scholarly journals 2844. Butyrogenic Bacteria After Acute Graft vs. Host Disease Associate with the Development of Steroid Refractory GVHD

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S68-S68
Author(s):  
Jonathan L Golob ◽  
Martha M DeMeules ◽  
Tillie Loeffelholz ◽  
Z Z Quinn ◽  
Michael K Dame ◽  
...  
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Electrical Resistance ◽  
Acute Gvhd ◽  
Host Disease ◽  
Direct Exposure ◽  
Increased Risk ◽  
Graft Vs Host Disease ◽  
Steroid Refractory ◽  
Acute Graft

Abstract Background Steroid refractory acute graft- vs. -host-disease (GVHD) after hematopoietic cell transplantation (HCT) is highly morbid with limited treatment options. Murine studies show protection from GVHD with butyrate exposure but direct exposure of stem/progenitor cells to butyrate inhibits colonic stem cell proliferation. Methods Stool samples were collected weekly in a cohort of HCT recipients (n = 210) undergoing allogeneic transplant, and underwent 16S rRNA sequencing to determine the number and relative abundance of butyrogens. Dissociated primary human colonoid cell aggregates (200,000 per well) were plated onto collagen IV-coated transwells (0.4 µm pore size, 0.33 cm2, PET) in stem cell medium for 24 hours. From 24 hours onwards, the basal-lateral chamber was switched to differentiation medium; the apical chamber was Hanks Buffered Salt Solution (HBSS), HBSS with 10 mM butyrate sodium salt early (24 hours onwards) or late (72hours onwards). Trans-epithelial electrical resistance was measured daily. Results Retrospective chart review identified 27 recipients who developed acute GVHD of the gut, stratified to be either steroid refractory GVHD (failed to respond to 2 mg/kg of methylprednisolone) or responsive. The presence of butyrogens in the gut microbiome after the onset of severe acute GHVD of the gut associated with increased risk of steroid refractory GVHD (Figure 1; P < 0.05). Direct exposure of human colonic stem/progenitor cells to butyrate inhibits the development of trans-epithelial electrical resistance; exposure after differentiation had no inhibition of barrier formation (Figure 2; P < 0.05 by T-test). Conclusion Butyrogens may help prevent the development of acute GVHD of the gut, but once severe GVHD has developed may inhibit recovery due to the loss of crypt architecture exposing colonic stem cells to microbe-produced butyrate with impaired differentiation and cell replacement. Disclosures All Authors: No reported Disclosures.

scholarly journals Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease Using Commercial Mesenchymal Stem Cell Products

2021 ◽  
Vol 12 ◽  
Author(s):  
Makoto Murata ◽  
Takanori Teshima
Keyword(s):  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Acute Gvhd ◽  
Eligibility Criteria ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Precise Position ◽  
A Prospective Study ◽  
Steroid Refractory ◽  
Acute Graft

Acute graft-versus-host disease (GVHD) is a life-threatening complication that can develop after allogeneic hematopoietic stem cell transplantation. In particular, the prognosis of patients with steroid-refractory acute GVHD is extremely poor. Ryoncil™ (remestemcel-L), a human bone marrow-derived mesenchymal stem cell (MSC) product, failed to show superiority over placebo in patients with steroid-refractory acute GVHD, but it was approved for use in pediatric patients in Canada and New Zealand based on the results of a subgroup analysis. Temcell®, an equivalent manufactured MSC product to remestemcel-L, was approved in Japan based on small single-arm studies by using a regulation for regenerative medicine in 2016. The efficacy of Temcell was evaluated in 381 consecutive patients treated with Temcell during the initial 3 years after its approval. Interestingly, its real-world efficacy was found to be equivalent to that observed in a prospective study of remestemcel-L with strict eligibility criteria. In this article, the potential of MSC therapy in the treatment of acute GVHD is discussed. A meticulous comparison of studies of remestemcel-L and Temcell, remestemcel-L/Temcell and ruxolitinib, and remestemcel-L/Temcell and thymoglobulin showed that the precise position of remestemcel-L/Temcell therapy in the treatment of acute GVHD remains to be determined.

