Hematopoietic Stem Cell Transplantation for Primary Immunodeficiencies

The field of primary immunodeficiencies has pioneered many of the advances in haematopoietic stem cell transplantation and cellular therapies over the last 50 years. The first patients to demonstrate sustained benefit and prolonged cure from the primary genetic defect following allogeneic haematopoietic stem cell transplantation were patients with primary immunodeficiencies. Although primary immunodeficiency patients began the modern era of haematopoietic stem cell transplantation, the history is nevertheless short-in answer to the question "what is the long term outcome of patients transplanted for primary immunodeficiencies?" we often have to say that we do not know. We believe that most patients who undergo haematopoietic stem cell transplantation for primary immunodeficiencies should live a normal lifespan with a fully corrected immune system. We are now beginning to understanding long term outcomes, the relationship to the underlying genetic defect, age, and pre-morbid condition of the patient at time of transplantation, stem cell source and donor, and effect of pre-transplant cytoreductive chemotherapy conditioning. The long term consequences of post-transplant complications such as graft vs. host disease, veno-occlusive disease, or immune dysregulation are also being recognized. Additionally, some genetic defects have a systemic distribution, and we are learning the natural history of these defects once the immunodeficiency has been removed

Population pharmacokinetics of treosulfan in paediatric patients undergoing hematopoietic stem cell transplantation

Aims: Treosulfan is an alkylating agent increasingly used prior to haematopoietic stem cell transplantation. The aim of this study was to develop a population pharmacokinetic (PK) model of treosulfan in paediatric haematopoietic stem cell transplantation recipients and to explore the effect of potential covariates on treosulfan PK. Also, a limited sampling model (LSM) will be developed to accurately predict treosulfan exposure suitable for a therapeutic drug monitoring setting. Methods: In this multicentre study, 91 patients, receiving a total dose of 30, 36 or 42 g/m2 treosulfan, administered over 3 consecutive days, were enrolled. A population PK model was developed and demographic factors, as well as laboratory parameters, were included as potential covariates. In addition, a LSM was developed using data from 28 patients. Results: A 2-compartment model with first order elimination best described the data. Bodyweight with allometric scaling and maturation function were identified as significant predictors of treosulfan clearance. Treosulfan clearance reaches 90% of adult values at 4 postnatal years. A model-based dosing table is presented to target an exposure of 1650 mg*h/L (population median) for different weight and age groups. Samples taken at 1.5, 4 and 7 hours after start of infusion resulted in the best limited sampling strategy. Conclusions: This study provides a treosulfan population PK model in children and captures the developmental changes in clearance. A 3-point LSM allows for accurate and precise estimation of treosulfan exposure

Carbonyl compounds indoors in a changing climate

<p>Abstract</p> <p>Background</p> <p>Formic acid, acetic acid and formaldehyde are important compounds in the indoor environment because of the potential for these acids to degrade calcareous materials (shells, eggs, tiles and geological specimens), paper and corrode or tarnish metals, especially copper and lead. Carbonyl sulfide tarnishes both silver and copper encouraging the formation of surface sulfides.</p> <p>Results</p> <p>Carbonyls are evolved more quickly at higher temperatures likely in the Cartoon Gallery at Knole, an important historic house near Sevenoaks in Kent, England where the study is focused. There is a potential for higher concentrations to accumulate. However, it may well be that in warmer climates they will be depleted more rapidly if ventilation increases.</p> <p>Conclusions</p> <p>Carbonyls are likely to have a greater impact in the future.</p

Optimizing diagnostic methods and stem cell transplantation outcomes in pediatric bone marrow failure: a 50-year single center experience

Peripheral blood cytopenia, a frequent presenting symptom in pediatric patients, can be caused by bone marrow failure (BMF). Timely identification of patients with non-reversible BMF is of crucial importance to reduce the risks of invasive infections and bleeding complications. Most pediatric patients with severe persistent cytopenia, independent of the underlying cause, are offered allogeneic hematopoietic stem cell transplantation (HSCT) as curative therapy. Here we report on our management guidelines and HSCT outcomes of pediatric BMF patients to pinpoint improvements and future challenges. We formulated recommendations based on this 50 years' experience, which were implemented at our center in 2017. By analysis of the HSCT cohort of 2017-2023, the 5-year outcome data is presented and compared to historical outcome data. In addition, outcomes of patients transplanted for identified inherited bone marrow failure syndromes (IBMFS) are compared to severe aplastic anemia (SAA) outcomes to underline the often multiorgan disease in IBMFS with implications for long-term survival. Survival of pediatric patients with irreversible BMF has improved tremendously. SAA patients transplanted after 2017 had a superior 5-year overall (OS) and event-free survival (EFS) of 97% and 85% compared to 68% and 59% in the cohort transplanted before 2017 (p = 0.0011 and p = 0.017). A similar trend was seen for BMF, with an OS and EFS of 89% for those transplanted after 2017 compared to 62% and 59% (p > 0.05). This improvement is mainly related to better survival in the first months after HSCT. The long-term survival after HSCT is lower in IBMFS patients as compared to SAA patients due to secondary malignancies and multiorgan toxicity.Conclusion: Unbiased protocolized in-depth diagnostic strategies are crucial to increase the frequency of identifiable causes within the heterogeneous group of pediatric BMF. A comprehensive approach to identify the cause of BMF can prevent treatment delay and be useful to tailor treatment and follow-up protocols.Transplantation and immunomodulatio

