Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency (CID) due to biallelic mutations in the gene encoding DOCK8. Major clinical phenomena are recurrent severe infections of the lungs and skin, atopic eczema, and predisposition to malignancy leading to a poor prognosis. Typical findings include highly elevated IgE and eosinophilia. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is indicated as the only curative treatment option. We present a patient with advanced disease undergoing alloHSCT at the age of 11 years after individualized pre-treatment using dupilumab and rituximab resulting in a decrease in IgE levels and clinical improvement of the skin condition. Additionally, in a review of the literature, we summarize morbidity and outcome in DOCK8-deficient patients older than 8 years of age receiving alloHSCT. Life-threatening infections, malignancy, and disease-related complications with organ damage pre-transplant are challenging in older DOCK8-deficient patients. The therapeutic role of dupilumab in DOCK8 deficiency should be evaluated in larger studies.

JAGN1 (Jagunal-homolog1) is a ER-resident transmembrane protein which is part of the early secretory pathway and granulocyte colony-stimulating factor receptor mediated signaling. Autosomal recessively inherited variants in the JAGN1 gene lead to congenital neutropenia, early-onset bacterial infections, aphthosis and skin abscesses due to aberrant differentiation and maturation of neutrophils. In addition, bone metabolism disorders and a syndromic phenotype, including facial features, short stature and neurodevelopmental delay, have been reported in affected patients. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a treatment option for patients who respond poorly to therapy with colony-stimulating factors (GM-CSF, G-CSF) and those who suffer from complicated infections despite treatment. In a retrospective multicenter study by EBMT IEWP in close collaboration with ESID and the French Neutropenia registry, data from 32 patients with JAGN1 deficiency were collected to describe the natural course of the disease, perform a phenotype-genotype analysis and evaluate the responses to various treatment modalities. Patients presented with nine distinct homozygous mutations in JAGN1. All patients experienced early-onset infectious complications. Twelve patients presented a syndromic phenotype with short stature and facial features. Neurodevelopmental delay was observed only in four patients from three families. The most common variant c.3G>A p.Met1, found in nine patients in our cohort was never connected to extramedullary symptoms except for a short stature in one patient, whereas patients with the variants c.63G>T, p.Glu21Asp and c130c>T p.His44 Tyr presented more often with syndromic facial features and bone metabolism disorders. Six patients received allogeneic stem cell transplantation due to therapy-refractory neutropenia and severe infections, and one received the graft because of myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML). Two patients had to undergo a second transplantation because of autologous reconstitution despite receiving myeloablative regimens. One untransplanted patient died at the age of five years due to pancolitis and septicemia. All 31 other patients were reported to be alive and healthy at the last follow-up under supportive care.

Allogeneic haematopoietic stem cell transplantation (HSCT) is an essential treatment component for high-risk paediatric acute myeloid leukaemia (AML), but the choice of the optimal conditioning regimen remains controversial. We compared outcomes of two widely used myeloablative regimens, BuCy (Busulfan, Cyclophosphamide) versus BuCyMel (Busulfan, Cyclophosphamide, Melphalan) in children aged under 2 years undergoing HSCT in 1st complete remission (CR1). This international, registry-based study was conducted by the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplant (EBMT) and included patients transplanted from 2000-2022. 335 patients, transplanted across 98 centres, were included, 185 (55.2%) patients received BuCy and 150 patients (44.8%) received BuCyMel. BuCyMel was associated with significantly better leukaemia-free survival (LFS) (4 y: 74.8% vs 58.8%, HR 0.52 (95%CI: 0.33-0.82), p = 0.004) and overall survival (OS) (4 y: 77.9% vs 66.2%, HR 0.55 (95%CI: 0.33-0.91), p = 0.02) compared with BuCy, and significantly lower relapse incidence (4 y: 18.1% BuCyMel vs 31.5% BuCy, HR 0.50 (95%CI 0.29-0.87), p = 0.01). Four-year non-relapse mortality (NRM) did not differ between groups. Our results suggest that BuCyMel is a better conditioning regimen compared with BuCy in children aged under 2 years undergoing HSCT for CR1 AML.