Pre-Engraftment Serum C-Reactive Protein (CRP) Value as a Predictor of Acute Graft-Versus-Host Disease and Non-Relapse Mortality.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1968-1968
Author(s):  
Shigeo Fuji ◽  
Sung-Won Kim ◽  
Takahiro Fukuda ◽  
Shin-ichiro Mori ◽  
Satoshi Yamasaki ◽  
...  
Keyword(s):  
Stem Cell ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Unrelated Donor ◽  
Primary Role ◽  
Host Disease ◽  
Graft Versus Host ◽  
Increased Risk ◽  
Grade Ii ◽  
Acute Graft

Abstract Background: In a mouse model, it has been shown that inflammatory cytokines play a primary role in the development of acute graft-versus-host disease (GVHD). Here, we evaluated whether the pre-engraftment CRP value, which is used as a surrogate marker of inflammation, could predict post-transplant complications including GVHD. Methods: The medical records of 224 adult patients (median age, 47 years; range, 18–68 y), who underwent conventional (CST, n=105) or reduced-intensity (RIST, n=119) allogeneic stem cell transplantation between January 2002 and July 2006 were reviewed retrospectively. Their diagnosis included AML (n=94), ALL (n=23), NHL (n=62), MDS (n=27) and others (n=18). Stem cell sources included bone marrow (n=108), peripheral blood stem cells (n=98) and cord blood cells (n=18). Patients were categorized according to the maximum CRP value during the pre-engraftment neutropenic period: the “low CRP” group (CRP &lt; 15 mg/dL) included 157 patients and the “high CRP” group (CRP≥15 mg/dL) included 67 patients. We assessed the occurrence of acute GVHD, non-relapse mortality (NRM) and overall survival. Results: The incidence of documented infections during neutropenia was higher in the high CRP group (34% vs 17%, P=0.004). The CRP value was significantly lower after RIST than after CST (P=0.017) or after related than after unrelated transplantation (P&lt;0.001). A multiple logistic regression analysis showed that male sex, unrelated donor and HLA-mismatched donor were associated with high CRP values. The high CRP group developed significantly more grade II-IV acute GVHD, grade III-IV acute GVHD and NRM as shown in Figure 1 and 2. A multivariate analysis showed that a high CRP level was associated with an increased risk of grade II-IV acute GVHD, poor OS and high NRM. Conclusion: The present findings suggest that the CRP value may reflect the net degree of tissue damage due to the conditioning regimen, inflammation, infection and allogeneic immune reactions, all of which lead to subsequent acute GVHD and NRM. Future clinical studies to evaluate the feasibility of earlier intervention and adjustment of GVHD prophylaxis based on monitoring of the early CRP value are warranted. Fig 1 grade II-IV acute GVHD Fig 1. grade II-IV acute GVHD Fig 2 non-relapse mortality Fig 2. non-relapse mortality

scholarly journals 2569. The Gut Microbiome and Acute Graft vs. Host Disease Risk in Hematopoietic Stem Cell Transplantation Recipients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S892-S893
Author(s):  
Emma E Ilett ◽  
Joanne Reekie ◽  
Mette Jørgensen ◽  
Daniel D Murray ◽  
Marc Noguera ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Gut Microbiome ◽  
Conditioning Regimen ◽  
Clinical Factors ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Vs Host Disease ◽  
Gene Richness ◽  
Acute Graft

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.

scholarly journals Acute graft-versus-host disease: analysis of risk factors after allogeneic marrow transplantation and prophylaxis with cyclosporine and methotrexate [see comments]

