young adult and pediatric patients. However, studies with larger amount of pediatric patients are rare. We retrospectively analyzed the data of children with AA who were treated with allogeneic HSCT and compared the therapeutic efficacy of Haplo‐HSCT and MRD/MUD group. A total of 62 patients were enrolled. Implantation was successfully performed in 58 patients. There was no significant difference in the time for reconstruction of hematopoietic function between patients in the two groups. Thirty‐two had grade I‐IV aGVHD with incidence of 51.61%. The incidence of aGVHD was 79.41% for patients in the Haplo‐HSCT, significantly higher than that of 17.86% for patients in the MRD/MUD group (P < .01). However, the incidence of cGVHD was not significantly different between patients in the two groups (26.47% vs 10.71%, P = .09), the incidence of CMV infection was 28.57% and 52.94% for patients in the MRD/MUD and Haplo group, respectively, showing no significant difference (P = .053). The incidence of EBV infection was 47.06% for patients in the Haplo group and 28.57% for patients in the MRD/MUD group, showing no significant difference (P = .11). However, the 3‐ and 5‐year cumulative OS and FFS rates showed statistically significant difference in the two groups, P = .012 and .045, respectively. Compared to Haplo‐HSCT, MRD/MUD is more economic. In this study, we achieved good Haplo transplantation results. The incidences of cGVHD and CMV/EBV were not significantly different between Haplo group and MRD/MUD group. Although OS and FFS of the Haplo group were not as good as those of the MRD/MUD group, it is still acceptable as an alternative treatment under emergency.     

Hematopoietic stem cell transplantation from non‐sibling matched family donors for patients with thalassemia major in Jordan

There are limited data on the outcome of patients with thalassemia receiving HSCT from non‐sibling matched family donors. Of the 341 patients with thalassemia major that underwent donor search at our center from January 2003 to December 2011, 236 (69.2%) had fully matched family donor of which 28 patients (8.2%) had non‐sibling matched family donors identified. We report on seven patients with a median age of eight yr (4–21) who underwent myeloablative (n = 4) or RIC (n = 3) HSCT. The median age of the donors was 33 yr (4–47), three were parents, two first cousins, one paternal uncle, and one paternal aunt. All patients achieved primary neutrophil and platelet engraftment at a median of 18 (13–20) and 16 days (11–20), respectively. One patient developed grade II acute GVHD, and two patients developed limited chronic GVHD. One patient experienced secondary GF requiring a second transplant. At a median follow‐up of 69 months (7–110), all patients are alive and thalassemia free. Our data emphasize the need for extended family HLA typing for patients with thalassemia major in regions where there is high rate of consanguinity. Transplant from non‐sibling matched family donor can result in excellent outcome.     

Stem cell transplantation in primary immunodeficiency disease patients

BACKGROUND: Primary immunodeficiency diseases (PID) are rare but have a high associated risk of death from overwhelming infection in early childhood. Stem cell transplantation (SCT) can be curative for PID, but standardized protocols for each disease have not yet been established. METHODS: Between May 1995 and May 2005, nine patients diagnosed with a PID received SCT at the Department of Pediatrics, Hokkaido University Hospital. The median age of the patients (eight boys and one girl) was 1.0 year (range: 6 months-4 years). Five patients had Wiskott-Aldrich syndrome (WAS), three had severe combined immunodeficiency (SCID), and one had X-linked hyper-IgM syndrome (X-HIGM). Four patients received bone marrow transplantation (BMT), and five received cord blood stem cell transplantation (CBSCT). All patients, including those with SCID, received a conditioning regimen: six (WAS and X-HIGM) received a myeloablative conditioning regimen, and three (SCID) received a reduced-intensity conditioning regimen. RESULTS: All the patients are alive and have stable, complete chimerism, based on a median follow-up period of 4 years. Moreover, all patients have good immune reconstitution, and none required immunoglobulin replacement therapy. Two patients had significant acute graft-versus-host disease (GVHD), and three patients had chronic GVHD. Four of the nine patients developed cytomegalovirus (CMV) infection after SCT. CONCLUSION: The transplantation procedures appear to have provided a permanent cure in nine PID patients. Early diagnosis and prompt performance of SCT with an optimal donor and conditioning regimen contributed to the favorable outcomes.     

