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Summary Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) is frequently associated with impaired oral intake and malnutrition, which potentially increases morbidity and mortality. Therefore, nutrition is one of the major challenges in the post-transplant period. Methods To document the current clinical approach in nutritional treatment, we designed a questionnaire concerning the current practice in nutrition after alloHSCT and distributed it to German speaking centers performing alloHSCT in Germany, Austria and Switzerland between November 2018 and March 2020. Twenty-eight (39%) of 72 contacted centers completed the survey, 23 from Germany, two from Austria and three from Switzerland, representing 50% of alloHSCT activity within the participating countries in 2018. Results All centers reported having nutritional guidelines for patients undergoing alloHSCT, whereby 86% (n = 24) provided a low-microbial diet during the neutropenic phase. The criteria to start parenteral nutrition (PN) directly after alloHSCT seemed to be consistent, 75% (n = 21) of the corresponding centers started PN if the oral nutritional intake or the bodyweight dropped below a certain limit. In the setting of intestinal graft-versus-host disease (GvHD) the current practice appeared to be more heterogenous. About 64% (n = 18) of the centers followed a special diet, added food stepwise modulated by GvHD symptoms, while only four centers regularly stopped oral intake completely (intestinal GvHD grade >1). Half of the centers (54%, n = 15) applied a lactose-free diet, followed by 43% (n = 12) which provided fat- and 18% (n = 5) gluten-free food in patients with intestinal GvHD. Supplementation of micronutrients in acute intestinal GvHD patients was performed by 54% (n = 15) of the centers, whereas vitamin D (89%, n = 25) and vitamin B12 (68%, n = 19) was added regularly independently of the presence of GvHD. Only 5 (18%) participating centers ever observed a food-associated infection during hospitalization, whereas food-associated infections were reported to occur more often in the outpatient setting (64%, n = 18). Conclusion The survey documented a general consensus about the need for nutritional guidelines for patients undergoing alloHSCT. However, the nutritional treatment in clinical practice (i.e. lactose-, gluten- or fat-free in intestinal GvHD) as well as the use of food supplements was very heterogeneous. In line with current general recommendations the centers seemed to focus on safe food handling practice rather than providing a strict neutropenic diet. More high-quality data are required to provide evidence-based nutrition to patients during and after alloHSCT.

Terapia profiláctica antibiótica; Niños; Vacunación Teràpia profilàctica antibiòtica; Nens; Vacunació Antibiotic prophylactic therapy; Children; Vaccination 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.

Summary Background The psychometric properties of an instrument, the Activity Scale for Kids-performance (ASKp), were assessed which was proposed to capture physical functioning after allogeneic hematopoietic stem cell transplantation (HSCT). Additionally, this multicenter observational prospective study investigated the influence of clinical correlates focusing on chronic graft-versus-host disease (cGVHD). Methods Patient-reported ASKp, clinician-reported Karnofsky/Lansky status (KPS/PSS), patient characteristics and cGVHD details were assessed of 55 patients with a median age of 12 years at baseline after day +100 post-HSCT and every 3 months during the next 18 months. The psychometric properties were evaluated and ASKp and KPS/PSS status was compared using ANOVAS and multiple regression models. Results The German version of the ASKp showed good psychometric properties except for ceiling effects. Discrimination ability of the ASKp was good regarding the need for devices but failed to predict cGVHD patients. Both the ASKp and the KPS/PSS were associated with patients after adoptive cell therapy being in need for devices, suffering from overlap cGVHD and from steroid side effects but not with patients’ age and gender. In contrast to the KPS/PSS the ASKp only showed significant differences after merging moderate and severe cGHVD patients when comparing them to No-cGVHD (F = 4.050; p = 0.049), being outperformed by the KPS/PSS (F = 20.082; p Conclusion The ASKp showed no clear advantages compared to KPS/PSS even though economical and patients’ effort was higher. Further application range may be limited through ceiling effects. Both should be taken into consideration. Therefore, the results may not support the usage of ASKp after HSCT and rather suggest KPS/PSS, both patient and clinician reported.

