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Key Points• Germline GATA2 mutations account for 15% of advanced and 7% of all primary pediatric MDS and do not influence overall survival. • The majority (72%) of adolescents with MDS and monosomy 7 carry an underlying GATA2 deficiency.Germline GATA2 mutations cause cellular deficiencies with high propensity for myeloid disease. We investigated 426 children and adolescents with primary myelodysplastic syndrome (MDS) and 82 cases with secondary MDS enrolled in 2 consecutive prospective studies of the European Working Group of MDS in Childhood (EWOG-MDS) conducted in Germany over a period of 15 years. Germline GATA2 mutations accounted for 15% of advanced and 7% of all primary MDS cases, but were absent in children with MDS secondary to therapy or acquired aplastic anemia. Mutation carriers were older at diagnosis and more likely to present with monosomy 7 and advanced disease compared with wild-type cases. For stratified analysis according to karyotype, 108 additional primary MDS patients registered with EWOG-MDS were studied. Overall, we identified 57 MDS patients with germline GATA2 mutations. GATA2 mutations were highly prevalent among patients with monosomy 7 (37%, all ages) reaching its peak in adolescence (72% of adolescents with monosomy 7). Unexpectedly, monocytosis was more frequent in GATA2-mutated patients. However, when adjusted for the selection bias from monosomy 7, mutational status had no effect on the hematologic phenotype. Finally, overall survival and outcome of hematopoietic stem cell transplantation (HSCT) were not influenced by mutational status. This study identifies GATA2 mutations as the most common germline defect predisposing to pediatric MDS with a very high prevalence in adolescents with monosomy 7. GATA2 mutations do not confer poor prognosis in childhood MDS. However, the high risk for progression to advanced disease must guide decision-making toward timely

Key Points• HLA-identical sibling transplantation for SCD offers excellent long-term survival. • Mortality risk is higher for older patients; event-free survival has improved in patients transplanted after 2006.Despite advances in supportive therapy to prevent complications of sickle cell disease (SCD), access to care is not universal. Hematopoietic cell transplantation is, to date, the only curative therapy for SCD, but its application is limited by availability of a suitable HLA-matched donor and lack of awareness of the benefits of transplant. Included in this study are 1000 recipients of HLA-identical sibling transplants performed between 1986 and 2013 and reported to the European Society for Blood and Marrow Transplantation, Eurocord, and the Center for International Blood and Marrow Transplant Research. The primary endpoint was event-free survival, defined as being alive without graft failure; risk factors were studied using a Cox regression models. The median age at transplantation was 9 years, and the median follow-up was longer than 5 years. Most patients received a myeloablative conditioning regimen (n 5 873; 87%); the remainder received reduced-intensity conditioning regimens (n 5 125; 13%). Bone marrow was the predominant stem cell source (n 5 839; 84%); peripheral blood and cord blood progenitors were used in 73 (7%) and 88 (9%) patients, respectively. The 5-year event-free survival and overall survival were 91.4% (95% confidence interval, 89.6%-93.3%) and 92.9% (95% confidence interval, 91.1%-94.6%), respectively. Eventfree survival was lower with increasing age at transplantation (hazard ratio [HR], 1.09; P < .001) and higher for transplantations performed after

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Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.

SummaryDuring periods of immunosuppression, such as postallogeneic stem cell transplantation (SCT), patients are at significant risk for severe viral infections. Human adenovirus (HAdV) infection is a serious complication post‐SCT, especially in children. Virus‐specific T cells are essential for the clearance of HAdV, as antiviral chemotherapy has revealed limited success. We present feasibility data for a new treatment option using virus‐specific donor T cells for adoptive transfer of immunity to patients with HAdV‐infection/reactivation. Virus‐specific donor T cells were isolated and infused into nine children with systemic HAdV infection after SCT. Isolation was based on γ‐interferon (IFN‐γ) secretion after short in vitro stimulation with viral antigen, resulting in a combination of CD4+ and CD8+ T cells. 1·2–50 × 103/kg T cells were infused for adoptive transfer. Isolated cells showed high specificity and markedly reduced alloreactivity in vitro. Adoptive transfer of HAdV‐specific immunity was successful in five of six evaluable patients, documented by a dose‐independent and sustained in vivo expansion of HAdV‐specific T cells, associated with a durable clearance/decrease of viral copies. T‐cell infusion was well tolerated in all nine patients, except one case with graft‐versus‐host disease II of the skin. In conclusion, induction of a specific T‐cell response through adoptive transfer was feasible and effective. When performed early in the course of infection, adoptive T‐cell transfer may protect from HAdV‐related complications.

Human adenovirus (HAdV) infections are increasingly recognized as important pathogens in immunocompromised hosts, especially in patients with severely suppressed T-cell function. The 4th European Conference of Infections in Leukemia (ECIL-4) has developed evidence-based guidelines for diagnosis and management of HAdV infections. The risk for HAdV-associated disease is increased in children, and risk factors for HAdV disease are T-cell depletion, unrelated and cord blood hematopoietic stem cell transplantation, graft-versus-host disease grades III-IV, and lymphopenia. The recommended technique for monitoring of high-risk patients is quantitative polymerase chain reaction. Cidofovir is the most used antiviral therapy, although no controlled study has been performed. HAdV-specific T-cell therapy is in development.