Allogeneic hematopoietic stem cell transplantation for infants with idiopathic myelofibrosis

IMF is a rare disease in children that can present during infancy and has a protracted course. The only known curative approach for this disease in adult patients is allogeneic HSCT. There are very few reports describing the long‐term outcome of young children following stem cell transplantation for IMF. We report on eight patients less than two yr of age with IMF that did not resolve with supportive care measures. All patients underwent myeloablative conditioning regimen with busulfan and cyclophosphamide ± ATG followed by HSCT from matched related (n = 6) or unrelated donor (n = 2). All patients achieved neutrophil and platelet engraftment. Four patients had grade II‐III acute GVHD, and chronic GVHD developed in five patients (three mild and two severe). At a median follow‐up of eight and a half yr (0.7–9), all patients are alive with complete resolution of their hematologic manifestations. At the last follow‐up, all patients had normal endocrine function except for one patient who developed hypothyroidism. To date, this is the largest cohort of young children with IMF treated successfully with HSCT, with the longest duration of follow‐up. In conclusion, our study showed that HSCT is a curative option for infants with IMF.     

Hematopoietic stem cell transplantation from a donor with Klinefelter syndrome for Wiskott-Aldrich syndrome

Abstract:  WAS is a rare X-linked recessive disorder characterized by primary progressive T cell immunodeficiency, impaired antipolysaccharide antibody response, thrombocytopenia with small platelet, and eczematoid dermatitis. Untreated patients with typical WAS have poor prognosis with the major causes of death being infection, bleeding, lymphoproliferative disorders, and malignancy. Due to the increased risk of infectious and hemorrhagic episodes the best results with HSCT are achieved in patients less than five yr of age and are recommended as early as possible. Here, we report a three-yr-old boy with WAS who underwent UCB and BMT from his genotypically identical brother with Klinefelter syndrome.     

Hematopoietic stem cell transplantation with reduced toxicity conditioning regimen in mitochondrial neurogastrointestinal encephalopathy syndrome

Background

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder due to mutations in the TYMP gene. Clinical findings are characterized by neurologic manifestations and severe gastrointestinal dysfunction. The syndrome is usually fatal, the most effective treatment appears to be hematopoietic stem cell transplantation (HSCT).

Procedure

In this retrospective study, we evaluated HSCT that was performed using a reduced toxicity myeloablative conditioning regimen in patients with MNGIE at our center.

Results

A total of six allogeneic transplant procedures were performed in four patients. Three patients had fully matched donors, and one patient had a haploidentical donor. Treosulfan-based myeloablative conditioning regimen was applied in five of six transplants. Bone marrow was used as a stem cell source. One patient is being followed up in the 4th year of posttransplant with full chimeric and without graft versus host disease (GVHD). One patient died of acute stage IV gastrointestinal system GVHD. Two patients underwent second transplantation due to engraftment failure, one of which was the patient who had a haploidentical transplant.

Conclusions

Treosulfan-based regimen is well tolerated, although engraftment failure with this conditioning regimen can be a significant problem. We share our haploidentical transplant experience, which will be the first reported case in the literature.     

Hematopoietic stem cell transplantation and acute kidney injury in children: A comprehensive review

AKI in the setting of HSCT is commonly investigated among adult patients. In the same way, malignancies requiring treatment with HSCT are not limited to the adult patient population, AKI following HSCT is frequently encountered within pediatric patient populations. However, inadequate information regarding epidemiology and pathophysiology specific to pediatric patients prevents development of appropriate and successful therapeutic strategies for those afflicted. Addressing AKI in the context of sinusoidal obstruction syndrome, chemotherapy, thrombotic microangiopathy and hypertension post chemotherapy, glomerulonephritis, and graft versus host disease provides greater insight into renal impairment associated with these HSCT‐related ailments. To obtain a better understanding of AKI among pediatric patients receiving HSCT, we investigated the current literature specifically addressing these areas of concern.     

Hematopoietic stem cell transplantation in Langerhans cell histiocytosis: case report and review of the literature

Abstract:  The prognosis in children with LCH who do not respond to the conventional therapies is very poor. SCT may be a new approach. However, there are limited data about the results of the transplantations. Herein we report a patient with refractory multisystem LCH who underwent allogeneic bone marrow transplantation and is disease and treatment free 54 months after transplantation. Further studies are required to establish the role of SCT in refractory LCH.