Guideline development for prevention of transfusion-associated graft-versus-host disease: reduction of indications for irradiated blood components after prestorage leukodepletion of blood components

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare, commonly fatal complication of transfusion preventable by irradiation of blood units. The revision of the Dutch transfusion guideline addressed the question whether irradiation is still necessary if blood components are prestorage leukodepleted. We searched for published cases of TA-GVHD following transfusion of prestorage leukodepleted blood and through contacting haemovigilance systems. Six presumed cases were found, dating from 1998 to 2013. Four out of six patients had received one or more non-irradiated units despite recognised indications for irradiated blood components. In the countries providing information, over 50 million prestorage leukodepleted, non-irradiated, non-pathogen-reduced cellular components were transfused in a 10-year period. Potential benefits of lifting indications for irradiation were considered. These include reduced irradiation costs (euro 1.5 million annually in the Netherlands) and less donor exposure for neonates. Findings were presented in an invitational expert meeting. Recommendations linked to human leukocyte antigen similarity between donor and recipient or intra-uterine transfusion were left unchanged. Indications linked to long-lasting deep T-cell suppression were defined with durations of 6 or 12 months after end of treatment (e.g. autologous or allogeneic stem cell transplantation). Need for continued alertness to TA-GVHD and haemovigilance reporting of erroneous non-irradiated transfusions was emphasised.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

The interplay between GPIb/IX-antibodies, platelet hepatic sequestration, and TPO levels in patients with chronic ITP.

Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder with an incompletely understood pathophysiology, but includes platelet-clearance in the spleen and liver via T-cells and/or platelet-autoantibodies. Strikingly, thrombopoietin (TPO) levels remain low in ITP. Platelet-glycoprotein (GP)Ibα has been described to be required for hepatic TPO generation, however, the role of GPIb-antibodies in relation to platelet hepatic sequestration and TPO-levels, with consideration of platelet counts, remains to be elucidated. Therefore, we performed a study in which we included 53 chronic and non-splenectomized ITP patients for which we conducted indium labeled autologous platelet scintigraphy, measured platelet-antibody profiles and TPO-levels. Upon stratification towards the severity of thrombocytopenia, no negative association was observed between GPIb/IX-antibodies and TPO levels, suggesting that GPIb/IX-antibodies do not inhibit or block TPO levels. Surprisingly, we observed a positive association between GPIb/IX-antibody levels and TPO levels, and GPIb/IX-antibodies and platelet hepatic sequestration, in patients with severe thrombocytopenia, but not in patients with mild or moderate thrombocytopenia. In addition, platelet hepatic sequestration and TPO levels were positively associated. This collectively indicates that GPIb/IX-antibodies may be associated with an increased platelet hepatic sequestration and elevated TPO levels in severe thrombocytopenic ITP patients, however, further research is warranted to elucidate the pathophysiological mechanisms.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Fibrodysplasia Ossificans Progressiva: What Have We Achieved and Where Are We Now? Follow-up to the 2015 Lorentz Workshop

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the ACVR1 gene was identified as the causative mutation of FOP in 2006. After this, the pathophysiology of FOP has been further elucidated through the efforts of research groups worldwide. In 2015, a workshop was held to gather these groups and discuss the new challenges in FOP research. Here we present an overview and update on these topics

Effect of alemtuzumab-based T-cell depletion on graft compositional change in vitro and immune reconstitution early after allogeneic stem cell transplantation

