Key Points• HLA-identical sibling transplantation for SCD offers excellent long-term survival. • Mortality risk is higher for older patients; event-free survival has improved in patients transplanted after 2006.Despite advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care is not universal. Hematopoietic cell transplantation is, to date, the only curative therapy for SCD, but its application is limited by availability of a suitable HLA-matched donor and lack of awareness of the benefits of transplant. Included in this study are 1000 recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the European Society for Blood and Marrow Transplantation, Eurocord, and the Center for International Blood and Marrow Transplant Research. The primary endpoint was event-free survival, defined as being alive without graft failure; risk factors were studied using a Cox regression models. The median age at transplantation was 9 years, and the median follow-up was longer than 5 years. Most patients received a myeloablative conditioning regimen (n 5 873; 87%); the remainder received reduced-intensity conditioning regimens (n 5 125; 13%). Bone marrow was the predominant stem cell source (n 5 839; 84%); peripheral blood and cord blood progenitors were used in 73 (7%) and 88 (9%) patients, respectively. The 5-year event-free survival and overall survival were 91.4% (95% confidence interval, 89.6%-93.3%) and 92.9% (95% confidence interval, 91.1%-94.6%), respectively. Eventfree survival was lower with increasing age at transplantation (hazard ratio [HR], 1.09; P < .001) and higher for transplantations performed after

BackgroundImmunodysregulation polyendocrinopathy enteropathy x-linked(IPEX) syndromeis a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined.ObjectiveThis analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors.MethodsClinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed.ResultsWe confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS.ConclusionsPatients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

• Children with sickle cell disease engrafted unrelated donor marrow after reduced intensity conditioning.• A high incidence of GVHD and associated mortality compromised safety of the trial.Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short-course methotrexate, and methylprednisolone. Transplant indications included stroke (n 5 12), transcranial Doppler velocity >200 cm/s (n 5 2), ‡3 vaso-occlusive pain crises per year (n 5 12), or ‡2 acute chest syndrome episodes (n 5 4) in the 2 years preceding enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection was 10%. The 1-and 2-year EFS rates were 76% and 69%, respectively. The corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the prespecified target of ‡75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis.

We examined the efficacy of unrelated cord blood (CB) transplantation in children with thalassemia (n = 35) and sickle cell disease (n = 16), using data reported to 3 registries. Donor-recipient pairs were matched at HLA-A and -B (antigen level) and DRB1 (allele level) in 7 or HLA mismatched at 1 (n = 18), 2 (n = 25), or 3 loci (n = 1). Transplant conditioning was myeloablative (n = 39) or reduced intensity (n = 12). Neutrophil recovery with donor chimerism was documented in 24 patients; 11 patients developed grade II-IV acute graft-versus-host disease (aGVHD) and 10 patients, chronic GVHD (cGVHD). Overall survival (OS) and disease-free survival (DFS) were 62% and 21% for thalassemia and 94% and 50% for sickle cell disease (SCD), respectively. In multivariate analysis, engraftment rate (hazard ratio [HR] 2.2, P =.05) and DFS (HR 0.4, P =.01) were higher with cell dose >5 × 107/kg. The 2-year probability of DFS was 45% in patients who received grafts with cell dose >5 × 107/kg and 13% with lower cell dose. Primary graft failure was the predominant cause of treatment failure occurring in 20 patients with thalassemia and 7 patients with SCD. Primary graft failure was fatal in 5 patients with thalassemia. These results suggest that only CB units containing an expected infused cell dose >5 × 107/kg should be considered for transplantation for hemoglobinopathy.

b-Thalassemia major and sickle cell disease (SCD) are among the most common hereditary disorders worldwide. The supportive treatment of b-thalassemia major requires chronic, life-long RBC transfusions, which cause progressive iron overload and the potential for impaired endocrine, cardiac and hepatic function. The phenotype of thalassemia major is reliably predicted by its genotype. In contrast, SCD is a variable genetic disease caused by a single amino acid substitution in the b chain of human hemoglobin. Manifestations of SCD are quite varied, but generally result from the tendency of Hb S to irreversibly polymerize under physiologic stressors such as hypoxemia and acidosis. The polymerization causes perturbations in the erythrocyte integrity that promote vaso-occlusion and which manifest as clinical events such as severe painful episodes, acute chest syndrome, splenic infarction, stroke and avascular necrosis of target joints. The only cure proved for these disorders is correction of the genetic defect by allogeneic hematopoietic cell transplantation (HCT). We illustrate the pediatric experience of HCT for hemoglobinopathies and discuss how these results affect future therapeutic decisions in children who inherit these disorders. Bone Marrow Transplantation (2008) 41, 109-117; doi:10.1038/sj.bmt.1705943; published online 3 December 2007 Keywords: hematopoietic cell transplantation; hemoglobinopathies; children; sickle cell disease; thalassemia Introduction b-Thalassemia major and sickle cell disease (SCD) are hereditary anemias that decrease lifespan and reduce the quality of life. While supportive therapies are available that minimize long-term sequelae, the only cure for these disorders is allogeneic hematopoietic cell transplantation (HCT). While the outcomes after HCT are quite similar in both disorders, the decision about when and if to pursue HCT follows very different time-lines. All patients with thalassemia are at risk for transfusion-related iron overload and its attendant negative impact on clinical well-being. As a result, many clinicians strongly consider HCT as a therapeutic option in children who are less than 17 years of age and who have an HLA-identical sibling donor, due to the excellent results of HCT in this setting. However, in patients with SCD, the clinical symptoms are diverse and most clinicians delay HCT until there is evidence of severe disease, such as in those who have had a stroke, even though the results after HCT for SCD are very similar to results after HCT for thalassemia. This review presents the current state-of-the-art of HCT for b-thalassemia and SCD and discusses future directions that might improve survival and decrease morbidity. b-Thalassemia major BackgroundThalassemias result from mutations of the globin genes that cause reduced or absent hemoglobin production, reducing oxygen delivery. 1 The thalassemias are the most common single-gene disorders, with 4.83% of the world population carrying a globin gene variant. 2 To treat the anemia and restore oxygen delivery to...

Hematopoietic cell transplantation (HCT) has become a standard treatment for many adult and pediatric conditions. Emerging evidence suggests that perturbations in the microbiota diversity increase recipients' susceptibilities to gut-mediated conditions such as diarrhea, infection and acute GvHD. Probiotics preserve the microbiota and may minimize the risk of developing a gutmediated condition; however, their safety has not been evaluated in the setting of HCT. We evaluated the safety and feasibility of the probiotic, Lactobacillus plantarum (LBP), in children and adolescents undergoing allogeneic HCT. Participants received oncedaily supplementation with LBP beginning on day − 8 or − 7 and continued until day +14. Outcomes were compliance with daily administration and incidence of LBP bacteremia. Administration of LBP was feasible with 97% (30/31, 95% confidence interval (CI) 83-100%) of children receiving at least 50% of the probiotic dose (median 97%; range 50-100%). We did not observe any case of LBP bacteremia (0% (0/30) with 95% CI 0-12%). There were not any unexpected adverse events related to LBP. Our study provides preliminary evidence that administration of LBP is safe and feasible in children and adolescents undergoing HCT. Future steps include the conduct of an approved randomized, controlled trial through Children's Oncology Group.

BU and CY (BU/CY; 200 mg/kg) before HLA-matched sibling allo-SCT in children with sickle cell disease (SCD) is associated with 85% EFS but is limited by the acute and late effects of BU/CY myeloablative conditioning. Alternatives include reduced toxicity but more immunosuppressive conditioning. We investigated in a prospective single institutional study, the safety and efficacy of a reduced-toxicity conditioning (RTC) regimen of BU 12.8-16 mg/kg, fludarabine 180 mg/m 2 , alemtuzumab 54 mg/m 2 (BFA) before HLA-matched sibling donor transplantation in pediatric recipients with symptomatic SCD. Eighteen patients, median age 8.9 years (2.3-20.2), M/F 15/3, 15 sibling BM and 3 sibling cord blood (CB) were transplanted. Mean whole blood and erythroid donor chimerism was 91% and 88%, at days +100 and +365, respectively. Probability of grade II-IV acute GVHD was 17%. Two-year EFS and OS were both 100%. Neurological, pulmonary and cardiovascular function were stable or improved at 2 years. BFA RTC and HLA-matched sibling BM and CB allo-SCT in pediatric recipients result in excellent EFS, long-term donor chimerism, low incidence of GVHD and stable/improved organ function.Bone Marrow Transplantation (2014) 49, 913-920;

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) with myeloablative conditioning is associated with a 10%-40% risk of day +100 transplantation-related mortality (TRM). We evaluated the feasibility and safety of reduced-toxicity conditioning and allo-HSCT in 100 consecutive children and adolescent recipients (mean age, 9.2 ± 6.8 years). The mean duration of follow-up was 1278 ± 1042 days. Fifty patients had malignant disease. The median time to neutrophil recovery was 18 days, and the median time to platelet recovery was 43 days. Median donor chimerism in engrafted patients was 98% on day +100 and 98% on day +365. The cumulative incidence of acute graft-versus-host disease (GVHD) was 20% (95% confidence interval [CI], 12.1%-27.9%), and that of chronic GVHD was 13.5% (95% CI, 6.6%-20.4%). TRM was 3% (95% CI, 0%-6.4%) by day +100 and 13.6% (95% CI, 6.7%-20.5%) for the entire study period. The incidence of primary graft failure (PGF) was 16% overall, 31.4% after umbilical cord blood transplantation (UCBT), and 0% after allo-HSCT with matched unrelated or matched sibling donors (P < .0001). The incidence of PGF in UCBT recipients was 46.7% (14 of 30) in chemotherapy-naive recipients, versus 9.5% (2 of 21) in non-chemotherapy-naive recipients (P = .019). Five-year event-free survival was 59.5% ± 5%, and 5-year overall survival was 72.9% ± 5%. Only PGF and poor-risk disease status were significantly associated with decreased overall survival (P = .03). Reduced-toxicity conditioning allo-HSCT in pediatric recipients is associated with low TRM; however, chemotherapy-naive UCBT recipients have a significantly higher incidence of PGF.