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1.
Molecular Biomarkers in Ocular Graft-versus-Host Disease: A Systematic Review
Bohlen, J., Gomez, C., Zhou, J., Martinez Guasch, F., Wandvik, C., Sunshine, S. B.
Biomolecules. 2024;14(1)
Abstract
Ocular graft-versus-host disease (oGVHD) affects ~50% of post-stem cell transplant patients and is the only form of GVHD diagnosed without a biopsy. As it must be distinguished from other dry eye diseases, there is a need to identify oGVHD biomarkers to improve diagnosis and treatment. We conducted a systematic review of 19 scholarly articles published from 2018 to 2023 including articles focused on adult patients diagnosed with oGVHD following allogeneic hematopoietic stem cell transplant and used biomarkers as the outcome measure. Articles that were not original investigations or were not published in English were excluded. These clinical investigations explored different molecular oGVHD biomarkers and were identified on 3 October 2023 from the Scopus, PubMed, and Embase databases by using search terms including ocular graft-versus-host disease, biomarkers, cytokines, proteomics, genomics, immune response, imaging techniques, and dry-eye-related key terms. The Newcastle-Ottawa scale for case-control studies was used to assess bias. From the 19 articles included, cytokine, proteomic, lipid, and leukocyte profiles were studied in tear film, as well as ocular surface microbiota and fluorescein staining. Our findings suggest that cytokine profiling is the most studied oGVHD biomarker. Additionally, variations correlating these biomarkers with disease state may lead to a more targeted diagnosis and therapeutic approach. Limitations include language bias, publication bias, and sampling bias, as well as a lack of appropriate controls for included studies.
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2.
A genome-wide association study on hematopoietic stem cell transplantation reveals novel genomic loci associated with transplant outcomes
Rosenberger, A., Crossland, R. E., Dressel, R., Kube, D., Wolff, D., Wulf, G., Bickeböller, H., Dickinson, A., Holler, E.
Frontiers in immunology. 2024;15:1280876
Abstract
INTRODUCTION Data on genomic susceptibility for adverse outcomes after hematopoietic stem cell transplantation (HSCT) for recipients are scarce. METHODS We performed a genome wide association study (GWAS) to identify genes associated with survival/mortality, relapse, and severe graft-versus-host disease (sGvHD), fitting proportional hazard and subdistributional models to data of n=1,392 recipients of European ancestry from three centres. RESULTS The single nucleotide polymorphism (SNP) rs17154454, intronic to the neuronal growth guidant semaphorin 3C gene (SEMA3C), was genome-wide significantly associated with event-free survival (p=7.0x10(-8)) and sGvHD (p=7.5x10(-8)). Further associations were detected for SNPs in the Paxillin gene (PXN) with death without prior relapse or sGvHD, as well as for SNPs of the Plasmacytoma Variant Translocation 1 gene (PVT1, a long non-coding RNA gene), the Melanocortin 5 Receptor (MC5R) gene and the WW Domain Containing Oxidoreductase gene (WWOX), all associated with the occurrence of sGvHD. Functional considerations support the observed associations. DISCUSSION Thus, new genes were identified, potentially influencing the outcome of HSCT.
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3.
Post-transplantation cyclophosphamide combined with tacrolimus and low-dose post-engraftment anti-thymoglobulin as GVHD prophylaxis for patients undergoing peripheral blood stem cell transplantation from haploidentical family donor: A single center analysis
Gao, W. H., Zhu, J. Y., Wang, L. N., Wan, M., Wang, L., Devillier, R., Jiang, J. L., Blaise, D., Hu, J.