SummaryInfertility and endocrine late effects (LE) are common sequelae after pediatric allogeneic hematopoietic stem cell transplantation (HSCT) after myeloablative conditioning. Nevertheless, the individual risk for these LE is not always easy to predict and therefore these issues are of ongoing interest to the clinical research community dealing with HSCT aftercare. This article describes the case of a young woman who received polychemotherapy and total body irradiation (TBI) containing conditioning for HSCT for a relapsed anaplastic large cell lymphoma (ALCL). She developed severe sclerotic chronic graft-versus-host disease (GVHD) with irreversible joint contractures and multiorgan involvement, requiring long-term multimodal immunosuppressive treatment. Subsequently showing a considerable number of LE including hypergonadotropic hypogonadism, she accepted that infertility would be quite likely. Her courageous personal life planning included part-time working and a partnership but not motherhood. This article reports the unexpected and spontaneous pregnancy and the extreme preterm birth of a surprisingly adequately developing child.

Graft-vs. -host disease (GvHD) is a serious and complex immunological complication of haematopoietic stem cell transplantation (HSCT) and is associated with prolonged immunodeficiency and non-relapse mortality. Standard treatment of chronic GvHD comprises steroids in combination with other immunosuppressive agents. Extracorporeal photopheresis (ECP), with its immunomodulatory mechanism, is applied as part of steroid-sparing regimens for chronic GvHD. Immunocompromised, chronically ill patients are at particular risk of severe disease courses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. T-cell immunity in SARS-CoV-2 infection is well-described but the role of the humoral immune responses is not fully understood. This case report describes a moderate course of SARS-CoV-2 infection in a patient low B cells and autoantibody expression, normalised. Moreover, we observed complete response of active chronic GvHD to treatment.

Immune reconstitution (IR) after allogeneic haematopoietic cell transplantation (HCT) represents a central determinant of the clinical post-transplant course, since the majority of transplant-related outcome parameters such as graft-vs.-host disease (GvHD), infectious complications, and relapse are related to the velocity, quantity and quality of immune cell recovery. Younger age at transplant has been identified as the most important positive prognostic factor for favourable IR post-transplant and, indeed, accelerated immune cell recovery in children is most likely the pivotal contributing factor to lower incidences of GvHD and infectious complications in paediatric allogeneic HCT. Although our knowledge about the mechanisms of IR has significantly increased over the recent years, strategies to influence IR are just evolving. In this review, we will discuss different patterns of IR during various time points post-transplant and their impact on outcome. Besides IR patterns and cellular phenotypes, recovery of antigen-specific immune cells, for example virus-specific T cells, has recently gained increasing interest, as certain threshold levels of antigen-specific T cells seem to confer protection against severe viral disease courses. In contrast, the association between IR and a possible graft-vs. leukaemia effect is less well-understood. Finally, we will present current concepts of how to improve IR and how this could change transplant procedures in the near future.

Despite advances in haematopoietic stem cell transplant (HSCT) techniques, the risk of serious side effects and complications still exists. Neurological complications, both acute and long term, are common following HSCT and contribute to significant morbidity and mortality. The aetiology of neurotoxicity includes infections and a wide variety of non-infectious causes such as drug toxicities, metabolic abnormalities, irradiation, vascular and immunologic events and the leukaemia itself. The majority of the literature on this subject is focussed on adults. The impact of the combination of neurotoxic drugs given before and during HSCT, radiotherapy and neurological complications on the developing and vulnerable paediatric and adolescent brain remains unclear. Moreover, the age-related sensitivity of the nervous system to toxic insults is still being investigated. In this article, we review current evidence regarding neurotoxicity following HSCT for acute lymphoblastic leukaemia in childhood. We focus on acute and long-term impacts. Understanding the aetiology and long-term sequelae of neurological complications in children is particularly important in the current era of immunotherapy for acute lymphoblastic leukaemia (such as chimeric antigen receptor T cells and bi-specific T-cell engager antibodies), which have well-known and common neurological side effects and may represent a future treatment modality for at least a fraction of HSCT-recipients.

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.

