546 results on '"Host disease"'
Search Results
52. Extracorporeal photopheresis vs standard therapies for steroid-refractory chronic graft-vs-host disease: Pharmacoeconomic assessment of hospital resource use in Spain
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Boluda, Blanca, Solana-Altabella, Antonio, Cano, Isafer, Acuna-Cruz, Evelyn, Rodriguez-Veiga, Rebeca, Ballesta-Lopez, Octavio, Megias-Vericat, Juan Eduardo, Martinez-Cuadron, David, Gomez, Ines, Solves, Pila, Lorenzo, Indignacio, Pinana, Jose Luis, Sanz, Jaime, Guerreiro, Manuel, Montoro Gomez, Juan, Diaz-Gonzalez, Alvaro, Marco, Javier, Blanco, Ana, Sanz, Miguel A, and Montesinos, Pau
- Subjects
host disease ,fluids and secretions ,cost comparison ,extracorporeal photopheresis ,education ,graft‐ ,vs‐ ,healthcare resource utilization - Abstract
Background This study assessed pharmacoeconomic costs associated with extracorporeal photopheresis (ECP) compared with other available second-line therapies for chronic graft-vs-host disease (cGvHD) in a tertiary Spanish institution. Methods Patients (>= 18 years) diagnosed with steroid-refractory cGvHD were eligible. Data were collected retrospectively from index date until 1 year or relapse. Patients were distributed in two cohorts (ECP vs non-ECP), matched by age ( 40), hematopoietic stem cell transplant (HLA-identical sibling donor or other) and number of previous immunosuppressive lines (1, 2, or >= 3). Costs were assigned using the 2016 diagnosis-related group (DRG) system: DRG 579 (euro22 383) overnight stay due to major complication (ie, sepsis, pneumonia, parenteral nutrition, or respiratory failure), and DRG 875 (euro5154) if no major complication. The primary endpoint was healthcare resource utilization per patient. Results Forty patients (n = 20 per cohort) were included. Median age was 49, and 37.5% were female. Mean total cost per patient was euro25 319 (95% CI: euro17 049-euro33 590) across the two cohorts, with a slightly lower mean cost per ECP-treated patient (euro23 120) compared with the non-ECP cohort (euro27 519; P = .597). Twenty-seven inpatient hospitalizations occurred among ECP-treated patients, vs 33 in the non-ECP cohort. Day hospital and external consultations were more frequent in the ECP cohort. However, fewer inpatient admissions included DRG 579 compared with the non-ECP cohort (44% vs 58%). Inpatient length of stay was slightly shorter in the ECP cohort (30 vs 49 days; P = .298). Conclusions ECP treatment may yield economic savings in Spain through resource savings and moving costs toward outpatient care.
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- 2021
53. Role of microbial metabolites in regulating host immunity
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Hamsa D. Tadepally
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Host immunity ,Immune system ,Host (biology) ,Microbiome ,Biology ,Host disease ,Gut homeostasis ,Microbiology - Abstract
Microbiota is the collection of all the microorganisms that are present in and on all mammals. The microbial communities are vastly diverse and actively contribute to the development and proper functioning of the immune system. Host-microbiota studies have seen an upswing with increasing technologies that help profile several microbial communities. Recent studies have uncovered how microbial metabolites play an important role in regulating host immunity. The host immune system has coevolved with the commensal microbiome for mutual regulation. Some metabolites even play a prominent role in increasing immune responses and decreasing harmful inflammatory responses. Studies involving microbial metabolites help unravel the molecular basis of host-microbiome interactions. Gut microbial metabolites have been shown to play an important role in gut homeostasis. This review throws light on microbial metabolites that play an important role in regulating host immunity and how an impaired microbiota contributes to host disease and metabolic disorders.
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- 2021
54. Anti-Thymocyte Globulin Exposure in CD34+T Cell Depleted Allogeneic Hematopoietic Cell Transplantation
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Gunjan L. Shah, Andrew L. Kung, Sean M. Devlin, Richard J. O'Reilly, Miguel-Angel Perales, Andromachi Scaradavou, Esperanza B. Papadopoulos, Jaap Jan Boelens, Roni Tamari, Elizabeth Klein, Madhavi Lakkaraja, Brian C. Shaffer, Scott Avecilla, Farid Boulad, Christina Cho, Barbara Spitzer, Josel D. Ruiz, Ichelle van Roessel, Ann A. Jakubowski, Sergio Giralt, Susan E. Prockop, Audrey Mauguen, Nancy A. Kernan, Kevin J. Curran, Michael Scordo, and Maria Cancio
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Oncology ,medicine.medical_specialty ,Hematopoietic cell ,business.industry ,Institutional review board ,Competing risks ,Anti-thymocyte globulin ,Transplantation ,Internal medicine ,Overall survival ,Medicine ,Cellular immunotherapy ,business ,Host disease - Abstract
Background: Traditional weight-based dosing results in variable rabbit anti-thymocyte-globulin (rATG) clearance that can delay CD4+Tcell immune reconstitution (CD4+IR) leading to higher mortality. Methods: In a retrospective, pharmacokinetic (PK)/pharmacodynamic analysis of patients undergoing their first CD34+ T-cell depleted (TCD) Allogeneic Hematopoietic Cell Transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area-under-the-curve (AUC;AU*d/L) using a validated population-PK model. We related rATG exposure to non-relapse mortality (NRM), CD4+IR (CD4+≥50/µL at two consecutive measures within 100 days after HCT), overall survival, relapse, and acute-graft versus host disease (GVHD) to define an optimal rATG-exposure. Cox-proportional hazard models, and multi-state competing risk models were used. Results: 554 patients were included (age 0.1-73 years). Median post-HCT rATG exposure was 47AU*d/L (range 0–101). Low post–HCT AUC ( 55AU*d/L and 30-55AU*d/L groups, respectively, compared to
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- 2021
55. MiMeNet: Exploring Microbiome-Metabolome Relationships using Neural Networks
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Derek Reiman, Yang Dai, and Brian T. Layden
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chemistry.chemical_compound ,Metabolomics ,Artificial neural network ,chemistry ,Interaction network ,Metabolite ,Metabolome ,Microbiome ,Computational biology ,Biology ,Host disease ,Guilt by association - Abstract
The advance in microbiome and metabolome studies has generated rich omics data revealing the involvement of the microbial community in host disease pathogenesis through interactions with their host at a metabolic level. However, the computational tools to uncover these relationships are just emerging. Here, we present MiMeNet, a neural network framework for modeling microbe-metabolite relationships. Using ten iterations of 10-fold cross-validation on three paired microbiome-metabolome datasets, we show that MiMeNet more accurately predicts metabolite abundances (mean Spearman correlation coefficients increase from 0.108 to 0.309, 0.276 to 0.457, and -0.272 to 0.264) and identifies more well-predicted metabolites (increase in the number of well-predicted metabolites from 198 to 366, 104 to 143, and 4 to 29) compared to state-of-art linear models for individual metabolite predictions. Additionally, we demonstrate that MiMeNet can group microbes and metabolites with similar interaction patterns and functions to illuminate the underlying structure of the microbe-metabolite interaction network, which could potentially shed light on uncharacterized metabolites through “Guilt by Association”. Our results demonstrated that MiMeNet is a powerful tool to provide insights into the causes of metabolic dysregulation in disease, facilitating future hypothesis generation at the interface of the microbiome and metabolomics.
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- 2020
56. Immunotoxin-Mediated Depletion of CD5+ T Cells from Bone Marrow for Graft-vs.-Host Disease Prophylaxis
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Cyril Bouloux, Barbara E. Bierer, Howard J. Weinstein, and Joseph H. Antin
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medicine.anatomical_structure ,Immunotoxin ,business.industry ,Cancer research ,medicine ,Bone marrow ,CD5 ,Host disease ,business - Published
- 2020
57. Extracorporeal Photopheresis in Pediatric Graft-vs-Host Disease
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J.A. Baquero Rey, M.L. Makiya, K.Y. Cueto Sarmiento, A. Andrade Miranda, Luis Daniel Mazzuoccolo, S.A. Bruey, and Paula A Enz
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medicine.medical_specialty ,Histology ,business.industry ,Dermatology department ,Treatment options ,Dermatology ,Disease ,030204 cardiovascular system & hematology ,Pathology and Forensic Medicine ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,Extracorporeal Photopheresis ,medicine ,Chronic gvhd ,Host disease ,business ,Adverse effect ,Complete response - Abstract
Background Extracorporeal photopheresis (ECP) is an immunomodulatory therapy used to treat graft-vs-host disease (GVHD) in adults and children. Few studies have examined its use in children. Objective To describe demographic characteristics, clinical response, adverse effects, and outcomes in a series of pediatric patients with acute or chronic GVHD treated with ECP. Material and methods We included all pediatric patients with acute or chronic GVHD treated with ECP by the dermatology department of Hospital Italiano de Buenos Aires between January 2012 and December 2018. We used the UVAR-XTS system (2 patients) and the CELLEX system (7 patients). Patients with acute GVHD received 2 sessions a week and were reassessed at 1 month, while those with chronic GVHD received 2 sessions every 2 weeks and were reassessed at 3 months. Treatment duration in both scenarios varied according to response. Results We evaluated 9 pediatric patients with corticosteroid-refractory, -dependent, and/or -resistant GVHD treated with ECP. Seven responded to treatment and 2 did not. Response was complete in 1 of the 9 patients with skin involvement and partial in 7. Complete response rates for the other sites of involvement were 60% (3/5) for the liver, 50% (1/2) for the gastrointestinal system, and 80% (4/5) for mucous membranes. Two patients died during the study period. Conclusion ECP is a good treatment option for pediatric patients with acute or chronic GVDS.
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- 2020
58. Gynecologic Care for Pediatric and Adolescent Patients Undergoing Hematopoietic Stem Cell Transplantation
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Nicole Todd and Katherine E. Debiec
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Oncology ,medicine.medical_specialty ,Adolescent ,media_common.quotation_subject ,medicine.medical_treatment ,Primary ovarian insufficiency ,Graft vs Host Disease ,Fertility ,Hematopoietic stem cell transplantation ,Perioperative Care ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Preoperative Care ,medicine ,Humans ,030212 general & internal medicine ,Host disease ,Child ,Reproductive health ,media_common ,030219 obstetrics & reproductive medicine ,business.industry ,Hematopoietic Stem Cell Transplantation ,Obstetrics and Gynecology ,General Medicine ,medicine.disease ,surgical procedures, operative ,Graft-versus-host disease ,Reproductive Health ,Pediatrics, Perinatology and Child Health ,Female ,Sexual Health ,business ,Genital Diseases, Female - Abstract
Hematopoietic stem cell transplantation is used to treat many chronic and acute malignant and nonmalignant conditions. We review hematopoietic stem cell transplantation and its effect on the gynecologic health of pediatric and adolescent patients, including pretransplantation evaluation, contraception, menstrual suppression, sexual health, fertility, primary ovarian insufficiency, and graft vs host disease. Comprehensive and team-based care provides optimal anticipatory counseling, evaluation, and management of acute and ongoing gynecologic issues.
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- 2020
59. Deep Neural Network Modeling for Phenotypic Prediction of Metagenomic Samples
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Yassin Mreyoud and Tae-Hyuk Ahn
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Whole genome sequencing ,0303 health sciences ,03 medical and health sciences ,0302 clinical medicine ,Abundance (ecology) ,Metagenomics ,Neural network modeling ,Computational biology ,Biology ,Host disease ,Phenotype ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
The increasing popularity of metagenomic sequencing has resulted in a plethora of 16S RNA and whole genome sequence data available. Microbes play an important role in the health and disease of humans, pets, and livestock. Characterizing such microbes and their relative abundances are important to identify sample phenotypes such as disease. In the past, machine learning based methods have been applied for prediction of host disease status and overall health based on taxonomic abundance profiles. Here we utilize deep neural network modeling with taxonomic profiles for faster, precise, and effective prediction of metagenomic sample phenotypes.
