scholarly journals Targeted Molecular Imaging of Translocator Protein (TSPO) Using 18FGE180-PET for the Diagnosis of Gastrointestinal Graft Versus host Disease (GI-GVHD)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3397-3397
Author(s):  
Ashleigh P Scott ◽  
Siok-Keen Tey ◽  
Paul Thomas ◽  
David Pattison ◽  
Glen A Kennedy
Keyword(s):  
Clinical Response ◽  
Graft Versus Host Disease ◽  
Conflicts Of Interest ◽  
Positron Emission Tomography Imaging ◽  
Endoscopic Biopsy ◽  
Translocator Protein ◽  
Histologic Diagnosis ◽  
Haematopoietic Progenitor Cell ◽  
Host Disease ◽  
Graft Versus Host

Abstract Introduction: Acute Gastrointestinal Graft Versus Host Disease (GI-GVHD) is a life-threatening complication following haematopoietic progenitor cell transplantation (HPCT). Recent data suggest that the current gold standard diagnostic test (endoscopic biopsy) fails to identify 26% of those patients requiring treatment. The mitochondrial translocator protein TSPO is upregulated in activated macrophages and inflammatory bowel diseases, and thus may be a biomarker of acute GI-GVHD. 18FGE180 is a novel TSPO-targeting radioligand for use in positron emission tomography imaging (18FGE180-PET). Methods: We performed a prospective observational pilot study evaluating 18FGE180-PET in adults with clinically suspected acute GI-GVHD occurring within 100 days following HPCT. Participants underwent a baseline 18FGE180-PET within 7 days of diagnostic endoscopy, and a follow-up 18FGE180-PET 1-4 weeks later. Tissue avidity was assessed visually in four sections of the gastrointestinal tract (GIT; stomach, duodenum, sigmoid and rectum) and rated by standardised uptake variable (SUV), with "positive" defined by SUV greater than mediastinal blood pool (MBP). Imaging findings were correlated with patient demographics, symptom severity (defined by modified Glucksberg stage), endoscopic findings, and histologic diagnosis. For patients in whom GI-GVHD treatment was initiated (defined as minimum prednisone 1mg/kg or equivalent), the clinical response was correlated with GIT avidity during the second 18FGE180-PET. Results: Six (6) patients were recruited, with median age 57 years (range 53-68 years), at a median 66 days post HPCT (range 26-95 days). Median Glucksberg stage of presumptive GI-GVHD was 2 (range 1-3). The histological diagnosis was GI-GVHD in 4 (66%) patients, and drug toxicity in the remaining two patients. Concordance between histological findings and 18FGE180-PET avidity by GIT section were 50% (stomach), 100% (duodenum), 100% (sigmoid) and 80% (rectum). 18FGE180-PET was highly accurate in duodenum and sigmoid (sensitivity 100%, specificity 100%), moderately accurate in rectum (sensitivity 66%, specificity 100%), and non-specific in stomach (sensitivity 100%, specificity 25%). Five (83%) patients subsequently underwent treatment for GI-GVHD, and of these 4 (80%) underwent repeat 18FGE180-PET for response assessment, seven days after the first. In these patients, high concordance between clinical response and 18FGE180-PET avidity was demonstrated in sigmoid (100%), rectum (100%) and duodenum (75%), compared with poor concordance in stomach (25%). The final patient, whose biopsies were negative for GI-GVHD and did not undergo GVHD treatment, was non-avid at all sites on both initial and subsequent 18FGE180-PET. Conclusion: 18FGE180-PET appears to show utility in the diagnosis of GI-GVHD in small and large bowel. Larger prospective studies, correlating with histological TSPO expression, are warranted. Disclosures No relevant conflicts of interest to declare.

