Gonadal impairment is an important late effect with a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after busulfan (Bu) or treosulfan (Treo) conditioning regimens in pre-and postpubertal children. This retrospective, multicenter study included children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemoradiotherapy before the transplant. We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range, 5 to 18); 89 patients were boys and 48 girls. Eighty-nine patients were prepubertal at transplant and 48 postpubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of girls treated with Treo in the prepubertal stage reached spontaneous puberty compared with those treated with Bu (P = .02). Spontaneous menarche was more frequent after Treo than after Bu (P < .001). Postpubertal boys and girls treated with Treo had significantly lower luteinizing hormone levels (P = .03 and P = .04, respectively) compared with the Bu group. Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population. Published by Elsevier Inc. on behalf of the American Society for Transplantation and Cellular Therapy.

Bone marrow mesenchymal stem cells (BM-MSCs) are promising candidates for regenerative medicine purposes. The effect of obesity on the function of BM-MSCs is currently unknown. Here, we assessed how obesity affects the function of BM-MSCs and the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) therein. BM-MSCs were obtained from healthy donors with a normal (<25) or high (>30) body mass index (BMI). High-BMI BM-MSCs displayed severely impaired osteogenic and diminished adipogenic differentiation, decreased proliferation rates, increased senescence, and elevated expression of ER stress-related genes ATF4 and CHOP. Suppression of ER stress using tauroursodeoxycholic acid (TUDCA) and 4-phenylbutyrate (4-PBA) resulted in partial recovery of osteogenic differentiation capacity, with a significant increase in the expression of ALPL and improvement in the UPR. These data indicate that BMI is important during the selection of BM-MSC donors for regenerative medicine purposes and that application of high-BMI BM-MSCs with TUDCA or 4-PBA may improve stem cell function. However, whether this improvement can be translated into an in vivo clinical advantage remains to be assessed.

DNA ligase IV deficiency syndrome (LIG4 syndrome) is a rare autosomal recessive disorder characterized by microcephaly, growth retardation, low birth weight, dysmorphic facial findings, immunodeficiency, pancytopenia, and radiosensitivity due to impaired repair of DNA double-strand breaks by non-homologous end-joining. Herein, we report two siblings with LIG4 syndrome with a novel mutation. One of the siblings, who had normocellular marrow, had autologous reconstitution after initial non-myeloablative conditioning and underwent successful second hematopoietic stem cell transplantation after conditioning with busulfan, cyclophosphamide, and anti-thymocyte globulin. Our findings indicate that transplantation with myeloablative conditioning can be used successfully in LIG4 syndrome patients.

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Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is curative for bone marrow failure in patients with Fanconi anemia (FA), but the presence of a malignant transformation is associated with a poor prognosis and the management of these patients is still challenging. We analyzed outcome of 74 FA patients with a diagnosis of myelodysplastic syndrome (n = 35), acute leukemia (n = 35) or with cytogenetic abnormalities (n = 4), who underwent allo‐HSCT from 1999 to 2016 in EBMT network. Type of diagnosis, pre‐HSCT cytoreductive therapies and related toxicities, disease status pre‐HSCT, donor type, and conditioning regimen were considered as main variables potentially influencing outcome. The 5‐year OS and EFS were 42% (30‐53%) and 39% (27‐51%), respectively. Patients transplanted in CR showed better OS compared with those transplanted in presence of an active malignant disease (OS:71%[48‐95] vs 37% [24‐50],P = .04), while none of the other variables considered had an impact. Twenty‐two patients received pre‐HSCT cytoreduction and 9/22 showed a grade 3‐4 toxicity, without any lethal event or negative influence on survival after HSCT(OS:toxicity pre‐HSCT 48% [20‐75%] vs no‐toxicity 51% [25‐78%],P = .98). The cumulative incidence of day‐100 grade II‐IV a‐GvHD and of 5‐year c‐GvHD were 38% (26‐50%) and 40% (28‐52%). Non‐relapse‐related mortality and incidence of relapse at 5‐years were 40% (29‐52%) and 21% (11‐30%) respectively, without any significant impact of the tested variables. Causes of death were transplant‐related events in most patients (34 out of the 42 deaths, 81%). This analysis confirms the poor outcome of transformed FA patients and identifies the importance of achieving CR pre‐HSCT, suggesting that, in a newly diagnosed transformed FA patient, a cytoreductive approach pre‐HSCT should be considered if a donor have been secured.

Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5-7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis.

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Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71% and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) GVHD. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and with higher HCT-CI scores. On multivariable analysis EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71% and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) GVHD. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and with higher HCT-CI scores. On multivariable analysis EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT.