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 in children with Griscelli syndrome: A single‐center experience

GS2 is a rare autosomal recessive disease characterized by hypopigmentation, variable immunodeficiency with HLH. HSCT is the only curative treatment for GS2. We analyzed the outcome of 10 children with GS2 who underwent HSCT at our center between October 1997 and September 2013. The median age of the patients at transplant was 13.5 months (range, 6‐58 months). All of the patients developed HLH before HSCT and received HLH 94 or HLH 2004 protocols. Donors were HLA‐identical relatives in 8 patients, HLA‐mismatched relatives in 2 patients. Engraftment was achieved in all except one patient. None of the patients developed acute GVHD. Chronic GVHD occurred in one and veno‐occlusive disease occurred in four patients. Eight of the patients are under remission without any neurologic sequelae—median time of disease‐free survival is 92.4 months. The present study shows successful transplant outcome without long‐term neurologic sequelae in patients with GS2 who underwent HSCT from HLA‐related donors.     

Hematopoietic stem cell transplantation for children with primary immunodeficiency diseases: Single center experience in Jordan

HSCT can be curative for many PID. Little is known about the outcome of HSCT for patients with PID in the developing countries. We retrospectively reviewed all children with PID who received HSCT at KHCC in Jordan between August 2003 and October 2011. Twenty‐eight patients were identified. The median age was 16 months (3 months–17 yr). Patients' diagnoses were SCID (n = 16), CHS (n = 3), HLH (n = 3), WAS (n = 2), Griscelli syndrome (n = 1), ALPS (n = 1), Omenn's syndrome (n = 1), and DiGeorge syndrome (n = 1). Seventeen patients received HLA‐matched related HSCT, eight received maternal un‐manipulated haploidentical HSCT, and three received unrelated cord blood transplantation. Nine patients (32%) developed BCGosis secondary to reactivation of pretransplant vaccination. Three died while still receiving anti‐tuberculosis drugs, one still on treatment, and all others have recovered. Six patients had graft failure; four of them received no conditioning regimens. At a median follow up of 32 months (range 1‐67), 21 patients are alive, with overall survival of 72%. We conclude that HSCT for PID patients can be performed with a good outcome in developing countries; however, delayed diagnosis or referral and BCG reactivation are unique challenges.     

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.     

Ibrutinib for the treatment of chronic graft‐vs‐host disease in pediatric hematopoietic stem cell transplant patients: A single‐center experience

cGVHD is a significant cause of morbidity and mortality after transplant. Ibrutinib has been studied as treatment for cGVHD in the adult population. Pediatric dosing and safety of ibrutinib are unknown. We conducted a retrospective review on the use of ibrutinib in 22 children with cGVHD at Cincinnati Children's Hospital Medical Center. All patients received a dose of 250 mg/m² orally, once daily. Responses were measured at 6 months after drug initiation using the 2014 NIH consensus panel response criteria. Twenty‐two patients of median age 13.5 years received ibrutinib. cGVHD grades were severe (n = 15), moderate (n = 6), and mild (n = 1). Eight patients stopped ibrutinib prior to 3 months due to adverse events or death and could not be evaluated for 6‐month response. Of the 14 evaluable patients, 12 achieved a partial response at 6 months and two patients had progressive disease. Seven evaluable patients with lung involvement had stable lung function at 6 months. One patient had EBV reactivation, and one patient developed pneumococcal sepsis despite appropriate prophylaxis while on ibrutinib therapy. No fungal infections occurred while on ibrutinib. Adverse events leading to discontinuation included recurrent fevers without a source, extensive bruising, oral bleeding, gastrointestinal distress, lower GI bleeding, dizziness, elevated transaminases, and pneumococcal sepsis. Ibrutinib administration of 250 mg/m² oral daily shows promising responses in pediatric cGVHD. Pediatric‐focused pharmacokinetic‐directed studies are needed to establish optimal dosing and define efficacy in children.     