Therapy for steroid-refractory (SR) acute graft-versus-host disease (aGVHD) involves intensive immunosuppression, which is associated with significant risk of infection. Extracorporeal photopheresis (ECP) is used to treat SR-aGVHD and is considered more immunomodulatory than immunosuppressive. However, pediatric data are mostly retrospective and often involve multistep ECP that includes apheresis followed by separate photosensitizing/reinfusion on another device. This study aimed to prospectively evaluate the efficacy and safety of a single-device ECP system in children with SR-aGVHD. In this open-label multicenter phase 3 study of the Therakos CellEx Photopheresis System in children/young adults age 1 to 21 years with SR-aGVHD. Patients were treated 3 times per week for 4 weeks, then twice weekly through week 12 while maintaining standard aGVHD prophylaxis. The primary efficacy endpoint was the proportion of patients achieving an overall response (OR) at day +28 without the addition of next-line systemic treatment. Secondary endpoints included the proportion of patients achieving OR at weeks 8 and 12; the mean weekly steroid dose at weeks 4, 8, and 12; and treatment-emergent adverse events (TEAEs). Twenty-nine children (median age, 8 years) were enrolled. OR was 55% by day 28, 74% by week 8, and 79% by week 12. Progressive improvements were observed in the skin and the gastrointestinal tract. The mean steroid dose was decreased from 1.54 mg/kg/day at baseline to 0.90 mg/kg/day at week 4; 35% of patients achieved a50% steroid dose reduction by week 4, and 75% achieved a50% steroid dose reduction by week 12. Of the 168 TEAEs reported among 25 patients (86%), 28 events (17%) were infections and 14 events (8%) were considered likely treatment related (all nonserious). Of 627 ECP treatments administered in children and young adults, 68% required blood priming. TEAEs related to Uvadex or ECP were rare, hypocalcemia was the most common (3 events total). Three deaths occurred and were deemed unrelated to ECP by the investigators. Use of the Therakos CellEx Photopheresis System was effective in children with SR-aGVHD, with more than one-half experiencing improvement by day 28 and further responses observed over 12 weeks. Very few TEAEs were attributable to ECP, and no new safety signals were observed.

Herein we review current practice regarding the management of chronic graft-vs.-host disease (cGvHD) in paediatric patients after allogeneic haematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukaemia (ALL). Topics covered include: (i) the epidemiology of cGvHD; (ii) an overview of advances in our understanding cGvHD pathogenesis; (iii) current knowledge regarding risk factors for cGvHD and prevention strategies complemented by biomarkers; (iii) the paediatric aspects of the 2014 National Institutes for Health-defined diagnosis and grading of cGvHD; and (iv) current options for cGvHD treatment. We cover topical therapy and newly approved tyrosine kinase inhibitors, emphasising the use of immunomodulatory approaches in the context of the delicate counterbalance between immunosuppression and immune reconstitution as well as risks of relapse and infectious complications. We examine real-world approaches of response assessment and tapering schedules of treatment. Furthermore, we report on the optimal timepoints for therapeutic interventions and changes in relation to immune reconstitution and risk of relapse/infection. Additionally, we review the different options for anti-infectious prophylaxis. Finally, we put forth a theory of a holistic view of paediatric cGvHD and its associated manifestations and propose a checklist for individualised risk evaluation with aggregated considerations including site-specific cGvHD evaluation with attention to each individual's GvHD history, previous medical history, comorbidities, and personal tolerance and psychosocial circumstances. To complement this checklist, we present a treatment algorithm using representative patients to inform the personalised management plans for patients with cGvHD after HSCT for ALL who are at high risk of relapse.

Thyroid disorders are well-studied after allogeneic haematopoietic stem cell transplantation (HSCT) following total body irradiation (TBI)-based conditioning, occurring in 15–30% of paediatric survivors. The toxic effect of TBI is known but data on the role of immunological dysregulation (ID) and chronic graft-versus-host-disease (cGvHD) are scarce. We studied functional and structural thyroid disorders in 97 paediatric ALL patients after TBI-based HSCT, assessing their correlation with patient/transplant characteristics including cGvHD, prolonged immunosuppression and ID. The 10- and 15-year cumulative incidence (CI) of functional disorders was 50 and 60%. Univariate analysis revealed TBI in 6 vs. 8 fractions (p = 0.01), an interval between ALL diagnosis and HSCT p = 0.038), and the application of ATG (p = 0.044) as risk factors. The 10- and 15-year CI of structural disorders was 60 and 80%. No correlation between patient/transplant characteristics and structural disorders was observed. cGvHD, prolonged immunosuppression and additional radiotherapy were not associated with any thyroid disease. We observed a significant correlation between ID and the development of thyroid dysfunction in patients with structural changes (10-year CI: 77% for patients with ID vs. 56% without ID, p = 0.02). The impact of our results on thyroid follow-up evaluations and the significance of hormonal replacement therapy are discussed.