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- 2020
60. Evaluation of the Cost of Survivorship Care After Allogeneic Hematopoeitic Stem Cell Transplantation–An Analysis of 2 German Transplantation Centers
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Wolff, Daniel, Bardak, Jelena, Edinger, Matthias, Klinger-Schindler, Ursula, Holler, Ernst, Lawitschka, Anita, Schoemans, Helene, Herr, Wolfgang, Kröger, Nikolaus, and Ayuk Ayuketang, Francis
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610 Medizin ,Graft vs Host Disease ,costs ,GvHD, Graft vs. Host disease, haematopoietic stem cell transplant, survivorship care model, costs,re-imbursement ,Survivorship ,haematopoietic stem cell transplant ,re-imbursement ,Host disease ,Ambulatory Care ,Humans ,Transplantation, Homologous ,MARROW-TRANSPLANTATION ,health care economics and organizations ,Public, Environmental & Occupational Health ,Original Research ,GvHD ,Graft vs ,ddc:610 ,Science & Technology ,lcsh:Public aspects of medicine ,Public Health, Environmental and Occupational Health ,Hematopoietic Stem Cell Transplantation ,lcsh:RA1-1270 ,survivorship care model ,Public Health ,Graft vs. Host disease ,Life Sciences & Biomedicine - Abstract
The aim of the presented study was to analyze the care expenditure for outpatients after allogeneic hematopoietic stem cell transplantation (alloHSCT) done in accordance with the national, European guidelines and the German Social Law. We performed an analysis of the National and European survivorship care guidelines and in parallel recorded the time expenditure and staff costs separated according to different occupational groups involved in outpatient care at two German transplantation centers [University Hospital Regensburg (UKR) and University Hospital Hamburg-Eppendorf (UKE)]. In addition, we performed a comparison of real costs vs. reimbursed costs according to the standard rating benchmark catalog (EBM), which was supplemented by a survey of German transplantation centers. The results showed that the staff costs are only covered by the EBM for patients without complications during long-term follow-up care-notably, this accounts for 15% of alloHSCT patients. Staff costs for patients requiring treatment of graft-vs.-host disease or relapse of the malignant underlying malignancy exceed to the factor 6.5 (UKR) to 12 (UKE) of the EBM revenue, caused both by the increased duration and frequency of the outpatient visits. As a result of the survey at German transplant centers, 15 out of 18 responding centers reported a lack of cost coverage for follow-up care. Two/15 centers reported that survivorship care is limited to a restricted time, independent of patient's needs, due to a lack of cost reimbursement. The results show that alloHSCT survivorship care of patients requires significant staff resources, which are not covered by the current version of the German EBM catalog. New approaches to finance labor intensive after care of transplant patients are required. ispartof: FRONTIERS IN PUBLIC HEALTH vol:8 ispartof: location:Switzerland status: published
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- 2020
61. The incidence, risk factors, and outcomes of acute graft‐vs‐host disease in pediatric T‐cell‐replete haploidentical hematopoietic stem cell transplantation
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Yi-Fei Cheng, Wei Han, Xiao-Hui Zhang, Xiao-Jun Huang, Fei-Fei Tang, Yu Wang, Chen-Hua Yan, Lan-Ping Xu, and Yu-Hong Chen
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Adult ,Male ,China ,medicine.medical_specialty ,Time Factors ,Transplantation Conditioning ,Adolescent ,T cell replete ,Biopsy ,T-Lymphocytes ,medicine.medical_treatment ,030232 urology & nephrology ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,030230 surgery ,Gastroenterology ,Disease-Free Survival ,Malignant disease ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Humans ,Medicine ,Cumulative incidence ,Child ,Host disease ,Retrospective Studies ,Immunity, Cellular ,Transplantation ,Hematology ,integumentary system ,business.industry ,Incidence ,Incidence (epidemiology) ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,Prognosis ,surgical procedures, operative ,Hematologic Neoplasms ,Pediatrics, Perinatology and Child Health ,Female ,business ,Follow-Up Studies - Abstract
The specific description, risk factors, and outcomes of aGVHD in pediatric haplo-HSCT using TCR protocols without PT-Cy have not been well described previously. We evaluated the incidence, risk factors, and outcomes of aGVHD in 350 consecutive pediatric patients receiving TCR haplo-HSCT without PT-Cy according to the Glucksberg and NIH aGVHD classifications between January 2015 and December 2017 at Peking University Institute of Hematology. The cumulative incidences of grade I, II, III, and IV aGVHD were 28%, 29.7%, 8.3%, and 5.1%, respectively. The type of aGVHD onset was classic in 243 patients (97.2%), and persistent/recurrent/late-onset aGVHD was in seven patients (2.8%). None of the considered variables significantly influenced the incidence of grade III-IV aGVHD. The 3-year OS, DFS, cumulative incidence of NRM, and relapse in malignant disease between severe aGVHD (III-IV) group and grade 0-II aGVHD group were 61.5% vs 77.2% (P = .027), 58.6% vs 75.1% (P = .014), 19.8% vs 5.3% (P = .002), and 21.6% vs 19.6% (P = .59), respectively; in non-malignant diseases, the 3-year OS, DFS, and NRM were 81.8% vs 97.4% (P = .05), 81.8% vs 97.4% (P = .05), and 18.2% vs 2.6% (P = .05), respectively. Under the protocol of pediatric TCR haplo-HSCT without PT-Cy, the persistent/recurrent/late-onset aGVHD was rare, and the incidence of severe aGVHD was acceptable and significantly contributed to NRM and lower survival in both malignant disease and non-malignant diseases.
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- 2020
62. Anti-Ro52 Autoantibodies Are Related to Chronic Graft-vs.-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation
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Kaibo Yang, Yanqiu Chen, Hanzhou Qi, Yiling Ye, Zhiping Fan, Fen Huang, Haiyan Zhang, Yuan Suo, Qifa Liu, and Hua Jin
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Adult ,Male ,lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,Adolescent ,medicine.medical_treatment ,Immunology ,Graft vs Host Disease ,anti-nuclear autoantibodies ,Disease ,Hematopoietic stem cell transplantation ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,B-Cell Activating Factor ,Humans ,Transplantation, Homologous ,Immunology and Allergy ,Medicine ,In patient ,allogeneic hematopoietic stem cell transplantation ,Risk factor ,Host disease ,B-cell activating factor ,Autoantibodies ,Original Research ,biology ,business.industry ,B-cell activating factor (BAFF) ,Hematopoietic Stem Cell Transplantation ,Autoantibody ,Middle Aged ,Up-Regulation ,030104 developmental biology ,Ribonucleoproteins ,chronic graft-vs.-host disease ,Antibodies, Antinuclear ,Immunoglobulin G ,Chronic Disease ,biology.protein ,Female ,Antibody ,lcsh:RC581-607 ,anti-Ro52 autoantibodies ,business ,030215 immunology - Abstract
Chronic graft-vs.-host disease (cGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Previous studies have shown that autoantibodies play an important role in the development of cGVHD. Anti-nuclear autoantibodies (ANA) is the most frequently detected autoantibodies in patients with cGVHD, but the role of anti-Ro52 autoantibodies (anti-Ro52) in cGVHD remains largely unknown. In this study, we analyzed autoantibodies from 84 patients after allo-HSCT, including 42 with active cGVHD and 42 without cGVHD. Autoantibodies were found in 36 (42.9%) patients. Among these autoantibody-positive patients, 28 (77.8%) patients had active cGVHD. The most frequent autoantibodies in patients with active cGVHD were ANA (50.0%), anti-Ro52 (28.6%) and anti-mitochondrial autoantibodies type 2 (4.8%). We further explored the association between anti-Ro52 and cGVHD. Patients with active cGVHD had higher anti-Ro52 levels than patients without cGVHD (P < 0.05). The increases of anti-Ro52 levels were more significant in patients with moderate/severe cGVHD compared to those of patients without cGVHD (P < 0.05). Stratified and multivariable logistic regression analysis demonstrated that moderate/severe cGVHD was an independent risk factor for the levels of anti-Ro52 (P < 0.01). ROC analysis confirmed anti-Ro52 as a risk factor for progression of skin cGVHD. Moreover, the anti-Ro52 levels were highly correlated with the levels of B cell-activating factor (BAFF) and IgG1 antibodies. Our study demonstrates that anti-Ro52 is associated with cGVHD. The increased levels of anti-Ro52 were associated with higher levels of BAFF and IgG1 antibodies, suggesting a mechanistic link between elevated anti-Ro52 levels and aberrant B cell homeostasis.
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- 2020
63. Association of Country-Specific Socioeconomic Factors With Survival of Patients Who Experience Severe Classic Acute Graft-vs.-Host Disease After Allogeneic Hematopoietic Cell Transplantation. An Analysis From the Transplant Complications Working Party of the EBMT
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Grzegorz W. Basak, Ahmet H. Elmaagacli, Igor Wolfgang Blau, Martin Bornhäuser, Christoph Scheid, Boris V. Afanasyev, Nicolaus Kröger, Gérard Socié, Olaf Penack, Gerald Wulf, Bernhard Kremens, Hildegard Greinix, Didier Blaise, Christophe Peczynski, Peter Dreger, Charlotte M. Niemeyer, Andrzej Frankiewicz, Ibrahim Yakoub-Agha, Sebastian Giebel, Christian P. Kratz, Claudia Rossig, Dietger Niederwieser, Alenca Harrington, Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,0301 basic medicine ,Medizin ,Graft vs Host Disease ,Disease ,Severity of Illness Index ,acute graft-vs.-host disease ,0302 clinical medicine ,Risk Factors ,Immunology and Allergy ,Medicine ,Registries ,ComputingMilieux_MISCELLANEOUS ,Original Research ,Univariate analysis ,Incidence ,Hematopoietic Stem Cell Transplantation ,Health Care Costs ,Transplant-Related Mortality ,Middle Aged ,Prognosis ,3. Good health ,Europe ,Treatment Outcome ,Acute Disease ,Disease Progression ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,health care expenditure ,Adult ,lcsh:Immunologic diseases. Allergy ,medicine.medical_specialty ,Adolescent ,Immunology ,transplant-related mortality ,Risk Assessment ,Young Adult ,03 medical and health sciences ,Transplant complications ,Internal medicine ,Humans ,Transplantation, Homologous ,hematopoietic cell transplantation ,Mortality ,Host disease ,Socioeconomic status ,Aged ,Retrospective Studies ,Hematopoietic cell ,business.industry ,Transplantation ,030104 developmental biology ,Socioeconomic Factors ,Health Care Surveys ,human development index ,business ,lcsh:RC581-607 ,030215 immunology - Abstract
Acute graft-vs.-host disease (aGvHD) is one of the most frequent causes of transplant-related mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). Its treatment is complex and costly. The aim of this study was to retrospectively analyze the impact of country-specific socioeconomic factors on outcome of patients who experience severe aGvHD. Adults with hematological malignancies receiving alloHCT from either HLA-matched siblings (n = 1,328) or unrelated donors (n = 2,824) developing grade 3 or 4 aGvHD were included. In univariate analysis, the probability of TRM at 2 years was increased for countries with lower current Health Care Expenditure (HCE, p = 0.04), lower HCE as % of Gross Domestic Product per capita (p = 0.003) and lower values of the Human Development Index (p = 0.02). In a multivariate model, the risk of TRM was most strongly predicted by current HCE (HR = 0.76, p = 0.006). HCE >median was also associated with reduced risk of the overall mortality (HR 0.73, p = 0.0006) and reduced risk of treatment failure (either relapse or TRM; HR 0.77, p = 0.004). We conclude that country-specific socioeconomic factors, in particular current HCE, are strongly associated with survival of patients who experience severe aGvHD. CA extern
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- 2020
64. Can Graft vs. Leukemia Effect Be Uncoupled From Graft vs. Host Disease? An Examination of Proportions
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Elizabeth Krieger and Amir A. Toor
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lcsh:Immunologic diseases. Allergy ,Opinion ,medicine.medical_specialty ,Graft-vs-Leukemia Effect ,T-Lymphocytes ,Immunology ,Receptors, Antigen, T-Cell ,Graft vs Host Disease ,Graft vs Leukemia Effect ,Gastroenterology ,whole exome sequencing ,Antigens, Neoplasm ,Internal medicine ,graft vs. leukemia effect ,medicine ,graft vs. host disease ,Humans ,Immunology and Allergy ,hematopoietic cell transplantation ,tumor vaccination ,Host disease ,Exome sequencing ,Leukemia ,business.industry ,Histocompatibility Antigens Class I ,Hematopoietic Stem Cell Transplantation ,High-Throughput Nucleotide Sequencing ,Tissue Donors ,Transplant Recipients ,business ,lcsh:RC581-607 - Published
- 2020
- Full Text
- View/download PDF
65. Short chain fatty acids: Postbiotics/metabolites and graft versus host disease colitis
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Mary Riwes and Pavan Reddy
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medicine.drug_class ,medicine.medical_treatment ,Antibiotics ,Allo hsct ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,Hematopoietic stem cell transplantation ,Article ,Cell therapy ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,medicine ,Humans ,Microbiome ,Colitis ,Host disease ,business.industry ,Hematology ,medicine.disease ,Fatty Acids, Volatile ,Gastrointestinal Microbiome ,surgical procedures, operative ,Graft-versus-host disease ,030220 oncology & carcinogenesis ,Immunology ,business ,030215 immunology - Abstract
Acute Graft versus host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo HSCT), a potent form of cellular therapy that has the potential to cure malignant and benign hematological conditions. Gastrointestinal (GI) GVHD is the principal cause of non-relapse mortality (NRM) after allo HSCT. Allo HSCT alters the intestinal microbiota and recent research uncovered a microbiome-metabolome axis that can affect intestinal homeostasis and mitigate the severity of experimental GI GVHD. This axis can potentially be manipulated via dietary intervention or through probiotics or postbiotics or antibiotics in humans. In this review we summarize major findings of how microbial metabolites and particularly short chain fatty acids (SCFAs) could impact acute GI GVHD.