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     

Haploidentical hematopoietic stem cell transplantation with post‐transplant high‐dose cyclophosphamide in high‐risk children: A single‐center study

Recently, haploidentical transplantations have been performed with unmanipulated BM or PBSC. This approach is becoming more widely adopted with the use of PTCY. However, there is limited evidence about this approach in children. We present 15 children who received 16 haploidentical HSCT with unmanipulated BM or PBSC using PTCY for GVHD prophylaxis. Post‐transplant CY(50 mg/kg IV) was given on the third and fifth day, and CsA or tacrolimus with MMF or MP was also used for GVHD prophylaxis. All patients engrafted at a median of 16 and 18 days for neutrophil and thrombocyte recovery, respectively. Grades II–III acute GVHD developed in seven patients, and mild chronic GVHD was found in two patients. Two patients died within the first 100 days due to sepsis (TRM 12.5%). Eleven patients are currently alive, with a median follow‐up of 12 months (range 6–22 months). The 12‐month OS and DFS were 75 ± 10.8% and 68.8 ± 11.6%, respectively. Our results with these high‐risk patients are encouraging for haploidentical HSCT in pediatric patients. Future studies should continue to assess haploidentical HSCT, including comparison of other modalities, in a primary pediatric population.     

Allogeneic hematopoietic stem cell transplantation in congenital disorders: A single‐center experience

Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is the treatment of choice for a variety of congenital disorders. We report the experience of children affected by congenital diseases other than bone marrow failure syndromes who received allo‐HSCT over a period of 25 years at G. Gaslini Paediatric Research Institute. HSCTs were performed in 57 children with congenital diseases (25 with congenital immunodeficiencies, 10 with severe combined immunodeficiencies, and 22 with metabolic diseases). Overall survival rate at 3 years in the whole group of patients was 76.9%, with a trend in favor of better outcome in children with metabolic diseases and in those who received cord blood cells (85.9%) vs bone marrow cells (72.4%).     

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.     

Social framework of pediatric heart recipients who have survived more than 15 post‐transplant years: A single‐center experience

To evaluate social development of pediatric heart transplant (tx) recipients who have lived 15 or more years after transplantation. Among 498 pediatric patients, age less than 18 years, who underwent heart transplantation, at a single institution, 337 were performed between 1985 and 1998. We identified all who survived more than 15 years and engaged them in a survey regarding employment, education, marital, and social status. One hundred and eighty‐three recipients (54.3%; 183/337) have survived greater than 15 years; of these, 150 (81.9%) subjects are alive with age ranging from 15.04 from 28 years (median, 23.6 years). Forty‐two patients (23%) are independent, 127 (69%) were living at home, and 14 (8%) have been lost to follow‐up. Ninety‐nine survivors (66%) responded to the survey study. Currently, five recipients are married. Seventy‐four completed high school, 21 are enrolled in high school, and four did not complete high school. Of the 47 recipients who started college, 27 are currently enrolled, 11 graduated, and nine did not finish college. Ninety‐four patients have health insurance, 40 are employed, and 31 receive financial assistance for a disability. The majority of recipients of pediatric heart transplantation are able to reach reasonable academic milestones, achieve social well‐being, and professional independence.     

Liver transplantation in children with hyper‐reduced grafts – A single‐center experience

