Klinička karakterizacija i ishodi kronične bolesti presatka protiv domaćina

Allogeneic hematopoietic stem cells in peripheral blood transplantation (alloPBSCT) or bone marrow transplantation (alloBMT) have different biological characteristics which may affect differently prognostic factors for incidence and severity of chronic graft-versus-host disease (cGVHD). The first study included 87 patients who survived at least 100 days after matched related donor myeloablative transplantation. Factors significantly associated with higher incidence of cGVHD after alloPBSCT included CMV-positive donor, acute skin GVHD, and diagnoses other than lymphoma. The data suggest there some cGVHD prognostic factors are unique to recipients of alloPBSCT. The second study was based on the donor-derived T cells, by analyzing their impact of ex vivo on cGVHD was analyzed in a randomized multicenter trial involving unrelated donor marrow transplants. A total of 404 patients diagnosed with hematologic malignancies received a total body irradiation–based myeloablative conditioning regimen. Survival at 3 years from diagnosis of cGVHD was similar, in the same way as the proportion of patients with cGVHD who discontinued immunosuppression. Incidence of serious infections and leukemia relapse were similar on both treatment arms. In spite of a significant reduction of acute GVHD, TCD did not reduce the incidence of cGVHD or improve survival in patients who developed it. Lastly, the National Institutes of Health (NIH) Chronic Graft-versus-Host Disease (GVHD) Consensus Response Criteria Working Group recommended several measures to document serial evaluations of chronic GVHD organ involvement. Provisional definitions of complete response, partial response, and progression were proposed for each organ and for the overall outcome. Based on publications over the last 9 years, the 2014 Working Group has updated its recommendations for measures and interpretation of organ and overall responses. Major changes include eliminating several clinical parameters from the determination of response, updating or adding new organ scales to assess response, and recognising that progression excludes minimal, clinically insignificant worsening that does not usually warrant a change in therapy. The response definitions have been revised to reflect these changes and are expected to enhance these measures' reliability and practical utility in clinical trials. Clarification is provided about response assessment after the addition of topical or organ-targeted treatment. Ancillary measures are strongly encouraged in clinical trials. Areas suggested for additional research include criteria to identify irreversible organ damage and validation of the modified response criteria, including in the pediatric population. A synergy of these papers provides an overview of the approaches to handling CGVHD disease in an evidence-based manner.Alogene hematopoetske matične stanice u transplantaciji periferne krvi (alloPBSCT) ili transplantaciji koštane srži (alloBMT) imaju različite biološke karakteristike koje mogu utjecati na prognostičke čimbenike za incidenciju i opseg reakcije presatka protiv domaćina (cGVHD). Prva studija uključila je 87 pacijenata koji su preživjeli najmanje 100 dana nakon mijeloablativne transplantacije srodnog donora. Čimbenici koji su značajno povezani s većom učestalošću cGVHD-a nakon aloPBSCT-a uključivali su CMV-pozitivnog davatelja, akutni kožni GVHD i druge dijagnoze osim limfoma. Podaci sugeriraju da su neki cGVHD prognostički čimbenici jedinstveni za primatelje aloPBSCT-a. Druga studija temeljila se na T stanicama dobivenim od donora, analizom njihovog utjecaja ex vivo na cGVHD u multicentričnom ispitivanju koje je uključivalo transplantacije srži nesrodnih donora. Ukupno 404 pacijenata s dijagnozom hematoloških zloćudnih bolesti primilo je režim mijeloablativnog kondicioniranja temeljen na zračenju cijelog tijela. Preživljenje nakon 3 godine bilo je slično, na isti način kao i udio pacijenata s cGVHD-om koji su prekinuli imunosupresiju. Učestalost ozbiljnih infekcija i recidiva leukemije bili su slični u obje skupine liječenja. Unatoč značajnom smanjenju akutnog GVHD-a, TCD nije smanjio incidenciju cGVHD-a niti poboljšao preživljenje pacijenata koji su se razvili. Naposljetku, radna skupina za kriterije odgovora Nacionalnog instituta za zdravlje (NIH) za kroničnu bolest transplantata protiv domaćina (GVHD) preporučila je nekoliko mjera za dokumentiranje serijskih procjena kronične zahvaćenosti GVHD organa. Za svaki organ i za ukupni ishod predložene su privremene definicije potpunog odgovora, djelomičnog odgovora i progresije. Na temelju publikacija u posljednjih 9 godina, radna skupina iz 2014. ažurirala je svoje preporuke za mjere i tumačenje odgovora organa i ukupnih odgovora. Glavne promjene uključuju eliminaciju nekoliko kliničkih parametara iz određivanja odgovora, ažuriranje ili dodavanje novih ljestvica organa za procjenu odgovora i prepoznavanje da progresija isključuje minimalno, klinički beznačajno pogoršanje koje obično ne opravdava promjenu terapije. Definicije odgovora su revidirane kako bi odražavale te promjene i očekuje se da će povećati pouzdanost i praktičnu korisnost ovih mjera u kliničkim ispitivanjima. Dano je pojašnjenje o procjeni odgovora nakon dodavanja lokalnog liječenja ili liječenja usmjerenog na organe. Pomoćne mjere snažno se potiču u kliničkim ispitivanjima. Područja predložena za dodatna istraživanja uključuju kriterije za prepoznavanje ireverzibilnog oštećenja organa i validaciju modificiranih kriterija odgovora, uključujući i pedijatrijsku populaciju. Sinergija ovih radova daje pregled pristupa liječenju cGVHD bolesti, na način utemeljen na dokazima