Frontiers in medicine. 2023;10:1140217
Abstract
INTRODUCTION Post-transplantation cyclophosphamide (PT-Cy) use is a recent graft-versus-host disease (GVHD) prophylaxis strategy for patients undergoing allogeneic stem cell transplantation (allo-HSCT). PT-Cy combined with two immunosuppressants is now widely used after haplo-identical (haplo) and HLA-matched peripheral blood stem cell (PBSC) transplantations with promising GVHD and relapsefree survival (GRFS) probabilities. Although appealing, these results may benefit from improvement notably outside matched sibling donor transplantation, and should be investigated in various ethnic populations. METHODS Therefore, we report our experience of GVHD prophylaxis regimen combining PT-Cy and tacrolimus with addition of post-engraftment low-dose anti-thymocyte globulin (ATG) in allogeneic stem cell transplantation from haplo-identical donors (Haplo). Sixtyseven patients were included in the analysis. All patients received myeloablative or intensified sequential conditioning regimen. RESULTS The median follow-up was 521 (range, 10~991) days. The cumulative incidences of 100-day grade II-IV acute GVHD was 14.9±4.4%, and no case of grade III-IV acute GVHD was documented. The cumulative incidences of 2-yearchronic GVHD and moderate-to-severe chronic GVHD were 25.4±5.4% and 11.9±4%, respectively. The non-relapse mortality at day+100 and 2year were 7.5±3.2% and 9.0±3.5%, respectively. The cumulative incidence of relapse at 2year was 16±6.4%. The 2-year probability of DFS and OS were 73.8% (95%CI, 61.5~88.4%) and 72.5% (95% CI, 57.1~92.1%), respectively. The 2-year GRFS was estimated as 63.6% (95%CI, 50.6~80%). DISCUSSION Our results suggested that a combination of PT-Cy, tacrolimus, and low-dose post-engraftment ATG was a promising GVHD prophylaxis with low incidence of acute GVHD in the haplo-transplantation setting.
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4.
Ikaros expression is associated with an increased risk of chronic graft-versus-host disease
Pereira, A. D., de Molla, V. C., Fonseca, Arbm, Tucunduva, L., Novis, Y., Pires, M. S., Popi, A. F., Arrais-Rodrigues, C. A.
Scientific reports. 2023;13(1):8458
Abstract
Immune reconstitution after hematopoietic stem cell transplantation (HSCT) is a complex and extremely variable process. The Ikaros transcription factor plays an important role in hematopoiesis in several cell lines, especially in the lymphoid lineage. We hypothesized that Ikaros might influence immune reconstitution, and consequently, the risk of opportunistic infections, relapse, and graft versus host disease (GVHD). Samples were collected from the graft and from the peripheral blood (PB) of the recipients 3 weeks after neutrophil recovery. Real-time polymerase chain reaction (RT-PCR) was performed to analyze the absolute and relative Ikaros expression. Patients were divided into two groups, according to Ikaros expression in the graft and in the recipients' PB based on the ROC curves for moderate/severe cGVHD. A cutoff of 1.48 was used for Ikaros expression in the graft, and a cutoff of 0.79 was used for Ikaros expression in the recipients' PB. Sixty-six patients were included in this study. Median age of patients was 52 years (range 16-80 years), 55% of them were male, and 58% of them had acute leukemia. Median follow-up period was 18 months (range 10-43 months). There was no association between Ikaros expression and the risk of acute GVHD, relapse, or mortality. However, a significant association was observed with the risk of chronic GVHD. Higher Ikaros expression in the graft was associated with a significantly higher cumulative incidence (CI) of moderate/severe chronic GVHD according to the National Institute of Health (NIH) classification at two years (54% vs. 15% for patients with lower expression, P = 0.03). A higher Ikaros expression in the recipients' PB 3 weeks after engraftment was also associated with a significantly higher risk of moderate/severe chronic GVHD (65% vs. 11%, respectively, P = 0.005). In conclusion, Ikaros expression in the graft and in the recipients' PB after transplantation was associated with a higher risk of moderate/severe chronic GVHD. Ikaros expression should be evaluated in larger prospective trials as a potential biomarker for chronic GVHD.
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5.
Post-transplant cyclophosphamide as sole GHVD prophylaxis after matched reduced-intensity conditioning allotransplant
Bourgeois, A. L., Jullien, M., Garnier, A., Peterlin, P., Béné, M. C., Guillaume, T., Chevallier, P.