Rituximab Reduces Anti-UL94 and Anti-NAG-2 Antibodies Titer and Is Effective against Skin-Chronic Graft Versus Host Disease Resembling Scleroderma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4654-4654
Author(s):  
Rocco Pastano ◽  
Chiara Dell'Agnola ◽  
Caterina Bason ◽  
Federica Gigli ◽  
Cristina Rabascio ◽  
...  
Keyword(s):  
Clinical Response ◽  
Graft Versus Host Disease ◽  
Molecular Mimicry ◽  
Conflicts Of Interest ◽  
Immunosuppressive Treatment ◽  
Potential Effect ◽  
Cell Transplant ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ul 94

Abstract Abstract 4654 We previously described a potential pathogenetic link between human Cytomegalovirus (hCMV) infection and scleroderma-like skin chronic graft versus host disease (cGVHD) in allogeneic stem cell transplant patients (HCT), through a mechanism of molecular mimicry between UL-94 viral protein and NAG-2 molecule. Antibodies against UL-94 and NAG-2 induce apoptosis of endothelial cells and fibroblasts proliferation as observed in Systemic Sclerosis ( SSc ) patients (ASH 2009, Abstract 1169; EBMT 2009, oral comunication 377). The observation that the anti-CD20 chimaeric monoclonal antibody Rituximab induces a significant clinical response in a proportion of HCT patients with refractory cGVHD prompted us to evaluate in our CMV IgG positive HCT patients, who developed scleroderma-like skin cGVHD, first the efficacy of Rituximab, second weather the potential effect of Rituximab would correlate with the anti-viral and anti-NAG-2 antibodies titer. Among 18 patients undergone HCT for hematological malignancies between 2003 and 2006 at Bone Marrow Transplant Unit of Division of Hematoncology, European Institute of Oncology, Milan, Italy, two of them (patients #2 and #3) both positive for anti-UL94 and anti-NAG-2 antibodies and with clinical evidence of diffuse SSc-like skin cGVHD following HCT were treated with Rituximab. Rituximab was administered with the following schedule: 375 mg/msq weekly for 4 weeks and then monthly up to 4 months. Patient #2 complited the schedule, patient #3 discontinued the therapy, after the second monthly dose, due to infectious pneumonia. Patients' plasma was monitored for anti-UL94 and anti-NAG-2 antibodies titer, by direct and competitive ELISA assays, before starting Rituximab administration, after the weekly therapy, and at the end of the schedule of treatment (patient #2) or after the last Rituximab infusion, in case of discontinuation (patient #3). In patient #2 we observed a dramatic reduction of the anti-NAG-2 antibodies titer immediately after completing the weekly administration of Rituximab, reaching a stable plateau after the monthly administration of the monocolonal therapy in parallel with an excellent clinical response. In the same patient anti-UL94 antibodies titer was already low after HCT and before Rituximab, and it kept stable low values during all the administration period. Worth of note, this patient is now off any immunosuppressive treatment. We observed also a reduction of both anti-CMV and anti-NAG-2 antibodies titer in patient #3 following Rituximab, however without reaching a plateau, mainly due to the early discontinuation of the treatment. This patient had also a good clinical response, even though he is still under immunosuppression therapy. In conclusion, our data show that Rituximab reduces anti-UL94 and anti-NAG2 antibodies titer in hCMV positive HCT patients in parallel with the clinical response of skin cGVHD resembling scleroderma. Disclosures: No relevant conflicts of interest to declare.

Sa1745 Diagnosis of Acute Gastrointestinal Graft-Versus-Host Disease: Are Total Colonoscopy and Endoscopic Biopsy Necessary?

2016 ◽  
Vol 83 (5) ◽  
pp. AB283
Author(s):  
Yosuke Mitani ◽  
Osamu Kikuchi ◽  
Yuichi Shimodate ◽  
Akira Doi ◽  
Naoyuki Nisimura ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Endoscopic Biopsy ◽  
Total Colonoscopy ◽  
Host Disease ◽  
Graft Versus Host

Case Report The Need for Endoscopic Biopsy in the Diagnosis of Upper Gastrointestinal Graft-Versus-Host Disease

1993 ◽  
Vol 16 (2) ◽  
pp. 183-185 ◽  
Author(s):  
A. L. Appleton ◽  
L. Sviland ◽  
A. D. J. Pearson ◽  
M. A. Green ◽  
E. J. Eastham ◽  
...  
Keyword(s):  
Case Report ◽  
Graft Versus Host Disease ◽  
Endoscopic Biopsy ◽  
Host Disease ◽  
Graft Versus Host ◽  
Upper Gastrointestinal

Allogeneic HY Antibodies 3 Months Following Sex-Mismatched HCT Predicts Chronic Graft-Versus-Host Disease and Non-Relapse Mortality

