In the setting of hematopoietic stem cell transplantation (HSCT), Rituximab (RTX) is used for the treatment and prevention of EBV-associated post-transplantation lymphoproliferative disease or... Show moreIn the setting of hematopoietic stem cell transplantation (HSCT), Rituximab (RTX) is used for the treatment and prevention of EBV-associated post-transplantation lymphoproliferative disease or autoimmune phenomena such as autoimmune hemolytic anemia (AIHA). Persistent hypogammaglobulinemia and immunoglobulin substitution dependence has been observed in several patients after RTX treatment despite the normalization of total B cell numbers. We aimed to study whether this is a B cell intrinsic phenomenon. We analyzed four patients with different primary diseases who were treated with myeloablative conditioning and matched unrelated donor HSCT who developed persistent hypogammaglobulinemia after receiving RTX treatment. They all received RTX early after HSCT to treat EBV infection or AIHA post-HSCT. All patients showed normalized total B cell numbers but absent to very low IgG positive memory B cells, and three lacked IgA positive memory B cells. All of the patients had full donor chimerism, and none had encountered graft-versus-host disease. Sorted peripheral blood naive B cells from these patients, when stimulated with CD40L, IL21, IL10 and anti-IgM, demonstrated intact B cell differentiation including the formation of class-switched memory B cells and IgA and IgG production. Peripheral blood T cell numbers including CD4 follicular T-helper (Tfh) cells were all within the normal reference range. In conclusion, in these four HSCT patients, the persistent hypogammaglobulinemia observed after RTX cannot be attributed to an acquired intrinsic B cell problem nor to a reduction in Tfh cell numbers. Show less
Bense, J.E.; Stiggelbout, A.M.; Lankester, A.C.; Pagter, A.P.J. de 2023
BackgroundSurvival rates have continued to increase for pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. Despite the crucial role of caregivers in this high... Show moreBackgroundSurvival rates have continued to increase for pediatric hematopoietic stem cell transplantation (HSCT) for nonmalignant diseases. Despite the crucial role of caregivers in this high-intensity treatment, knowledge about long-term parental impact is lacking.ProcedureThis cross-sectional study assessed parental distress and everyday problems in parents of patients 2 years and older after pediatric HSCT for a nonmalignant disease using Distress Thermometer for Parents (DT-P), and compared outcomes to matched Dutch parents of healthy children and Dutch parents of children with a chronic condition (CC).ResultsMedian follow-up was 5.3 years (interquartile range [IQR]: 2.9-8.6). Underlying diseases were inborn errors of immunity (N = 30), hemoglobinopathies (N = 13), and bone marrow failure (N = 27). Mothers of pediatric HSCT recipients (N = 70) reported comparable overall distress levels to mothers of healthy children, but experienced more distress related to parenting problems, specifically managing their child's emotions, discussing disease consequences, and fostering independence. Fathers of HSCT recipients (N = 45) reported higher overall distress levels and had more emotional distress compared to fathers of healthy children.ConclusionsOverall, parental distress and everyday problems of parents of HSCT recipients are comparable to those of parents of children with CC. However, there is ongoing parental burden, both emotional and in parenting, long-term after HSCT compared to parents of healthy children, and the type of burden differs between mothers and fathers. These results indicate that individualized parental supportive care should not remain restricted to the acute hospitalization phase, but also be actively offered during long-term follow-up after pediatric HSCT. Show less
Lebbink, C.A.; Bresters, D.; Tersteeg, J.P.B.; Bos, C. van den; Dierselhuis, M.P.; Lentjes, E.G.W.M.; ... ; Santen, H.M. van 2023
Background Thyroid dysfunction (hypo- and hyperthyroidism) has been reported as a late effect after hematopoietic stem cell transplantation (HSCT) in children. Short-term effects of HSCT on thyroid... Show moreBackground Thyroid dysfunction (hypo- and hyperthyroidism) has been reported as a late effect after hematopoietic stem cell transplantation (HSCT) in children. Short-term effects of HSCT on thyroid function parameters are, however, unclear. Methods We prospectively evaluated thyroid function parameters before and 3 months after HSCT in all children (<21 years) who underwent HSCT during a 2-year period in the Princess Maxima Center, the Netherlands. Results Among 72 children, none had thyroidal hypothyroidism or hyperthyroidism 3 months after HSCT. Changes in thyroid function parameters (either aberrant thyroid-stimulating hormone [TSH] or free thyroxine [FT4] concentrations) were found in 16% before and in 10% 3 months after HSCT. Reverse triiodothyronine (rT3) was found elevated in 9.3% before and in 37% 3 months after HSCT, which could be related to poor physical condition. An individual decline in FT4 concentration of & GE;20% was found in 10.5% (6/57) 3 months after HSCT. Conclusion In conclusion, thyroidal hypo- and hyperthyroidism are very rare 3 months after HSCT. These results indicate that surveillance for hypo- and hyperthyroidism may start later in time. The changes in thyroid function parameters found 3 months after HSCT might reflect euthyroid sick syndrome. Show less