Blood ◽  
1992 ◽  
Vol 80 (7) ◽  
pp. 1838-1845 ◽  
Author(s):  
RA Nash ◽  
MS Pepe ◽  
R Storb ◽  
G Longton ◽  
M Pettinger ◽  
...  
Keyword(s):  
Risk Factors ◽  
Graft Versus Host Disease ◽  
Marrow Transplantation ◽  
Malignant Disease ◽  
Acute Gvhd ◽  
Host Disease ◽  
Cox Regression Analysis ◽  
Graft Versus Host ◽  
Increased Risk ◽  
Acute Graft

Abstract Previous studies of risk factors for acute graft-versus-host disease (GVHD) involved patients receiving predominantly single-agent prophylaxis. Therefore, a retrospective analysis was performed on 446 patients, from a single institution, who received transplants of marrow from HLA-identical siblings and the combination of cyclosporine (CSP) and methotrexate (MTX) to determine risk factors for acute GVHD associated with this more effective form of GVHD prophylaxis. The incidences of Grades II-IV and Grades III-IV (severe) acute GVHD were 35% and 16%, respectively. Increased clinical grades of acute GVHD in patients without advanced malignant disease were associated with a decreased survival. In a multivariate Cox regression analysis, risk factors associated with the onset of Grades II-IV acute GVHD were sex mismatch and donor parity (P = .001), increased dose of total body irradiation (TBI) (P = .001), and reduction to less than 80% of the scheduled dose of MTX (P = .02) or CSP (P = .02). The multivariate analysis indicated a relative risk of 1.37 for acute GVHD in a group defined as having advanced malignant disease at transplant; however, this difference failed to reach conventional levels of statistical significance (P = .07). Reduction of MTX and CSP occurred in up to 36% and 44% of patients, respectively, primarily because of renal or hepatic dysfunction. The periods of increased risk for the onset of acute GVHD were up to 1 week after a reduction of MTX and 2 weeks after a reduction in CSP. When only patients who developed Grades II-IV acute GVHD were considered, the more severe acute GVHD of Grades III-IV was associated with increased patient age of 40 years or greater (P = .05) and dose reductions of CSP (P = .008). Serologic status of patient and donor for cytomegalovirus (CMV), HLA antigens in the A and B loci, and isolation in a laminar air flow room during marrow transplantation, all previously identified as risk factors for acute GVHD, were not confirmed as risk factors in this study population. The toxicity of MTX and CSP and the development of acute GVHD from inadequate immunosuppression because of dose reduction warrants further trials with potentially less toxic immunosuppressive agents. Risk factors for acute GVHD should be considered in clinical management and in the design of clinical trials.

Infliximab for the Treatment of Chronic Graft Versus Host Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2889-2889
Author(s):  
Ethan Tolbert ◽  
Ned Waller ◽  
H. Jean Khoury ◽  
Mary Jo Lechowicz ◽  
Christopher Flowers ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Survival ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Response Rate ◽  
The Other ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α ◽  
Steroid Refractory