Clinical and translational medicine. 2023;13(4):e1242
Abstract
BACKGROUND Post-transplant cyclophosphamide (PTCY) alone as graft-versus-host disease (GVHD) prophylaxis may avoid/reduce short- and mid-term toxicities of drugs commonly used for GVHD prophylaxis, accelerate immune reconstitution after the graft to decrease infections and facilitate the early integration of adjunct maintenance therapies to prevent relapse. OBJECTIVE A prospective phase 2 study was designed in order to assess the feasibility and safety of PTCY as a sole GVHD prophylaxis in adult patients receiving a Baltimore-based reduced-intensity conditioning (RIC) peripheral blood (PB) allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with a matched donor. STUDY DESIGN Patients were planned to be included stepwise up to 59 evaluable PTCY recipients, in order to be able to stop the protocol in case of excessive corticosteroid resistant grade 3-4 severe acute GVHD (aGVHD). Because a high incidence of grade 2-4 aGVHD was observed after analysis of the first 27 patients, the protocol was amended to test the addition of 1 day of anti-thymoglobulin to PTCY. In spite of this, the trial had to be stopped after 38 treated patients, because of an unacceptable rate of grade 3-4 aGVHD. Donors were matched related to 12 patients and unrelated to 26. RESULTS With a median follow-up of 29.6 months, 2-year overall, disease-free and GVHD-free relapse-free (GRFS) survivals were respectively 65.4%, 62.1% and 46.9%. Cumulative incidences of grade 2-4 and 3-4 aGVHD at day 100 were 52.6% and 21.1%, respectively, while that of moderate/severe chronic(c) GVHD was 15.7% at 2 years. Addition of ATG to PTCY did influence neither aGVHD, cGVHD nor GRFS. CONCLUSION Despite paradoxically good survivals, especially GRFS, this study failed to demonstrate that PTCY (± ATG) alone can be used for Baltimore-based RIC PB Allo-HSCT with matched donors. Other combinations should be tested to try and avoid long-term use of immunosuppressive drugs following Allo-HSCT in this setting.
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6.
Longitudinal dynamics of gut microbiota in the pathogenesis of acute graft-versus-host disease
Qi, L., Peng, J., Huang, X., Zhou, T., Tan, G., Li, F.
Cancer medicine. 2023
Abstract
AIM: The gut microbiota has been reported to be associated with acute graft-versus-host disease (aGvHD) in hematopoietic stem cell transplantation (HSCT). Dynamic surveillance of the microbiota is required to understand the detailed pathogenesis involved in the process of aGvHD. METHODS Fecal samples were collected prospectively at four timepoints, including pre-HSCT (T1), graft infusion (T2), neutrophil engraftment (T3), and 30 days after transplantation (T4). Fecal samples were profiled by 16S ribosomal RNA gene sequencing to assess the microbiota composition. RESULTS From the T1 to T4 timepoint, the diversity of the gut microbiota decreased, and the dominant species also changed, with a decrease in the obligate anaerobic bacteria and a shift toward a "pathogenic community". Compared with non-aGvHD patients, aGvHD patients had a lower abundance of Roseburia at T1 and a higher abundance of Acinetobacter johnsonii at T2. Furthermore, Acinetobacter johnsonii was negatively correlated with the secretion of IL-4 and TNF-α. At T3, Rothia mucilaginos was demonstrated to be linked with a decreased risk of aGvHD, which was accompanied by decreased secretion of IL-8. At T4, higher abundances of Lactobacillus paracasei and Acinetobacter johnsonii were identified to be related with aGvHD. Lactobacillus paracasei was associated with the downregulation of IL-10, and Acinetobacter johnsonii was associated with the downregulation of IL-2 and TNF-α. CONCLUSIONS Dynamic changes in gut microbiota composition and related cytokines were found to be related to aGvHD, including pathogenic or protective changes. These findings suggested that manipulation of gut microbiota at different timepoints might be a promising avenue for preventing or treating this common complication.
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7.
Chronic GVHD after steroid-sensitive, -dependent, and -refractory acute GVHD: incidence and clinical outcomes
Herzog, S., Weisdorf, D. J., Shanley, R., Rayes, A., Holtan, S. G., Young, J. A., MacMillan, M. L., El Jurdi, N.
Blood advances. 2023
Abstract
Chronic graft-versus-host disease (cGVHD) is a major limitation to the long-term success of allogeneic hematopoietic cell transplant (HCT). Our prior study of acute graft-versus-host disease (aGVHD) defined distinct treatment-response groups based on response to first-line corticosteroids: steroid-sensitive (SS), steroid-resistant (SR), and steroid-dependent (SD) aGVHD. We conducted a retrospective, single-institution, cohort study to assess the incidence, risk factors, and clinical outcomes of patients with cGVHD after a previous diagnosis of SS, SD, or SR aGVHD compared to those with no history of aGVHD. Among 784 consecutive adult and pediatric HCT recipients for hematologic malignancies between 2008 and 2016, 347 (44%) developed aGVHD with 13% SS, 12% SD, and 19% SR aGVHD. 3-year cumulative incidence of cGVHD was 25%. Among those with cGVHD, 39% had no prior aGVHD diagnosis, while those with a prior aGVHD diagnosis, 16% had SS, 24% had SD, and 21% had SR aGVHD. Mild or moderate cGVHD was highest among those with preceding SD aGVHD, while severe cGVHD was most frequent among those with previous SR aGVHD. We identified SD acute GVHD and SR acute GVHD as independent significant risk factors for development of chronic GVHD after allogeneic HCT, whereas SS acute GVHD is not a risk factor. Our study demonstrates that cGVHD after SD aGVHD did not have an intermediate prognosis between SR and SS groups as hypothesized, rather chronic GVHD following both SD and SR acute GVHD have similar prognosis. Our findings suggest that previous aGVHD response states are important predictors of cGVHD severity and outcomes.
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8.
Chronic graft-versus-recipient disease: Systematic review of joint and fascial involvement
Hidalgo Calleja, C., Sánchez González, M. D., Medina Luezas, J., López Corral, L.
Reumatologia clinica. 2023
Abstract
BACKGROUND AND OBJECTIVE Chronic graft-versus-host disease (cGVRD) is a systemic immune-mediated complication that occurs in approximately half of the patients undergoing allogeneic haematopoietic stem cell transplantation (allo-HCT) and, although it is associated with beneficial graft versus tumour effects and lower relapse rates, it remains the leading cause of late morbidity and mortality in these patients. The aim of this systematic review of the literature is to provide a current overview on the diagnostic musculoskeletal manifestations of cGVRD, its clinical evaluation, and therapeutic possibilities. METHODS We ran a systematic search in PubMed, Embase, and Cochrane Library. Studies from the last 20 years were included. Priority was given to cross-sectional studies to evaluate diagnostic methods and to clinical trials in the case of articles referring to treatment. The search was limited to humans and articles published in English or Spanish. RESULTS We identified 6423 studies, of which we selected 86 (37 on clinical and diagnostic evaluation and 49 on treatments). Specific studies on fascial and joint complications are scarce and of low quality, including only isolated clinical cases or case series. Fasciitis is the most relevant musculoskeletal manifestation, and isolated joint involvement is low, sometimes unnoticed and underdiagnosed, if a thorough exploration of joint motion is not performed. Early detection of cGVRD with fascial and/or joint involvement requires careful and repeated evaluation. CONCLUSIONS The search for new biomarkers or advanced imaging techniques that allow early diagnosis is necessary. Physiotherapy is essential to improve functionality and prevent disease progression. Controlled studies are needed to establish recommendations on second lines of treatment. Because of its multisystemic nature, cGVRD requires a multidisciplinary approach.
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9.
Low-dose PTCy plus low-dose ATG as GVHD prophylaxis after UD-PBSCT for hematologic malignancies: a prospective, multicenter, randomized controlled trial
Zu, Y., Gui, R., Li, Z., Wang, J., Zhang, Y., Yu, F., Zhao, H., Zhan, X., Wang, Z., Xing, P., et al
Blood Cancer Journal. 2023;13(1):10
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10.
Systematic review and meta-analysis of anti-thymocyte globulin dosage as a component of graft-versus-host disease prophylaxis
Zuckermann, J., Castro, B. M., Cunha, T. A., Paz, A., Moreira, L. B.
PloS one. 2023;18(4):e0284476
Abstract
Rabbit anti-thymocyte globulin (ATG) has been used in allogeneic hematopoietic stem cell transplantation (Allo-HSCT) for graft-versus-host disease (GvHD) prophylaxis. Since the best dose has not been defined yet, this study aimed to determine the efficacy and safety of different doses of ATG in Allo-HSCT. Data sources were MEDLINE/PUBMED, EMBASE, Cochrane Library, Web of Science, LILACS, and SciELO. Studies were eligible when comparing doses of ATG. The higher dose was in the intervention group. A total of 22 articles (2002-2022) were included. Higher doses (4-12 mg/kg) of ATG-T reduced the incidence of grade III-IV acute GvHD (RR 0.60; 95%CI 0.42-0.84) and limited chronic GvHD (RR 0.64 95%CI 0.45-0.92) compared with lower doses (2-7.5 mg/kg). Higher doses increased the Epstein-Barr virus (RR 1.90 95% CI 1.49-2.42) and Cytomegalovirus reactivation (RR, 1.30; 95% CI 1.03-1.64). Relapse rates were higher in the higher dose group (RR 1.34, 95% CI 1.07-167). The ATG-T dose ≥7mg/kg versus the lower dose showed a number needed to treat 7.4 for acute GvHD III-IV, with a number to harm of 7.7 for relapse at one year in the higher dose group. A dose lower than 7 mg/kg suggests a better risk-benefit ratio than a higher one. Well-designed RCT is needed to define the best risk-benefit doses. Trial registration: Trial registration number: PROSPERO https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020173449.