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- 2020
66. Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Graft- versus -host disease
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Andréa Z Pereira, Afonso Celso Vigorito, Alessandro de Moura Almeida, Alexandre de Almeida Candolo, Ana Carolina Leão Silva, Ana Elisa de Paula Brandão-Anjos, Bianca Laselva de Sá, Catarina Lôbo Santos de Souza, Cláudio Galvão de Castro Junior, José Salvador Rodrigues de Oliveira, Juliana Bernardo Barban, Elaine Maria Borges Mancilha, Juliana Todaro, Lilian Pinheiro Lopes, Maria Cristina Martins de Almeida Macedo, Morgani Rodrigues, Paulo Cesar Ribeiro, Roberto Luiz da Silva, Telma Sigolo Roberto, Thays de Cássia Ruiz Rodrigues, Vergilio Antonio Rensi Colturato, Eduardo José de Alencar Paton, George Maurício Navarro Barros, Rosana Ducatti Souza Almeida, Maria Claudia Rodrigues Moreira, and Mary Evelyn Flowers
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Gastrointestinal Diseases ,Consensus Development Conferences as Topic ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Nutrição ,Graft versus host disease ,Bioinformatics ,Severity of Illness Index ,Special Article ,03 medical and health sciences ,0302 clinical medicine ,Artigo Especial ,Doença enxerto-hospedeiro ,Humans ,Medicine ,030212 general & internal medicine ,Host disease ,Nutrition ,business.industry ,Nutritional Requirements ,General Medicine ,Congresses as Topic ,Transplante de células-tronco hematopoéticas ,medicine.disease ,surgical procedures, operative ,Graft-versus-host disease ,030220 oncology & carcinogenesis ,Nutrition Therapy ,business ,Complication ,Brazil - Abstract
The Brazilian Consensus on Nutrition in Hematopoietic Stem Cell Transplantation: Graft- versus -host disease was approved by Sociedade Brasileira de Transplante de Medula Óssea , with the participation of 26 Brazilian hematopoietic stem cell transplantation centers. It describes the main nutritional protocols in cases of Graft- versus -host disease, the main complication of hematopoietic stem cell transplantation.
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- 2020
67. Feasibility of thiotepa addition to the fludarabine-busulfan conditioning with tacrolimus/sirolimus as graft vs host disease prophylaxis
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José Luis Piñana, Francesc Bosch, Guillermo Ortí, Irene García-Cadenas, Albert Esquirol, Anna Bosch Vilaseca, Olga Salamero, Elisa Roldán, Jordi Sierra, Silvana Saavedra, Pere Barba, Maria Laura Fox, Guillermo Villacampa, Juan Montoro, Rodrigo Martino, Jaime Sanz, Ariadna Pérez, Juan Carlos Hernández-Boluda, Carlos Solano, and David Valcárcel
- Subjects
Cancer Research ,medicine.medical_specialty ,Transplantation Conditioning ,Urology ,Graft vs Host Disease ,chemical and pharmacologic phenomena ,ThioTEPA ,Reduce intensity conditioning ,sirolimus and tacrolimus ,graft vs host disease prophylaxis ,Tacrolimus ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,reduce intensity conditioning ,medicine ,Humans ,Host disease ,Busulfan ,Retrospective Studies ,Sirolimus ,allogeneic hematopoietic cell transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Fludarabine ,surgical procedures, operative ,Oncology ,030220 oncology & carcinogenesis ,Feasibility Studies ,Conditioning ,Thiotepa-fludarabine-busulfan ,business ,Thiotepa ,Vidarabine ,030215 immunology ,medicine.drug - Abstract
In classical reduced-intensity conditioning (RIC) regimens, including the fludarabine and busulphan (BF) combination, sirolimus and tacrolimus (SIR-TAC) as graft vs host disease (GVHD) prophylaxis has shown acceptable results. The outcomes of SIR-TAC in a more intense RIC regimen as Thiotepa-fludarabine-busulfan (TBF) have been hardly investigated. This retrospective study included all consecutive patients receiving an allogeneic hematopoietic stem cell transplantation for myeloid malignancies (January 2009-2017) conditioned with either TBF or BF and receiving SIR-TAC. Patients receiving TBF presented higher non-relapse mortality (31.6 vs 12.3%,p = .01), along with shorter overall survival (51.8% vs 77.8%,p < .01) at 2 years than patients treated with BF. There were no significant differences in the cumulative incidence of grade II-IV acute GVHD or moderate-severe chronic GVHD or relapse between both groups. These results suggest that TBF does not seem to improve the traditional RIC BF regimen, at least when associated with SIR-TAC prophylaxis.
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- 2020
68. Extracorporeal Photopheresis (ECP) and the Potential of Novel Biomarkers in Optimizing Management of Acute and Chronic Graft vs. Host Disease (GvHD)
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Matthew Mankarious, Nick C. Matthews, John A. Snowden, and Arun Alfred
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lcsh:Immunologic diseases. Allergy ,0301 basic medicine ,medicine.medical_specialty ,extracorporeal photopheresis ,medicine.medical_treatment ,Immunology ,Graft vs Host Disease ,Disease ,Hematopoietic stem cell transplantation ,Review ,immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,Extracorporeal Photopheresis ,medicine ,Immunology and Allergy ,Effective treatment ,Animals ,Humans ,In patient ,dendritic cells ,Relapse risk ,Intensive care medicine ,Host disease ,GvHD ,business.industry ,apoptosis ,Hematopoietic Stem Cell Transplantation ,biomarkers ,030104 developmental biology ,surgical procedures, operative ,Photopheresis ,Chronic gvhd ,lcsh:RC581-607 ,business ,030215 immunology - Abstract
As the use of hematopoietic stem cell transplantation (HSCT) has become a more widespread and effective treatment for hematological malignant and non-malignant conditions, the need to minimize the harmful effects of graft- vs.-host disease (GvHD) has become more important in achieving good outcomes. With diagnosis of GvHD reliant on its clinical manifestations, research into biomarkers for the diagnosis, progression, and even for the prediction of disease, is imperative to combating the high levels of morbidity and mortality post-HSCT. Despite the development of novel treatment approaches to GvHD, corticosteroids remain the standard first-line treatment, with immunosuppressant therapies as second-line options. These strategies however have significant limitations and associated complications. Extracorporeal Photopheresis (ECP) has shown to be effective and safe in treating patients with symptomatic GvHD. ECP has been shown to have varied effects on multiple parts of the immune system and does not appear to increase the risk of relapse or infection in the post HSCT setting. Even so, ECP can be logistically more complex to organize and requires patients to be sufficiently stable. This review aims to summarize the potential role of biomarkers to help guide individualized treatment decisions in patients with acute and chronic GvHD. In relation to ECP, robust biomarkers of GvHD will be highly useful in informing patient selection, intensity and duration of the ECP schedule, monitoring of response and other treatment decisions alongside the concurrent administration of other GvHD therapies. Further research is warranted to establish how GvHD biomarkers are best incorporated into ECP treatment pathways with the goal of tailoring ECP to the needs of individual patients and maximizing benefit.
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- 2020
69. Establishing a standardized system for review and adjudication of chronic graft-vs-host disease data in accordance with the National Institutes Consensus criteria
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Samira Fatmi, Susan E. Prockop, Miguel-Angel Perales, Cristi Ciolino, Jimmy Nieves, Nicholas Webb, Chamberlain Nwanne, Doris M. Ponce, Djamilia Dierov, and Kara Mosesso
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medicine.medical_specialty ,business.industry ,Standardized approach ,General Engineering ,Consensus criteria ,Standardized test ,chemical and pharmacologic phenomena ,Article ,surgical procedures, operative ,immune system diseases ,Review of systems ,General Earth and Planetary Sciences ,Medicine ,Chronic gvhd ,Single institution ,business ,Intensive care medicine ,Host disease ,General Environmental Science ,Adjudication - Abstract
GVHD is a frequent complication following allo-HCT. The NIH consensus group established new guidelines for the evaluation of chronic GVHD. However, GVHD assessment remains challenging due its complexity and requirement for laborious evaluation. We, therefore, established a standardized approach for the assessment of chronic GVHD in accordance with the NCC guidelines. At a single institution, all allograft recipients were evaluated for GVHD within the first-year post allo-HCT following a 3-step workflow (real-time assessment, consensus review, and documentation). A GVHD adjudication committee was created and a dynamic electronic GVHD data capture form was developed guiding the clinician through a comprehensive review of systems following the NCC guidelines. We found that the assessment and reporting of GVHD reached 100% compliance. The establishment of an institutional GVHD adjudication committee enabled standardized assessment of GVHD. Our workflow can be adopted by other centers to create a similar framework for dedicated GVHD evaluation.
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- 2019
70. Dexamethasone palmitate is a feasible option for the treatment of chronic graft‐vs‐host disease, particularly with macrophage hyperactivation
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Tomonari Shigemura, Miyuki Tanaka, Daisuke Morita, Yozo Nakazawa, Mitsuo Motobayashi, Kazutoshi Komori, Yoshinaga Kurosawa, and Takumi Shibazaki
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Transplantation ,Hyperactivation ,business.industry ,Pediatrics, Perinatology and Child Health ,Immunology ,Medicine ,Macrophage ,Host disease ,business ,medicine.disease ,Serositis ,Dexamethasone ,medicine.drug - Published
- 2019
71. Diarrhea Post-HSCT
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Beatriz Morillo-Gutierrez and Mary Slatter
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medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,chemical and pharmacologic phenomena ,Effective management ,Immunosuppression ,Hematopoietic stem cell transplantation ,medicine.disease ,Diarrhea ,surgical procedures, operative ,Graft-versus-host disease ,immune system diseases ,Extracorporeal Photopheresis ,medicine ,medicine.symptom ,business ,Host disease ,Intensive care medicine - Abstract
Acute graft-versus host disease (GVHD) is one of most frequent complications of hematopoietic stem cell transplantation Acute GVHD is still a cause of significant morbidity and mortality and effort needs to be made in achieving an accurate diagnosis to guide effective management The diagnosis of acute GVHD is mostly clinical The backbone of treatment is induction of immunosuppression depending on the staging of GVHD Prevention of GVHD is of prime importance with the use of good donor matching or specific graft manipulations and adequate pretransplant conditioning
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- 2019
72. Extracorporeal photopheresis for graft-vs-host disease: A literature review and treatment guidelines proposed by the Nordic ECP Quality Group
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Stina Wichert, Fredrik Toss, Marietta Nygaard, and Gösta Berlin
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medicine.medical_specialty ,Side effect ,Quality Assurance, Health Care ,media_common.quotation_subject ,medicine.medical_treatment ,Graft vs Host Disease ,Disease ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,0302 clinical medicine ,Photopheresis ,Extracorporeal Photopheresis ,Medicine ,Animals ,Humans ,Transplantation, Homologous ,Quality (business) ,Host disease ,Intensive care medicine ,media_common ,Quality of Health Care ,Trauma Severity Indices ,business.industry ,Hematopoietic Stem Cell Transplantation ,Disease Management ,Hematology ,General Medicine ,medicine.disease ,Graft-versus-host disease ,030220 oncology & carcinogenesis ,Acute Disease ,Chronic Disease ,Practice Guidelines as Topic ,business ,030215 immunology - Abstract
Extracorporeal photopheresis (ECP) is one of the most used and established therapies for steroid-refractory graft-vs-host disease (GvHD), with a good effect to side effect profile. In this review, we present a summary of present literature and provide evidence-based treatment guidelines for ECP in GvHD. The guidelines constitute a consensus statement formed by the Nordic ECP Quality Group representing all ECP centres in the Nordic countries, and aims to facilitate harmonisation and evidence-based practice. In developing the guidelines, we firstly conducted a thorough literature search of original articles and existing guidelines. In total, we identified 26 studies for ECP use in acute GvHD and 36 in chronic GvHD. The studies were generally small, retrospective and heterogeneous regarding patient characteristics, treatment schedule and outcome assessment. In general, a majority of patients achieved partial response or better, but response rates varied by the organs affected. Head-to-head comparisons to other treatment modalities were lacking. Overall, we consider the quality of evidence to be low-moderate (GRADE) and encourage future prospective multi-armed trials to strengthen the present recommendations. However, despite limitations in evidence strength, standardised treatment schedules and regular follow-up are imperative to ensure the best possible patient outcome.
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- 2019
73. Interleukin-6 as Biomarker for Acute GvHD and Survival After Allogeneic Transplant With Post-transplant Cyclophosphamide
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Raffaella Greco, Francesca Lorentino, Rosamaria Nitti, Maria Teresa Lupo Stanghellini, Fabio Giglio, Daniela Clerici, Elisabetta Xue, Lorenzo Lazzari, Simona Piemontese, Sara Mastaglio, Andrea Assanelli, Sarah Marktel, Consuelo Corti, Massimo Bernardi, Fabio Ciceri, Jacopo Peccatori, Greco, R., Lorentino, F., Nitti, R., Lupo Stanghellini, M. T., Giglio, F., Clerici, D., Xue, E., Lazzari, L., Piemontese, S., Mastaglio, S., Assanelli, A., Marktel, S., Corti, C., Bernardi, M., Ciceri, F., and Peccatori, J.