ABO incompatibility affects approximately 40% of allogeneic stem cell transplants in Caucasian patient populations. Because bone marrow (BM), the preferred graft from paediatric sibling donors and for non-malignant diseases, has a red blood cell (RBC) content similar to blood, anti-donor isoagglutinins must either be depleted from the recipient or RBCs removed from the graft. To achieve tolerability of unmanipulated BM grafts, we used controlled infusions of donor ABO-type RBC units to deplete isoagglutinins before the transplant. This retrospective study evaluates the outcomes of 52 ABO major incompatible BM transplants performed at our centre between 2007 and 2019. The use of donor-type RBC transfusions was well tolerated. They effectively reduced isoagglutinins levels, typically achieving target titres after one (60%) or two (29%) transfusions. The approach allowed for successful and uneventful infusions of unmanipulated BM which provided timely engraftment. The transplant outcomes were not inferior to those of a matched-pair control group of patients with ABO-identical donors.

Summary Patients with inborn errors of immunity (IEI) can suffer from treatment‐refractory inflammatory bowel disease (IBD) causing failure to thrive and consequences of long‐term multiple immunosuppressive treatments. Allogeneic haematopoietic stem cell transplantation (alloHSCT) can serve as a curative treatment option. In this single‐centre retrospective cohort study we report on 11 paediatric and young adult IEI patients with IBD and failure to thrive, who had exhausted symptomatic treatment options and received alloHSCT. The cohort included chronic granulomatous disease (CGD), lipopolysaccharide‐responsive and beige‐like anchor protein (LRBA) deficiency, STAT3 gain‐of‐function (GOF), Wiskott–Aldrich syndrome (WAS), dedicator of cytokinesis 8 (DOCK8) deficiency and one patient without genetic diagnosis. All patients achieved stable engraftment and immune reconstitution, and gastrointestinal symptoms were resolved after alloHSCT. The overall survival was 11/11 over a median follow‐up of 34.7 months. Graft‐versus‐host disease (GVHD) was limited to grade I–II acute GVHD ( n = 5), one case of grade IV acute GVHD and one case of limited chronic GVHD. Since treatment recommendations are limited, this work provides a centre‐specific approach to treatment prior to transplant as well as conditioning in IEI patients with severe IBD.

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23–dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.

Human herpes virus (HHV) 6 is a β-herpesvirus mostly known for causing the common childhood illness exanthema subitum. Nearly all children had contact with HHV 6 at the age of 2 [1] with a peak incidence between 9 and 21 months [2]. Primary infection typically leads to fever for 3 to 5 days with sudden onset of a maculopapular rash upon defervescence, [3] hence the name exanthema subitum. HHV 6 persists in monocytes and salivary glands and can be reactivated when immunity is impaired [4]. As a neurotropic herpes virus, HHV 6 also overcomes the blood-brain barrier and can cause multiple neurological symptoms: primary infection coincides with febrile seizures and accounts for one third of all febrile seizures in children up to the age of two years [3,5]. It can also present as an acute encephalitis in immunocompetent populations [6,7] leading to headaches and seizures [8-11]. As HHV-6-associated encephalitis is described to be located in the limbic system, patients often show altered behavior, e.g. disorientation and confusion [9], drowsiness [8,12], aphasia [13-14], decreased appetite [10] and hallucinations [15]. Furthermore, HHV 6 is able to persist in the central nervous system [16] and reactivation has been associated with encephalitis and encephalopathy [17,18]. It has even been linked to neurodegenerative disorders such as multiple sclerosis [16].

Background: Pediatric patients younger than two years of age with acute myeloid leukemia (AML) commonly receive a chemotherapy-based myeloablative conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT). The optimal choice of cytotoxic agents is still controversial.

Specific protocols define eligibility, conditioning, donor selection, graft composition and prophylaxis of graft vs. host disease for children and young adults undergoing hematopoietic stem cell transplant (HSCT). However, international protocols rarely, if ever, detail supportive care, including pharmaceutical infection prophylaxis, physical protection with face masks and cohort isolation or food restrictions. Supportive care suffers from a lack of scientific evidence and implementation of practices in the transplant centers brings extensive restrictions to the child's and family's daily life after HSCT. Therefore, the Board of the Pediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) held a series of dedicated workshops since 2017 with the aim of initiating the production of a set of minimal recommendations. The present paper describes the consensus reached within the field of infection prophylaxis.

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.

