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Numbers of Hematopoietic cell transplantation (HCT) in Europe and collaborating countries continues to rise with 48,512 HCT in 43,581 patients, comprising of 19,798 (41%) allogeneic and 28,714 (59%) autologous, reported by 700 centers in 51 countries during 2019. Main indications were myeloid malignancies 10,764 (25%), lymphoid malignancies 27,895 (64%), and nonmalignant disorders 3173 (7%). A marked growth in CAR-T cellular therapies from 151 in 2017 to 1134 patients in 2019 is observed. This year’s analyses focus on changes over 30 years. Since the first survey in 1990 where 143 centers reported 4234 HCT, the number has increased to 700 centers and 48,512 HCT. Transplants were reported in 20 countries in 1990, and 51, 30 years later. More than 800,000 HCT in 715,000 patients were reported overall. Next to the massive expansion of HCT technology, most notable developments include the success of unrelated donor and haploidentical HCT, an increase followed by decrease in the number of cord blood transplants, use of reduced intensity HCT in older patients, and the phenomenal rise in cellular therapy. This annual report of the European Society for Blood and Marrow Transplantation (EBMT) reflects current activity and highlights important trends vital for health care planning.

The hypothesis that elimination of facultative and strict anaerobic microorganisms from the gastro-intestinal tract by antimicrobial drugs in the period of time around allogeneic bone marrow transplantation (BMT) prevents acute graft-versus-host disease (GVHD), was examined in a cohort of 112 children grafted between 1989 and 2002 for hematological malignancies. All patients received T-cell replete marrow from human leukocyte antigens (HLA) matched sibling donors under identical transplantation conditions. To eliminate microorganisms from the gastro-intestinal tract, total gastro-intestinal decontamination (GID) was applied by high doses of non-absorbable antimicrobial drugs while the graft recipient was maintained in strict protective isolation. About half of the children (51%) proved to be successfully decontaminated, and about half (49%) unsuccessfully. One recipient got acute GVHD in the first group and 8 in the second group (p = 0.013). The degree of success of total GID was decisive for the occurrence of acute GVHD, irrespective of the presence of other risk factors such as higher age of recipient and/or donor, female donor for male recipient and carriership or reactivation of herpesviruses. Our results demonstrate that successful total GID of the graft recipient prevents moderate to severe acute GVHD. We suppose that substantial translocation of gastro-intestinal microorganisms or parts of these, functioning as microbial-associated molecular patterns (MAMP's), triggering macrophages/dendritic cells via pattern recognizing receptors (PRR's) is prohibited. As a consequence the initiation and progression of an inflammatory process leading to acute GVHD is inhibited.

B cell reconstitution after hematopoietic stem cell transplantation (HSCT) is variable and influenced by different patient, donor, and treatment related factors. In this review we describe B cell reconstitution after pediatric allogeneic HST, including the kinetics of reconstitution of the different B cell subsets and the development of the B cell repertoire, and discuss the influencing factors. Observational studies show important roles for stem cell source, conditioning regimen, and graft vs. host disease in B cell reconstitution. In addition, B cell recovery can play an important role in post-transplant infections and vaccine responses to encapsulated bacteria, such as pneumococcus. A substantial number of patients experience impaired B cell function and/or dependency on Ig substitution after allogeneic HSCT. The underlying mechanisms are largely unresolved. The integrated aspects of B cell recovery after HSCT, especially BCR repertoire reconstitution, are awaiting further investigation using modern techniques in order to gain more insight into B cell reconstitution and to develop strategies to improve humoral immunity after allogeneic HSCT.