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Male ,0301 basic medicine ,Multivariate analysis ,Post transplant cyclophosphamide ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Gastroenterology ,0302 clinical medicine ,immune system diseases ,Immunology and Allergy ,Original Research ,Bone Marrow Transplantation ,biology ,Hematopoietic Stem Cell Transplantation ,Transplant-Related Mortality ,Middle Aged ,Prognosis ,surgical procedures, operative ,Acute Disease ,Biomarker (medicine) ,Female ,Immunosuppressive Agents ,medicine.drug ,Adult ,lcsh:Immunologic diseases. Allergy ,medicine.medical_specialty ,Adolescent ,Cyclophosphamide ,overall survival ,Immunology ,transplant-related mortality ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,allogeneic hematopoietic stem cell transplantation ,Interleukin 6 ,Host disease ,Aged ,Proportional Hazards Models ,business.industry ,graft-vs.-host disease ,interleukin-6 ,Reproducibility of Results ,030104 developmental biology ,ROC Curve ,biology.protein ,business ,lcsh:RC581-607 ,Biomarkers ,030215 immunology - Abstract
Background: Although the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) has dramatically improved in the past decade, it is still compromised by transplant-related mortality (TRM), mainly caused by Graft-vs. -Host Disease (GvHD). Methods: We conducted a prospective observational study to ascertain the potential of serum interleukin-6 (IL6) levels, measured before conditioning and 7 days after allo-HSCT, in predicting acute GvHD, TRM and survival after allo-HSCT with Post-Transplant Cyclophosphamide (PT-Cy) based GvHD prophylaxis. Results: Between April 2014 and June 2017, we collected samples from 166 consecutive allo-HSCT patients. By ROC analysis, we identified a threshold of 2.5 pg/ml for pre-transplant IL6 and 16.5 pg/ml for post-transplant IL6. Both univariate and multivariate analyses confirmed the ability of high baseline IL6 levels to predict worse OS (HR 4.3; p < 0.01) and grade II–IV acute GvHD (HR 1.8; p = 0.04), and of high post-transplant IL6 to identify patients with worse OS (HR 3.3; p < 0.01) and higher risk of grade II–IV (HR 5; p < 0.01) and grade III–IV acute GvHD (HR 10.2; p < 0.01). In multivariate analysis, both baseline (HR 6.7; p < 0.01) and post-transplant high IL6 levels (HR 3.5; p = 0.02) predicted higher TRM. Conclusions: IL6 may contribute to the risk stratification of patients at major risk for aGvHD and TRM, potentially providing a window for additional prophylactic or preemptive strategies to improve the quality of life in the early post-transplant phase and the outcome of allo-HSCT.
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- 2019
74. PHARMACOECONOMIC ANALYSIS OF DIFFERENT METHODS FOR THE TREATMENT OF STEROID-REFRACTORY GRAFT-VERUS-HOST DISEASE: SINGLE-CENTER STUDY
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I. S. Moiseev, E. A. Burmina, B. V. Afanasyev, T. L. Galankin, E. I. Darskaya, A. V. Kozlov, Y. G. Fedukova, T. A. Bikova, L. S. Zubarovskaya, and A. A. Dotsenko
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Medicine (General) ,medicine.medical_specialty ,steroid-refractory ,business.industry ,Single Center ,Gastroenterology ,R5-920 ,pharmacoeconomics ,Internal medicine ,graft-versus-host disease ,Medicine ,allogeneic hematopoietic stem cell transplantation ,business ,Host disease ,Steroid refractory - Abstract
Introduction. Steroid-refractory graft-versus-host disease (srGVHD) is one of the most severe and life-threatening complications of allogeneic hematopoietic stem cell transplantation. Currently, there is no standard treatment for this complication. In addition, there is no data on the pharmacoeconomics of various methods in the Russian Federation. The objective is to compare the effectiveness and cost of treatment of acute and chronic srGVHD, as well as the use of different approaches in therapy. Material and methods. We have conducted a pilot study in 12 srGVHD patients treated with ruxolitinib and in 24 patients of wellmatched historical control, who treated with etanercept for the acute srGVHD and with extracorporeal photopheresis for chronic srGVHD. Results. The 6-month therapy of acute GVHD was associated with significantly higher cost than therapy of chronic GVHD (4.138±2.672 vs 1.862±1.122 thd. rub., р=0.004). The major factors driving up the costs were bacterial infections (р=0.022), opportunistic viral infections (р
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- 2018
75. HEMATOPOIETIC STEM CELL TRANSPLANTATION AND NEPHROPATHY
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N. N. Smirnova and N. B. Kuprienko
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medicine.medical_specialty ,Thrombotic microangiopathy ,Hematopoietic cell ,business.industry ,Acute kidney injury ,medicine.disease ,Gastroenterology ,Transplantation ,surgical procedures, operative ,immune system diseases ,Nephrology ,Internal medicine ,medicine ,Chronic gvhd ,Host disease ,business ,Target organ ,Kidney disease - Abstract
Hematopoietic cell transplantation (HCT) is becoming an increasing common treatment modality for a variety of diseases. Kidneys are recognized as a target organ of acute and chronic graft-versus host disease (GvHD).Glomerulopathy significantly limits patient life-time. Acute kidney injury occurs on average in 100 days after HCT in 15 – 73% of patients due to treatmentrelated toxity and radiation. Chronic GvHD is associated with chronic kidney disease. The majority of CKD after transplantation is idiopathic syndrome, thrombotic microangiopathy and nephrоtic syndrome.
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- 2018
76. ABO Blood Grouping Mismatch in Hematopoietic Stem Cell Transplantation and Clinical Guides
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Gholamhossein Tamaddon and Negin Shokrgozar
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medicine.medical_treatment ,Pure red cell aplasia ,chemical and pharmacologic phenomena ,Hematopoietic stem cell transplantation ,Review Article ,lcsh:RC254-282 ,immune system diseases ,ABO blood group system ,hemic and lymphatic diseases ,medicine ,Host disease ,Transplantation ,business.industry ,Hematopoietic stem cell transplantation, Major ABO mismatch, Minor ABO mismatch, Transfusion strategy ,Transfusion strategy ,Hematology ,Minor ABO mismatch ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Red blood cell ,medicine.anatomical_structure ,surgical procedures, operative ,Oncology ,Immunology ,Hemolytic reactions ,Major ABO mismatch ,business ,therapeutics - Abstract
Hematopoietic stem cell transplantation (HSCT) is a useful treatment. In contrast to solid organ transplantations, the use of ABO blood group mismatch is acceptable in HSCT. Immediate or late hemolytic reactions, pure red cell aplasia, delayed red blood cell recovery, and graft-versus -host disease are the results of this situation. This review shows the consequences of ABO-mismatched HSCT and its impacts on HSCT parameters, as well as providing clinical guides in this situation.
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- 2018
77. A Randomized Phase II Trial Comparing a Calcineurin Inhibitor-Free Graft-Versus-Host Disease Prophylaxis Regimen with Post-Transplantation Cyclophosphamide and Abatacept to Standard of Care
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Dimitrios Tzachanis, Carolyn Mulroney, James K. Mangan, Jodi Garrett, Michelle Padilla, Caitlin Costello, Peggy Breslin, Kimberly McConnell, Divya Koura, Edward D. Ball, Aaron M. Goodman, and Joseph Maroge
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medicine.medical_specialty ,Standard of care ,Free graft ,business.industry ,Abatacept ,Post transplantation cyclophosphamide ,Immunology ,Urology ,Cell Biology ,Hematology ,Biochemistry ,Calcineurin ,Regimen ,medicine ,Host disease ,business ,medicine.drug - Abstract
Background: Graft versus host disease (GVHD) is one the major causes of mortality and morbidity after an allogeneic stem cell transplantation. We hypothesized that we can induce post-transplant tolerance by using the combination of post-transplant cyclophosphamide (PTCy) and abatacept (CTLA4Ig) for GVHD prophylaxis. PTCy when given on Days +3 and +4 can eliminate host-reactive donor T cells. CTLA4Ig blocks the costimulatory signals given through CD28 to naïve donor T cells thus favoring an anergic phenotype that promotes tolerance towards recipient derived antigens. CTLA4Ig gives an activating signal to NK cells and therefore has the ability to preserve the graft-versus-tumor effect. Methods: We have initiated a 50 patient randomized clinical trial. Patients with hematologic malignancies in need of a transplant and with an 8/8 matched donor are randomized 1:1 to tacrolimus and methotrexate for GVHD prophylaxis (standard of care arm) or PTCy on days +3 and +4 followed by CTLA4Ig on days +5, +14,+28, +56, +84, +112, +140 and +168. Patients are stratified by conditioning regimen (myeloablative vs reduced intensity) and by donor type (matched sibling vs matched unrelated donor). The primary endpoint is chronic GVHD at 1 year as a marker of tolerance induction. Secondary endpoints include acute GVHD rate, relapse rate, overall survival, GVHD-relapse-free-survival, transplant related mortality and infection rate. Post-transplantation immune reconstitution studies include measuring T cell and NK cell phenotype, PD-1 expression, and alloreactivity to recipient and third party at predetermined time points. Results: 25 patients have been treated on this study, 10 of which are on the experimental arm. Patients on the experimental arm have been followed for up to 516 days post-transplant. So far no cases of chronic GVHD or grade 3-4 acute GVHD have been observed in the experimental arm. All the patients have engrafted and there have been no treatment related deaths. Conclusions: The combination of PTCy and CTLA4Ig for GVHD prophylaxis is feasible. This ongoing study will examine its ability to induce post-transplant tolerance. Disclosures Tzachanis: Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Partner: Consultancy; Fate Therapeutics: Research Funding; Genentech: Research Funding; Bristol Myers Squibb: Research Funding; Incyte: Research Funding; EUSA: Consultancy; Takeda: Consultancy, Speakers Bureau; Magenta: Consultancy; Kyowa Kirin: Consultancy. Goodman: Seattle Genetics: Consultancy, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria. Mangan: Elevate Bio: Other: ad board. OffLabel Disclosure: abatacept: using as part of graft versus host disease prophylaxis
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- 2021
78. Patient-Reported Outcomes (PROs) Among Patients With Steroid-Refractory or -Dependent Chronic Graft-vs-Host Disease (cGVHD) Randomized to Ruxolitinib (RUX) vs Best Available Therapy (BAT)
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Franco Locatelli, Tommaso Stefanelli, Valkal Bhatt, Shashikant Apte, Nada Hamad, Stephanie J. Lee, Francesca Bonifazi, Takanori Teshima, Jackie Han, Kentaro Fukushima, Maanasa Gowda, Ivan S. Moiseev, Juan Carlos Vallejo Llamas, Joseph Pidala, Francis Ayuk, Robert Zeiser, Tsila Zuckerman, and Mike Zuurman
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Oncology ,Ruxolitinib ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Internal medicine ,Medicine ,business ,Host disease ,Steroid refractory ,medicine.drug - Abstract
BACKGROUND Approximately 50% of patients (pts) who receive initial cGVHD therapy are steroid refractory or dependent (SR/D); standard second-line therapy has yet to be established. Quality of life (QOL) in these pts is poor and worsens with disease severity. In the phase 3 REACH3 study in SR/D cGVHD (NCT03112603), RUX demonstrated superior efficacy compared with BAT, with a higher overall response rate at wk 24 (primary endpoint), longer failure-free survival, and a higher proportion of pts with a significant improvement in symptoms on the cGVHD-specific modified Lee Symptom Scale (mLSS; 24.2% vs 11.0% at wk 24; P=0.001) (Zeiser NEJM 2021). Given the significant impact of symptoms on QOL, the collection of PROs is recommended by NIH consensus criteria, and assessing QOL via PRO measures specifically designed to capture cGVHD symptoms (ie, the mLSS) is important in evaluating treatment. We present an analysis of PROs in REACH3 and compare mLSS subscale results with objective organ responses (data cutoff: May 8, 2020). METHODS Pts ≥12 years old with moderate or severe SR/D cGVHD were randomized (1:1) to RUX 10 mg twice daily or investigator-selected BAT (prespecified from 10 options). Randomized treatment was administered for ≥6 cycles (28 d/cycle) along with corticosteroids ± a calcineurin inhibitor. Addition or initiation of a new systemic agent for cGVHD was considered treatment failure. PROs were collected at baseline and at 4-wk intervals through wk 24 or until treatment failure or discontinuation from the main study period. The rate of responders per improvement of ≥7 points from baseline in mLSS summary score (0 [no symptoms] to 100 [worst symptoms]) at wk 24 was a key secondary endpoint (alpha controlled). Additional endpoints were individual organ response and changes in other PROs (Functional Assessment of Cancer Therapy-Bone Marrow Transplantation [FACT-BMT], EQ-5D-5L, Patient Global Impression of Severity [PGIS], Patient Global Impression of Change [PGIC]). mLSS data at wk 24 were available for 55.8% of RUX pts (92/165) and 53.0% of BAT pts (87/164) (see Table for pts evaluable for other PROs) . RESULTS A total of 329 pts received RUX (n=165) or BAT (n=164). Baseline