Background Although children, adolescents and young adult patients with ALL have in general a good prognosis relapses occur and patients with a second relapse, a relapse after allogeneic SCT or patients with primary refractory disease have a poor prognosis. In this patient group several studies using second generation CD19 chimeric antigen receptor T- cells (CAR-T cells) demonstrated high efficacy with survival rates of up to 65%. Here we report our first results using commercially available CAR-T-cell product Tisagenlecleucel in patients with ALL. Methods, Patients Between May 2016 and August 2019 twenty-six patients received a peripheral blood apheresis for CAR-T cell generation. Twenty-four patients had relapsed after allogeneic HSCT (92%), one patient suffered from second r/relapse (4%) or from primary r/ALL (4%). In 23/26 (88%) patients CAR-T cell production was possible after first apheresis, in 2 patients (4%) a second apheresis was necessary after failure of the first transduction.Patients’ median age was 13.5 years (range: 1.1-33.2 years). Between apheresis and start of lymphodepleting chemotherapy (LDC) 24 patients received low dose maintenance chemotherapy according to the FRAPOSTALL protocol (Willasch et al. 2016) and two patients were treated with inotuzumab. Disease status at start of LDC was CR w/o MRD (n=12), and persistence of blasts (n=11). Results CAR-T cells could be transfused to 23/26 patients at a median dose of 1.5 Mio/kgBW (range 0.145 to 8.5) /kgBW. In two patients (8%) CAR-T cell production was not possible and in one patient, in whom a second viral transduction procedure was necessary, CAR-T cell transfusion could not be performed because of diseases progression and deterioration of the patients’ general condition.Cytokine release syndrome (CRS) grade I-IV was observed in seven patients (30%); 14/23 patients (70%) did not develop CRS. Cytokine related encephalopathy syndrome (CRES) grade II was observed in 4/23 patients (17%).At day +28 17/23 patients (74%) achieved MRD negative CR. Three patients (13%) did not respond and three patients died before day +28. Thereof two patients (8%) with progressive disease at time of LDC who did not respond, and unfortunately one patient (4%) died in CR based on infection before day +28.As of 8/20/2019 median follow-up was 9.5 months. Patients with <5% of blasts at beginning of LDC (n=12; 52%) had a probability of (p)EFS of 75% and a pOS of 100% at 12 months. However, patients with more ≥5% of blasts (n=11; 48%) had a pEFS and a pOS of at 18% and 44%, respectively. This difference achieved significance with p=0.056 and p=0.013, respectively. Conclusion These results confirm that commercial available CAR-T cell product Tisagenlecleucel (Kymriah®) showed high efficacy in ALL patients. Response to bridging chemotherapy and level of residual diseases prior to CAR-T infusion might impact the pEFS and survival of the patients.

Up to 40% of donor-recipient pairs in SCT have some degree of ABO incompatibility, which may cause severe complications. The aim of this study was to describe available options and survey current practices by means of a questionnaire circulated within the EBMT Pediatric Diseases Working Party investigators. Major ABO incompatibility (donor's RBCs have antigens missing on the recipient's cell surface, towards which the recipient has circulating isohemagglutinins) requires most frequently an intervention in case of bone marrow grafts, as immediate or delayed hemolysis, delayed erythropoiesis and pure red cell aplasia may occur. RBC depletion from the graft (82%), recipient plasma-exchange (14%) were the most common practices, according to the survey. Graft manipulation is rarely needed in mobilized peripheral blood grafts. In case of minor incompatible grafts (donor has isohemagglutinins directed against recipient RBC antigens), isohemagglutinin depletion from the graft by plasma reduction/centrifugation may be considered, but acute tolerability of minor incompatible grafts is rarely an issue. According to the survey, minor ABO incompatibility was either managed by means of plasma removal from the graft, especially when isohemagglutinin titer was above a certain threshold, or led to no intervention at all (41%). Advantages and disadvantages of each method are discussed.

Detection of minimal residual disease (MRD) pre- and post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non-total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.

Allogeneic hematopoietic stem cell transplantation (HSCT) is widely performed in children and adolescents with hematologic diseases, including very high-risk leukemia. With increasing success and survival rates, the long-term sequelae of HSCT have become important. Here, we provide guidance to the prevention and treatment of the most common bone morbidities—osteoporosis and osteonecrosis—emerging in the context of HSCT in children and adolescents. We give an overview on definitions, symptoms, and diagnostics and propose an algorithm for clinical practice based on discussions within the International Berlin Frankfurt Münster (BFM) Stem Cell Transplantation Committee and the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation, our expert knowledge, and a literature review.