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 147-147
Author(s):  
Hideki Nakasone ◽  
Lu Tian ◽  
Takakazu Kawase ◽  
Bita Sahaf ◽  
Rakesh Popli ◽  
...  
Keyword(s):  
B Cell ◽  
Graft Versus Host Disease ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Cumulative Number ◽  
Clinical Factors ◽  
Roc Curve Analysis ◽  
Host Disease ◽  
Graft Versus Host ◽  
Increased Risk

Abstract Background B-cells play a significant role in chronic graft-versus-host disease (cGVHD). Male patients with female donors (F→M) are at a higher risk of developing cGVHD. B cell responses against minor histocompatibility antigens encoded on the Y chromosome, called H-Y antigens, develop following F→M HCT patients in association with cGVHD (Miklos, Blood. 2005 & Sahaf, PNAS. 2013). Here we present our novel HY microarray and use this sensitive technology to determine temporal development of HY antibody (Ab) preceding cGVHD. Multivariate analyses demonstrate that HY-Ab detection 3 months (3m) post HCT predicts cGHVD incidence and non-relapse mortality (NRM). Methods We studied 136 adult male recipients of F→M HCT between 2005 and 2012 who survived without relapse for at least 3m post-HCT with 3m plasma available. Median patient age was 53 (21-74). Related donors were transplanted in 85 (63%) and 128 (94%) were PBSC grafts. Reduced intensity conditioning accounted for 61 (45%) and anti-thymocyte globulin (ATG) was used in 71 (52%). Thirty-one patients (23%) experienced grade II-IV acute GVHD. We measured IgG against six HY antigens (DBY, UTY, ZFY, SMCY, EIF1AY, and RBS4Y) from plasma collected 3m post-HCT using a novel proteomic microarray here presented for the first time. The cut-off value for seropositivity was defined as the third quartile + 2x the interquartile range, determined from plasma of 60 male donors. HY-score was defined as the cumulative number of HY antigen targeted by Abs at 3m post-HCT. Results The frequencies of HY antigen-specific Ab are presented in Table 1, showing that SMCY and UTY were most frequently detected and overall, 78 (57%) had developed allo-Ab against any of these 6 HY antigens. Each HY-Ab was significantly associated with the development of cGVHD and DBY was greatest. LASSO analysis suggested that DBY, UTY, and ZFY were the most predictive for the development of cGVHD (Table 1). Univariate analysis failed to identify associations between clinical features and the development of HY-Ab at 3m. The detection of HY-Ab gradually increased within the 1st year post HCT and seropositivity for each HY-IgG (except RPS4Y) persisted. Considering each HY-IgG response by principal component analysis, a higher HY-score was associated with an increased risk for the development of cGVHD and NRM, after adjusting for usual alloHCT clinical factors (Table 2). In addition, the severity of cGVHD was significantly associated with the HY-score: the proportion of severe/moderate cGVHD was 33% in 0, 30% in 1, 60% in 2-3, and 70% in 4-6 (P<0.01). Receiver operating characteristic (ROC) curve analysis revealed that HY-score in combination with clinical factors enhanced the predictive potential for the development of cGVHD [area under the curve (AUC): 0.76], in comparison with either of only HY-score (AUC: 0.66) or clinical factors (AUC: 0.69). Conclusion Here, we show that HY Ab detection 3m following sex-mismatch HCT actually predicts the development of cGVHD, independently from clinical risk factors. In addition, the combination of HY-score and clinical factors had a greater predictive potential than clinical factors alone for the development of cGVHD in F→M HCT. HY-Ab development 3m post HCT may stratify cGVHD risk and support B-cell-depletion therapy beginning 3 months or earlier to prevent cGVHD development. Disclosures: No relevant conflicts of interest to declare.

Acute Graft Versus Host Disease after Donor Lymphocyte Infusion: A Single Center Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5807-5807
Author(s):  
Fiona C. He ◽  
Daniel J. Weisdorf ◽  
Erica D. Warlick ◽  
Jeffrey S. Miller ◽  
Shernan G. Holtan ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Conflicts Of Interest ◽  
Significant Risk ◽  
Donor Lymphocyte Infusion ◽  
Myelogenous Leukemia ◽  
Host Disease ◽  
Graft Versus Host ◽  
Grade Ii ◽  
Acute Graft