characteristics, including symptom burden, were balanced between arms; 48% and 52% of pts had moderate or severe cGVHD, respectively. The baseline median summary mLSS score was 18.7 (RUX) vs 18.5 (BAT), indicating a moderate symptom burden. More pts receiving RUX had an mLSS response at wk 24, at any time up to wk 24, and for ≥2 consecutive visits than those receiving BAT (Table). RUX was associated with a rapid and continued reduction in mean summary mLSS symptom score, whereas only an initial reduction at wk 4 was seen with BAT (Figure 1). In subset analysis, mLSS response was similar in RUX pts with moderate and severe cGVHD. Among pts achieving a complete or partial cGVHD response, those treated with RUX were more likely to have an mLSS response (RUX, 40.2%; BAT, 28.6%). Response rates in mLSS subscales were higher with RUX vs BAT (odds ratio, >1.7; P More pts receiving RUX than BAT reported "no symptoms" (28.6% vs 17.3%) according to PGIS and were "very much better" or "moderately better" (63.1% vs 39.5%) based on PGIC. RUX treatment also had a positive effect on non-cGVHD-specific PRO measures (EQ-5D-5L and FACT-BMT) at wk 24. CONCLUSIONS Compared with BAT, RUX resulted in more substantial improvement in PROs, with rapid, continued symptom improvement and benefits across mLSS subscales, indicating that RUX is superior to BAT not only in physician-assessed responses but also in terms of treating patients' cGVHD symptoms. EQ-5D-5L and FACT-BMT scores were numerically higher with RUX than BAT, but the smaller changes suggest that these measures are too generic to fully capture the impact of cGVHD on QOL while confirming that multidimensional QOL was not reduced with RUX or BAT. Importantly, the pt experience of organ-specific symptom improvements was consistent with physician-assessed objective organ responses and both were greater with RUX. Figure 1 Figure 1. Disclosures Lee: Amgen: Research Funding; AstraZeneca: Research Funding; Incyte: Other: Membership on Steering Committee, Research Funding; Kadmon: Research Funding; Novartis: Research Funding; Pfizer: Consultancy, Research Funding; Syndax: Research Funding; Takeda: Research Funding; 4SC: Consultancy; EMD Serono: Consultancy, Research Funding; Genzyme: Consultancy; Merck Sharpe Dohme: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; BMS: Research Funding; Wolters Kluwer: Research Funding. Locatelli: Miltenyi: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Ayuk: Gilead: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene/BMS: Honoraria; Miltenyi Biomedicine: Honoraria; Novartis: Honoraria. Zuckerman: Gilead Sciences: Honoraria, Speakers Bureau; Novartis: Honoraria; AbbVie: Honoraria; BioSight Ltd: Honoraria; Orgenesis Inc.: Honoraria; Janssen: Honoraria; Cellect Biotechnology: Honoraria. Pidala: Pharmacyclics: Other: Clinical trial support, Research Funding; BMS: Other: Clinical trial support, Research Funding; Novartis: Other: Clinical trail support; Takeda: Other: Clinical trail support; Jannssen: Other: Clinical trial support; Johnson and Johnson: Other; AbbVie: Other; BMS: Other; Incyte: Consultancy; Regeneron: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zeiser: Incyte, Mallinckrodt, Novartis: Honoraria, Speakers Bureau. Bhatt: Incyte: Current Employment. Gowda: Novartis: Current Employment. Han: Novartis: Current Employment. Stefanelli: Novartis: Current Employment, Current equity holder in publicly-traded company. Zuurman: Novartis: Current Employment. Teshima: Pfizer Inc.: Honoraria; Astellas Pharma Inc.: Research Funding; TEIJIN PHARMA Limited: Research Funding; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Nippon Shinyaku Co., Ltd.: Research Funding; Bristol Myers Squibb: Honoraria; Gentium/Jazz Pharmaceuticals: Consultancy; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; Janssen Pharmaceutical K.K.: Other; Fuji pharma CO.,Ltd: Research Funding; Sanofi S.A.: Research Funding.
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- 2021
79. Selective Targeting of Immune Modulatory Proteins to Mitigate Fibrosis and Inflammation in Sclerodermatous Graft-Vs-Host Disease
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Sally Arai, Cristabelle De Souza, Lu Cui, Kerri E. Rieger, Bernice Y. Kwong, Sebastian Fernandez-Pol, Ryanne A. Brown, Tristan Lerbs, Gerlinde Wernig, Atif Saleem, Jessica Poyser, Judith A. Shizuru, Maryam Kooshesh, and Antonia Ms Mueller
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business.industry ,Immunology ,Inflammation ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Immune system ,Fibrosis ,medicine ,medicine.symptom ,business ,Host disease - Abstract
Chronic graft-vs-host disease (cGVHD) is a major obstacle to the success of allogeneic hematopoietic stem cell transplantation (HCT) in patients. This debilitating condition is characterized by chronic inflammation, cell-mediated and humoral immunity, and ultimately tissue fibrosis. There is currently little or no understanding of the molecular pathogenesis of chronic cGVHD resulting in poor effective treatment strategies. Sclerodermatous GVHD (sclGVHD) is one of the more severe forms of cGVHD associated with poor prognosis and low sensitivity to immune suppressive therapy. Methods: To address the current gap in knowledge pertaining to the underlying pathophysiology of sclGVHD we used single cell RNA sequencing analyses on fresh patient biopsy specimens. In vivo studies were carried out by sub lethal irradiation of BALB.k recipients which underwent HCT from miAg-mismatched AKR/J donors. Recipient sclerodermatous-tissues were analyzed using FACS, IHC and IF staining. Human studies were conducted on (i) Primary samples from patients with severe sclGVHD using tissue microarrays (TMA) by Immuno-histofluorescence (IHF) and IF. (ii) Dermal fibroblasts from sclGVHD samples were subjected to ATACseq and ChiPseq CRISPR-Cas9 JUN deletion. (iii) Also, dermal fibroblasts from human scl-GVHD were implanted under the kidney capsule of NSG mice to study the effects of inhibiting pro-fibrotic pathways in vivo. Results: We show for the first time that in a mouse model of sclGVHD (male), recipients of female T-cell replete grafts developed severe scleroderma with massive skin thickening and collagen deposition. Fibroblasts strongly expressed JUN, which is part of AP-1, a transcription factor involved in the acute phase response that regulates gene expression in response to stimuli from cytokines, growth factors and pathogens. We have previously demonstrated JUN as a key player in the molecular pathogenesis of other fibrotic diseases (Wernig G et al. PNAS 2017, Cui et al. Nature comm. 2020, Lerbs et al. JCI i 2020). Likewise, CD47, an immune checkpoint protein that prevents removal of Mϕ, was strongly co-expressed in fibroblasts in sclGVHD - but not in the control mice (Fig A+B). Here we show that (i) In humans, (n = 45 sclGVHD patients), there is a strong expression and activation of JUN and CD47 in dermal fibroblasts which was not observed in control samples. Mixed inflammatory infiltrates were dominated by Mϕ and granulocytes. (ii) Isolated primary fibroblasts from fresh human sclGVHD skin biopsies analyzed for chromatin accessibility across the genome by ATAC-seq showed wide open accessibility to the JUN promoter, IL-6 promoter and CD47 enhancer and promoter indicating that they play a critical role in regulating the pathogenesis of sclGVHD. In contrast, normal fibroblasts displayed only minimal accessibility to the JUN promoter. We further validated our data using CRISPR-Cas9 knock-down studies on sclGVHD fibroblasts and show that the IL-6 promoter, enhancer and promoter of CD47 are regulated by JUN, with JUN deletion resulting in significant decrease in the promoter binding accessibility to IL-6 and CD47 (Fig C). Further, JUN activity appears to regulate key members of the Hh signaling pathway (GLI1, PTCH1 and PTCH2), as their chromatin accessibility was decreased with JUN deletion. These correlative findings were confirmed by JUN ChIP seq, an assay that identifies binding sites of DNA-associated proteins. (iii) To test our findings in vivo we established xenograft models of primary human sclGVHD by implanting cells under the kidney capsule of NSG mice.All treatments (except placebo) resulted in decreased fibrosis (Fig D), presumably by blocking the activation of JUN (pJUN) and its profibrotic downstream pathway members IL-6 and pSTAT3, as assessed by phospho flow. Conclusion: In our studies we demonstrate that in established SclGVHD, combinatorial therapy consisting of anti-CD47 antibody together with IL6 blockade has the highest potential to translate into a therapeutic intervention given its ability to be more effective than currently used antifibrotic and anti-inflammatory agents in clinic. The findings from our study are significant because we show an important mechanism underlying SclGVHD onset, identify a novel genetic signature that can be targeted, describe a new mouse model and a clinical assay that has a high throughput readout and suggest a treatment regimen for patients. Figure 1 Figure 1. Disclosures Arai: Magenta Therapeutics: Research Funding. Shizuru: Forty seven Inc: Other: Inventor on a patent licenses by Forty Seven. Forty seven was acquired by Gilead in 2020; Jasper Therapeutics, Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Chair of scientific advisory board.
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- 2021
80. A Calcineurin Inhibitor Free Graft Versus Host Disease (GVHD) Prophylaxis for Patients Undergoing Matched Related (MRD) and Matched Unrelated Donor (MUD) Allogeneic Hematopoietic Cell Transplant (Allo-HCT)
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Mohamed A. Kharfan-Dabaja, Ernesto Ayala, Zhuo Li, Madiha Iqbal, Kaitlyn M Brannick, Felipe Andres Mendieta Nieto, Vivek Roy, James M. Foran, and Hemant S. Murthy
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Hematopoietic cell ,Free graft ,business.industry ,Immunology ,Cell Biology ,Hematology ,Matched Unrelated Donor ,Biochemistry ,Calcineurin ,surgical procedures, operative ,Gvhd prophylaxis ,Medicine ,Host disease ,business - Abstract
Introduction Post-transplantation cyclophosphamide (PTCy) and calcineurin inhibitor (CNI) based GVHD prophylaxis has shown lower rates of acute and chronic GVHD when compared with the traditional prophylaxis of calcineurin inhibitor (CNI) and methotrexate (MTX) in matched donor (related and unrelated) allo-HCT. The combination of PTCy with sirolimus as a calcineurin inhibitor-free GVHD prophylaxis has shown promising results with cumulative rates of grade II-IV acute and chronic GVHD in the range of 15-27% and 20-27% respectively in patients undergoing matched and haploidentical allo-HCT. We report a single center, nonrandomized comparison of patients undergoing matched donor allo-HCT receiving PTCy in combination with sirolimus (PTCy/Siro) with those receiving the standard GVHD prophylaxis of tacrolimus and MTX (Tac/MTX). Methods One hundred and sixteen consecutive patients who had undergone a MRD or MUD allo-HCT between January 2018 to January 2021 and received either PTCy with sirolimus or tacrolimus with methotrexate as GVHD prophylaxis regimens were eligible for inclusion. The selection of PTCy with sirolimus or tacrolimus with methotrexate as GVHD prophylaxis regimen was based on physician choice. Primary endpoints were cumulative incidence of acute (grade II to IV) and chronic GVHD. Secondary endpoints were a) neutrophil and platelet engraftment; b) overall survival (OS); c) non-relapse mortality (NRM); d) relapse; e) clinical infections and f) time to immunosuppression (IS) withdrawal. Kaplan-Meier method was used to estimate 1-year and 2-year freedom from long term adverse events, including chronic GVHD, relapse, NRM and OS. All tests were two-sided with alpha level set at 0.05 for statistical significance. Results Out of a total of 116 patients undergoing MRD and MUD allo-HCT, 29 received PTCy/Siro and 87 Tac/MTX. Baseline characteristics were similar between the two arms except patients in PTCy/Siro were younger with median of 48 (range: 24-69) years vs. 61 (range: 20-73) years (p=0.004) in Tac/MTX. There was difference in primary indication for allo-HCT between the two arms with non-hodgkin lymphoma (NHL) being the most common in PTCy/Siro and acute myeloid leukemia (AML) in the Tac/MTX group. Patients receiving PTCy/Siro had a significantly higher median CD3 day 100 chimerism at 100 (90-100) vs. 90 (40-100) % ( Conclusion In this study, the combination of PTCy/Siro is associated with a significantly lower risk of chronic GVHD when compared against the traditional GVHD prophylaxis of CNI and methotrexate, despite significantly earlier IS withdrawal. Other long-term outcomes of interest remained comparable between the two arms. Chronic GVHD contributes to significant morbidity and mortality in patients undergoing allo-HCT. Newer strategies to limit the impact of chronic GVHD are needed. The results of our study warrant validation in a large, multicenter, randomized prospective trial. Figure 1 Figure 1. Disclosures Murthy: CRISPR Therapeutics: Research Funding. Foran: gamida: Honoraria; takeda: Research Funding; novartis: Honoraria; trillium: Research Funding; boehringer ingelheim: Research Funding; OncLive: Honoraria; abbvie: Research Funding; certara: Honoraria; sanofi aventis: Honoraria; syros: Honoraria; taiho: Honoraria; revolution medicine: Honoraria; bms: Honoraria; servier: Honoraria; pfizer: Honoraria; actinium: Research Funding; aptose: Research Funding; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.