Abstract Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity and non relapse mortality after allogeneic stem cell transplantation. Tumor necrosis factor alpha (TNF-α) is a cytokine involved in the pathogenesis of GVHD. Infliximab is a murine-human chimeric monoclonal antibody that binds TNF-α, preventing interaction with its receptor and its ability to mediate the development of GVHD. Infliximab is active in the treatment of steroid refractory acute GVHD, particularly for patients with GI GVHD (Couriel et al Blood. 2004 Aug 1;104(3):649–54).We performed a retrospective analysis to evaluate the activity of infliximab in 22 patients with AML/MDS (n=5), lymphoma (n=8), ALL (n=3), and others (n=6) with steroid refractory chronic extensive GVHD. Response was measured according to standard response criteria (Pavletic et al. Biology of Blood and Marrow Transplantation 2006 Mar;12(3):252–66). The median age of the patients was 50 years (range 20 – 64). Fourteen (64%) patients had matched sibling donors, 8 (36%) had matched unrelated donors, 9 (41%) underwent nonmyeloablative conditioning, one patient had a bone marrow transplant and the other 21 patients had peripheral blood stem cell transplants. All patients were given standard doses of tacrolimus or cyclosporine for GVHD prophylaxis with either short course methotrexate or mycophenolate mofetil. All patients were treated with systemic steroids at the onset of GVHD. Fifty percent of the patients initially presented with acute GVHD that progressed to chronic extensive GVHD. The other half presented with late onset or de novo chronic extensive GVHD. Nineteen had skin involvement (86%), 15 (68%) had gastrointestinal involvement, and 10 (45%) had liver involvement at the time of treatment with infliximab. All patients were considered refractory to tacrolimus/cyclosporine and systemic steroids, had intolerable side effects from steroids or could not be successfully tapered off steroids prior to infliximab administration. Median time from transplant to infliximab administration was 337days (range 122 to 932 days). The patients received a median of 4 weekly courses (range 1–20 courses) of infliximab at 10mg/kg. The overall response rate was 64% (n=14); 11 (50%) experienced a complete response (CR); 3 (14%) experienced a partial response (PR); 8 (36%) had progressive GVHD. The response rate for skin GVHD was 68%, GI was 60% and liver was 50%. One patient suffered an acute infusion reaction after the first infliximab dose and had no further drug administered. Median survival of all patients following initiation of infliximab was 223 days. Median survival of all responders was 625 days after infliximab, while median survival of the non-responders was 70 days after infliximab. Six patients remain alive at a median follow-up of 55 months (27%). Three of six survivors are on minimal immunosuppression with limited cGVHD and three are off all immunosuppression with no evidence of cGVHD. Of the patients who died, 7 (32%) died from infectious complications, 5 (23%) died from complications of progressive cGVHD, 4 (18%) died from hemorrhagic or embolic strokes, 2 died from complications of post-transplant lymphoproliferative disorder (PTLD), and one patient from relapse. In conclusion, infliximab has activity for cGVHD. Prospective trials investigating the activity of infliximab, the infectious risks, predictive measures responding patients and optimal timing of administration are needed.

Treatment Options in Steroid-Refractory Acute Graft-Versus-Host Disease Following Hematopoietic Stem Cell Transplantation

2007 ◽  
Vol 41 (9) ◽  
pp. 1436-1444 ◽  
Author(s):  
Sara S Kim
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Gvhd ◽  
Treatment Options ◽  
Hematopoietic Stem ◽  
Graft Versus Host ◽  
Pharmacologic Agents ◽  
Steroid Refractory ◽  
Acute Graft

Objective: To evaluate the treatment options in steroid-refractory acute graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. Data Sources: Literature was obtained by searching MEDLINE (1966–May 2007) and EMBASE (1980–May 2007). Study Selection and Data Extraction: All pertinent clinical trials, retrospective studies, case reports, and compassionate use studies were identified and evaluated for safety and efficacy of the pharmacologic agents. Data Synthesis: Steroid-refractory acute GVHD is associated with high rates of morbidity and mortality. Although various pharmacologic agents have been studied in the treatment of steroid-refractory acute GVHD, no treatments have been established as a salvage therapy. Preliminary data on different pharmacologic agents have been identified and evaluated for their efficacy and tolerability in the treatment of steroid-refractory acute GVHD. The effects of the pharmacologic agents varied significantly among patients: severity of the disease, involvement of different organs, and the patient's age seem to be the major factors that affect an individual's response to drug therapy. In addition, the treatments are further challenged by the high incidence of potentially fatal opportunistic infections that occur during the therapy. Conclusions: Selection of pharmacologic agents for the treatment of steroid-refractory acute GVHD should be based on the target organs, adverse drug reactions, and economic factors. Further studies with larger sample sizes are warranted to better understand the roles of these agents in the treatment of steroid-refractory acute GVHD.

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