Abstract Donor lymphocyte infusion (DLI) is an option for relapsed hematologic malignancies following allogeneic hematopoietic cell transplantation (HCT). We analyzed the incidence and manifestations of acute graft versus host disease (GVHD) in patients with malignant and non-malignant conditions treated with DLI. At the University of Minnesota, we gave 171 DLI to 120 patients from 1995-2013. The cumulative incidence of grade II-IV acute GVHD was 31.6% (CI 25-42%,n = 40); grade III-IV 23.3% (CI 16-32%,n = 29). GVHD after DLI (n = 46) included involvement of skin in 70% (n = 32), lower gastrointestinal (GI) 65% (n = 30), upper GI 43% (n = 20), and liver 35% (n = 16). Patients receiving chemotherapy prior to DLI (chemo-DLI) had more frequent acute GVHD and GI GVHD. Significant risk factors for grade II-IV acute GVHD included: age > 40, chemo-DLI, malignant disease, and time from HCT to DLI < 200 days. Response to treatment of acute GVHD at 8 weeks was complete in 40% and complete/partial in 52%. Patients developing GVHD had frequent disease response. In chronic myelogenous leukemia (CML) patients, responses were excellent (80%) with or without GVHD. The CR rate was 34% for non-CML malignancies; only 9% achieved CR without acute GVHD. Non-malignant diseases showed poor prognosis following acute GVHD and good prognosis without. Overall survival at 2 years for CML patients was similar (83% vs 79%, p = 0.89) with or without grade II-IV acute GVHD, but in non-CML malignancies survival was better in absence of acute GVHD (41% vs 22%, p = 0.04). We observed frequent, yet therapy-responsive acute GVHD following DLI. DLI often induced remission in CML, but less so for non-CML malignancies without chemo-DLI, particularly in absence of acute GVHD. Improvements in DLI efficacy and GVHD management are still needed. Disclosures No relevant conflicts of interest to declare.

The Chemerin/ChemR23 Axis Plays a Pivotal Role in the Pathogenesis of Intestinal Damage in a Murine Model of Graft Versus Host Disease

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3077-3077 ◽  
Author(s):  
Paola Vinci ◽  
Camilla Recordati ◽  
Donatella Bardelli ◽  
Claudia Cappuzzello ◽  
Valeria Fumagalli ◽  
...  
Keyword(s):  
Large Intestine ◽  
Graft Versus Host Disease ◽  
Bone Marrow Cells ◽  
Conflicts Of Interest ◽  
Haematopoietic Stem Cell ◽  
Intestinal Damage ◽  
Cell Trafficking ◽  
Host Disease ◽  
Graft Versus Host ◽  
Target Organs

Abstract Allogeneic haematopoietic-stem-cell transplantation (HSCT) is the treatment of choice for many malignant and non-malignant disorders. However, Graft-versus -Host Disease (GvHD), the major complication of allogeneic HSCT, limits its wider application. Among different sites that can be involved, gastrointestinal GvHD represents the major cause of patients morbidity and mortality. The infiltration of different cell subsets into target organs is an important step in GvHD pathogenesis, and the modulation of cell trafficking could represent a promising strategy for GvHD prophylaxis and treatment. Chemerin has been recently identified as a chemotactic protein, which is produced by several tissues during inflammation and binds the G protein-coupled receptor ChemR23, expressed by immature myeloid and plasmacytoid Dendritic Cells, macrophages and natural killer cells. The aim of this study was to evaluate the potential role of Chemerin/ChemR23 axis in the pathogenesis of GvHD, in order to identify disease-specific pathways exploitable for developing new potential therapeutic targets. For this purpose, lethally irradiated Balb/C recipient mice were transplanted with bone marrow cells and splenocytes obtained from ChemR23deficient (ChemR23-/-) C57BL6 mice. After transplantation, mice were monitored daily for survival and GvHD severity. Recipient mice were sacrificed at different time points to evaluate Chemerin production and leukocytes infiltration in skin, lung, liver, and gut by using different techniques, such as ELISA, histopathology, FACS and PCR. Starting from day +6 after transplantation, Chemerin plasma levels appeared significantly higher in both wild type (WT) and ChemR23-/- mice who developed GvHD (WT mean level=86.8 ng/ml; range=80.1-91.9; ChemR23-/- mean level=83.8 ng/ml; range=70.5-103.6, n=6, day+7) compared to syngeneic controls (mean level=62.8 ng/ml; range=49.2-82.5, n=6, day+7), p=0.02. Interestingly, ChemR23-/- mice developed a more severe GvHD compared to mice transplanted with WT cells. In particular, ChemR23-/- transplantedmice showed a higher mortality rate (at day +28 after HSCT: 85% mortality in ChemR23-/- vs 25% in WT, p=0.0004, n=45) (Fig. 1). Differences in GvHD score between ChemR23-/- and WT transplanted mice resulted by a significantly increase in weight loss, associated to severe diarrhea. In accordance, histopathologic analysis performed on GvHD target organs showed a significantly higher GvHD score in large intestine of ChemR23-/- transplanted mice, whereas no differences were found in other GvHD target organs. In addition, a deeper histological analysis on large intestine showed that tissue damage is characterized by crypt hyperplasia and atrophy, epithelium apoptosis and colitis. Moreover, FACS analysis of large intestine infiltrating leukocytes showed an higher neutrophils frequency in ChemR23-/- transplantedmice compared to WT (neutrophils=10.39%, range 6.5%-15.1% versus neutrophils=5.84%, range 2.6%-12.8%, respectively, p=0.001, n=10). This observation was also obtained by analyzing the mesenteric lymphnode. The higher neutrophils infiltration was also confirmed by immunohistochemistry evaluating the number of myeloperoxidase (MPO) positive cells and by quantitative PCR detecting MPO expression (ChemR23-/- mean 2-ΔΔCt =22.35, range 2.43-46.05; WT mean 2-ΔΔCt =6.42, range 0.20-19.23; p=0.04, n=8). All these findings suggest that the Chemerin/ChemR23 axis play a crucial role in intestinal GVHD. Further studies are needed to better understand the mechanisms underling the severe damage observed in the gastrointestinal tract of mice transplanted with ChemR23-/- cells. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Complete Resolution of Extensive Chronic Graft-Versus-Host Disease with Ibrutinib

