Acute graft-versus-host-disease in acute myeloid leukemia: Clinicopathological correlation based on autopsy findings.

We present a case of acute myeloid leukemia developing acute graft-versus-host-disease (GVHD) in the post transplant phase. The patient had GVHD of skin, liver and gastro-intestinal tract (resolved) with polymicrobial sepsis. The clinical course, treatment and pathological findings on autopsy including the cause of death have been discussed.

Graft-versus-host disease: a disorder of tissue regeneration and repair.

Regenerative failure at barrier surfaces and maladaptive repair leading to fibrosis are hallmarks of graft-versus-host disease (GVHD). Although immunosuppressive treatment can control inflammation, impaired tissue homeostasis leads to prolonged organ damage and impaired quality of life. In this Blood Spotlight, we review recent research that addresses the critical failures in tissue regeneration and repair that underpin treatment-resistant GVHD. We highlight current interventions designed to overcome these defects and provide our assessment of the future therapeutic landscape.

Early remodeling of the colonic mucosa after allogeneic hematopoietic stem cells transplantation: An open-label controlled pilot study on 19 patients.

BACKGROUND: Graft-versus-host disease (GVHD), particularly acute digestive GVHD (aDGVHD), is a severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is necessary to identify predictive factors of GVHD to adapt prophylactic treatment. OBJECTIVE: In this context, our pilot study aimed (i) to determine whether an early remodeling of the colonic mucosa occurred after allo-HSCT and (ii) to identify potential predictive mucosal markers of aDGVHD after allo-HSCT. METHODS: Between day 21 and day 28 after the allo-HSCT, 19 allo-HSCT patients were included and had a rectosigmoidoscopy with probe-based confocal laser endomicroscopy (pCLE) recording and biopsies. Sixteen patients were included in the control group. Morphological (pCLE), functional (intestinal permeability), and inflammatory parameters (cytokine multiplex immunoassay) were assessed. RESULTS: Among allo-HSCT patients, 11 patients developed GVHD, and 6 of them developed aDGVHD. Morphological and functional changes of the colonic mucosa occurred after allo-HSCT. Indeed, the perimeter of colonic crypts was significantly increased in allo-HSCT patients compared to controls as well as crypt lumen fluorescein leakage (53% vs. 9%), whereas crypts sphericity, roundness, Feret diameter, and mean vessel area were significantly decreased in allo-HSCT patients compared to the control group. In addition, interleukin-6 (IL-6), IL-33, and IL-15 levels in the supernatants of 24 h explant cultures of colonic biopsies were significantly increased in allo-HSCT patients compared to controls. Finally, there was no difference in pCLE parameters, intestinal permeability, and inflammatory cytokines between patients who developed aDGVHD and those who did not. CONCLUSION: This pilot study identified early colonic mucosa remodeling after allo-HSCT conditioning therapy, that is morphological and functional mucosal alterations as well as mucosal inflammation. As to whether these changes are first steps in GVHD initiation and could be considered as predictive biomarkers of aDGVHD need to be determined in a larger cohort of patients.

A Review of Ocular Graft-versus-Host Disease: Pathophysiology, Clinical Presentation and Management.

Graft-versus-host disease is a common complication following allogeneic hematopoetic stem cell transplantation that can affect multiple organ systems, including the eyes. Ocular GVHD (oGVHD) is characterized by a T cell-mediated immune response that leads to immune cell infiltration and inflammation of ocular structures, including the lacrimal glands, eyelids, cornea and conjunctiva. oGVHD has a significant negative impact on visual function and quality of life and successful management requires a multi-disciplinary approach with frequent monitoring. Here, we review the pathophysiology and clinical presentation of oGVHD, along with current therapeutic strategies based on our clinical experience and the reported literature.

Interfering With Inflammation: Heterogeneous Effects of Interferons in Graft-Versus-Host Disease of the Gastrointestinal Tract and Inflammatory Bowel Disease.

