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Have we improved in preventing and treating acute graft-versus-host disease?

ABSTRACT: Acute graft-versus-host disease (GVHD) is a considerable source of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Accordingly, progress in the prevention and primary therapy of this complication is needed to improve patient outcomes.Guided by insights into acute GVHD pathogenesis, investigators have explored novel cellular and pharmacologic approaches to acute GVHD prevention that demonstrates promise. Although pan-T-cell depletion has reduced GVHD, novel strategies that selectively deplete alloreactive T cells or modulate the balance of effector T cells and regulatory T cells offer promise to selectively abrogate acute GVHD while retaining protection from primary disease relapse and infectious complications.Divergent approaches in the primary therapy of acute GVHD have explored both combination approaches with standard dose glucocorticoids and additional immunosuppressive agents and conversely steroid-sparing approaches including topical agents such as beclomethasone or sirolimus as a steroid-free approach to acute GVHD therapy. Mature results of high-quality clinical trials are needed to determine the optimal therapy that results in effective control of the syndrome and limited toxicity. These complementary outcomes represent the therapeutic goal for future investigation in acute GVHD therapy.

SUBMITTER: Perez L

PROVIDER: S-EPMC3432261 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Have we improved in preventing and treating acute graft-versus-host disease?

Perez Lia L Anasetti Claudio C Pidala Joseph J

Current opinion in hematology 20111101 6

<h4>Purpose of review</h4>Acute graft-versus-host disease (GVHD) is a considerable source of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Accordingly, progress in the prevention and primary therapy of this complication is needed to improve patient outcomes.<h4>Recent findings</h4>Guided by insights into acute GVHD pathogenesis, investigators have explored novel cellular and pharmacologic approaches to acute GVHD prevention that demonstrates promise. Alth ...[more]

PMID: 21912253

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Project description:The therapeutic efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is limited by the development of graft-versus-host disease (GVHD). In GVHD, rigorous pre-conditioning regimen resets the immune landscape and inflammatory milieu causing immune dysregulation, characterized by an expansion of alloreactive cells and a reduction in immune regulatory cells. In acute GVHD (aGVHD), the release of damage- and pathogen- associated molecular patterns from damaged tissue caused by the conditioning regimen sets the stage for T cell priming, activation and expansion further exacerbating tissue injury and organ damage, particularly in the gastrointestinal tract. Studies have shown that donor T cells utilize multiple energetic and biosynthetic pathways to mediate GVHD that can be distinct from the pathways used by regulatory T cells for their suppressive function. In chronic GVHD (cGVHD), donor T cells may differentiate into IL-21 producing T follicular helper cells or tissue resident T helper cells that cooperate with germinal center B cells or memory B cells, respectively, to produce allo- and auto-reactive antibodies with subsequent tissue fibrosis. Alternatively, donor T cells can become IFN- γ/IL-17 cytokine expressing T cells that mediate sclerodermatous skin injury. Patients refractory to the first line standard regimens for GVHD treatment have a poor prognosis indicating an urgent need for new therapies to restore the balance between effector and regulatory immune cells while preserving the beneficial graft-versus-tumor effect. Emerging data points toward a role for metabolism in regulating these allo- and auto-immune responses. Here, we will discuss the preclinical and clinical data available on the distinct metabolic demands of acute and chronic GVHD and recent efforts in identifying therapeutic targets using metabolomics. Another dimension of this review will examine the changing microbiome after allo-HSCT and the role of microbial metabolites such as short chain fatty acids and long chain fatty acids on regulating immune responses. Lastly, we will examine the metabolic implications of coinhibitory pathway blockade and cellular therapies in allo-HSCT. In conclusion, greater understanding of metabolic pathways involved in immune cell dysregulation during allo-HSCT may pave the way to provide novel therapies to prevent and treat GVHD.

Project description:A cute graft-versus-host disease remains a major threat to a successful outcome after allogeneic hematopoietic cell transplantation. While improvements in treatment and supportive care have occurred, it is unknown whether these advances have resulted in improved outcome specifically among those diagnosed with acute graft-versus-host disease. We examined outcome following diagnosis of grade II-IV acute graft-versus-host disease according to time period, and explored effects according to original graft-versus-host disease prophylaxis regimen and maximum overall grade of acute graft-versus-host disease. Between 1999 and 2012, 2,905 patients with acute myeloid leukemia (56%), acute lymphoblastic leukemia (30%) or myelodysplastic syndromes (14%) received a sibling (24%) or unrelated donor (76%) blood (66%) or marrow (34%) transplant and developed grade II-IV acute graft-versus-host disease (n=497 for 1999-2001, n=962 for 2002-2005, n=1,446 for 2006-2010). The median (range) follow-up was 144 (4-174), 97 (4-147) and 60 (8-99) months for 1999-2001, 2002-2005, and 2006-2010, respectively. Among the cohort with grade II-IV acute graft-versus-host disease, there was a decrease in the proportion of grade III-IV disease over time with 56%, 47%, and 37% for 1999-2001, 2002-2005, and 2006-2012, respectively (P<0.001). Considering the total study population, univariate analysis demonstrated significant improvements in overall survival and treatment-related mortality over time, and deaths from organ failure and infection declined. On multivariate analysis, significant improvements in overall survival (P=0.003) and treatment-related mortality (P=0.008) were only noted among those originally treated with tacrolimus-based graft-versus-host disease prophylaxis, and these effects were most apparent among those with overall grade II acute graft-versus-host disease. In conclusion, survival has improved over time for tacrolimus-treated transplant recipients with acute graft-versus-host disease.

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Have we improved in preventing and treating acute graft-versus-host disease?

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Have we improved in preventing and treating acute graft-versus-host disease?

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