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5474-5474
Author(s):  
Audrey Scholoff ◽  
Gloria Obi ◽  
Kelty R. Baker ◽  
George Carrum ◽  
Rammurti T Kamble
Keyword(s):  
Graft Versus Host Disease ◽  
Complete Resolution ◽  
Conflicts Of Interest ◽  
Complete Response ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Oral Ulcers

Abstract We herein document a complete response of extensive chronic graft-versus-host disease (cGvHD) to a Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib. A 41 years old female with primary refractory MCL underwent mismatched unrelated donor (MMUD) allogeneic hematopoietic stem cell transplantation in December 2011 (conditioning with CY/TBI and alemtuzumab, graft=6.6x 106/kg CD-34+ cells, tacrolimus alone for GVHD prevention). Following engraftment on day 11, she developed grade III acute GvHD involving the skin and gut on day 17 of transplantation that persisted beyond 100 days post-transplant. Her cGvHD was treated with steroids, but remained active and extensive. Despite persistent cGvHD and 100% donor chimerism she relapsed in July 2012. Treatment with radiation and bendamustine with rituximab failed. By December 2013, the patient had extensive cGvHD manifesting as scleromatous skin thickening, oral ulcers and sclerosis of the buccal mucosa, ocular dryness and diarrhea, and was started on ibrutinib1 560 mg once daily for relapsed MCL. After 8 weeks of therapy, cGvHD had begun to improve. Oral steroids were reduced and ultimately stopped after 26 weeks of ibrutinib; after 30 weeks treatment all cGvHD manifestations resolved completely. A complete remission for MCL was documented at 8 weeks of ibrutinib initiation. Currently she continues to be on 560 mg daily ibrutinib without cGvHD exacerbation or MCL relapse for 22 weeks and 52 weeks, respectively. Chronic graft versus host disease (cGvHD) is mediated donor T cells. The role of B cells in the pathogenesis of cGvHD is increasingly recognized. Two murine studies have explored the role of ibrutinib in cGVHD-like syndromes, one in which there is T cell driven sclerodermatous cGvHD and a second in which there is Ab driven multiorgan system cGvHD that includes bronchiolitis obliterans (BO). Administration of ibrutinib decreased the incidence and severity of sclerodermatous, and improved pre-existing lesions and also improved pulmonary fibrosis and reduced BO. Animals lacking BTK and ITK did not develop cGVHD, indicating that these molecules are critical to cGVHD development. Our report provides the evidence that BTK inhibition led to complete resolution of cGvHD and supports exploration of its role in future clinical trials. Disclosures No relevant conflicts of interest to declare.

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