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- 2021
81. Corticosteroid Treatment Impairs Epithelial Regeneration, Limiting Intestinal Recovery in Experimental Graft Vs Host Disease
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Chen Liu, Shuichiro Takashima, Marliek van Hoesel, Jason Kuttiyara, Govindarajan Thangavelu, Bruce R. Blazar, Paola Vinci, Alan M. Hanash, Suze A. Jansen, Caroline A. Lindemans, Winston Chang, Marco Calafiore, Anastasiya Egorova, and Viktor Arnhold
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business.industry ,Regeneration (biology) ,Immunology ,Corticosteroid treatment ,Medicine ,Cell Biology ,Hematology ,Limiting ,Host disease ,business ,Biochemistry - Abstract
Corticosteroids (CS) represent first-line treatment for gastrointestinal graft vs host disease (GI GVHD), and CS failure is associated with severe morbidity and mortality. While the immune system is the intended target of CS treatment, the glucocorticoid receptor (GR) is widely expressed, and there is limited understanding of the direct effects of CS on intestinal epithelium following immune-mediated damage. We thus investigated how CS treatment could impact intestinal homeostasis and regeneration following experimental bone marrow transplantation (BMT). In healthy C57BL/6 (B6) mice, in vivo administration of clinically relevant CS doses reduced Ki67 + epithelial proliferation in the ileum (p We next investigated CS effects on epithelial cells during immune-mediated damage. Pre-treatment of mice with 2 mg/kg MP x 7 days in vivo prior to crypt harvest and organoid culture increased organoid sensitivity to T-cell-mediating killing ex vivo (p Despite potential harmful side effects, CS are frequently necessary for treatment of clinical GVHD. We hypothesized that CS-mediated epithelial suppression could be mitigated by concurrent administration of agents capable of inducing tissue regeneration. Interleukin-(IL)-22 has been shown to promote epithelial proliferation and recovery following GI damage. We thus investigated whether IL-22 treatment could counterbalance CS-induced impairment of epithelial recovery in GVHD. Indeed, addition of IL-22 to MP-treated organoids promoted organoid growth without inducing toxicity/organoid loss in both murine and human SI organoid cultures (p In summary, these findings indicate that CS treatment can suppress epithelial proliferation in the intestines and exacerbate GI damage if it fails to control the pathologic immune response. However, deleterious CS side effects can be counterbalanced by promotion of epithelial regeneration, providing rationale for combining immunosuppression with tissue-supporting therapeutics such as IL-22 to optimize intestinal recovery in GVHD. Figure 1 Figure 1. Disclosures Blazar: Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; BlueRock Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rheos Medicines: Research Funding; Equilibre Pharmaceuticals Corp: Research Funding; Carisma Therapeutics, Inc: Research Funding; Tmunity Therapeutics: Other: Co-founder. Hanash: Evive Biotech: Ended employment in the past 24 months.
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- 2021
82. Graft-Vs-Host Disease (GvHD) Prophylaxis with Post-Transplant Cyclophosphamide (PTCy) and Thymoglobulin (ATG) Are More Important Determinants of Cytomegalovirus (CMV) Reactivation after Allogeneic Hematopoietic Cell Transplantation (HCT) Than Ex-Vivo T-Cell Depletion in the Era of Pre-Emptive Therapy
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Liang Piu Koh, Chun Tsu Lee, Michelle Poon, Lip Kun Tan, Yin Teng Koh, Yang Liang Boo, Lip Leong Chong, and Chelsea Chia
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Thymoglobulin ,Hematopoietic cell ,Post transplant cyclophosphamide ,business.industry ,Immunology ,Congenital cytomegalovirus infection ,Cell Biology ,Hematology ,Cmv reactivation ,medicine.disease ,Biochemistry ,Transplantation ,medicine ,Host disease ,business ,Ex vivo - Abstract
Background: Cytomegalovirus (CMV) is a common cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) despite major advances in diagnostic techniques and antiviral prophylactic strategies. The relative impacts of donor/recipient CMV serologic status, disease-specific and transplant-related prognostic factors on the risk of CMV reactivation and survival are undefined. Methods: We studied the outcome of 199 patients (median age, 46 years; range 17-71 years) receiving allogeneic HCT at National University Cancer Institute of Singapore (NCIS) between January 2016 and December 2020. Their hematologic diseases included AML (n=92), ALL (n=46), MDS (n=19), lymphomas (n=19), MPN (n=7) and others (n=16) such as refractory myelomas and aplastic anemias. The conditioning regimens used were either myeloablative (n=80) or reduced intensity conditioning (n=119) prior to an allograft from different donor sources. T-cell depletion (TCD) was used for GVHD prophylaxis in 124 patients; and this included post-transplant cyclophosphamide (PTCy, n=31), ex-vivo T-cell receptor alpha-beta / CD45RA depletion (TCRab/CD45RA) (ex-vivo TCD, n=31) for haploidentical HCT, or thymoglobulin (ATG, n=62) for matched unrelated donor (MUD) HCT. Results: With a median follow-up duration of 15.6 months (range, 0.2-63.6 months), 136 (68.3%) patients had CMV reactivation (median onset, 27.5 days) while 6 (3.0 %) patients developed clinically significant CMV disease, such as colitis, retinitis and encephalitis. The cumulative incidences of CMV reactivation within the first 100 days among the recipients of matched unrelated donor (MUD) (n=60), mismatched related donor or unrelated donor (MMRD/MMUD) (n=60), umbilical cord blood (UCB) (n=18) and matched related donor (MRD) (n=61) HCT were 71.6 %, 61.7 %, 50.0 % and 32.7 %, respectively (p There were no statistically significant differences in overall survival (OS, p=0.830) and disease-free survival (DFS, p=0.983) at 5 years between CMV-seropositive (D+/R+ or D-/R+, n=181) and CMV-seronegative recipients (D-/R- or D+/R-, n=18). There were also no significant differences in the cumulative incidences of CMV reactivation within 100 days (p=0.879), CMV end-organ disease (p=0.522) and non-relapse mortality (NRM, p=0.202), respectively. HCT-CI score of ≥1 (p=0.005) and the use of reduced intensity conditioning regimen (p The secondary objective of this study was to determine the risk factors associated with CMV reactivation within the first 100 days post-transplant. There was no statistically significant impact of the donor or recipient CMV serostatus (p=0.790) on the risk of CMV reactivation. In multivariable analysis, the use of any T-cell depletion (p Conclusions: Our study concluded that CMV serologic status did not affect the incidence of CMV reactivation, NRM, OS and DFS in patients undergoing allogeneic HCT. The use of PTCy and ATG for GVHD prophylaxis, remains the most important risk factor for CMV reactivation in the era of pre-emptive therapy and hence, the need for aggressive prevention strategies in this vulnerable group of patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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- 2021
83. Incidence and Risk Factors Associated with Fatal Graft Vs Host Disease after Solid Organ Transplantation in United Network of Organ Transplant Database
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Pranav Tenneti, Jiaxian He, Edward A. Copelan, Belinda R. Avalos, Pavan Tenneti, Peter N. Lalli, Michael R. Grunwald, and Srinivasa R. Sanikommu
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medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Organ transplantation ,surgical procedures, operative ,Internal medicine ,medicine ,Solid organ transplantation ,Host disease ,business - Abstract
INTRODUCTION Graft vs host disease (GVHD) is a rare complication after solid organ transplantation ( ̴ 1-2% with liver and ̴ 5.6% with intestines), but is associated with high mortality (70-80%). In contrast to GVHD following hemopoietic stem cell transplant, bone marrow infiltration by donor T lymphocytes leading to cytopenia ( ̴ 80%) is a common manifestation of GVHD after solid organ transplantation (Murali et. al., 100(12), Transplantation, January 2016). The risk factors associated with GVHD occurring after solid organ transplantation have not been well characterized, but single institution studies have suggested donor/recipient (D/R) HLA mismatch, ABO incompatibility and gender mismatch playing important roles. However, some studies have identified that similarities in HLA type which permit mismatches unrecognized by the recipient as a common mechanism preventing rejection of donor lymphocytes, which then can cause GVHD in the recipient. In order to evaluate potential risk factors, we reviewed the transplant data of patients in whom GVHD was listed as the cause of death from United Network of Organ transplant database (UNOS), the database that contains all US organ transplant data. METHODS From the UNOS database we obtained information of patients that underwent liver or intestinal transplantation between 1987-2020 in the US. The patients for whom GVHD was reported as the cause of death were identified. Baseline D/R and transplant variables were collected. Patient or transplant related characteristics were presented via descriptive statistics. Corresponding P-values were determined using Chi-square test for categorical variables and two-sample t-test for continuous variables. The incidence of mortality caused by GVHD was estimated using the cumulative incidence method, accounting for non-GVHD related death as a competing risk. All statistical tests were two sided, and a P-value < 0.05 was considered significant. RESULTS Of a total of 179,355 patients that underwent liver transplantation, 216 (0.1%) patients had GVHD identified as the primary cause of death (GVHD group). The HLA mismatch information was available in 86,434 patients (48.2%). HLA mismatch was grouped into low level (0-3) and high level (4-6). Low level HLA mismatch was 24.6% in the GVHD group compared to 16.2% in patients that are alive or died of non-GVHD related causes (non-GVHD group). High level mismatch was 75.4% in GVHD group and 83.8% in the non-GVHD group (P=0.013). Other risk factors including gender mismatch (40.3% vs 42.5%, P=0.536), ABO incompatibility between D/R (0.5% vs 1.4%, P=0.42) and use of live donors (1.9% vs 4.3%, p= 0.09) were similar between the two groups. Patients in the GVHD group were older with median age of recipient being 59 years compared to 53 years in the non-GVHD (P Of a total of 3,153 patients that underwent intestinal transplantation, 20 (0.6%) patients had GVHD identified as the primary cause of death (GVHD group). The HLA mismatch information was available in 2859 patients (90.6%).The high-level HLA mismatch (83.3% vs 84.7%, P=0.749), gender mismatch (40% vs 47.1%, P=0.655) and ABO incompatibility (0% vs 0.2%, P=0.757) between D/R were similar between the GVHD group and non-GVHD group among intestinal transplant patients. Conclusions In patients that undergo hematopoietic stem cell transplant, HLA and gender mismatch between D/R have been recognized as risk factors for GVHD. Based on the largest analysis of solid organ transplant database, traditionally considered GVHD risk factors like HLA and gender mismatch between D/R do not appear to be significantly associated with severe GVHD leading to death. Recipient age and graft failure are significantly associated with GVHD related deaths in liver transplant patients. These findings suggest that other risk factors for severe GVHD leading to death after solid organ transplant than those previously reported in single institution studies should be examined and underscore the need for additional studies. Figure 1 Figure 1. Disclosures Grunwald: Med Learning Group: Other; Agios: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Research Funding; Amgen: Consultancy; Pfizer: Consultancy; PRIME: Other; PER: Other; Karius: Consultancy; Sierra Oncology: Consultancy; Blueprint Medicines: Consultancy; Incyte: Consultancy, Research Funding; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy; Stemline: Consultancy; Gilead: Consultancy; Cardinal Health: Consultancy; Trovagene: Consultancy; MDEdge: Other. Copelan: Amgen: Consultancy.