The first successful European hematopoietic stem cell transplantation (HSCT) was performed in 1968 as treatment in a newborn with IL2RG deficiency using an HLA-identical sibling donor. Because of... Show moreThe first successful European hematopoietic stem cell transplantation (HSCT) was performed in 1968 as treatment in a newborn with IL2RG deficiency using an HLA-identical sibling donor. Because of declining naive T and natural killer (NK) cells, and persistent human papilloma virus (HPV)-induced warts, the patient received a peripheral stem cell boost at the age of 37 years. NK and T cells were assessed before and up to 14 years after the boost by flow cytometry. The boost induced renewed reconstitution of functional NK cells that were 14 years later enriched for CD56(dim)CD27(+) NK cells. T-cell phenotype and T-cell receptor (TCR) repertoire were simultaneously analyzed by including TCR V beta antibodies in the cytometry panel. Naive T-cell numbers with a diverse TCR V beta repertoire were increased by the boost. Before and after the boost, clonal expansions with a homogeneous TIGIT and PD-1 phenotype were identified in the CD27(-) and/or CD28(-) memory population in the patient, but not in the donor. TRB sequencing was applied on sorted T-cell subsets from blood and on T cells from skin biopsies. Abundant circulating CD8 memory clonotypes with a chronic virus-associated CD57(+)KLRG1(+)CX3CR1(+) phenotype were also present in warts, but not in healthy skin of the patient, suggesting a link with HPV. In conclusion, we demonstrate in this IL2RG-deficient patient functional NK cells, a diverse and lasting naive T-cell compartment, supported by a stem cell boost, and an oligoclonal memory compartment half a century after HSCT. Show less
Benchmarking is commonly used in many healthcare settings to monitor clinical performance, with the aim of increasing cost-effectiveness and safe care of patients. The funnel plot is a popular tool... Show moreBenchmarking is commonly used in many healthcare settings to monitor clinical performance, with the aim of increasing cost-effectiveness and safe care of patients. The funnel plot is a popular tool in visualizing the performance of a healthcare center in relation to other centers and to a target, taking into account statistical uncertainty. In this paper, we develop a methodology for constructing funnel plots for survival data. The method takes into account censoring and can deal with differences in censoring distributions across centers. Practical issues in implementing the methodology are discussed, particularly in the setting of benchmarking clinical outcomes for hematopoietic stem cell transplantation. A simulation study is performed to assess the performance of the funnel plots under several scenarios. Our methodology is illustrated using data from the European Society for Blood and Marrow Transplantation benchmarking project. Show less
Schetelig, J.; Baldauf, H.; Koster, L.; Kuxhausen, M.; Heidenreich, F.; Wreede, L.C. de; ... ; Robin, M. 2021
Hematopoietic stem cell transplantation decision-making for hemoglobinopathy patients is a complex process, and it remains difficult for health care professionals to decide whether and when a... Show moreHematopoietic stem cell transplantation decision-making for hemoglobinopathy patients is a complex process, and it remains difficult for health care professionals to decide whether and when a hematopoietic stem cell transplantation should be offered. Gaining insight into health care professionals' considerations is required to understand and optimize this decision-making process. A qualitative interview study using semi-structured interviews with eighteen health care professionals. Data were thematically analyzed. Two main themes emerged from the data: (1) Experiencing the influence of a frame of reference and (2) Feeling responsible for a guided decision-making. The frame of reference, meaning the health care professionals' knowledge and experiences regarding hematopoietic stem cell transplantation, influenced the guided decision-making process. Subsequently, three subthemes evolved from the second theme: (a) weighing up disease severity against possible complications, (b) making an effort to inform, and (c) supporting