Economic burden of livestock disease and drought in Northern Tanzania

Livestock-dependent communities face considerable livestock disease and drought risk, which can impact herd value, income and consumption. This paper summarizes economic data collected from 404 households in Arusha and Manyara regions of Northern Tanzania in 2016. They provide estimates for (i) herd loss due to disease and drought as a fraction of herd value and income, (ii) the relative risk of disease and drought in small versus large ruminants and (iii) the relationship between livestock disease outcomes and household expenditures. We find that disease and drought losses comprise 10 to 4% of sheep, cattle and goat herd value, and amount to an estimated 62.1% of household income. The drought and disease risk ratios for small versus large ruminants indicate that small stock face higher disease risk, while large ruminants are affected more by drought. Furthermore, cattle abortions are negatively related to schooling expenditure and positively associated with increases in off-farm food expenditure related to livestock management, presumably through increased investments in prevention and therapy. These results suggest that climatic variability and livestock diseases are an important source of economic vulnerability and reducing this burden may help alleviate poverty in livestock-dependent communities

Characterization of human mesenchymal stem cells from Ewing sarcoma patients. Pathogenetic implications

Ewing Sarcoma (EWS) is a mesenchymal-derived tumor that generally arises in bone and soft tissue. Intensive research regarding the pathogenesis of EWS has been insufficient to pinpoint the early events of Ewing sarcomagenesis. However, the Mesenchymal Stem Cell (MSC) is currently accepted as the most probable cell of origin

Decision making for hematopoietic stem cell transplantation in pediatric, adolescent, and young adult patients with a hemoglobinopathy: shared or not?

Transplantation and immunomodulatio

High interpatient variability of treosulfan exposure is associated with early toxicity in paediatric HSCT: a prospective multicentre study

Treosulfan-based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drug's relationship with regimen-related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30&nbsp;g/m2, administered over 3 consecutive days in infants &lt;1&nbsp;year old (n&nbsp;=&nbsp;12) and 42&nbsp;g/m2 in children ≥1&nbsp;year old (n&nbsp;=&nbsp;65). Mean day 1 treosulfan exposure was 1744&nbsp;±&nbsp;795&nbsp;mg*h/l (10&nbsp;g/m2) and 1561&nbsp;±&nbsp;511&nbsp;mg*h/l (14&nbsp;g/m2), with an inter-individual variability of 56 and 33% in the respective groups. High treosulfan exposure (&gt;1650&nbsp;mg*h/l) was associated with an increased risk of mucosal [Odds ratio (OR) 4·40; 95% confidence interval (CI) 1·19–16·28, P&nbsp;=&nbsp;0·026] and skin toxicity (OR 4·51; 95% CI 1·07–18·93, P&nbsp;=&nbsp;0·040). No correlation was found between treosulfan exposure and the early clinical outcome parameters: engraftment, acute graft-versus-host disease and donor chimerism. Our study provides the first evidence in a large cohort of paediatric patients of high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long-term disease-specific outcome and late treatment-related toxicity

How to facilitate decision-making for hematopoietic stem cell transplantation in patients with hemoglobinopathies: the perspectives of healthcare professionals

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 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.Transplantation and immunomodulatio

Second-line treatment for acute graft-versus-host disease with mesenchymal stromal cells. a decision model

Objective: No standard second-line treatment exists for acute graft-versus-host disease steroid-refractory (SR-aGvHD), and long-term outcomes remain poor. Mesenchymal stromal cells (MSCs) have been evaluated as treatment, but no disease model (DM) exists that integrates and extrapolates currently available evidence. The aim of this study was to develop such a DM to describe the natural history of SR-aGvHD and to predict long-term outcomes. Method: The DM was developed in collaboration with experts in haematology-oncology. Subsequently, a model simulation was run. Input parameters for transition and survival estimates were informed by published data of clinical trials on MSC treatment for SR-aGvHD. Parametric distributions were used to estimate long-term survival rates after MSCs. Results: The newly developed DM is a cohort model that consists of eight health states. For the model simulation, we obtained data on 327 patients from 14 published phase II trials. Due to limited evidence, DM structure was simplified and several assumptions had to be made. Median overall survival was 3.2 years for complete response and 0.5 years for no complete response. Conclusion: The DM provides a comprehensive overview on the second-line treatment pathway for aGvHD and enables long-term predictions that can be used to perform a cost-effectiveness analysis comparing any treatment for SR-aGvHD