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- 2021
84. Florida Pediatric Bone Marrow Transplant and Cell Therapy Consortium (FPBCC) Use of Rituximab in Conditioning and Effects on Survival and Chronic Graft Vs Host Disease (cGVHD)
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Michael Joyce, Jorge Galvez Silva, Gauri Sunkersett, Fan Yang, Biljana Horn, Benjamin Oshrine, Deepak Chellapandian, Paul Castillo, Jing Zhao, Jessica Cline, Warren Alperstein, and Edward Ziga
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Oncology ,Transplantation ,medicine.medical_specialty ,Bone marrow transplant ,business.industry ,Cell Biology ,Hematology ,Cell therapy ,Internal medicine ,medicine ,Molecular Medicine ,Immunology and Allergy ,Rituximab ,Host disease ,business ,medicine.drug - Published
- 2021
85. Interim Analysis of a Prospective Study of Itolizumab for Treatment of Chronic Graft VS Host Disease Following Haematopoietic Stem Cell Transplantation
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Sharat Damodar, K.S. Nataraj, Bharath Ram, Shilpa Prabhu, and Aditi Shah
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Oncology ,Transplantation ,medicine.medical_specialty ,business.industry ,Itolizumab ,Cell Biology ,Hematology ,Interim analysis ,Haematopoiesis ,Internal medicine ,medicine ,Molecular Medicine ,Immunology and Allergy ,Stem cell ,Prospective cohort study ,business ,Host disease ,medicine.drug - Published
- 2021
86. Failure of Pre-Emptive Graft-Vs-Host Disease (GVHD) Therapy Due to Irreproducibility of GVHD-Predicting Biomarkers
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Faisal Masood Khan, Andrew Daly, Amit Kalra, Rutvij A. Khanolkar, and Jan Storek
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Transplantation ,business.industry ,Immunology ,Molecular Medicine ,Immunology and Allergy ,Medicine ,Cell Biology ,Hematology ,Host disease ,business - Published
- 2021
87. Pneumatosis Is a Rare but Serious Manifestation of Gastrointestinal Graft-Vs.-Host Disease Following Allogeneic Stem Cell Transplant
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William J. Hogan, Kimberly J. Langer, Hassan B. Alkhateeb, Mark R. Litzow, Mithun V. Shah, and Jason R. Young
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Transplantation ,business.industry ,Immunology ,Molecular Medicine ,Immunology and Allergy ,Medicine ,Cell Biology ,Hematology ,Stem cell ,Host disease ,business - Published
- 2021
88. A Phase 2/3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Alpha-1 Antitrypsin (AAT) for the Prevention of Acute Graft Vs Host Disease (aGVHD) in Patients Receiving Hematopoietic Cell Transplant (HCT)
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John Magenau, Christine Voigt, John Mallee, Scott Adler, and H. Joachim Deeg
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Transplantation ,medicine.medical_specialty ,Hematopoietic cell ,business.industry ,Placebo-controlled study ,Alpha (ethology) ,Cell Biology ,Hematology ,Gastroenterology ,Double blind ,Internal medicine ,medicine ,Molecular Medicine ,Immunology and Allergy ,In patient ,Host disease ,business - Published
- 2021
89. Ruxolitinib (RUX) Vs Best Available Therapy (BAT) in Patients (Pts) with Glucocorticoid-Refractory Chronic Graft-Vs-Host Disease (cGVHD): Primary Findings from the Phase 3, Randomized REACH3 Study
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Norbert Hollaender, Ronjon Chakraverty, Maanasa Gowda, Franco Locatelli, Stephanie J. Lee, Ron Ram, Tommaso Stefanelli, Shahrukh K. Hashmi, Takanori Teshima, Peter Langmuir, Nicola Polverelli, and Robert Zeiser
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Oncology ,Transplantation ,medicine.medical_specialty ,Ruxolitinib ,business.industry ,Cell Biology ,Hematology ,Refractory ,Internal medicine ,medicine ,Molecular Medicine ,Immunology and Allergy ,In patient ,Host disease ,business ,Glucocorticoid ,medicine.drug - Published
- 2021
90. Intestinal Pneumatosis and Perforation Are a Rare but Serious Manifestation of Gastrointestinal Graft-Vs.-Host Disease Following Allogeneic Stem Cell Transplant
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Jason R. Young, Mithun V. Shah, Hassan B. Alkhateeb, William J. Hogan, Mark R. Litzow, and Kimberly J. Langer
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Transplantation ,medicine.medical_specialty ,business.industry ,Perforation (oil well) ,Cell Biology ,Hematology ,Gastroenterology ,Internal medicine ,Molecular Medicine ,Immunology and Allergy ,Medicine ,Stem cell ,business ,Host disease - Published
- 2021
91. Initial Systemic Therapy of Chronic Graft Vs. Host Disease: Analysis of Practice Variation and Failure-Free Survival
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George Chen, Jennifer White, Betty K. Hamilton, Paul A. Carpenter, Mukta Arora, Stephanie J. Lee, Carrie L. Kitko, Sally Arai, Joseph Pidala, Mary E.D. Flowers, Corey Cutler, Paul J. Martin, and Lynn Onstad
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Transplantation ,medicine.medical_specialty ,business.industry ,Cell Biology ,Hematology ,Gastroenterology ,Systemic therapy ,Failure free survival ,Variation (linguistics) ,Internal medicine ,Molecular Medicine ,Immunology and Allergy ,Medicine ,Host disease ,business - Published
- 2021
92. Biomarker Analysis in Patients (pts) with Steroid-Refractory Acute Graft-Vs-Host Disease (aGVHD) Treated with Ruxolitinib (RUX) or Best Available Therapy (BAT) in the Randomized, Phase 3 REACH2 Study
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Jeff Szer, Gérard Socié, Karen Sinclair, Shalini Chaturvedi, Mohamad Mohty, Jason Butler, Anirudh Prahallad, Eva Wagner, Edouard Forcade, C. Wilke, Tsila Zuckerman, David Ritchie, Nikolas von Bubnoff, Giovanni Grillo, Dietger Niederwieser, Sinem Civriz Bozdag, Domenico Russo, Reuven Or, Robert Zeiser, and Jaime Sanz Caballer
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Oncology ,medicine.medical_specialty ,Ruxolitinib ,business.industry ,Immunology ,Cell Biology ,Hematology ,Exploratory analysis ,Serum samples ,Biochemistry ,Internal medicine ,medicine ,Current employment ,In patient ,Host disease ,business ,Steroid refractory ,health care economics and organizations ,Treatment Arm ,medicine.drug - Abstract
BACKGROUND aGVHD, a common complication of allogeneic stem cell transplant (alloSCT), is driven by proinflammatory cytokines and chemokines that activate the immune system, resulting in end-organ damage. Steroids are first-line treatment but up to 50% of pts are steroid refractory (SR), resulting in high mortality and morbidity. RUX, a JAK1/JAK2 inhibitor, inhibits cytokine-dependent activation of the JAK-STAT pathway and cell proliferation and differentiation, which prevents worsening of aGVHD and allows recovery. JAK pathway inhibition by RUX may also lead to modulation of proinflammatory cytokines and prognostic GVHD biomarkers. The phase 3 randomized REACH2 trial (NCT02913261) in SR aGVHD demonstrated superiority of RUX vs BAT, with a significantly higher overall response rate (ORR; complete [CR] + partial response [PR]) at D28 (62% vs 39%; P < .001) and higher durable ORR at D56 (40% vs 22%; P < .001) (Zeiser R, et al. N Engl J Med. 2020). In this exploratory analysis of REACH2, we assessed whether baseline (BL) levels of proinflammatory cytokines and GVHD markers were prognostic for response and how this changed over time related to treatment. METHODS Pts (N = 309; ≥ 12 y old with grade II-IV SR aGVHD after alloSCT) were randomized 1:1 to RUX (starting at 10 mg bid) or investigator-selected BAT and stratified by aGVHD grade; 295 pts had valid biomarker levels. Serum samples were collected at BL, D14, and D28 and biomarkers, including inflammatory cytokines, soluble receptors of cytokines, chemokines, and tissue-specific markers for gastrointestinal (GI), liver, and skin GVHD, were assessed (Table). Biomarker levels at BL were stratified by response (CR, PR, none [NR]) at D28 for each treatment arm; those that differed by response were analyzed by logistic regression (LR) to assess the association (CR+PR vs NR), adjusting for treatment. The analysis was repeated, adjusting for key covariates that had significant impact on the biomarker-response relationship. Change in biomarkers over time (BL to D28) was assessed via geometric mean values at each visit, along with fold change from BL for each treatment arm. RESULTS Of 22 GVHD biomarkers assessed, 17 (77%) were evaluable (Table). Higher median BL levels of proinflammatory cytokines (IL-6, IL-8, TNF-α), soluble cytokine receptors (IL2RA, TNFRSF1A, ST2) and tissue-specific GVHD markers (REG3A, HGF) were generally observed in NR vs CR pts (Table) and were further analyzed. Higher BL levels of these markers were significantly associated with a lower probability of OR (P[OR]) in the LR analysis (Figure). An interaction term was investigated to assess whether there was a differing biomarker effect within treatment groups; however, this was insignificant and not retained. The addition of skin involvement to the LR for all biomarkers had an impact on P(OR), with increased P(OR) for pts with skin involvement at BL. Liver involvement at BL was added to the LR for HGF, IL6, REG3A, TNFα, and TNFRSF1A. The LR models showed a significant decrease in P(OR) for pts with liver involvement at BL. GI involvement did not have a significant impact for any biomarker. Geometric mean levels of TNFα, TNFRSF1A, IL2RA, REG3A, and ST2 decreased from BL to D14 in CR pts in the RUX arm but increased with BAT. NR pts had increases in these biomarkers regardless of treatment; however, longer follow-up is needed. Treatment had an underlying impact on P(OR) but no further impact on the effect of biomarkers on P(OR). Maximum change from BL was observed at D14; a slight return to BL levels was observed at D28 in CR pts. Surprisingly, IL6 levels increased with RUX regardless of response. IL6, like TNFα, is directly modulated by the JAK-STAT pathway and was therefore expected to decrease with RUX. CONCLUSIONS This is the first biomarker study in a phase 3 trial in GVHD. BL levels of IL6, IL8, TNFα, IL2RA, TNFRSF1A, ST2, REG3A, and HGF tended to be higher in NR vs CR pts; higher levels were associated with lower P(OR) when adjusted for treatment arm. Skin and liver involvement also had an impact on response. Skin involvement was associated with higher P(OR), regardless of biomarker BL levels, possibly because no skin involvement implied other organ involvement and tended to be associated with a higher overall severity grade at BL. CR pts in the RUX group had lower BL levels of TNFα and showed trends toward decreases from BL to D14 in the soluble cytokine receptors ST2, TNFRSF1A, and IL2RA and tissue-specific marker REG3A. Disclosures Socié: Elsalys: Honoraria; Alexion: Consultancy, Honoraria, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau. Niederwieser:Amgen: Speakers Bureau; Daiichi: Research Funding; Novartis: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees. Von Bubnoff:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Clinical biomarker research, steering committee, Patents & Royalties: Research support, Research Funding; Astra Zeneca: Honoraria, Other: Lectures, Patents & Royalties: Astra Zeneca. Mohty:BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; Stemline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Szer:Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; Pfizer: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Or:Hadassah Hebrew University Medical Center: Consultancy, Current Employment. Wagner:Novartis: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Medac: Other: Travel grand; Shire: Other: Travel grand. Forcade:JAZZ: Other: Travel grant for congress; NEOVII: Other: Travel grant for congress; Gilead: Speakers Bureau; Sanofi: Other: Travel grant for congress; Novartis: Other: Travel grant for congress. Civriz Bozdag:Novartis: Research Funding. Chaturvedi:Novartis: Current Employment. Wilke:Novartis Pharma AG: Current Employment, Other: Stock owner. Zeiser:Novartis: Honoraria; Incyte: Honoraria; Malinckrodt: Honoraria.
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- 2020
93. [Acute and chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation].
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Barzin A, Geurten C, Willems E, Baron F, Beguin Y, and Servais S
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- Acute Disease, Chronic Disease, Humans, Transplantation, Homologous adverse effects, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Acute and/or chronic graft-versus-host disease (GVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). It is a multisystemic inflammatory and/or fibrotic disease that occurs when the immune cells derived from the graft (and therefore originating from the donor) recognize recipient's healthy tissues as foreign and react against them. Acute GVHD is one of the main causes of non-relapse mortality after alloHSCT. Chronic GVHD can be very disabling in its severe form and can also be responsible for late mortality, mainly due to long-term immune deficiency and opportunistic infections. In contrast, GVHD can be associated with certain beneficial effects in patients transplanted for hematological malignancies, through simultaneous «graft versus tumour» positive effects. Therefore, one of the challenges of alloHSCT is the prevention and treatment of severe forms of GVHD without losing the beneficial anti-tumour effects of the graft.