Enhancing the intracellular delivery and performance of RNA-guided CRISPR-Cas9 nucleases (RGNs) remains in demand. Here, we show that nuclear translocation of commonly used Streptococcus pyogenes Cas9 (SpCas9) proteins is suboptimal. Hence, we generated eCas9.4NLS by endowing the high-specificity eSpCas9(1.1) nuclease (eCas9.2NLS) with additional nuclear localization signals (NLSs). We demonstrate that eCas9.4NLS coupled to prototypic or optimized guide RNAs achieves efficient targeted DNA cleavage and probe the performance of SpCas9 proteins with different NLS compositions at target sequences embedded in heterochromatin versus euchromatin. Moreover, after adenoviral vector (AdV)-mediated transfer of SpCas9 expression units, unbiased quantitative immunofluorescence microscopy revealed 2.3-fold higher eCas9.4NLS nuclear enrichment levels than those observed for high-specificity eCas9.2NLS. This improved nuclear translocation yielded in turn robust gene editing after nonhomologous end joining repair of targeted double-stranded DNA breaks. In particular, AdV delivery of eCas9.4NLS into muscle progenitor cells resulted in significantly higher editing frequencies at defective DMD alleles causing Duchenne muscular dystrophy (DMD) than those achieved by AdVs encoding the parental, eCas9.2NLS, protein. In conclusion, this work provides a strong rationale for integrating viral vector and optimized gene-editing technologies to bring about enhanced RGN delivery and performance.

Hematopoietic stem cell transplantation is a high-risk procedure. Auditing and yearly outcome reviews help keep optimal quality of care and come with increased survival, but also has significant recurring costs. When data has been entered in a standardized registry, outcome analyses can be automated, which reduces work and increases standardization of performed analyses. To achieve this, we created the Yearly Outcome Review Tool (YORT), an offline, graphical tool that gets data from a single center EBMT registry export, allows the user to define filters and groups, and performs standardized analyses for overall survival, event-free survival, engraftment, relapse rate and non-relapse mortality, complications including acute and chronic Graft vs Host Disease (GvHD), and data completeness. YORT allows users to export data as analyzed to allow you to check data and perform manual analyses. We show the use of this tool on a two-year single-center pediatric cohort, demonstrating how the results for both overall and event-free survival and engraftment can be visualized. The current work demonstrates that using registry data, standardized tools can be made to analyze this data, which allows users to perform outcome reviews for local and accreditation purposes graphically with minimal effort, and help perform detailed standardized analyses. The tool is extensible to be able to accommodate future changes in outcome review and center-specific extensions.

Background and Objective Alemtuzumab (Campath ® ) is used to prevent graft-versus-host disease and graft failure following pediatric allogeneic hematopoietic cell transplantation. The main toxicity includes delayed immune reconstitution, subsequent viral reactivations, and leukemia relapse. Exposure to alemtuzumab is highly variable upon empirical milligram/kilogram dosing. Methods A population pharmacokinetic (PK) model for alemtuzumab was developed based on a total of 1146 concentration samples from 206 patients, aged 0.2–19 years, receiving a cumulative intravenous dose of 0.2–1.5 mg/kg, and treated between 2003 and 2015 in two centers. Results Alemtuzumab PK were best described using a two-compartment model with a parallel saturable and linear elimination pathway. The linear clearance pathway, central volume of distribution, and intercompartmental distribution increased with body weight. Blood lymphocyte counts, a potential substrate for alemtuzumab, did not impact clearance. Conclusion The current practice with uniform milligram/kilogram doses leads to highly variable exposures in children due to the non-linear relationship between body weight and alemtuzumab PK. This model may be used for individualized dosing of alemtuzumab.

Anti-thymocyte globulin (ATG) is a lymphocyte depleting agent applied in hematopoietic stem cell transplantation (HSCT) to prevent rejection and Graft-vs.-Host Disease (GvHD). In this study, we compared two rabbit ATG products, ATG-Genzyme (ATG-GENZ), and ATG-Fresenius (ATG-FRES), with respect to dosing, clearance of the active lymphocyte binding component, post-HSCT immune reconstitution and clinical outcome. Fifty-eigth pediatric acute leukemia patients ( = 42 ATG-GENZ, = 16 ATG-FRES), who received a non-depleted bone marrow or peripheral blood stem cell graft from an unrelated donor were included. ATG-GENZ was given at a dosage of 6-10 mg/kg; ATG-FRES at 45-60 mg/kg. The active component of ATG from both products was cleared at different rates. Within the ATG-FRES dose range no differences were found in clearance of active ATG or T-cell re-appearance. However, the high dosage of ATG-GENZ (10 mg/kg), in contrast to the low dosage (6-8 mg/kg), correlated with prolonged persistence of active ATG and delayed T-cell reconstitution. Occurrence of serious acute GvHD (grade III-IV) was highest in the ATG-GENZ-low dosage group. These results imply that dosing of ATG-GENZ is more critical than dosing of ATG-FRES due to the difference in clearance of active ATG. This should be taken into account when designing clinical protocols.