Objectives: Chronic graft-versus-host disease (cGvHD) following haematopoietic stem cell transplantation (HSCT) shares many similarities with de novo autoimmune disorders, being associated with the presence of autoantibodies. However, data on the implication of autoantibodies in paediatric HSCT recipients are scarce. In this single-centre study of paediatric patients with acute lymphoblastic leukaemia (ALL) surviving longer than 3 months, our objectives were to evaluate autoantibody expression and investigate the correlation with cGvHD and immune reconstitution using serially monitored parameters.Methods: We investigated circulating autoantibodies together with cellular and humoral parameters [including major T- and B-cell subsets, natural killer (NK) cells, and immunoglobulin levels] in 440 samples from 74 patients (median age 10.9 years, range 2.7–22.2 years) serially during long-term follow-up of median 8 years (range 0.4–19.3 years). Evaluations comprised of patient and transplant characteristics, precisely reviewed details of National Institute of Health (NIH)-defined cGvHD, and outcome data such as relapse, overall survival (OS) and mortality. Analysis of these clinical parameters was performed to identify possible associations.Results: Autoantibodies were detected in 65% (48/74) of patients. Anti-nuclear antibodies were the most common, occurring in 75% (36/48) of patients with autoantibodies. When comparing demographic data and transplant characteristics, there were no significant differences between patients with and without autoantibody expression; 5-year OS was excellent, at 96.4 and 95.8%, respectively. Neither the expression of autoantibodies nor the occurrence of cGvHD correlated with significantly worse OS or relapse rate. Furthermore, there was no significant association between autoantibody profiles and the incidence, overall severity or organ involvement of cGvHD. Patients with autoantibodies showed significantly better immune reconstitution, with overall higher numbers of T cells, B cells, and serum immunoglobulins. In autoantibody-positive patients with cGvHD, autoantibody production positively correlated with the expansion of CD56+ NK cells (236.1 vs. 165.6 × 103 cells/mL, respectively; p = 0.023) and with signs of B-cell perturbation, such as higher CD21low B cells (23.8 vs. 11.8 × 103 cells/mL, respectively; p = 0.044) and a higher ratio of CD21low B cells/CD27+ memory B cells (1.7 vs. 0.4, respectively; p = 0.006) in comparison to autoantibody-positive patients without cGvHD. Furthermore, when assessing the correlation between autoantibody positivity and the activity of cGvHD at time of analysis, indicators of aberrant B-cell homeostasis were substantiated by a lower proportion of CD27+ memory B cells (9.1 vs. 14.9%, respectively; p = 0.028), a higher ratio of class-switched CD27+IgD−/CD27+ memory B cells (3.5 vs. 5.1%, respectively; p = 0.013), significantly elevated numbers of CD21low B cells (36.8 vs. 11.8 × 103 cells/mL, respectively; p = 0.013) and a higher ratio of CD21lowB cells/CD27+ memory B cells (2.4 vs. 0.4, respectively; p = 0.034) in the active vs. the no cGvHD group. We then assessed the potential role of autoantibody expression in the context of elevated CD19+CD21low B cells (cutoff >7%), a well-known marker of cGvHD. Surprisingly we found a significant higher proportion of those cases where elevated CD21low B cells correlated with active cGvHD in samples from the autoantibody-negative group vs. the antibody-positive group (82 vs. 47%, respectively; p = 0.0053).When comparing immune parameters of the large proportion of survivors (89%) with the small proportion of non-survivors (11%), data revealed normalisation within the B-cell compartment of survivors: there were increased numbers of CD27+ memory B cells (54.9 vs. 30.6 × 103 cells/mL, respectively; p = 0.05), class-switched CD27+IgD− B cells (21.2 vs. 5.0 × 103 cells/mL, respectively; p < 0.0001), and immunoglobulin G4 (40.9 vs. 19.4 mg/dL, respectively; p < 0.0001). Overall mortality was significantly associated with an elevated proportion of CD21low B cells (13.4 vs. 8.8%, respectively; p = 0.039) and CD56+ NK cells (238.8 vs. 314.1 × 103 cells/mL, respectively; p = 0.019). In multivariate analysis, better OS was significantly associated with lower numbers of CD56+ NK cells [hazard ratio (HR) 0.98, p = 0.041] and higher numbers of CD27+ memory B cells [(HR) 1.62, p = 0.014].Conclusion: Our data shows that autoantibody profiles are not suitable biomarkers for diagnosing cGvHD in children or for predicting cGvHD severity, disease course and outcome. We identified a number of indicators of aberrant immune homeostasis associated with active cGvHD in paediatric ALL patients after HSCT. These findings confirm published results and suggest that candidate B cell subpopulations may serve as a surrogate measure for characterisation of cGvHD in paediatric HSCT for malignant diseases, and warrants confirmation in larger, multicentre studies.