Klinička karakterizacija i ishodi kronične bolesti presatka protiv domaćina

Allogeneic hematopoietic stem cells in peripheral blood transplantation (alloPBSCT) or bone marrow transplantation (alloBMT) have different biological characteristics which may affect differently prognostic factors for incidence and severity of chronic graft-versus-host disease (cGVHD). The first study included 87 patients who survived at least 100 days after matched related donor myeloablative transplantation. Factors significantly associated with higher incidence of cGVHD after alloPBSCT included CMV-positive donor, acute skin GVHD, and diagnoses other than lymphoma. The data suggest there some cGVHD prognostic factors are unique to recipients of alloPBSCT. The second study was based on the donor-derived T cells, by analyzing their impact of ex vivo on cGVHD was analyzed in a randomized multicenter trial involving unrelated donor marrow transplants. A total of 404 patients diagnosed with hematologic malignancies received a total body irradiation–based myeloablative conditioning regimen. Survival at 3 years from diagnosis of cGVHD was similar, in the same way as the proportion of patients with cGVHD who discontinued immunosuppression. Incidence of serious infections and leukemia relapse were similar on both treatment arms. In spite of a significant reduction of acute GVHD, TCD did not reduce the incidence of cGVHD or improve survival in patients who developed it. Lastly, the National Institutes of Health (NIH) Chronic Graft-versus-Host Disease (GVHD) Consensus Response Criteria Working Group recommended several measures to document serial evaluations of chronic GVHD organ involvement. Provisional definitions of complete response, partial response, and progression were proposed for each organ and for the overall outcome. Based on publications over the last 9 years, the 2014 Working Group has updated its recommendations for measures and interpretation of organ and overall responses. Major changes include eliminating several clinical parameters from the determination of response, updating or adding new organ scales to assess response, and recognising that progression excludes minimal, clinically insignificant worsening that does not usually warrant a change in therapy. The response definitions have been revised to reflect these changes and are expected to enhance these measures' reliability and practical utility in clinical trials. Clarification is provided about response assessment after the addition of topical or organ-targeted treatment. Ancillary measures are strongly encouraged in clinical trials. Areas suggested for additional research include criteria to identify irreversible organ damage and validation of the modified response criteria, including in the pediatric population. A synergy of these papers provides an overview of the approaches to handling CGVHD disease in an evidence-based manner.Alogene hematopoetske matične stanice u transplantaciji periferne krvi (alloPBSCT) ili transplantaciji koštane srži (alloBMT) imaju različite biološke karakteristike koje mogu utjecati na prognostičke čimbenike za incidenciju i opseg reakcije presatka protiv domaćina (cGVHD). Prva studija uključila je 87 pacijenata koji su preživjeli najmanje 100 dana nakon mijeloablativne transplantacije srodnog donora. Čimbenici koji su značajno povezani s većom učestalošću cGVHD-a nakon aloPBSCT-a uključivali su CMV-pozitivnog davatelja, akutni kožni GVHD i druge dijagnoze osim limfoma. Podaci sugeriraju da su neki cGVHD prognostički čimbenici jedinstveni za primatelje aloPBSCT-a. Druga studija temeljila se na T stanicama dobivenim od donora, analizom njihovog utjecaja ex vivo na cGVHD u multicentričnom ispitivanju koje je uključivalo transplantacije srži nesrodnih donora. Ukupno 404 pacijenata s dijagnozom hematoloških zloćudnih bolesti primilo je režim mijeloablativnog kondicioniranja temeljen na zračenju cijelog tijela. Preživljenje nakon 3 godine bilo je slično, na isti način kao i udio pacijenata s cGVHD-om koji su prekinuli imunosupresiju. Učestalost ozbiljnih infekcija i recidiva leukemije bili su slični u obje skupine liječenja. Unatoč značajnom smanjenju akutnog GVHD-a, TCD nije smanjio incidenciju cGVHD-a niti poboljšao preživljenje pacijenata koji su se razvili. Naposljetku, radna skupina za kriterije odgovora Nacionalnog instituta za zdravlje (NIH) za kroničnu bolest transplantata protiv domaćina (GVHD) preporučila je nekoliko mjera za dokumentiranje serijskih procjena kronične zahvaćenosti GVHD organa. Za svaki organ i za ukupni ishod predložene su privremene definicije potpunog odgovora, djelomičnog odgovora i progresije. Na temelju publikacija u posljednjih 9 godina, radna skupina iz 2014. ažurirala je svoje preporuke za mjere i tumačenje odgovora organa i ukupnih odgovora. Glavne promjene uključuju eliminaciju nekoliko kliničkih parametara iz određivanja odgovora, ažuriranje ili dodavanje novih ljestvica organa za procjenu odgovora i prepoznavanje da progresija isključuje minimalno, klinički beznačajno pogoršanje koje obično ne opravdava promjenu terapije. Definicije odgovora su revidirane kako bi odražavale te promjene i očekuje se da će povećati pouzdanost i praktičnu korisnost ovih mjera u kliničkim ispitivanjima. Dano je pojašnjenje o procjeni odgovora nakon dodavanja lokalnog liječenja ili liječenja usmjerenog na organe. Pomoćne mjere snažno se potiču u kliničkim ispitivanjima. Područja predložena za dodatna istraživanja uključuju kriterije za prepoznavanje ireverzibilnog oštećenja organa i validaciju modificiranih kriterija odgovora, uključujući i pedijatrijsku populaciju. Sinergija ovih radova daje pregled pristupa liječenju cGVHD bolesti, na način utemeljen na dokazima