Patients with inborn errors of immunity or DNA repair defects are at significant risk of developing malignancy and this complication of their underlying condition represents a substantial cause of morbidity and mortality. Whilst this risk is increasingly well-recognized, our understanding of the causative mechanisms remains incomplete. Diagnosing cancer is challenging in the presence of underlying co-morbidities and frequently other inflammatory and lymphoproliferative processes. We lack a structured approach to management despite recognizing the competing challenges of poor response to therapy and increased risk of toxicity. Finally, clinicians need guidance on how to screen for malignancy in many of these predisposing immunodeficiencies. In order to begin to address these challenges, we brought together representatives of European Immunology and Pediatric Haemato-Oncology to define the current state of our knowledge and identify priorities for clinical and research development. We propose key developmental priorities which our two communities will need to work together to address, collaborating with colleagues around the world.

In most patients with aplastic anemia (AA), the diagnosis is limited to a description of the symptoms. Lack of understanding of the underlying pathophysiological mechanisms causing bone marrow failure (BMF), hampers tailored treatment. In these patients, auto-immune cell-mediated destruction of the bone marrow is often presumed to be the causative mechanism. The status of the bone marrow microenvironment, particularly the mesenchymal stromal cell (MSC) component, was recently suggested as a potential player in the pathophysiology of AA. Therefore, functional, and immune modulatory characteristics of bone marrow MSCs might represent important parameters for AA. To conduct a systematic review to evaluate functional properties of MSCs derived from patients with AA compared to healthy controls. According to PRISMA guidelines, a comprehensive search strategy was performed by using online databases (Pubmed, ISI Web of Science, Embase, and the Cochrane Library). Studies reporting on phenotypical characterization, proliferation potential, differentiation capacity, immunomodulatory potential, and ability to support hematopoiesis were identified and screened using the Rayyan software tool. 23 articles were included in this systematic review, describing a total of 324 patients with AA and 285 controls. None of the studies identified a significant difference in expression of any MSC surface marker between both groups. However, AA-MSCs showed a decreased proliferation potential, an increased tendency to differentiate into the adipogenic lineage and decreased propensity towards osteogenic differentiation. Importantly, AA-MSCs show reduced capacity of immunosuppression and hematopoietic support in comparison to healthy controls. We conclude that there are indications for a contribution of MSCs in the pathophysiology of AA. However, the current evidence is of poor quality and requires better defined study populations in addition to a more robust methodology to study MSC biology at a cellular and molecular level. Future studies on bone marrow microenvironment should aim at elucidating the interaction between MSCs, hematopoietic stem cells (HSCs) and immune cells to identify impairments associated with/causing BMF in patients with AA.

Introduction The assessment of using patient‐reported outcomes (PROs) within comprehensive care follow‐up programmes, specifically focused on health screening, remains largely unexplored. PROs were implemented in our late effects and comprehensive care programme after paediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. The programme focuses solely on screening of physical and mental health and on discussing PROs during the consultation. Methods The primary method of this study was semistructured interviews to explore the perspective of both patients and healthcare providers' (HCP) on the use of PROs, which were thematically analyzed. Additionally, an explorative quantitative approach with patient‐reported experience measures (PREMS) was used, with a pretest–posttest design, to assess whether the use of PROs was accompanied by more patient‐centred care. Results From the patient‐interviews (N = 15) four themes were extracted: use of PROs (1) help to discuss topics; (2) make the patients feel understood; (3) create a moment of self‐reflection; and (4) make consultations more efficient. Pre‐ and postimplementation analysis of PREMs (N = 40) did not show significant differences in terms of patient‐centeredness. Conclusion Our results demonstrate the added value of integrating PROs for health screening purposes within the long‐term follow‐up programme after paediatric HSCT, as perceived by both patient and HCP. With the active use of PROs, patients are stimulated to consciously assess their health status. Patient Contribution This study included patients as participants. Caregivers were approached if patients were below a certain age. Additionally, preliminary results were shared with all patients (including nonparticipants) during a patient conference day.