Background Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder of red blood cells in human subjects, causing hemolytic anemia linked to impaired nicotinamide ...adenine dinucleotide phosphate (NADPH) production and imbalanced redox homeostasis in erythrocytes. Because G6PD is expressed by a variety of hematologic and nonhematologic cells, a broader clinical phenotype could be postulated in G6PD-deficient patients. We describe 3 brothers with severe G6PD deficiency and susceptibility to bacterial infection. Objective We sought to study the molecular pathophysiology leading to susceptibility to infection in 3 siblings with severe G6PD deficiency. Methods Blood samples of 3 patients with severe G6PD deficiency were analyzed for G6PD enzyme activity, cellular oxidized nicotinamide adenine dinucleotide phosphate/NADPH levels, phagocytic reactive oxygen species production, neutrophil extracellular trap (NET) formation, and neutrophil elastase translocation. Results In these 3 brothers strongly reduced NADPH oxidase function was found in granulocytes, leading to impaired NET formation. Defective NET formation has thus far been only observed in patients with the NADPH oxidase deficiency chronic granulomatous disease, who require antibiotic and antimycotic prophylaxis to prevent life-threatening bacterial and fungal infections. Conclusion Because severe G6PD deficiency can be a phenocopy of chronic granulomatous disease with regard to the cellular and clinical phenotype, careful evaluation of neutrophil function seems mandatory in these patients to decide on appropriate anti-infective preventive measures. Determining the level of G6PD enzyme activity should be followed by analysis of reactive oxygen species production and NET formation to decide on required antibiotic and antimycotic prophylaxis.
Summary Background Hepatic veno-occlusive disease is a leading cause of morbidity and mortality after haemopoietic stem-cell transplantation (HSCT). We aimed to assess whether defibrotide can reduce ...the incidence of veno-occlusive disease in this setting. Methods In our phase 3 open-label, randomised controlled trial, we enrolled patients at 28 European university hospitals or academic medical centres. Eligible patients were younger than 18 years, had undergone myeloablative conditioning before allogeneic or autologous HSCT, and had one or more risk factor for veno-occlusive disease based on modified Seattle criteria. We centrally assigned eligible participants on the basis of a computer-generated randomisation sequence (1:1), stratified by centre and presence of osteopetrosis, to receive intravenous defibrotide prophylaxis (treatment group) or not (control group). The primary endpoint was incidence of veno-occlusive disease by 30 days after HSCT, adjudicated by a masked, independent review committee, in eligible patients who consented to randomisation (intention-to-treat population), and was assessed with a competing risk approach. Patients in either group who developed veno-occlusive disease received defibrotide for treatment. We assessed adverse events to 180 days after HSCT in all patients who received allocated prophylaxis. This trial is registered with ClinicalTrials.gov , number NCT00272948. Findings Between Jan 25, 2006, and Jan 29, 2009, we enrolled 356 eligible patients to the intention-to-treat population. 22 (12%) of 180 patients randomly allocated to the defibrotide group had veno-occlusive disease by 30 days after HSCT compared with 35 (20%) of 176 controls (risk difference −7·7%, 95% CI −15·3 to −0·1; Z test for competing risk analysis p=0·0488; log-rank test p=0·0507). 154 (87%) of 177 patients in the defibrotide group had adverse events by day 180 compared with 155 (88%) of 176 controls. Interpretation Defibrotide prophylaxis seems to reduce incidence of veno-occlusive disease and is well tolerated. Thus, such prophylaxis could present a useful clinical option for this serious complication of HSCT. Funding Gentium SpA, European Group for Blood and Marrow Transplantation.
Table I5 and Fig 1, A, show this patient's immunologic evaluations before hematopoietic cell transplantation (subject 4) in comparison with other patients with hypomorphic recombination-activating ...gene (RAG) mutations undergoing transplantation at our center (patients 1-3 and 6, see Table E1 in this article's Online Repository at www.jacionline.org). Because of his recurrent infections, enteropathy, autoimmune phenomena, and immunologically combined immunodeficiency, the possibility of a hypomorphic mutation in one of the genes known to cause classical SCID was considered. Â Subject 1 Subject 2 Subject 3 Subject 4 Subject 6 Genetic defect RAG1 RAG1 RAG1 RAG1 RAG2 Sex Female Male Female Male Female Age at diagnosis (y) 3 7 8 9 11 Donor MUDlow * MUD MUD HLA-haploidentical father MUD Preconditioning regimen RIT (BM 20 Gy) Fludarabin, 150 mg/m2ATG, 10 mg/kg RIT (BM 17.7 Gy) Treosulfan, 36 g/m2Fludarabin, 150 mg/m2ATG, 10 mg/kg RIT (BM 17 Gy) Fludarabin, 150 mg/m2Melphalan, 140 mg/m2ATG, 10 mg/kg TBI 12 Gy Fludarabin, 160 mg/m2ATG, 15 mg/kg RIT (BM 27 Gy) Treosulfan, 36 g/m2Fludarabin, 150 mg/m2Alemtuzumab (MabCampath), 0.5 mg/kg Table E1 Characteristics of patients undergoing hematopoietic stem cell transplantation ATG, Anti-thymocyte globulin; BM, bone marrow; RIT, radioimmunotherapy with yttrium-coupled CD66 antibodies; TBI, total body irradiation.
Background Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with ...high mortality. For these patients, investigation of more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT), is warranted. Objective We sought to define the outcomes of HSCT for patients with CVID. Methods Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012. Results Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved. Conclusion This multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients; however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome.
Background Rare DNA breakage repair disorders predispose to infection and lymphoreticular malignancies. Hematopoietic cell transplantation (HCT) is curative, but coadministered chemotherapy or ...radiotherapy is damaging because of systemic radiosensitivity. We collected HCT outcome data for Nijmegen breakage syndrome, DNA ligase IV deficiency, Cernunnos–XRCC4-like factor (Cernunnos-XLF) deficiency, and ataxia-telangiectasia (AT). Methods Data from 38 centers worldwide, including indication, donor, conditioning regimen, graft-versus-host disease, and outcome, were analyzed. Conditioning was classified as myeloablative conditioning (MAC) if it contained radiotherapy or alkylators and reduced-intensity conditioning (RIC) if no alkylators and/or 150 mg/m2 fludarabine or less and 40 mg/kg cyclophosphamide or less were used. Results Fifty-five new, 14 updated, and 18 previously published patients were analyzed. Median age at HCT was 48 months (range, 1.5-552 months). Twenty-nine patients underwent transplantation for infection, 21 had malignancy, 13 had bone marrow failure, 13 received pre-emptive transplantation, 5 had multiple indications, and 6 had no information. Twenty-two received MAC, 59 received RIC, and 4 were infused; information was unavailable for 2 patients. Seventy-three of 77 patients with DNA ligase IV deficiency, Cernunnos-XLF deficiency, or Nijmegen breakage syndrome received conditioning. Survival was 53 (69%) of 77 and was worse for those receiving MAC than for those receiving RIC ( P = .006). Most deaths occurred early after transplantation, suggesting poor tolerance of conditioning. Survival in patients with AT was 25%. Forty-one (49%) of 83 patients experienced acute GvHD, which was less frequent in those receiving RIC compared with those receiving MAC (26/56 46% vs 12/21 57%, P = .45). Median follow-up was 35 months (range, 2-168 months). No secondary malignancies were reported during 15 years of follow-up. Growth and developmental delay remained after HCT; immune-mediated complications resolved. Conclusion RIC HCT resolves DNA repair disorder–associated immunodeficiency. Long-term follow-up is required for secondary malignancy surveillance. Routine HCT for AT is not recommended.
Background Absent T-cell immunity resulting in life-threatening infections provides a clear rationale for hematopoetic stem cell transplantation (HSCT) in patients with severe combined ...immunodeficiency (SCID). Combined immunodeficiencies (CIDs) and “atypical” SCID show reduced, not absent T-cell immunity. If associated with infections or autoimmunity, they represent profound combined immunodeficiency (P-CID), for which outcome data are insufficient for unambiguous early transplant decisions. Objectives We sought to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. Methods In this prospective and retrospective observational study, we recruited nontransplanted patients with P-CID aged 1 to 16 years to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunologic and/or clinical parameters may be predictive for outcome. Results A total of 51 patients were recruited (median age, 9.6 years). Thirteen of 51 had a genetic diagnosis of “atypical” SCID and 14 of 51 of CID. About half of the patients had less than 10% naive T cells, reduced/absent T-cell proliferation, and at least 1 significant clinical event/year, demonstrating their profound immunodeficiency. Nineteen patients (37%) underwent transplantation within 1 year of enrolment, and 5 of 51 patients died. Analysis of the HSCT decisions revealed the anticipated heterogeneity, favoring an ongoing prospective matched-pair analysis of patients with similar disease severity with or without transplantation. Importantly, so far neither the genetic diagnosis nor basic measurements of T-cell immunity were good predictors of disease evolution. Conclusions The P-CID study for the first time characterizes a group of patients with nontypical SCID T-cell deficiencies from a therapeutic perspective. Because genetic and basic T-cell parameters provide limited guidance, prospective data from this study will be a helpful resource for guiding the difficult HSCT decisions in patients with P-CID.
The use of HLA-haploidentical family donors requires T-cell depletion to avoid graft-versus-host disease (GVHD), which increases the risk of graft rejection, particularly for patients with forms of ...primary immunodeficiency other than severe combined immune deficiency.3 Various T-cell depletion strategies have been used to minimize GVHD and maximize sustained engraftment and early immune reconstitution, such as enrichment of CD34+ cells or depletion of CD3+ and CD19+ cells to prevent post-transplant lymphoproliferative disorder. The drawback of positive CD34+ selection is that a large number of effector cells, such as natural killer (NK), myeloid, and plasmacytoid dendritic cells--which aid engraftment and also decrease the risk of infection--are lost.
The initial clinical and hematologic presentation of infantile malignant osteopetrosis may be indistinguishable from that of juvenile myelomonocytic leukemia in infants. Timely radiographic imaging, ...however, allows straightforward delineation of these 2 severe diseases and facilitates immediate initiation of appropriate therapy.
WAS is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation ...(HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% CI 78-87) at 15 years and 70% (61-80) at 30 years of age. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hotspot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared to 71% (62-81) and 48% (34-68) in patients with any other variant (class II; p<0.0001). The cumulative incidence rates of disease-related complications such as severe bleeding (p=0.007), life-threatening infection (p<0.0001), and autoimmunity (p=0.004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (p=0.6) was not different between classes I and II. This study represents the largest cohort of WAS patients studied so far. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of variant is a biomarker to predict the outcome for WAS patients.
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