Chronic graft versus host disease (cGVHD) affects patients after allogeneic hematopoietic stem cell transplantation (alloHSCT). This orphan disease poses a challenge for clinicians and researchers. The purpose of the cGVHD Dictionary is to provide a standardized structure for cGVHD databases on an international level, reconciling differences in data retrieval and facilitate database merging. It is derived from several consensus meetings of the EUROGRAFT consortium (European Cooperation in Science and Technology-COST Action CA17138) followed by a consensus process involving European Society for Blood and Marrow Transplantation (EBMT), US GvHD consortium and Center for International Bone Marrow Transplant Registry (CIBMTR). Databases used for the dictionary were: the National Institutes of Health (NIH) database, the Center for International Blood and Marrow Transplant Research, Applying Biomarkers to Minimize Long Term Effects of Childhood/Adolescent Cancer Treatment - Pediatric Blood and Marrow Transplant Consortium database, EBMT registry, the German-Austrian-Swiss GvHD registry, Italian Blood and Marrow Transplantation Society registry and Regensburg-Göttingen-Newcastle HSCT dataset. A four-part cGVHD Dictionary was formed based on the databases, consensus, and evidence in the literature. The Dictionary is divided into: (1) Patient characteristics, (2) Transplant characteristics, (3) cGVHD characteristics and (4) patient-reported quality of life, symptom burden and functional indicators.

Pediatric allogeneic hematopoietic cell transplantation (HCT) practices differ from those of adults, particularly the heterogeneity of transplantable nonmalignant diseases and the lower incidence of graft-versus-host disease (GVHD). Several guidelines regarding the management of acute (a) GVHD in adult HCT have been published. We aimed to capture the real-life approaches for pediatric aGVHD prophylaxis/treatment, and data from 75/193 (response rate 39%) EBMT centers (26 countries) were included, representing half (48%) of the pediatric EBMT-HCT activity. Results with >= 75% approval from respondents (74/75) for GVHD prophylaxis after myeloablative HCT for malignancies partially contradict published guidelines: Single-agent cyclosporine A (CsA) was used for matched sibling donor HCT in 47%; blood CsA levels were reported lower; the relapse risk in malignant diseases influenced GVHD prophylaxis with early withdrawal of CsA; distinct longer duration of CsA was employed in nonmalignant diseases. Most centers used additional anti-thymocyte globulin for matched unrelated and mismatched donor HCT, but not for matched siblings. Regarding prophylaxis in nonmyeloablative conditioning (mainly for nonmalignant diseases), responses showed broad heterogeneity. High conformity was found for first-line treatment; however, results regarding steroid-refractory aGVHD indicate an earlier diagnosis in children. Our findings highlight the need for standardized pediatric approaches toward aGVHD prophylaxis/treatment differentiated for malignant and nonmalignant underlying diseases.

Sickle cell disease is one of the most common, life-threatening, non-communicable diseases in the world and a major public health problem. Following the implementation of simple preventive and therapeutic modalities, infant mortality has almost been abolished in high-income countries, but only a small amount of progress has been made in improving survival in adulthood. Progressive end-organ damage, partly related to a systemic vasculopathy, is increasingly recognised. With the availability of a variety of novel disease-modifying drugs, gene addition and gene editing strategies, matched sibling donor haematopoietic stem cell transplantation (HSCT) in children (offering an overall survival rate of 95% and an event-free survival rate of 92%), and encouraging outcomes after alternative donor HSCT, the new challenge is to risk stratify patients, revise transplantation indications, and define the best therapeutic approach for each patient. The ultimate challenge will be to enable these advances in low-income and middle-income countries, where disease prevalence is highest and where innovative strategies are most needed.

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