The intestine can be the target of several immunologically mediated diseases, including graft-versus-host disease (GVHD) and inflammatory bowel disease (IBD). GVHD is a life-threatening complication that occurs after allogeneic hematopoietic stem cell transplantation. Involvement of the gastrointestinal tract is associated with a particularly high mortality. GVHD development starts with the recognition of allo-antigens in the recipient by the donor immune system, which elicits immune-mediated damage of otherwise healthy tissues. IBD describes a group of immunologically mediated chronic inflammatory diseases of the intestine. Several aspects, including genetic predisposition and immune dysregulation, are responsible for the development of IBD, with Crohn's disease and ulcerative colitis being the two most common variants. GVHD and IBD share multiple key features of their onset and development, including intestinal tissue damage and loss of intestinal barrier function. A further common feature in the pathophysiology of both diseases is the involvement of cytokines such as type I and II interferons (IFNs), amongst others. IFNs are a family of protein mediators produced as a part of the inflammatory response, typically to pathogens or malignant cells. Diverse, and partially paradoxical, effects have been described for IFNs in GVHD and IBD. This review summarizes current knowledge on the role of type I, II and III IFNs, including basic concepts and controversies about their functions in the context of GVHD and IBD. In addition, therapeutic options, research developments and remaining open questions are addressed.

Connective Tissue Growth Factor Is Overexpressed in Explant Lung Tissue and Broncho-Alveolar Lavage in Transplant-Related Pulmonary Fibrosis.

Background: Connective tissue growth factor (CTGF) is an important mediator in several fibrotic diseases, including lung fibrosis. We investigated CTGF-expression in chronic lung allograft dysfunction (CLAD) and pulmonary graft-versus-host disease (GVHD). Materials and Methods: CTGF expression was assessed by quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry in end-stage CLAD explant lung tissue (bronchiolitis obliterans syndrome (BOS), n=20; restrictive allograft syndrome (RAS), n=20), pulmonary GHVD (n=9). Unused donor lungs served as control group (n=20). Next, 60 matched lung transplant recipients (BOS, n=20; RAS, n=20; stable lung transplant recipients, n=20) were included for analysis of CTGF protein levels in plasma and broncho-alveolar lavage (BAL) fluid at 3 months post-transplant, 1 year post-transplant, at CLAD diagnosis or 2 years post-transplant in stable patients. Results: qPCR revealed an overall significant difference in the relative content of CTGF mRNA in BOS, RAS and pulmonary GVHD vs. controls (p=0.014). Immunohistochemistry showed a significant higher percentage and intensity of CTGF-positive respiratory epithelial cells in BOS, RAS and pulmonary GVHD patients vs. controls (p<0.0001). BAL CTGF protein levels were significantly higher at 3 months post-transplant in future RAS vs. stable or BOS (p=0.028). At CLAD diagnosis, BAL protein content was significantly increased in RAS patients vs. stable (p=0.0007) and BOS patients (p=0.042). CTGF plasma values were similar in BOS, RAS, and stable patients (p=0.74). Conclusions: Lung CTGF-expression is increased in end-stage CLAD and pulmonary GVHD; and higher CTGF-levels are present in BAL of RAS patients at CLAD diagnosis. Our results suggest a potential role for CTGF in CLAD, especially RAS, and pulmonary GVHD.

Diversity, localization, and (patho)physiology of mature lymphocyte populations in the bone marrow.

The bone marrow (BM) is responsible for generating and maintaining lifelong output of blood and immune cells. In addition to its key hematopoietic function, the BM acts as an important lymphoid organ, hosting a large variety of mature lymphocyte populations, including B cells, T cells, natural killer T cells, and innate lymphoid cells. Many of these cell types are thought to visit the BM only transiently, but for others, like plasma cells and memory T cells, the BM provides supportive niches that promote their long-term survival. Interestingly, accumulating evidence points toward an important role for mature lymphocytes in the regulation of hematopoietic stem cells (HSCs) and hematopoiesis in health and disease. In this review, we describe the diversity, migration, localization, and function of mature lymphocyte populations in murine and human BM, focusing on their role in immunity and hematopoiesis. We also address how various BM lymphocyte subsets contribute to the development of aplastic anemia and immune thrombocytopenia, illustrating the complexity of these BM disorders and the underlying similarities and differences in their disease pathophysiology. Finally, we summarize the interactions between mature lymphocytes and BM resident cells in HSC transplantation and graft-versus-host disease. A better understanding of the mechanisms by which mature lymphocyte populations regulate BM function will likely improve future therapies for patients with benign and malignant hematologic disorders.