Background aims: To reduce the risk of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloSCT), T-cell depletion (TCD) of grafts can be performed by the addition of alemtuzumab (ALT) "to the bag" (in vitro) before transplantation. In this prospective study, the authors analyzed the effect of in vitro incubation with 20 mg ALT on the composition of grafts prior to graft infusion. Furthermore, the authors assessed whether graft composition at the moment of infusion was predictive for T-cell reconstitution and development of GVHD early after TCD alloSCT.Methods: Sixty granulocyte colony-stimulating factor-mobilized stem cell grafts were obtained from >= 9/10 HLA-matched related and unrelated donors. The composition of the grafts was analyzed by flow cytometry before and after in vitro incubation with ALT. T-cell reconstitution and incidence of severe GVHD were monitored until 12 weeks after transplantation.Results: In vitro incubation of grafts with 20 mg ALT resulted in an initial median depletion efficiency of T-cell receptor (TCR) alpha/beta T cells of 96.7% (range, 63.5-99.8%), followed by subsequent depletion in vivo. Graft volumes and absolute leukocyte counts of grafts before the addition of ALT were not predictive for the efficiency of TCR alpha/beta T-cell depletion. CD4(pos) T cells were depleted more efficiently than CD8(pos) T cells, and naive and regulatory T cells were depleted more efficiently than memory and effector T cells. This differential depletion of T-cell subsets was in line with their reported differential CD52 expression. In vitro depletion efficiencies and absolute numbers of (naive) TCR alpha/beta T cells in the grafts after ALT incubation were not predictive for T cell reconstitution or development of GVHD postalloSCT.Conclusions: The addition of ALT to the bag is an easy, fast and generally applicable strategy to prevent GVHD in patients receiving alloSCT after myeloablative or non-myeloablative conditioning because of the efficient differential depletion of donor-derived lymphocytes and T cells. (C) 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Fibrodysplasia Ossificans Progressiva: what have we achieved and where are we now? follow-up to the 2015 Lorentz Workshop

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the ACVR1 gene was identified as the causative mutation of FOP in 2006. After this, the pathophysiology of FOP has been further elucidated through the efforts of research groups worldwide. In 2015, a workshop was held to gather these groups and discuss the new challenges in FOP research. Here we present an overview and update on these topics

Adherence and profile of non-persistence in patients treated for osteoporosis—a large-scale, long-term retrospective study in The Netherlands

We analyzed 12-month compliance for all ten oral osteoporosis drugs in the Netherlands by medication possession ratio (MPR a parts per thousand yenaEuro parts per thousand 80%) in 105,506 patients, and persistence in 8,626 starters indicated high MPR (91%), low persistence (43%), and no restart in 78% of the stoppers after 18 months. We studied compliance and persistence for all available oral osteoporosis medications on a national scale in the Netherlands. We analyzed the IMS Health's longitudinal prescription database, which represents 73% of all pharmacies in the Netherlands. Twelve-month compliance was measured by medication possession ratio (MPR) in a cross-sectional cohort of 105,506 patients who received at least three prescriptions. Twelve-month persistence (no gap in refills for > 6 months) was measured in all 8,626 consecutive patients starting therapy, with a further follow-up in non-persistent patients during an additional 18 months for evaluation of switching, restart, or definitive stopping oral medication. Multivariate logistic regression analysis was used to analyze the odds ratios (ORs) with 95% confidence intervals (CI) of characteristics of non-persistence. MPR of a parts per thousand yen80% was found in 91% of patients. Persistence was 43% (range, 29-52%). Persistence was related to age > 60 years (ORs, 1.41 to 1.64), pharmacy outside very dense urban area (ORs, 1.39 to 1.44), additional use of calcium and/or vitamin D supplementation (OR, 1.26 and CI, 1.13, 1.39) and use of glucocorticoids (OR, 0.65 and CI, 0.59, 0.72) or cardiovascular medication (OR, 0.88 and CI, 0.79, 0.97). Of non-persistent patients, 22% restarted within 18 months with oral osteoporosis drugs. One-year compliance for all available oral osteoporosis medications was high, but 1-year persistence was low. Most stoppers did not restart or switch during an additional 18-month follow-up. These data indicate a major failure to adequately treat patients at high risk for fractures in daily practice.Amgen provided funds to IMS for data analysis. The preparation of this article was not supported by external funding. J.C. Netelenbos and P.P. Geusens have no conflict of interest, including specific financial interest and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript. Buijs and Ypma are employees of IMS Health

Fibrodysplasia ossificans progressiva: what have we achieved and where are we now?: Follow-up to the 2015 Lorentz workshop

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare progressive genetic disease effecting one in a million individuals. During their life, patients with FOP progressively develop bone in the soft tissues resulting in increasing immobility and early death. A mutation in the ACVR1 gene was identified as the causative mutation of FOP in 2006. After this, the pathophysiology of FOP has been further elucidated through the efforts of research groups worldwide. In 2015, a workshop was held to gather these groups and discuss the new challenges in FOP research. Here we present an overview and update on these topics.Diabetes mellitus: pathophysiological changes and therap