the best fitting decision for the individual patient. The health care professionals' frame of reference determined the hematopoietic stem cell transplantation decision-making process. This demands reflection on the health care professionals' own frame of reference and its influence on decision-making. Furthermore, reflection on the frame of reference is needed by exchange of knowledge and experiences between referring and referred-to healthcare professionals in an open and two-way direction. The transplantation teams have a responsibility of keeping the frame of reference of their referring colleagues up to date and referring health care professionals should share their feelings regarding hematopoietic stem cell transplantation. To guide patients, a shared decision-making approach is supportive, in which eliciting the patients' preferences is highly important. Health care professionals can refine the decision-making process by guiding patients in eliciting their preferences and including these in the decision. Show less
Hematopoietic stem cell transplantation (HSCT) is widely used in pediatric patients as a successful curative therapy for life-threatening conditions. The treatment is intensive, with risks of... Show moreHematopoietic stem cell transplantation (HSCT) is widely used in pediatric patients as a successful curative therapy for life-threatening conditions. The treatment is intensive, with risks of serious complications and lethal outcomes. This study aimed to provide insight into current data on the place and cause of death of transplanted children, the available specialized pediatric palliative care services (SPPCS), and what services HSCT professionals feel the SPPCS team should provide. First, a retrospective database analysis on the place and cause of death of transplanted pediatric HSCT patients was performed. Second, a survey was performed addressing the availability of and views on SPPCS among HSCT professionals. Database analysis included 233 patients of whom the majority died in-hospital: 38% in the pediatric intensive care unit, 20% in HSCT units, 17% in other hospitals, and 14% at home or in a hospice (11% unknown). For the survey, 98 HSCT professionals from 54 centers participated. Nearly all professionals indicated that HSCT patients should have access to SPPCS, especially for pain management, but less than half routinely referred to this service at an early stage. We, therefore, advise HSCT teams to integrate advance care planning for pediatric HSCT patients actively, ideally from diagnosis, to ensure timely SPPCS involvement and maximize end-of-life preparation. Show less
Maas, N.G. van der; Asmuth, E.G.J. von; Berghuis, D.; Schouwenburg, P.A. van; Putter, H.; Burg, M. van der; Lankester, A.C. 2021
Reduced total and memory B-cell numbers in peripheral blood long term after hematopoietic stem cell transplantation (HSCT) are associated with an increased incidence of infections and immune... Show moreReduced total and memory B-cell numbers in peripheral blood long term after hematopoietic stem cell transplantation (HSCT) are associated with an increased incidence of infections and immune complications. Using novel modelling strategies, baseline factors influencing B-cell reconstitution can be comprehensively studied. This study aims to investigate the numerical total and memory B-cell reconstitution in children and the association with baseline determinants 0.5-2 years after allogeneic HSCT. Eligible for inclusion were children transplanted in our center between 2004-2017 who received a first HSCT for malignant or non-malignant disorders. The continuous absolute counts of total and memory B-cells were evaluated as outcome measure. Exploratory analysis at one year was done to identify possible determinants. Linear mixed effect modelling was used to analyze the association of these determinants with total and memory B-cell reconstitution 0.5-2 years after HSCT. In a cohort of 223 evaluable patients analyzed at 1-year after HSCT donor age, stem cell source, donor type, recipient age and conditioning were identified as significant determinants for total and memory B-cell numbers. Multivariable analysis revealed that both donor and recipient age were inversely correlated with the size of total and memory B-cell reconstitution. In contrast, no correlation was found with stem cell source, donor type and conditioning. Making use of linear mixed modelling both stem cell donor and recipient age were identified as independent determinants of total and memory B-cell reconstitution 0.5-2 years after HSCT. Show less
Schetelig, J.; Baldauf, H.; Koster, L.; Kuxhausen, M.; Heidenreich, F.; Wreede, L.C. de; ... ; Robin, M. 2021