Large diameter scleral lens benefits for Asians with intractable ocular surface diseases: a prospective, single-arm clinical trial.

To report the efficacy and safety of large diameter scleral lenses and determine their suitability in Asian subjects with intractable ocular surface diseases. This prospective study enrolled intractable ocular surface diseases subjects with uncorrected visual acuity > counting finger but ≥ 0.3 logMAR and best-corrected visual acuity (BCVA) ≥ 0.3 logMAR, to fit large diameter scleral lenses for 12 weeks. 21 eyes (13 subjects) consisting ten eyes (47.6%) with persistent epithelial defects, 6 (28.6%) with graft-versus-host disease, 4 (19.0%) with Stevens-Johnson syndrome and one (4.8%) with severe dry eye were ultimately enrolled. Primary outcome measures were the visual acuity, corneal and conjunctival fluorescein staining, Ocular Surface Disease Index (OSDI), and National Eye Institute 25-Item Visual Function Questionnaire (NEI-VFQ-25). At week 12 with large diameter scleral lenses, BCVA improved from 0.77 logMAR to 0.27 logMAR (P < 0.001). High-grade corneal and conjunctival fluorescein staining proportion decreased from 61.90 to 14.29% and 52.38 to 9.52%, respectively (P = 0.0036 and 0.0063, respectively). OSDI and NEI-VFQ-25 improved from 67.89 to 34.69 and 51.40 to 64.48, respectively (P < 0.001). No adverse effects were observed. In Asians with intractable ocular surface diseases, large diameter scleral lens improves visual acuity and alleviates signs and symptoms of ocular surface diseases without any significant complications.Trial registration Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (Project No. HI12C0015 (A120018)). Clinical Trials.gov, NCT04535388. Registered 18 August 2020-Retrospectively registered, http://clinicaltrials.gov/ct2/show/NCT04535388 .

Long-term Outcomes of Punctal Cauterization in the Management of Ocular Surface Diseases.

PURPOSE: To evaluate the long-term outcomes of surgical occlusion of lacrimal puncta using thermal cautery in the management of ocular surface diseases. METHODS: We reviewed medical records of 80 consecutive patients from a single academic center who underwent punctal cauterization. Patient demographics, ocular history, symptoms, and signs of ocular surface diseases pre- and post-cauterization were recorded. RESULTS: A total of 80 patients (171 puncta) were included, with an average age of 59 years and a follow-up duration of 27 months. The most common ocular morbidity was ocular graft-versus-host disease (n = 36), followed by primary keratoconjunctivitis sicca (n = 15). Indications for punctal cauterization included plug loss (n = 51), difficulty in plug fitting (n = 11), plug-related complications (n = 6), recanalization of previous cauterization (n = 7), and severe ocular surface disease requiring permanent punctal closure (n = 4). After punctal cauterization, the percentage of eyes with severe (21%) and moderate (25%) dry eye decreased significantly (8% and 19% at 3 months and 6% and 17% at 12 months, P = 0.0006). Fifty-four percent of patients reported improvement in their symptoms. The rate of recanalization was 21% during the follow-up period. The use of topical corticosteroids was associated with higher recanalization rate. Associated complications were limited to temporary pain and swelling. CONCLUSIONS: Punctal cauterization is an effective modality in treating severe ocular surface diseases in patients who repeatedly lose punctal plugs, and it can be easily performed in a clinic setting without major complications. However, cauterization may need to be repeated in up to a quarter of cases because of recanalization.

Mulheres submetidas ao transplante de medula óssea: impacto dos quimioterápicos e da doença do enxerto contra o hospedeiro sobre o sistema reprodutor / Women undergoing bone marrow transplantation: impact of chemotherapy and graft-versus-host disease (GVHD) on the feminine reproductive system

O transplante de medula óssea (TMO) é um procedimento indicado para o tratamento de doenças hematológicas, que afetam muitas mulheres jovens. O aperfeiçoamento dos cuidados durante o TMO proporciona altos índices de cura e de sobrevida. No entanto, pode deixar sequelas em vários órgãos e sistemas, entre eles o sistema reprodutor e os órgãos genitais, impactando negativamente a qualidade de vida das receptoras do TMO. O objetivo desta publicação foi realizar uma revisão narrativa sobre o tema e propor um protocolo assistencial que torne acessível os cuidados relacionados à saúde sexual e reprodutiva a esse grupo especial de mulheres, baseado em dados clínicos de um ambulatório de assistência ginecológica às mulheres transplantadas no Hospital Amaral Carvalho, em Jaú, no interior de São Paulo.(AU)

Bone marrow transplantation (BMT) is indicated for the treatment of hematological diseases which affect many young women. The improvement of care during BMT procedures provides higher cure and survival rates. however, it can cause sequelae in various organs and systems, including the reproductive system and genitals, negatively impacting quality of life. The purpose of this publication is to present a narrative review related to this theme and to propose a healthcare protocol that allows sexual and reproductive care in this special group of patients, based on the clinical experience of a gynecological outpatient clinic at the Amaral Carvalho Hospital, in Jaú (SP) which specifically care for these women.(AU)

Prevalence of Persistent Corneal Epithelial Defects in Chronic Ocular Graft-Versus-Host Disease.

PURPOSE: To establish the prevalence, clinical characteristics, and risk factors for persistent corneal epithelial defects (PED) in patients with chronic ocular graft-versus-host disease (oGVHD) and to determine visual outcomes after healing. DESIGN: Retrospective cohort study. METHODS: A chart review was conducted of patients in whom chronic oGVHD was diagnosed between January 2011 and December 2018 and their demographic and clinical characteristics were collected. Data were analyzed to determine prevalence of PED, and multivariate logistic regression was performed to determine the risk factors associated with it. RESULTS: A total of 405 patients at a mean age of 60 ± 13 years in whom chronic oGVHD was diagnosed; 58% were men. The prevalence of PED was 8.1%. The median time for PED development after hematopoietic stem cell transplantation was approximately 24 months. Median time to PED resolution was 4.5 weeks after starting therapy. The mean best-corrected visual acuity declined by 2 lines post-PED resolution. The prevalence rates of corneal ulcer and perforation were 6.2% and 4.0%, respectively, over 8 years. Logistic regression analysis, used to determine factors associated with PED, showed diabetes (P = .006), limbal stem cell deficiency (LSCD) (P = .02), filamentary keratitis (P = .02), subconjunctival fibrosis (P = .02), and a higher National Institutes of Health (NIH) oGVHD score (P = .01) were significant risk factors for PED development. CONCLUSIONS: The study found the prevalence rate of PED, corneal ulceration, and corneal perforation in chronic oGVHD to be 8.1%, 6.2%, and 4%, respectively. Analysis showed that oGVHD patients with diabetes, LSCD, filamentary keratitis, subconjunctival fibrosis, and a high NIH score were at higher risk of developing severe corneal disease.

Topical Corticosteroids a Viable Solution for Oral Graft Versus Host Disease? A Systematic Insight on Randomized Clinical Trials.

Background and Objectives: This research attempts to provide a clear view of the literature on randomized clinical trials (RCTs) concerning the efficacy of topical dexamethasone, clobetasol and budesonide in oral graft versus host disease (GVHD). Materials and Methods: An electronic search of the PubMed, Web of Science and Scopus databases was carried out for eligible RCTs. Studies were included if they had adult patients with oral GVHD treatment with topical corticosteroids, and if the RCT study was published in English. The Cochrane Risk of Bias tool was used to assess the quality of these studies. Overall, three RCTs were included (an Open, Randomized, Multicenter Trial; a Randomized Double-Blind Clinical Trial; and an Open-Label Phase II Randomized Trial). Results: The trials involved 76 patients, of which 44 patients received topical dexamethasone, 14 patients received topical clobetasol and 18 patients received topical budesonide. Topical agents were most frequently used when oral tissues were the sole site of involvement. It appears that the best overall response is present for budesonide with no difference between the four arms, followed by clobetasol, and then by dexamethasone. The limitation of the current study is mainly represented by the fact that overall response was derived in two of the studies from other parameters. Moreover, both budesonide and clobetasol were used in only one study each, while two assessed dexamethasone. Conclusions: Based on the clinical trials, all three agents seem to be effective in treating oral GVHD and had a satisfactory safety profile. There is still a need for assessing high quality RCTs to assess the efficacy of these therapies on a larger cohort.

Autologous Hematopoietic Recovery after Unrelated Umbilical Cord Blood Transplantation with Myeloablative Conditioning for Acute Myelogenous Leukemia.

Autologous hematopoietic recovery after allogeneic hematopoietic cell transplantation (allo-HCT) is rare in patients who receive myeloablative conditioning (MAC). Autologous hematopoietic recovery suggests graft rejection, leading to concerns about subsequent disease relapse. We herein report a rare case of a patient with acute leukemia who experienced autologous hematopoietic recovery after cord blood transplantation (CBT) with total body irradiation-based MAC. Chromosomal abnormalities were repeatedly detected without any disease relapse for eight months. The accumulation of similar cases is required to accurately assess the incidence and clinical outcomes of autologous hematopoietic recovery after CBT with MAC.

Engraftment Syndrome and Acute Graft-versus-Host Disease: A Meta-Analysis.

Engraftment syndrome (ES) has been associated with the surge of neutrophils and cytokines, which is similar to the presumed underlying pathophysiology behind acute graft-versus-host disease (aGVHD). However, there has been no meta-analysis to evaluate the association; therefore, the team attempted to verify an association between ES and aGVHD through meta-analysis. The team searched for titles of articles in MEDLINE (PubMed), the Cochrane Library, and the EMBASE database up until December 2018 that evaluated the association between ES and aGVHD and conducted a random effect meta-analysis of 8 studies involving a total of 1,945 participants to report the pooled odds ratio (OR) for association of ES and aGVHD. The team found a significantly increased odds of developing aGVHD in patients with ES with the pooled OR of 2.76 (95% confidence interval [CI]: 1.64-4.63) and an I2= 64.5%. In conclusion, patients with ES have significantly higher odds of developing aGVHD compared to patients without ES.

Evolving Therapeutic Options for Chronic Graft-versus-Host Disease.

Despite improvements in prevention and treatment of acute graft-versus-host disease (GVHD), chronic GVHD (cGVHD) remains a significant contributor to morbidity and mortality of allogeneic transplant patients. Chronic GVHD remains a leading cause of late complications posttransplant and is impacted by donor-, patient-, and transplant-related (hematopoietic cell transplant [HCT]) factors. Advances in the biological understanding of cGVHD have provided opportunities to improve clinical interventions for prevention and treatment. Expansion of posttransplantation cyclophosphamide beyond haploidentical HCTs has transformed alternative donor, matched, and mismatch GVHD outcomes and is currently being investigated in two upcoming clinical trials network prophylaxis studies. Although corticosteroids remain the cornerstone therapy, several clinical trials are prospectively investigating the utility of using novel agents in combination with corticosteroids as upfront therapy to mitigate prolonged steroid exposure. Several treatment options for patients with steroid-refractory cGVHD are currently being investigated, and advances have resulted in ibrutinib becoming the first cGVHD agent approved by the U.S. Food and Drug Administration. We review recent advances in understanding of cGVHD pathophysiology and new approaches for the prevention and treatment of cGVHD.

Innate lymphoid cells in treatment-induced gastrointestinal pathogenesis.

PURPOSE OF REVIEW: Tissue injury often occurs as collateral damage after chemotherapy and radiotherapy and is associated with significant comorbidity and mortality. The arsenal of options to prevent tissue injury other than dose reduction is limited, and treatment is mostly aimed at symptom relief and prevention of complications, such as bacterial translocation and malnourishment. Novel approaches directed at prevention and early repair of damaged tissues are highly anticipated. RECENT FINDINGS: Innate lymphoid cells (ILC) are important in tissue homeostasis and wound healing. Most knowledge of ILC is based on studies in mice, and the contribution of ILC to repair therapy-induced tissue damage in humans is relatively understudied. A picture is nevertheless emerging, suggesting that ILC have several means to maintain tissue homeostasis. Subsets of ILC produce, for example, interleukin (IL)-22 or amphiregulin (AREG) that induce epithelial tissue repair and the release of microbiome modulating proteins. In addition, ILC have immune-regulatory capacities given that adoptive transfer of ILC in a mouse model of graft versus host disease (GvHD) attenuated tissue inflammation. SUMMARY: ILC are important in tissue maintenance and damage repair and as such have the potential to be developed as (adoptive) therapy to prevent and repair therapy-induced tissue damage.

Extracellular Vesicles After Allogeneic Hematopoietic Cell Transplantation: Emerging Role in Post-Transplant Complications.

Extracellular vesicles (EVs) play an important role in the cellular crosstalk by transferring bioactive molecules through biological barriers from a cell to another, thus influencing recipient cell functions and phenotype. Therefore, EVs are increasingly being explored as biomarkers of disease progression or response to therapy and as potential therapeutic agents in different contexts including in hematological malignancies. Recently, an EV role has emerged in allogeneic hematopoietic cell transplantation (allo-HCT) as well. Allogeneic hematopoietic cell transplantation often represents the only curative option in several hematological disorders, but it is associated with potentially life-threatening complications that can have a significant impact on clinical outcomes. The most common complications have been well-established and include graft-versus-host disease and infections. Furthermore, relapse remains an important cause of treatment failure. The aim of this review is to summarize the current knowledge, the potential applications, and clinical relevance of EVs in allo-HCT. Herein, we will mainly focus on the immune-modulating properties of EVs, in particular those derived from mesenchymal stromal cells, as potential therapeutic strategy to improve allo-HCT outcome. Moreover, we will briefly describe the main findings on EVs as biomarkers to monitor graft-versus-host disease onset and tumor relapse.

Human placenta derived mesenchymal stromal cells alleviate GVHD by promoting the generation of GSH and GST in PD-1+T cells.

AIMS: To investigate whether placenta-derived mesenchymal stromal cells (hPMSCs) have immunoregulatory effects on PD-1+ T cell generation by controlling ROS production and thus alleviating GVHD. MAIN METHODS: Flow cytometry was used to analyze the percentage of PD-1+ T cells, as well as the generation of ROS, GSH and GST in PD-1+ T cells. The expression of GST in the spleen and liver was analyzed by western blotting. KEY FINDINGS: The percentage of PD-1+ T cells was increased, but the ratio of GSH/GSSG was decreased in GVHD patients and the GVHDhigh mouse model compared with that in the normal control group. hPMSCs downregulated the level of malondialdehyde (MDA) and upregulated the ratio of GSH/GSSG and the expression of glutathione S transferase (GST) in the plasma, spleen and liver of GVHD mice compared with those of PBS-treated GVHD mice. Further studies showed that the ROS level, as well as the expression of PD-1, in both CD3+ and CD4+ T cells from the spleen and liver of hPMSC-treated GVHD mice were decreased compared with those observed in PBS-treated mice. SIGNIFICANCE: hPMSCs downregulated ROS generation by increasing GSH and GST levels and further reduced the expression of PD-1 on T cells, thereby alleviating inflammation in GVHD mice.