Peripheral blood stem cell transplantation (PBSCT) with in vivo lymphodepletion can provide faster neutrophil recovery with limited risk of severe graft-versus-host disease (GVHD) in children with... Show morePeripheral blood stem cell transplantation (PBSCT) with in vivo lymphodepletion can provide faster neutrophil recovery with limited risk of severe graft-versus-host disease (GVHD) in children with nonmalignant disorders (NMDs). We aimed to provide an historical comparison of these 2 strategies regarding the prevalence of GVHD, viral reactivation, timing of immune reconstitution, and final outcomes. Data on 98 children undergoing PBSCT were collected from 5 European pediatric transplantation centers. Only patients with NMDs receiving treosulfan or myeloablative busulfan conditioning and 9-10/10 HLA-matched transplant were included. The patients were divided into 2 groups according to in vivo lymphodepletion with antithymocyte globulin (ATG) or with alemtuzumab. We compared rates of acute and chronic GVHD; Epstein-Barr virus, cytomegalovirus, and adenovirus reactivation; chimerism; lymphocyte recovery; overall survival (OS) and event-free survival (EFS) between the 2 groups. The rate of severe acute GVHD (grade III-IV) was significantly higher in patients receiving ATG (26% vs 10% in alemtuzumab recipients; P <.05), whereas viral reactivations occurred with a similar rate in the 2 groups (alemtuzumab, 56%; ATG, 57%). Alemtuzumab was the major risk factor for delayed T cell immune reconstitution in the first 3 months after transplantation (odds ratio [OR], 6.0; 95% confidence interval [CI], 1.8 to 19; P <.005). Extended chronic GVHD, ADV reactivation, slower CD3(+) cell recovery, and HLA-mismatch reduced the probability of survival. Infections were the main cause of mortality in our cohort, and delayed T cell recovery was significantly associated with mortality in multivariate analysis (OR, 12; 95% CI, 1.2 to 114; P <.05). Ultimately, no differences in OS and EFS survival were seen between the ATG and alemtuzumab groups. ATG and alemtuzumab showed similar impacts on outcomes of children undergoing PBSCT for NMDs. The 2 strategies of in vivo lymphodepletion showed specific drawbacks that were counterbalanced by benefits that ultimately led to a comparable survival rate. A patient-centered lymphodepletion strategy can be advised in children undergoing PBSCT for NMDs, by favoring T cell recovery in the presence of invasive infection or GVHD prevention in high-risk mismatched donor transplantation. (C) 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved. Show less
Miano, M.; Eikema, D.J.; Fuente, J. de la; Bosman, P.; Ghavamzadeh, A.; Smiers, F.; ... ; Dufour, C. 2021
Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA... Show moreData on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients. (C) 2021 Published by Elsevier Inc. on behalf of The American Society for Transplantation and Cellular Therapy. Show less
Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first... Show moreAgammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondria! numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1(-/-) animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of I immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity. Show less
Gluckman, E.; Fuente, J. de la; Cappelli, B.; Scigliuolo, G.M.; Volt, F.; Tozatto-Maio, K.; ... ; Paediat Dis PDWP Inborn Errors Wor 2020
We report the results of an analysis of unrelated allogeneic hematopoietic stem cell transplantations (HSCT) in 71 patients with sickle cell disease (SCD) transplanted in EBMT centers between 2005... Show moreWe report the results of an analysis of unrelated allogeneic hematopoietic stem cell transplantations (HSCT) in 71 patients with sickle cell disease (SCD) transplanted in EBMT centers between 2005 and 2017. Median age was 9.3 years; graft type was bone marrow in 79% and peripheral blood in 21%. Recipient-donor HLA match at high resolution typing was 10/10 in 31, 9/10 in 20, and 8/10 in 4 patients; the other patients had intermediate resolution typing. The most frequent conditioning regimens were fludarabine-thiotepa-treosulfan (64%) or busulfan-cyclophosphamide (12%). Cumulative incidence of neutrophil engraftment was 92%; platelet engraftment was 90%. Eleven patients (15%) experienced graft failure. Grade II-IV acute graft-vs.-host disease (GvHD) was 23%; 3-year chronic GvHD was 23%. Three-year overall survival (OS) was 88 +/- 4%. GRFS was 62 +/- 6%. HLA matching was the most significant risk factor for OS: 3-year OS was 96 +/- 4% in 10/10 group vs. 75 +/- 10% in 9-8/10 (p = 0.042); GRFS was 69 +/- 9% vs. 50 +/- 12% (p = 0.114), respectively. In conclusion, unrelated donor HSCT is a valid option for SCD patients who lack an HLA-identical sibling donor, preferably in the context of clinical trials. Using a 10/10 HLA-matched unrelated donor yields better survival indicating that HLA matching is an important donor selection factor in this nonmalignant disease. Show less
X-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are... Show moreX-linked lymphoproliferative disease (XLP1) is a rare immunodeficiency characterized by severe immune dysregulation and caused by mutations in the SH2D1A/SAP gene. Clinical manifestations are varied and include hemophagocytic lymphohistiocytosis (HLH), lymphoma and dysgammaglobulinemia, often triggered by Epstein-Barr virus infection. Historical data published before improved treatment regimens shows very poor outcome. We describe a large cohort of 91 genetically defined XLP1 patients collected from centers worldwide and report characteristics and outcome data for 43 patients receiving hematopoietic stem cell transplant (HSCT) and 48 untransplanted patients. The advent of better treatment strategies for HLH and malignancy has greatly reduced mortality for these patients, but HLH still remains the most severe feature of XLP1. Survival after allogeneic HSCT is 81.4% with good immune reconstitution in the large majority of patients and little evidence of posttransplant lymphoproliferative disease. However, survival falls to 50% in patients with HLH as a feature of disease. Untransplanted patients have an overall survival of 62.5% with the majority on immunoglobulin replacement therapy, but the outcome for those untransplanted after HLH is extremely poor (18.8%). HSCT should be undertaken in all patients with HLH, because outcome without transplant is extremely poor. The outcome of HSCT for other manifestations of XLP1 is very good, and if HSCT is not undertaken immediately, patients must be monitored closely for evidence of disease progression. (Blood. 2011;117(1):53-62) Show less
