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CMV Seropositive Status Increases Heparanase SNPs Regulatory Activity, Risk of Acute GVHD and Yield of CD34(+) Cell Mobilization
Ostrovsky, O., Beider, K., Morgulis, Y., Bloom, N., Cid-Arregui, A., Shimoni, A., Vlodavsky, I., Nagler, A.
Cells. 2021;10(12)
Abstract
Heparanase is an endo-β-glucuronidase that is best known for its pro-cancerous effects but is also implicated in the pathogenesis of various viruses. Activation of heparanase is a common strategy to increase viral spread and trigger the subsequent inflammatory cascade. Using a Single Nucleotide Polymorphisms (SNP)-associated approach we identified enhancer and insulator regions that regulate HPSE expression. Although a role for heparanase in viral infection has been noticed, the impact of HPSE functional SNPs has not been determined. We investigated the effect of cytomegalovirus (CMV) serostatus on the involvement of HPSE enhancer and insulator functional SNPs in the risk of acute graft versus host disease (GVHD) and granulocyte-colony stimulating factor related CD34(+) mobilization. A significant correlation between the C alleles of insulator rs4364254 and rs4426765 and CMV seropositivity was found in healthy donors and patients with hematological malignancies. The risk of developing acute GVHD after hematopoietic stem cell transplantation was identified only in CMV-seropositive patients. A significant correlation between the enhancer rs4693608 and insulator rs28649799 and CD34(+) cell mobilization was demonstrated in the CMV-seropositive donors. It is thus conceivable that latent CMV infection modulates heparanase regulatory regions and enhances the effect of functional SNPs on heparanase function in normal and pathological processes.
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Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in haematopoietic stem cell transplantation recipients
Shem-Tov, N., Yerushalmi, R., Danylesko, I., Litachevsky, V., Levy, I., Olmer, L., Lusitg, Y., Avigdor, A., Nagler, A., Shimoni, A., et al
British journal of haematology. 2021
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Editor's Choice
Abstract
The immunogenicity and safety of Pfizer-BioNTech BNT162b2 mRNA vaccine in allogeneic haematopoietic stem cell transplantation (HSCT) recipients are unknown. We prospectively followed 152 HSCT recipients who were at least six months following transplantation and with no active acute graft-versus-host disease (GVHD). Blood samples were taken 2-4?weeks after the second vaccination and analyzed for receptor-binding domain (RBD) antibodies and neutralizing antibodies (NA). 272 immunocompetent healthcare workers served as controls. At a median of 28?days after the second vaccination, 118 patients (77·6%) developed RBD immunoglobulin G (IgG) with a geometric mean titre (GMT) of 2·61 [95% CI (confidence interval), 2·16-3·16]. In the control group 269/272 (98·9%) developed RBD IgG, with a GMT of 5·98 (95% CI 5·70-6·28), P?0·0001. The GMT of NA in HSCT recipients and controls was 116·0 (95% CI 76·5-175·9), and 427·9 (95% CI 354·3-516·7) respectively (P?0001). Multivariate logistic regression analysis revealed that HSCT recipients with no chronic GVHD and no immunosuppressive therapy at the time of vaccination had significantly higher levels of NA following the second vaccination. Adverse events were minimal and were less common than in healthy controls. In conclusion; the BNT162b2 mRNA vaccination is safe and effective in HSCT recipients, especially those who are immunosuppression-free. A significant fraction developed protecting NA.
PICO Summary
Population
Patients who were at least six months post HSCT at a single centre in Israel (n=152)
Intervention
Vaccination against COVID-19 with Pfizer-BioNTech BNT162b2 mRNA vaccine
Comparison
Immunocompetent healthcare workers (n=272)
Outcome
At a median of 28 days after the second vaccination, 118 patients (77·6%) developed RBD immunoglobulin G (IgG) with a geometric mean titre (GMT) of 2·61 [95% CI (confidence interval), 2·16-3·16]. In the control group 269/272 (98·9%) developed RBD IgG, with a GMT of 5·98 (95% CI 5·70-6·28). The GMT of neutralising antibodies (NA) in HSCT recipients and controls was 116·0 (95% CI 76·5-175·9), and 427·9 (95% CI 354·3-516·7) respectively. Multivariate logistic regression analysis revealed that HSCT recipients with no chronic GVHD and no immunosuppressive therapy at the time of vaccination had significantly higher levels of NA following the second vaccination. Adverse events were minimal and were less common than in healthy controls.