Klinička karakterizacija i ishodi kronične bolesti presatka protiv domaćina

Allogeneic hematopoietic stem cells in peripheral blood transplantation (alloPBSCT) or bone marrow transplantation (alloBMT) have different biological characteristics which may affect differently prognostic factors for incidence and severity of chronic graft-versus-host disease (cGVHD). The first study included 87 patients who survived at least 100 days after matched related donor myeloablative transplantation. Factors significantly associated with higher incidence of cGVHD after alloPBSCT included CMV-positive donor, acute skin GVHD, and diagnoses other than lymphoma. The data suggest there some cGVHD prognostic factors are unique to recipients of alloPBSCT. The second study was based on the donor-derived T cells, by analyzing their impact of ex vivo on cGVHD was analyzed in a randomized multicenter trial involving unrelated donor marrow transplants. A total of 404 patients diagnosed with hematologic malignancies received a total body irradiation–based myeloablative conditioning regimen. Survival at 3 years from diagnosis of cGVHD was similar, in the same way as the proportion of patients with cGVHD who discontinued immunosuppression. Incidence of serious infections and leukemia relapse were similar on both treatment arms. In spite of a significant reduction of acute GVHD, TCD did not reduce the incidence of cGVHD or improve survival in patients who developed it. Lastly, the National Institutes of Health (NIH) Chronic Graft-versus-Host Disease (GVHD) Consensus Response Criteria Working Group recommended several measures to document serial evaluations of chronic GVHD organ involvement. Provisional definitions of complete response, partial response, and progression were proposed for each organ and for the overall outcome. Based on publications over the last 9 years, the 2014 Working Group has updated its recommendations for measures and interpretation of organ and overall responses. Major changes include eliminating several clinical parameters from the determination of response, updating or adding new organ scales to assess response, and recognising that progression excludes minimal, clinically insignificant worsening that does not usually warrant a change in therapy. The response definitions have been revised to reflect these changes and are expected to enhance these measures' reliability and practical utility in clinical trials. Clarification is provided about response assessment after the addition of topical or organ-targeted treatment. Ancillary measures are strongly encouraged in clinical trials. Areas suggested for additional research include criteria to identify irreversible organ damage and validation of the modified response criteria, including in the pediatric population. A synergy of these papers provides an overview of the approaches to handling CGVHD disease in an evidence-based manner.Alogene hematopoetske matične stanice u transplantaciji periferne krvi (alloPBSCT) ili transplantaciji koštane srži (alloBMT) imaju različite biološke karakteristike koje mogu utjecati na prognostičke čimbenike za incidenciju i opseg reakcije presatka protiv domaćina (cGVHD). Prva studija uključila je 87 pacijenata koji su preživjeli najmanje 100 dana nakon mijeloablativne transplantacije srodnog donora. Čimbenici koji su značajno povezani s većom učestalošću cGVHD-a nakon aloPBSCT-a uključivali su CMV-pozitivnog davatelja, akutni kožni GVHD i druge dijagnoze osim limfoma. Podaci sugeriraju da