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- 2022
94. Development of a Population-Based Cost-Effectiveness Model of Chronic Graft-Versus-Host Disease in Spain
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Crespo, Carlos, Pérez-Simón, José Anton, Rodríguez, José Manuel, Sierra, Jordi, and Brosa, Max
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STEM cell transplantation , *COST effectiveness , *GRAFT versus host disease , *HEALTH outcome assessment , *QUALITY of life , *TREATMENT effectiveness - Abstract
Abstract: Background: Chronic graft-versus-host disease (cGvHD) is the leading cause of late nonrelapse mortality (transplant-related mortality) after hematopoietic stem cell transplant. Given that there are a wide range of treatment options for cGvHD, assessment of the associated costs and efficacy can help clinicians and health care providers allocate health care resources more efficiently. Objective: The purpose of this study was to assess the cost-effectiveness of extracorporeal photopheresis (ECP) compared with rituximab (Rmb) and with imatinib (Imt) in patients with cGvHD at 5 years from the perspective of the Spanish National Health System. Methods: The model assessed the incremental cost-effectiveness/utility ratio of ECP versus Rmb or Imt for 1000 hypothetical patients by using microsimulation cost-effectiveness techniques. Model probabilities were obtained from the literature. Treatment pathways and adverse events were evaluated taking clinical opinion and published reports into consideration. Local data on costs (2010 Euros) and health care resources utilization were validated by the clinical authors. Probabilistic sensitivity analyses were used to assess the robustness of the model. Results: The greater efficacy of ECP resulted in a gain of 0.011 to 0.024 quality-adjusted life-year in the first year and 0.062 to 0.094 at year 5 compared with Rmb or Imt. The results showed that the higher acquisition cost of ECP versus Imt was compensated for at 9 months by greater efficacy; this higher cost was partially compensated for (€517) by year 5 versus Rmb. After 9 months, ECP was dominant (cheaper and more effective) compared with Imt. The incremental cost-effectiveness ratio of ECP versus Rmb was €29,646 per life-year gained and €24,442 per quality-adjusted life-year gained at year 2.5. Probabilistic sensitivity analysis confirmed the results. The main study limitation was that to assess relative treatment effects, only small studies were available for indirect comparison. Conclusion: ECP as a third-line therapy for cGvHD is a more cost-effective strategy than Rmb or Imt. [Copyright &y& Elsevier]
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- 2012
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95. Diagnosis of Intestinal Graft-versus-Host Disease and Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation.
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Yamada-Fujiwara, Minami, Miyamura, Koichi, Fujiwara, Tohru, Tohmiya, Yasuo, Endo, Katsuya, Onishi, Yasushi, Ishizawa, Kenichi, Kameoka, Junichi, Ito, Masafumi, and Harigae, Hideo
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Severe diarrhea is a serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Acute graft-versus-host disease (GVHD) has been one of the major causes of diarrhea after HSCT, which is triggered by donor-derived cytotoxic T-lymphocytes. On the other hand, intestinal thrombotic microangiopathy (TMA) sometimes coexists with acute GVHD, and intensified immunosuppression to treat acute GVHD could exacerbate intestinal TMA, presumably through the vascular endothelial cell damage. The differential diagnosis between intestinal TMA and acute GVHD of the gut has mainly relied on the pathological findings, as clinical diagnosis of intestinal TMA has not been established. Therefore, we aimed to assess the feasibility of our clinical diagnosis for the patients with diarrhea after HSCT. We made tentative clinical criteria for intestinal TMA and acute GVHD of the gut, based on the clinical manifestations, laboratory data and colonoscopic findings, and started treatment before pathological diagnosis were made. Subsequently, a pathologist retrospectively assessed the accuracy of clinical diagnosis in a blind manner. In this study, we enrolled 19 patients complicating watery diarrhea after HSCT, and diagnosed as having acute GVHD (n = 10), intestinal TMA (n = 3), or both (n = 6) according to our criteria. We demonstrated that our clinical diagnosis for intestinal TMA and acute GVHD of the gut was overall correct, in terms of the response to the therapy and the pathological diagnosis. The present study may provide a clue on making clinical diagnosis of patients with watery diarrhea after HSCT, which enables us to start a prompt therapy. [ABSTRACT FROM AUTHOR]
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- 2012
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96. Prospective longitudinal evaluation of microbiome diversity in patients with hematological malignancy undergoing allogeneic hematopoietic stem cell transplantation (HSCT)
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Mary-Jane Lombardo, Emily A. Walsh, Liyang Diao, Lisa von Moltke, Maria J G T Vehreschild, Barbara H. McGovern, Matthew R. Henn, Jessica A. Bryant, Christopher B. Ford, and Anastasia Tsakmaklis
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Cancer Research ,business.industry ,medicine.medical_treatment ,Microbial diversity ,media_common.quotation_subject ,Antibiotic exposure ,Hematopoietic stem cell transplantation ,surgical procedures, operative ,Oncology ,immune system diseases ,Hematological malignancy ,Immunology ,medicine ,In patient ,Microbiome ,business ,Host disease ,Diversity (politics) ,media_common - Abstract
7005 Background: Studies suggest that decreased microbial diversity due to chemotherapeutic and antibiotic exposure may be associated with acute graft vs host disease (aGvHD) and mortality in patients undergoing allogeneic HSCT. In addition, disruption of the microbiome by antibiotics may lead to intestinal domination by pro-inflammatory bacteria, resulting in increased risk of aGvHD. This relationship has been described in settings with prophylactic antibiotic use, a standard of care in most transplant centers. Here we assessed how the microbiome and GvHD outcomes differ when prophylactic use of antibiotics is avoided. Methods: We collaborated on an observational study (COLLECT) to evaluate changes in microbial diversity over time in subjects undergoing allogeneic HSCT. According to protocol at the University Hospital of Cologne, antibiotics were administered only as empiric treatment for febrile neutropenia or as targeted treatment. Stool was collected weekly from 65 subjects at baseline (pre-HSCT) to day 28 with additional time points taken at day 56, day 90, day 365, and upon diagnosis of intestinal GvHD (GvHD-day 0 and GvHD-day 7). Patients were monitored for incidence of GvHD, including acute GvHD of the liver, intestine, and skin. Microbiome 16SV4 profiles were generated from 381 stool samples. Linear effects models were developed to evaluate the association between Shannon diversity, intestinal domination, and the incidence of intestinal GvHD and mortality. Results: Of the 65 subjects, 28 subjects (42%) went on to develop intestinal GvHD, and 16 subjects (25%) did not survive to day 365. A decline in Shannon diversity was observed during the neutropenic period following HSCT. Subjects who went on to develop intestinal GvHD had significantly lower Shannon diversity at the time of stem cell engraftment (p < 0.0468). Furthermore, lower diversity was observed throughout the study period in subjects experiencing intestinal GvHD. We developed a linear model evaluating the association between mortality and Shannon diversity and found a significant relationship at days 28 and 90 post HSCT (p < 0.0001 and 0.0121, resp). Intestinal domination by Enterobacteriaceae or Enterococcus was significantly associated with the incidence of intestinal GvHD (p < 0.0082) or mortality (p < 0.001), respectively. Conclusions: Data from this observational study (COLLECT) suggests decreases in microbial diversity over time occur in subjects undergoing allogeneic HSCT despite the lack of prophylactic antibiotics. Investigation of whether administration of microbiome therapeutic drugs prior to transplant and/or at the time of engraftment can reduce morbidity and mortality in this high-risk patient population is warranted. Clinical trial information: NCT03148197.
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- 2021
97. Interferon-gamma prelicensed allogeneic bone marrow MSCS do not mitigate graft vs host disease in the animal model of major mismatched bone marrow transplantation
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Keith A. Kunugi, Christian M. Capitini, Jacques Galipeau, Raghavan Chinnadurai, Paul D. Bates, Randall J. Kimple, Kwangok P. Nickel, and Larry A. DeWerd
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Cancer Research ,Transplantation ,Bone marrow transplantation ,business.industry ,Immunology ,Mesenchymal stem cell ,Cell Biology ,Animal model ,Oncology ,Immunology and Allergy ,Medicine ,Interferon gamma ,Autogenous bone ,Host disease ,business ,Genetics (clinical) ,medicine.drug - Published
- 2021
98. Immunophenotypic and molecular comparison between allogeneic and autologous graft-vs-host disease of the skin: A retrospective study using immunohistochemical and proteomics methods
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Surendra Dasari, Patrick M. Vanderboom, Martha Q. Lacy, Francis K. Buadi, William J. Hogan, Mark R. Litzow, Alexander Meves, Lawrence E. Gibson, Rokea A. el-Azhary, Hillard M. Lazarus, Shahrukh K. Hashmi, Julia S. Lehman, and Mrinal S. Patnaik
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Histology ,Proteomics methods ,Autologous graft ,Retrospective cohort study ,Dermatology ,Biology ,Proteomics ,Pathology and Forensic Medicine ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immunity ,Interferon ,030220 oncology & carcinogenesis ,Immunology ,medicine ,Immunohistochemistry ,Host disease ,medicine.drug - Published
- 2017
99. Mononuclear cell collection for extracorporeal photopheresis: Concentrate characteristics for off-line UV-A irradiation procedure
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Nicola Piccirillo, Giuseppina Massini, Gina Zini, Patrizia Chiusolo, Simona Sica, Rossana Putzulu, and Assunta Gessica Fiore
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Chromatography ,business.industry ,Blood volume ,Hematology ,General Medicine ,030204 cardiovascular system & hematology ,Peripheral blood mononuclear cell ,03 medical and health sciences ,0302 clinical medicine ,Nucleated cell ,Immunology ,Extracorporeal Photopheresis ,Medicine ,Platelet ,Irradiation ,Host disease ,business ,Off line ,030215 immunology - Abstract
Background and objective Extracorporeal photopheresis (ECP) is the most represented cell therapy for treatment of cutaneous T-cell lymphoma, graft-versus host disease and organ rejection. We analyzed our experience in ECP using 2 cell separators (Cobe Spectra and Spectra Optia) focusing on leukapheretic product characteristics, UV-A irradiation procedure and entire ECP process. Materials and methods We collected data of patients undergoing ECP between January 2012 and February 2015 in order to evaluate collection procedures performed using Cobe Spectra and Spectra Optia, mononuclear cell product, UV-A photoirradiation procedure by Pit System. Results We performed 484 ECP procedures in 27 patients. Cobe-derived mononuclear cell products were characterized by higher cell yields while Optia-derived mononuclear cell products were characterized by smaller volume, comparable mononuclear cell content but lower erythrocytes, granulocytes, and platelets contamination. Conclusion Our study confirms good results for both cell separators. Blood volume processed being equal, Cobe collects a number of total nucleated cells significantly higher than Optia. Optia, collecting only target cells without significant erythrocytes, granulocytes and platelets contamination, is able to collect a leukapheretic product particularly suitable for ECP.
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- 2017
100. 2569. The Gut Microbiome and Acute Graft vs. Host Disease Risk in Hematopoietic Stem Cell Transplantation Recipients
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Gedske Daugaard, Joanne Reekie, Marie Helleberg, Jens Christian Nørgaard, Henrik Sengeløv, Emma E Ilett, Cameron Ross MacPherson, Roger Paredes, Mette Jørgensen, Daniel D Murray, Jens D Lundgren, and Marc Noguera
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business.industry ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Stool specimen ,Gut microbiome ,Abstracts ,Infectious Diseases ,Oncology ,Poster Abstracts ,Immunology ,Medicine ,Microbiome ,Intestinal bacteria ,Allogeneic hematopoietic stem cell transplant ,business ,Host disease ,RNA RIBOSOMAL 16S - Abstract
Background 16S rRNA gene-based studies report that allogeneic hematopoietic stem cell transplant (aHSCT) recipients with low bacterial diversity and certain bacteria close to engraftment have increased risk of developing acute graft-vs.-host disease (aGvHD). Using shotgun metagenomic data, we aim to confirm and extend these observations in a larger cohort. Methods Adult aHSCT recipients with stool samples collected days −30 to +100 relative to aHSCT, but prior to aGvHD, were included. One sample was selected per patient and time point: pre-aHSCT (T1), post-aHSCT pre-engraftment (T2). Complete ascertainment of aGvHD (grades ≥ 2) until day +100 was performed. Bacterial microbiome factors (α-diversity, gene richness and 16 a priori bacteria) and clinical factors were tested for associations with aGvHD across T1:2 in univariable models. Significant factors (P < 0.1) were included in a multivariable model. Results Of 147 aHSCT recipients, 35 developed aGvHD a median of 35 days (IQR 24–51) post-aHSCT. We found that higher gene richness was significantly associated with lower aGvHD risk in T2, but not T1, samples (OR 0.65 (95% CI 0.42–1.00), P = 0.04 vs. OR 1.14 (95% CI 0.67–1.94), P = 0.64 per doubling of unique genes). A decreased abundance of Akkermansia muciniphila, Proteobacteria, Blautia and Gammaproteobacteria was observed in those that developed aGvHD, again in T2 samples only (Figure 1). Among clinical factors, donor sex, donor/recipient (related/unrelated) and conditioning regimen (adjusted OR = 0.34 for non-myeloablative vs myeloablative (95% CI 0.15–0.77)) were significantly associated with aGvHD. Conditioning regimen was also strongly associated with microbiome changes; myeloablative recipients had lower gene richness and differences in bacterial abundance, including decreased abundance of aforementioned bacteria, compared with non-myeloablative recipients at T2 (Figures 2and 3). Conclusion Post-aHSCT pre-engraftment was a crucial timepoint where microbial changes, including lower gene richness and abundance of certain bacteria, were associated with development of aGvHD. Myeloablative regimes were also associated with both aGvHD and microbiome changes, suggesting that intense conditioning may affect aGvHD risk through perturbation of the gut microbiome. Disclosures All authors: No reported disclosures.
- Published
- 2019
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