Results from registry studies suggest that harnessing Natural Killer (NK) cell reactivity mediated through Killer cell Immunoglobulin-like Receptors (KIR) could reduce the risk of relapse after... Show moreResults from registry studies suggest that harnessing Natural Killer (NK) cell reactivity mediated through Killer cell Immunoglobulin-like Receptors (KIR) could reduce the risk of relapse after allogeneic Hematopoietic Cell Transplantation (HCT). Several competing models have been developed to classify donors as KIR-advantageous or disadvantageous. Basically, these models differ by grouping donors based on distinct KIR-KIR-ligand combinations or by haplotype motif assignment. This study aimed to validate different models for unrelated donor selection for patients with Myelodysplatic Syndromes (MDS) or secondary Acute Myeloid Leukemia (sAML). In a joint retrospective study of the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) registry data from 1704 patients with secondary AML or MDS were analysed. The cohort consisted mainly of older patients (median age 61 years) with high risk disease who had received chemotherapy-based reduced intensity conditioning and anti-thymocyte globulin prior to allogeneic HCT from well-matched unrelated stem cell donors. The impact of the predictors on Overall Survival (OS) and relapse incidence was tested in Cox regression models adjusted for patient age, a modified disease risk index, performance status, donor age, HLA-match, sex-match, CMV-match, conditioning intensity, type of T-cell depletion and graft type. KIR genes were typed using high-resolution amplicon-based next generation sequencing. In univariable and multivariable analyses none of the models predicted OS and the risk of relapse consistently. Our results do not support the hypothesis that optimizing NK-mediated alloreactivity is possible by KIR-genotype informed selection of HLA-matched unrelated donors. However, in the context of allogeneic transplantation, NK-cell biology is complex and only partly understood. KIR-genes are highly diverse and current assignment of haplotype motifs based on the presence or absence of selected KIR genes is over-simplistic. As a consequence, further research is highly warranted and should integrate cutting edge knowledge on KIR genetics, and NK-cell biology into future studies focused on homogeneous groups of patients and treatment modalities. Show less
Objectives:To gain insight into the experiences of patients with diffuse cutaneous systemic sclerosis during and after autologous hematopoietic stem cell transplantation.Methods:Semi-structured... Show moreObjectives:To gain insight into the experiences of patients with diffuse cutaneous systemic sclerosis during and after autologous hematopoietic stem cell transplantation.Methods:Semi-structured interviews were conducted with patients who underwent hematopoietic stem cell transplantation in four university hospitals in the Netherlands. Interviews were transcribed verbatim and thematically analyzed.Results:Nine male and seven female patients were interviewed, median age 47 years (range: 27-68). Patients mentioned their life was severely disrupted before hematopoietic stem cell transplantation and remained unsettled a long time after treatment. Uncertainty because of disease progression, loss of control over health and the sense of time and fear of treatment-related adverse events were common during hospitalization. After hematopoietic stem cell transplantation, patients experienced more physical limitations than they had expected, and recovery took longer and was mentally taxing. Going back to work and finding a new balance in personal relations and social life was complicated. Patients described various strategies to deal with challenges. Family and friends provided essential support, although many experienced a dwindling social circle. Most patients also appreciated peer support. All patients were satisfied with the low threshold for contact with physicians and nurses during hospitalization. However, aftercare focused on medical aspects rather than on psychological well-being and social issues. Moreover, patients would have preferred to be better prepared on what to expect after discharge, and lacked information about self-management, prognosis, optimal recovery, work, sexuality, and family planning.Conclusion:Hematopoietic stem cell transplantation has a major physical and psychological impact on patients with diffuse cutaneous systemic sclerosis. The course of recovery after this intensive therapy was unexpectedly long for some patients and offer of support was far less pro-active post-HSCT compared to pre-HSCT and during HSCT. Show less
Background: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but... Show moreBackground: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant.Objective: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant.Method: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices.Results: Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome.Conclusion: The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT. Show less