su neki cGVHD prognostički čimbenici jedinstveni za primatelje aloPBSCT-a. Druga studija temeljila se na T stanicama dobivenim od donora, analizom njihovog utjecaja ex vivo na cGVHD u multicentričnom ispitivanju koje je uključivalo transplantacije srži nesrodnih donora. Ukupno 404 pacijenata s dijagnozom hematoloških zloćudnih bolesti primilo je režim mijeloablativnog kondicioniranja temeljen na zračenju cijelog tijela. Preživljenje nakon 3 godine bilo je slično, na isti način kao i udio pacijenata s cGVHD-om koji su prekinuli imunosupresiju. Učestalost ozbiljnih infekcija i recidiva leukemije bili su slični u obje skupine liječenja. Unatoč značajnom smanjenju akutnog GVHD-a, TCD nije smanjio incidenciju cGVHD-a niti poboljšao preživljenje pacijenata koji su se razvili. Naposljetku, radna skupina za kriterije odgovora Nacionalnog instituta za zdravlje (NIH) za kroničnu bolest transplantata protiv domaćina (GVHD) preporučila je nekoliko mjera za dokumentiranje serijskih procjena kronične zahvaćenosti GVHD organa. Za svaki organ i za ukupni ishod predložene su privremene definicije potpunog odgovora, djelomičnog odgovora i progresije. Na temelju publikacija u posljednjih 9 godina, radna skupina iz 2014. ažurirala je svoje preporuke za mjere i tumačenje odgovora organa i ukupnih odgovora. Glavne promjene uključuju eliminaciju nekoliko kliničkih parametara iz određivanja odgovora, ažuriranje ili dodavanje novih ljestvica organa za procjenu odgovora i prepoznavanje da progresija isključuje minimalno, klinički beznačajno pogoršanje koje obično ne opravdava promjenu terapije. Definicije odgovora su revidirane kako bi odražavale te promjene i očekuje se da će povećati pouzdanost i praktičnu korisnost ovih mjera u kliničkim ispitivanjima. Dano je pojašnjenje o procjeni odgovora nakon dodavanja lokalnog liječenja ili liječenja usmjerenog na organe. Pomoćne mjere snažno se potiču u kliničkim ispitivanjima. Područja predložena za dodatna istraživanja uključuju kriterije za prepoznavanje ireverzibilnog oštećenja organa i validaciju modificiranih kriterija odgovora, uključujući i pedijatrijsku populaciju. Sinergija ovih radova daje pregled pristupa liječenju cGVHD bolesti, na način utemeljen na dokazima

Von Willebrand Factor, Factor VIII, and Other Acute Phase Reactants as Biomarkers of Inflammation and Endothelial Dysfunction in Chronic Graft-Versus-Host Disease

Chronic graft-versus-host disease (cGvHD) is an immune mediated late complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). Discovery of adequate biomarkers could identify high-risk patients and provide an effective pre-emptive intervention or early modification of therapeutic strategy, thus reducing prevalence and severity of the disease among long-term survivors of alloHSCT. Inflammation, endothelial injury, and endothelial dysfunction are involved in cGvHD development. Altered levels of acute phase reactants have shown a strong correlation with the activity of several immune mediated disorders and are routinely used in clinical practice. Since elevated von Willebrand factor (VWF) and factor VIII (FVIII) levels have been described as acute phase reactants that may indicate endothelial dysfunction and inflammation in different settings, including chronic autoimmune diseases, they could serve as potential candidate biomarkers of cGvHD. In this review we focused on reported data regarding VWF and FVIII as well as other markers of inflammation and endothelial dysfunction, evaluating their potential role in cGvHD

