Myeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?—A multicenter EBMT-PDWP study

Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2-18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective "real-world-practice" study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.Transplantation and immunomodulatio

Hematopoietic cell transplantation in severe combined immunodeficiency : The SCETIDE 2006-2014 European cohort

Publisher Copyright: © 2021 The AuthorsBackground: Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. Objective: We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. Methods: HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. Results: Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P 0.5 × 10e3/μL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. Conclusion: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.Peer reviewe

: Les cavités karstiques françaises à haute valeur patrimoniale

International audienc

Efficiency and safety of five procedures for percutaneous native kidney biopsy: a multicentric comparative study.

International audienceAbstractBackground and objectivesRenal biopsy(RB) is necessary for the diagnosis, prognosis, and therapy guidance of native kidney diseases. Few studies have compared outcomes of RB procedures. We compared the efficiency and safety of five biopsy procedures.Design, setting, participants, and measurementsNumber of glomeruli on light microscopy(LM) and on immunofluorescence(IF) and serious adverse events following RB performed in five nephrology units(C1-C5) were retrospectively collected.C1 performed ultrasound assessment before RB and used a 14-gauge core-cutting needle biopsy gun, C2 ultrasound guidance and a 14-gauge needle, C3 tomodensitometry guidance and a 14-gauge needle, C4 ultrasound guidance and a 16-gauge needle, and C5 tomodensitometry guidance and a 16-gauge needle.ResultsData from 943 RB performed between January 2006 and July 2010 were collected (C1: 408; C2: 254; C3: 81; C4: 136; C5: 64). On LM, mean number of glomeruli on biopsy core was 14.2±8.6. It was higher in C1 and C2 than in C3, C4, and C5(p=0.01). At least 10 glomeruli were found in 69% of biopsies. This rate was higher in C1 and C2 than in C3, C4, and C5(p=0.004). On IF, mean number of glomeruli was 4.4±3.3. It was higher in C1 and C2 than in C3, C4, and C5(p<0.001). In multivariate analysis, the only factor that influenced number of glomeruli on LM(p=0.004) and IF(p=0.004) was the nephrology unit. Serious adverse events occurred in 1.5% of biopsies. Complication rate was not different between nephrology units.ConclusionsRB is safe but radiological guidance, needle-size, and experience influence the quality of biopsies

Risk factors affecting outcome of unrelated cord blood transplantation for children with familial haemophagocytic lymphohistiocytosis

Allogeneic haematopoietic stem cell transplantation is still the only available curative option for Familial Haemophagocytic Lymphohistiocytosis (FHLH). Most studies report outcomes after bone marrow or peripheral blood stem cell transplantation. We analysed the outcomes of 118 children with FHLH undergoing single-unit umbilical cord blood transplantation performed from 1996 to 2014. Myeloablative conditioning regimen was given to 90% of the patients, and was mostly busulfan-based (n&nbsp;=&nbsp;81, 76%), including anti-thymocyte globulin or alemtuzumab (n&nbsp;=&nbsp;102, 86%). The cumulative incidence of Day 60 neutrophil engraftment was 85%; and that of non-relapse mortality and acute graft-versus-host disease (GvHD) was 21% and 33% at 100&nbsp;days, respectively. The 6-year cumulative incidence of chronic GvHD was 17% and the 6-year probability of overall survival was 55%. In multivariate analysis, children receiving a graft with a total nucleated cell dose greater than 9·9&nbsp;×&nbsp;10 7 /kg had a better overall survival (hazard ratio [HR]: 0·49, 95% CI: 0·27–0·88, P&nbsp;=&nbsp;0·02). Degree of human leucocyte antigen (HLA) matching was associated with improved disease-free survival (5/6 vs. 6/6 HR: 2·11, 95% confidence interval [CI]: 1·01–4·4, P&nbsp;=&nbsp;0·05 and ≤4/6 vs. 6/6, HR: 2·82, CI: 1·27–6·23, P&nbsp;=&nbsp;0·01). Umbilical cord blood transplantation with a high cell dose and good HLA match is a suitable alternative option to haematopoietic stem cell transplantation in children with FHLH who lack a HLA-matched donor

Risk factors affecting outcome of unrelated cord blood transplantation for children with familial haemophagocytic lymphohistiocytosis

Allogeneic haematopoietic stem cell transplantation is still the only available curative option for Familial Haemophagocytic Lymphohistiocytosis (FHLH). Most studies report outcomes after bone marrow or peripheral blood stem cell transplantation. We analysed the outcomes of 118 children with FHLH undergoing single-unit umbilical cord blood transplantation performed from 1996 to 2014. Myeloablative conditioning regimen was given to 90% of the patients, and was mostly busulfan-based (n&nbsp;=&nbsp;81, 76%), including anti-thymocyte globulin or alemtuzumab (n&nbsp;=&nbsp;102, 86%). The cumulative incidence of Day 60 neutrophil engraftment was 85%; and that of non-relapse mortality and acute graft-versus-host disease (GvHD) was 21% and 33% at 100&nbsp;days, respectively. The 6-year cumulative incidence of chronic GvHD was 17% and the 6-year probability of overall survival was 55%. In multivariate analysis, children receiving a graft with a total nucleated cell dose greater than 9·9&nbsp;×&nbsp;107/kg had a better overall survival (hazard ratio [HR]: 0·49, 95% CI: 0·27–0·88, P&nbsp;=&nbsp;0·02). Degree of human leucocyte antigen (HLA) matching was associated with improved disease-free survival (5/6 vs. 6/6 HR: 2·11, 95% confidence interval [CI]: 1·01–4·4, P&nbsp;=&nbsp;0·05 and ≤4/6 vs. 6/6, HR: 2·82, CI: 1·27–6·23, P&nbsp;=&nbsp;0·01). Umbilical cord blood transplantation with a high cell dose and good HLA match is a suitable alternative option to haematopoietic stem cell transplantation in children with FHLH who lack a HLA-matched donor

Risk factors affecting outcome of unrelated cord blood transplantation for children with familial haemophagocytic lymphohistiocytosis

Transplantation and immunomodulatio

Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency

BackgroundAutosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in IκBα that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor κ light chain enhancer of activated B cells (NF-κB) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in IκBα have impaired noncanonical NF-κB activity and defective lymphorganogenesis.ObjectiveWe sought to establish genotype-phenotype correlation in patients with AD EDA-ID.MethodsA disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-κB signaling in skin-derived fibroblasts.ResultsDisease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-κB-dependent IL-6 secretion and upregulation of the NF-κB subunit 2/p100 and RELB proto-oncogene, NF-κB subunit (RelB) components of the noncanonical NF-κB pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-κB-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus α-lymphotoxin β receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations.ConclusionsIκBα point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and&nbsp;noncanonical NF-κB activity in patients with AD EDA-ID