Thomas N, Thomas G, Verran D, Stormon M, O’Loughlin E, Shun A. Liver transplantation in children with hyper‐reduced grafts – A single‐center experience. Pediatr Transplantation 2010: 14:426–430. © 2010 John Wiley & Sons A/S. Abstract: In small infants and babies who receive split or living‐related adult left lateral segmental liver grafts, further reduction (hyper‐reduction) of the graft may be necessary to optimize the size of the graft for the child. We report our experience with hyper‐reduction of adult left lateral segment grafts in nine children. A retrospective review of the medical records of children who received hyper‐reduced grafts at the Children’s Hospital at Westmead, Australia was performed. Of 215 liver transplants performed on 186 children between 1986 and May 2009, 147 were reduced grafts. Nine grafts were further reduced (hyper‐reduced) after an on‐table assessment of graft size relative to the available abdominal space was made. Mean graft size reduction was by 30%. The pledgetted technique of resection was used in four patients. All required delayed closure of the abdomen, and in three patients, fascial closure was not possible and a Surgisis^® patch (Cook Surgical International, West Lafayette, IN, USA) was placed to augment the abdominal capacity. Two children had hepatic artery thrombosis. One was successfully thrombectomized. In the other, technical problems with the donor liver contributed to death 10 days post‐transplant. Two bile leaks, one from the cut surface and the other at the anastomotic site, were oversewn at the time of abdominal closure. On follow‐up (median 33 months), two developed biliary strictures requiring dilatation. Hyper‐reduction of segmental grafts can be safely performed when needed. In view of its versatility, it may be preferable to hyper‐reduce a graft rather than use a monosegment graft. Comparable long‐term results are possible. The pledgetted technique of resection is easy, quick, and safe. The fact that it can be performed after revascularization with minimal blood loss adds great flexibility to this technically challenging procedure.     

Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: An analysis of 18 Japanese cases

Oshima K, Hanada R, Kobayashi R, Kato K, Nagatoshi Y, Tabuchi K, Kato S; for the Hematopoietic Stem Cell Transplantation Committee of the Japanese Society of Pediatric Hematology. Hematopoietic stem cell transplantation in patients with severe congenital neutropenia: An analysis of 18 Japanese cases.
Pediatr Transplantation 2010: 14:657–663. © 2010 John Wiley & Sons A/S. Abstract: We studied the outcome of allogeneic HSCT in patients with SCN. Between 1989 and 2005, 18 patients with SCN in Japan received HSCT for reasons other than malignant transformation, i.e., because of the lack of or a partial response to treatment with r‐HuG‐CSF. The median age of the patients at the first HSCT was three and a half yr (range 0.2–16.7 yr). Nine patients received stem cells from an HLA‐identical sibling donor and nine from an alternative donor. Twelve and six patients received myeloablative and non‐myeloablative conditioning regimens, respectively. Engraftment occurred at the first HSCT in 12 patients, four patients received a second HSCT for graft failure, and two patients died. The cause of death was renal failure and graft failure at the first and second HSCT, respectively. The cumulative incidence of grade II–IV acute GVHD and TRM at the first transplantation was 11% and 5.6%, respectively. Of our patients, 16 are alive and in complete remission, with a median follow‐up of six and a half yr. Our results suggest that HSCT is beneficial for patients with SCN refractory to r‐HuG‐CSF treatment.     

Incidence of bloodstream infections in small bowel transplant recipients receiving selective decontamination of the digestive tract: A single‐center experience

Pediatric patients undergoing small bowel transplantation are susceptible to postoperative CLABSI. SDD directed against enteric microbes is a strategy for reducing CLABSI. We hypothesized that SDD reduces the frequency of CLABSI, infections outside the bloodstream, and allograft rejection during the first 30 days following transplant. A retrospective chart review of 38 pediatric small bowel transplant recipients at CCHMC from 2003 to 2011 was conducted. SDD antimicrobials were oral colistin, tobramycin, and amphotericin B. The incidence of CLABSI, infections outside the bloodstream, and rejection episodes were compared between study periods. The incidence of CLABSI did not differ between study periods (6.9 CLABSI vs. 4.6 CLABSI per 1000 catheter days; p = 0.727), but gram positives and Candida predominated in the first 30 days. Incidence of bacterial infections outside the bloodstream did not differ (p = 0.227). Rejection occurred more frequently during the first month following transplant (p = 0.302). SDD does not alter the incidence of CLABSI, bacterial infections outside the bloodstream, or allograft rejection in the immediate 30 days post‐transplantation. However, SDD does influence CLABSI organism types (favoring gram positives and Candida) and Candidal infections outside the bloodstream.     

Liver transplantation for urea cycle disorders in pediatric patients: A single‐center experience

LT has emerged as a surgical treatment for UCDs. We hypothesize that LT can be safely and broadly utilized in the pediatric population to effectively prevent hyperammonemic crises and potentially improve neurocognitive outcomes. To determine the long‐term outcomes of LT for UCDs, charts of children with UCD who underwent LT were retrospectively reviewed at an academic institution between July 2001 and May 2012. A total of 23 patients with UCD underwent LT at a mean age of 3.4 yr. Fifteen (65%) patients received a whole‐liver graft, seven patients (30%) received a reduced‐size graft, and one patient received a living donor graft. Mean five‐yr patient survival was 100%, and allograft survival was 96%. Mean peak blood ammonia (NH₃) at presentation was 772 μmol/L (median 500, range 178–2969, normal <30–50). After transplantation, there were no episodes of hyperammonemia. Eleven patients were diagnosed with some degree of developmental delay before transplantation, which remained stable or improved after transplantation. Patients without developmental delay before transplantation maintained their cognitive abilities at long‐term follow‐up. LT was associated with the eradication of hyperammonemia, removal of dietary restrictions, and potentially improved neurocognitive development. Long‐term follow‐up is underway to evaluate whether LT at an early age (<1 yr) will attain improved neurodevelopmental outcomes.     

Urological complications following kidney transplantation in pediatric age: A single‐center experience

Surgical complications during kidney transplantation can seriously affect renal outcomes. We assess occurrence, risk factors, and results of all urological complications in a series of renal transplants in a single center. Children who underwent renal transplant between January 2008 and December 2014 were retrospectively evaluated. Postoperative urological complications were reviewed. Demographic details, cause of ESRD, donor type, and surgical procedures at transplant were analyzed. For statistical analysis, the chi‐square test or Fisher's exact test were used as appropriate. One hundred and twenty‐one kidney transplants were performed in 117 children (median age 12 yr). Sixty‐two of 121 (53%) had an underlying urological malformation. At a median follow‐up of three yr, 28 urological complications were recorded (23%): 12 lymphocele (10%), 10 ureteral obstruction (8%), three urinary leakage (2.5%), two symptomatic VUR (1.7%), and one hydropyonephrosis. When lymphocele was excluded, the complication incidence rate dropped to 13%. Ureteral obstruction mostly occurred late after transplant (more than six months). Presence of urological malformation was the only factor related to increased occurrence of urological complication (p = 0.007) and, in particular, ureteral obstruction (p = 0.018). Children with urological malformations presented a statistically significant risk of developing urological complications after kidney transplantation, ureteral obstruction being the most common complication.     

Reduced ATG‐F dosage for induction in pediatric renal transplantation: A single‐center experience

Rabbit antithymocyte globulin (ATG‐F) is an extensively used induction agent. To our knowledge, no study to date has assessed reduced ATG‐F dosage in children undergoing renal transplantation. This was a retrospective analysis of pediatric renal recipients in the Department of Kidney Transplantation, The First Affiliated Hospital of Zhengzhou University, from May 2007 to February 2013. Thirty‐nine children underwent renal transplantation including 25 living related and 14 cardiac deceased donor transplantation. Each recipient received ATG‐F 1.5 mg/kg/d once daily for 4 days. Of the 39 recipients, five (12.8%) showed delayed graft function, including one of 25 recipients (4%) of living donor and four of 14 recipients (28.6%) of deceased donor transplantation (p < 0.05). Six of the 39 recipients (15.4%) showed acute rejection on renal biopsy. Follow‐up in these children ranged from 6 to 87 months. The one‐, three‐, and five‐yr recipients and grafts survival rates postoperation were each 94.9% and 97.3%, 97.3%, and 94.6%, respectively. The incidence of postoperative infection was 35.9% (14/39), and did not differ significantly in the living related and deceased donor groups (p > 0.05). Low‐dose ATG‐F can be safely used as an immune induction agent in pediatric renal transplantation.