Long-Term Immune Recovery After Hematopoietic Stem Cell Transplantation for ADA Deficiency: a Single-Center Experience

Unconditioned hematopoietic stem cell transplantation (HSCT) is the recommended treatment for patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency with an HLA-matched sibling donor (MSD) or family donor (MFD). Improved overall survival (OS) has been reported compared to the use of unrelated donors, and previous studies have demonstrated that adequate cellular and humoral immune recovery can be achieved even in the absence of conditioning. Detailed insight of the long-term outcome is still limited. We aim to address this by studying a large single-center cohort of 28 adenosine deaminase-deficient patients who underwent a total of 31 HSCT procedures, of which more than half were unconditioned. We report an OS of 85.7% and event-free survival of 71% for the entire cohort, with no statistically significant differences after procedures using related or unrelated HLA-matched donors. We find that donor engraftment in the myeloid compartment is significantly diminished in unconditioned procedures, which typically use a MSD or MFD. This is associated with poor metabolic correction and more frequent failure to discontinue immunoglobulin replacement therapy. Approximately one in four patients receiving an unconditioned procedure required a second procedure, whereas the use of reduced intensity conditioning (RIC) prior to allogeneic transplantation improves the long-term outcome by achieving better myeloid engraftment, humoral immune recovery, and metabolic correction. Further longitudinal studies are needed to optimize future management and guidelines, but our findings support a potential role for the routine use of RIC in most ADA-deficient patients receiving an HLA-identical hematopoietic stem cell transplant, even when a MSD or MFD is available

High intensity neutrino oscillation facilities in Europe

The EUROnu project has studied three possible options for future, high intensity neutrino oscillation facilities in Europe. The first is a Super Beam, in which the neutrinos come from the decay of pions created by bombarding targets with a 4 MW proton beam from the CERN High Power Superconducting Proton Linac. The far detector for this facility is the 500 kt MEMPHYS water Cherenkov, located in the Fréjus tunnel. The second facility is the Neutrino Factory, in which the neutrinos come from the decay of μ+ and μ− beams in a storage ring. The far detector in this case is a 100 kt magnetized iron neutrino detector at a baseline of 2000 km. The third option is a Beta Beam, in which the neutrinos come from the decay of beta emitting isotopes, in particular He6 and Ne18, also stored in a ring. The far detector is also the MEMPHYS detector in the Fréjus tunnel. EUROnu has undertaken conceptual designs of these facilities and studied the performance of the detectors. Based on this, it has determined the physics reach of each facility, in particular for the measurement of CP violation in the lepton sector, and estimated the cost of construction. These have demonstrated that the best facility to build is the Neutrino Factory. However, if a powerful proton driver is constructed for another purpose or if the MEMPHYS detector is built for astroparticle physics, the Super Beam also becomes very attractive

Impact of conditioning regimen on outcomes for children with acute myeloid leukemia undergoing transplantation in first complete remission. An analysis on behalf of the Pediatric Disease Working Party of the European Group for Blood and Marrow Transplantation

Hematopoietic stem cell transplantation (HSCT) represents the cornerstone of treatment in pediatric high-risk and relapsed acute myeloid leukemia (AML). The aim of the present study was to compare outcomes of pediatric patients with AML undergoing HSCT using 3 different conditioning regimens: total body irradiation (TBI) and cyclophosphamide (Cy); busulfan (Bu) and Cy; or Bu, Cy, and melphalan (Mel). In this retrospective study, registry data for patients > 2 and <18 years age undergoing matched allogeneic HSCT for AML in first complete remission (CR1) in 204 European Group for Blood and Marrow Transplantation centers between 2000 and 2010 were analyzed. Data were available for 631 patients; 458 patients received stem cells from a matched sibling donor and 173 from a matched unrelated donor. For 440 patients, bone marrow was used as stem cell source, and 191 patients received peripheral blood stem cells. One hundred nine patients received TBICy, 389 received BuCy, and 133 received BuCyMel as their preparatory regimen. Median follow-up was 55 months. Patients receiving BuCyMel showed a lower incidence of relapse at 5 years (14.7% versus 31.5% in BuCy versus 30% in TBICy, P < .01) and higher overall survival (OS) (76.6% versus 64% versus 64.5%, P = .04) and leukemia-free survival (LFS) (74.5% versus 58% versus 61.9%, P < .01), with a comparable nonrelapse mortality (NRM) (10.8% versus 10.5% versus 8.1%, P = .79). Acute graft-versus-host disease (GVHD) grades III and IV but not chronic GVHD, was higher in patients receiving BuCyMel. Older age at HSCT had an adverse impact on NRM and the use of peripheral blood as stem cell source was associated with increased chronic GVHD and NRM as well as lower LFS and OS. Among pediatric patients receiving HSCT for AML in CR1, the use of BuCyMel conditioning proved superior to TBICy and BuCy in reducing relapse and improving LFS