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Incidence, Risk Factors and Long-Term Outcome of Acute Leukemia Patients with Early Candidemia after Allogeneic Stem Cell Transplantation. A Study by the Acute Leukemia and Infectious Diseases Working Parties of EBMT
Cesaro, S., Tridello, G., Blijlevens, N., Ljungman, P., Craddock, C., Michallet, M., Martin, A., Snowden, J. A., Mohty, M., Maertens, J., et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018
Abstract
Objectives: To assess the incidence of, and risk factors for, Candida infection in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT) and the impact on long-term survival. Methods: outcome analysis of 28,542 acute leukemia patients who underwent HSCT from 2000 to 2012: 347 with candidemia by day +100, and 28,195 without candidemia or any other type of Candida infection. Results: The incidence of candidemia by day +100 was 1.2% (347/28542) and occurred at a median of 22 days after HSCT (range 1-100). A higher 100-day non-relapse-mortality (NRM) (HR 3.0, p <0.0001), and a lower 100-day overall-survival (OS) (HR 2.5, p<0.0001) were observed in patients with candidemia. The case fatality rate by day +100 in patients with candidemia was 22% (76/347). Factors associated with candidemia occurrence were: gender female, bone marrow or cord blood stem cell source, T-cell depletion, use of total body irradiation, and acute graft versus host disease. Among the patients alive at day +100, the 5-year NRM and OS after a median follow-up of 5.6 years (95% CI 5.5 - 5.7) for patients with and without candidemia were 22.5% vs. 13.5%, p <0.0001, and 45.6% vs. 53.4%, p=0.0003, respectively. In multivariate analysis, the occurrence of a candidemia episode by day +100 was an independent risk factor for higher NRM, HR 1.7, p=0.001, and lower OS, HR 1.4, p=0.001. Conclusions: despite the general improvements in prophylaxis and treatment, the early occurrence of candidemia after HSCT is still associated with higher NRM and lower short-and-long-term OS.
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Influence of pre-existing invasive aspergillosis on allo-HSCT outcome: a retrospective EBMT analysis by the Infectious Diseases and Acute Leukemia Working Parties
Penack, O., Tridello, G., Hoek, J., Socie, G., Blaise, D., Passweg, J., Chevallier, P., Craddock, C., Milpied, N., Veelken, H., et al
Bone Marrow Transplantation. 2016;51(3):418-23
Abstract
Historically, invasive aspergillosis (IA) has been a major barrier for allogeneic hematopoietic stem cell transplantation (allo-HSCT). The influence of invasive IA on long-term survival and on transplant-related complications has not been investigated in a larger patient cohort under current conditions. Our aim was to analyze the long-term outcome of patients undergoing allo-HSCT with a history of prior IA. We used European Society for Blood and Marrow Transplantation database data of first allo-HSCTs performed between 2005 and 2010 in patients with acute leukemia. One thousand one hundred and fifty patients with data on IA before allo-HSCT were included in the analysis. The median follow-up time was 52.1 months. We found no significant impact of IA on major transplant outcome variables such as overall survival, relapse-free survival, non-relapse mortality, cumulative incidence of acute GvHD grade II-IV, chronic GvHD, pulmonary complications and leukemia relapse. However, we found a trend toward lower overall survival (P=0.078, hazard ratio (HR) (95% confidence interval (CI)): 1.16 (0.98, 1.36)) and higher non-relapse mortality (P=0.150, HR (95% CI): 1.19 (0.94, 1.50)) in allo-HSCT recipients with pre-existing IA. Our data suggest that a history of IA should not generally be a contraindication when considering the performance of allo-HSCT in patients with acute leukemia.
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Impact of Donor Epstein-Barr Virus Serostatus on the Incidence of Graft-Versus-Host Disease in Patients With Acute Leukemia After Hematopoietic Stem-Cell Transplantation: A Study From the Acute Leukemia and Infectious Diseases Working Parties of the European Society for Blood and Marrow Transplantation
Styczynski, J., Tridello, G., Gil, L., Ljungman, P., Hoek, J., Iacobelli, S., Ward, K. N., Cordonnier, C., Einsele, H., Socie, G., et al
Journal of Clinical Oncology. 2016;34(19):2212-20
Abstract
PURPOSE We investigated the effect of Epstein-Barr virus (EBV) serostatus on the overall outcome of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). PATIENTS AND METHODS The study included 11,364 patients who underwent allogeneic peripheral-blood or bone marrow transplantation for acute leukemia between 1997 and 2012. We analyzed the impact of donor and recipient EBV serologic status on overall survival, relapse-free survival, relapse incidence, nonrelapse mortality, and incidence of graft-versus-host disease (GVHD) after allo-HSCT. RESULTS Patients receiving grafts from EBV-seropositive donors had the same overall survival as patients who received grafts from EBV-seronegative donors (hazard ratio [HR], 1.05; 95% CI, 0.97 to 1.12; P = .23). Seropositive donors also had no influence on relapse-free survival (HR, 1.04; 95% CI, 0.97 to 1.11; P = 0.31), relapse incidence (HR, 1.03; 95% CI, 0.94 to 1.12; P = .58), and nonrelapse mortality (HR, 1.05; 95% CI, 0.94 to 1.17; P = .37). However, in univariate analysis, recipients receiving grafts from seropositive donors had a higher risk of chronic GVHD than those with seronegative donors (40.8% v 31.0%, respectively; P < .001; HR, 1.42; 95% CI, 1.30 to 1.56). When adjusting for confounders, higher risk was identified for both acute and chronic GVHD. In seronegative patients with seropositive donors, the HR for chronic GVHD was 1.30 (95% CI, 1.06 to 1.59; P = .039). In seropositive patients with seropositive donors, the HR was 1.24 (95% CI, 1.07 to 1.45; P = .016) for acute GVHD and 1.43 (95% CI, 1.23 to 1.67; P < .001) for chronic GVHD. Seropositive patients with seronegative donors did not have an increased risk of GVHD. CONCLUSION Our data suggest that donor EBV status significantly influences development of acute and chronic GVHD after allo-HSCT. Copyright © 2016 by American Society of Clinical Oncology.