Background In pediatric hematopoietic stem cell transplantation (HSCT), the end-of-life (EOL) phase and the loss of the child is often characterized by a sudden deterioration of the child following... Show moreBackground In pediatric hematopoietic stem cell transplantation (HSCT), the end-of-life (EOL) phase and the loss of the child is often characterized by a sudden deterioration of the child following a period of intensive curative treatment. This demands a fast transition for parents. Therefore, an understanding of the parents' perspective on decision-making in such a complex situation is needed. This study aims to gain insight in parental experiences in EOL decision-making in allogeneic pediatric HSCT.Methods A qualitative descriptive study was performed among parents of eight families. Data were thematically analyzed.Results All parents were aware of their child's deterioration. Six families were confronted with a rapid deterioration, while two families experienced a gradual realization that their child would not survive. Parental EOL decision-making in pediatric HSCT shows a reflective perspective on the meaning of parenthood in EOL decision-making. Two central themes were identified: "survival-oriented decision-making" and "struggling with doubts in hindsight." Six subthemes within the first theme described the parents' goal of doing everything to achieve survival.Discussion Parents experienced EOL decision-making mainly as a process guided by health care professionals (HCPs) based on the child's condition and treatment possibilities. The decision-making is characterized by following opportunities and focusing on hope for cure. In hindsight parents experienced doubts about treatment steps and their child's suffering. HCPs can strengthen the parental role by an early integration of palliative care, providing timely support to parents in the process of imminent loss. Advance care planning can be used to support communication processes, defining preferences for future care. Show less
HLA expression levels have been suggested to be genetically controlled by single nucleotide polymorphisms (SNP) in the untranslated regions (UTR), and expression variants have been associated with... Show moreHLA expression levels have been suggested to be genetically controlled by single nucleotide polymorphisms (SNP) in the untranslated regions (UTR), and expression variants have been associated with the outcome of chronic viral infection and hematopoietic stem cell transplantation (HSCT). In particular, the 3'UTR rs9277534-G/A SNP in HLA-DPB1 has been associated with graft-versus-host-disease after HSCT (Expression model); however its relevance in different immune cells and its mode of action have not been systematically addressed. In addition, there is a strong though not complete overlap between the rs9277534-G/A SNP and structural HLA-DPB1 T cell epitope (TCE) groups which have also been associated with HSCT outcome (TCE Structural model). Here we confirm and extend previous findings of significantly higher HLA-DPB1 expression in B cell lines, unstimulated primary B cells, and monocytes homozygous for rs9277534-G compared to those homozygous for rs9277534-A. However, these differences were abrogated by interferon-g stimulation or differentiation into dendritic cells. We identify at least seven 3'UTR rs9277534-G/A haplotypes differing by a total of 37 SNP, also characterized by linkage to length variants of a short tandem repeat (STR) in intron 2 and TCE group assignment. 3'UTR mapping did not show any significant differences in post-transcriptional regulation assessed by luciferase assays between two representative rs9277534-G/A haplotypes for any of eight overlapping fragments. Moreover, no evidence for alternative splicing associated with the intron 2 STR was obtained by RT-PCR. In an exemplary cohort of 379 HLA-DPB1 mismatched donor-recipient pairs, risk prediction by the Expression model and the Structural TCE model was 36.7% concordant, with the majority of discordances due to non-applicability of the Expression model. HLA-DPB1 from different TCE groups expressed in the absence of the 3'UTR at similar levels by transfected HeLa cells elicited significantly different mean alloreactive CD4+ T-cell responses, as assessed by CD137 upregulation assays in 178 independent cultures. Taken together, our data provide new insights into the cell type-specific and mechanistic basis of the association between the rs9277534-G/A SNP and HLA-DPB1 expression, and show that, despite partial overlap between both models in HSCT risk-prediction, differential alloreactivity determined by the TCE structural model occurs independently from HLA-DPB1 differential expression. Show less
Meurer, T.; Arrieta-Bolanos, E.; Metzing, M.; Langer, M.M.; Balen, P. van; Falkenburg, J.H.F.; ... ; Crivello, P. 2018