Correction: Long-term outcome after allogeneic hematopoietic stem cell transplantation for Shwachman–Diamond syndrome: a retrospective analysis and a review of the literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP-EBMT)

An amendment to this paper has been published and can be accessed via a link at the top of the paper

A risk factor analysis of outcomes after unrelated cord blood transplantation for children with Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome is a severe X-linked recessive immune deficiency disorder. A scoring system of Wiskott-Aldrich syndrome severity (0.5-5) distinguishes 2 phenotypes: X-linked thrombocytopenia and classic Wiskott-Aldrich syndrome. Hematopoietic cell transplantation is curative for Wiskott-Aldrich syndrome, however the use of unrelated umbilical cord blood transplantation has seldom been described. We analyzed umbilical cord blood transplantation outcomes for 90 patients. Median age at umbilical cord blood transplantation was 1.5 years. Patients were classified according to clinical scores (2 (23%), 3 (30%), 4 (23%) and 5 (19%)). Most patients received HLA mismatched umbilical cord blood transplantation and myeloablative conditioning with anti-thymocyte globulin. Cumulative incidence of neutrophil recovery at day-60 was 89% and day-100 acute graft-versus-host disease grade II-IV was 38%; use of methotrexate for graft-versus- host disease prophylaxis delayed engraftment (p=0.02), but decreased acute graft-versus-host disease (p=0.03). At 5-year, overall survival and event-free survival were 75% and 70%, respectively. Estimated 5 year- event-free survival was 83%, 73% and 55% for patients with clinical score 2, 4-5 and 3, respectively. In multivariate analysis, age<2years at umbilical cord blood transplantation and clinical phenotype X-linked thrombocytopenia were associated with improved event-free survival. Overall survival tended to be improved after 2007 (p=0.09). In conclusion, umbilical cord blood transplantation is a good alternative option for young children with Wiskott-Aldrich syndrome lacking an HLA identical stem cell donor

Treatment dilemmas in asymptomatic children with primary hemophagocytic lymphohistiocytosis

Asymptomatic carriers (ACs) of pathogenic biallelic mutations in causative genes for primary hemophagocytic lymphohistiocytosis (HLH) are at high risk of developing life-threatening HLH, which requires allogeneic hematopoietic stem cell transplantation (HSCT) to be cured. There are no guidelines on the management of these asymptomatic patients. We analyzed the outcomes of pairs of index cases (ICs) and subsequently diagnosed asymptomatic family members carrying the same genetic defect. We collected data from 22 HSCT centers worldwide. Sixty-four children were evaluable. ICs presented with HLH at a median age of 16 months. Seven of 32 ICs died during first-line therapy, and 2 are alive after chemotherapy only. In all, 23/32 underwent HSCT, and 16 of them are alive. At a median follow-up of 36 months from diagnosis, 18/32 ICs are alive. Median age of ACs at diagnosis was 5 months. Ten of 32 ACs activated HLH while being observed, and all underwent HSCT: 6/10 are alive and in complete remission (CR). 22/32 ACs remained asymptomatic, and 6/22 have received no treatment and are in CR at a median follow-up of 39 months. Sixteen of 22 underwent preemptive HSCT: 15/16 are alive and in CR. Eight-year probability of overall survival (pOS) in ACs who did not have activated HLH was significantly higher than that in ICs (95% vs 45%; P = .02), and pOS in ACs receiving HSCT before disease activation was significantly higher than in ACs receiving HSCT after HLH activation (93% vs 64%; P = .03). Preemptive HSCT in ACs proved to be safe and should be considered