Significant Associations of IgG Glycan Structures With Chronic Graft-Versus-Host Disease Manifestations: Results of the Cross-Sectional NIH Cohort Study

Chronic graft-versus-host disease (cGvHD) is a systemic alloimmune and autoimmune disorder and a major late complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). The disease is characterized by an altered homeostasis of the humoral immune response. Immunoglobulin G (IgG) glycoprotein is the main effector molecule of the humoral immune response. Changes in IgG glycosylation are associated with a number of autoimmune diseases. IgG glycosylation analysis was done by the means of liquid chromatography in the National Institutes of Health (NIH) cohort of 213 cGvHD patients. The results showed statistically significant differences with regards to cGvHD NIH joint/fascia and skin score, disease activity and intensity of systemic immunosuppression. ROC analysis confirmed that IgG glycosylation increases specificity and sensitivity of models using laboratory parameters and markers of inflammation associated with cGvHD (eosinophil count, complement components C3 and C4 and inflammation markers: albumin, CRP and thrombocyte count). This research shows that IgG glycosylation may play a significant role in cGvHD pathology. Further research could contribute to the understanding of the disease biology and lead to the clinical biomarker development to allow personalized approaches to chronic GvHD therapy

Chronic gvhd dictionary—eurograft cost action initiative consensus report

Chronic graft versus host disease (cGVHD) affects patients after allogeneic hematopoietic stem cell transplantation (alloHSCT). This orphan disease poses a challenge for clinicians and researchers. The purpose of the cGVHD Dictionary is to provide a standardized structure for cGVHD databases on an international level, reconciling differences in data retrieval and facilitate database merging. It is derived from several consensus meetings of the EUROGRAFT consortium (European Cooperation in Science and Technology—COST Action CA17138) followed by a consensus process involving European Society for Blood and Marrow Transplantation (EBMT), US GvHD consortium and Center for International Bone Marrow Transplant Registry (CIBMTR). Databases used for the dictionary were: the National Institutes of Health (NIH) database, the Center for International Blood and Marrow Transplant Research, Applying Biomarkers to Minimize Long Term Effects of Childhood/Adolescent Cancer Treatment - Pediatric Blood and Marrow Transplant Consortium database, EBMT registry, the German-Austrian-Swiss GvHD registry, Italian Blood and Marrow Transplantation Society registry and Regensburg-Göttingen-Newcastle HSCT dataset. A four-part cGVHD Dictionary was formed based on the databases, consensus, and evidence in the literature. The Dictionary is divided into: (1) Patient characteristics, (2) Transplant characteristics, (3) cGVHD characteristics and (4) patient-reported quality of life, symptom burden and functional indicators

B regulatory cells and monocyte subpopulations in patients with chronic graft-vs-host disease

Aim: To assess the correlations of B regulatory cells (Bregs) and monocyte subsets in peripheral blood with the National Institutes of Health (NIH)-consensus-defined clinical manifestations of chronic graft-vs-host disease (cGvHD), in an attempt to establish their role as cellular biomarkers. ----- Methods: This multidisciplinary prospective study enrolled adult cGVHD patients treated in the University Hospital Center Zagreb and University of Zagreb School of Medicine. Immunophenotypic subpopulations of CD24highCD38high Bregs (CD27-, CD27+, and total) and monocyte (classical, intermediate, and non-classical) counts were correlated with demographic, transplant, and cGVHD-related data. Bivariate correlation analysis was performed to evaluate the correlations between Bregs and monocytes subsets and cGVHD organ involvement, as well as cGVHD severity and immunosuppression intensity. ----- Results: Twenty-two adult patients (54.5% female) with cGVHD were enrolled. The median (range) age was 44.5 years (24-65). All patients were transplanted for hematologic malignancies and 40.9% had severe NIH cGVHD global score. The median time from cGVHD diagnosis to the analysis was 16.6 months (0-176). The organ most frequently affected with cGVHD were the eyes (68.2%), skin (45.5%), lungs (45.5%), and liver (40.9%). Lower total and CD27-Bregs counts were correlated with worse cGVHD severity, higher immunosuppression intensity, and lung cGVHD, in terms of cell count, but also with skin cGVHD, in terms of percentages. Patients with liver and joint/fascia cGVHD had a lower percentage of non-classical monocytes and patients with more severe global NIH score had a higher classical monocytes count. ----- Conclusion: Different organs affected by cGVHD are differently associated with different subpopulations of Bregs and monocytes