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Background: Anti-Thymocyte Globulin (ATG) is commonly used to prevent graft-versus-host disease (GVHD), but the optimal dosage and type of ATG remains to be determined. Objective: We compared retrospectively the safety and efficacy outcomes of allogeneic transplantation using low-dose ATG-Fresenius (15mg/kg) and ATG-Thymoglobulin (10mg/kg) for GVHD prevention. Study design: Ninety-eight patients were included, with 46 in the ATG-T group and 52 in the ATG-F group. The median age was 48 years in the ATG-T group (range 20-71) and 50 years in the ATG-F group (range 18-73). Baseline characteristics were similar, with slightly more HLA mismatched donors and single-agent cyclosporine GVHD prophylaxis use in the ATG-T group. Additionally, the ATG-F group had more myeloid leukemia and myelodysplastic syndrome patients, while the ATG-T group had more lymphoma patients. Results: The cumulative incidence of acute GVHD (aGVHD) grade II-IV and chronic GVHD (cGVHD) showed no significant differences. Multivariate analysis indicated that donor HLA mismatch influenced aGVHD risk significantly (p=0.005), and myeloablative conditioning increased cGVHD risk. Bacteremia and CMV reactivation rates were similar, but EBV DNA viremia was higher in the ATG-T group (22% vs. 8%, p=0.047), with one case of Post-Transplant Lymphoproliferative Disorder (PTLD) in the ATG-T group. Cumulative incidence of overall survival (OS), relapse incidence, non-relapse mortality (NRM) and GVHD free, Relapse free Survival (GRFS) did not significantly differ. Conclusions: This study highlights the safety and efficacy of low-dose ATG-F compared to a relatively high dose ATG-T. Prospective studies are necessary to validate the safety and efficacy of low dose ATG-F for GVHD prevention. [ABSTRACT FROM AUTHOR]

Patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT) face an elevated risk of infection-related mortality, particularly during the pre-engraftment period. Although systemic antibiotic prophylaxis (SAP) is commonly employed during neutropenia, it is linked to disruptions in the intestinal microbiome, increasing the risk of graft-versus-host disease (GVHD), Clostridium difficile infection (CDI), and colonization with multi-drug resistant (MDR) bacteria. In our retrospective analysis, we evaluated the safety and efficacy of an exclusively interventional antibiotic treatment (IAT) compared to SAP in adult alloHSCT patients. In comparison to SAP, IAT resulted in a significantly reduced duration of antibiotic therapy (24 vs. 18 days, p < 0.001), although the cumulative incidence (CI) of bloodstream infections (BSI) by day + 100 post-HSCT was significantly higher in the IAT group compared to SAP (40% vs. 13%, p < 0.001). However, this did not lead to a significant increase in ICU transfers (13% vs. 6%, p = ns) or a higher CI of non-relapse mortality (NRM) at 3 years (11% vs. 10%, p = ns). With a median follow-up of 1052 days, the 3-year overall survival (OS) rates were 69% and 66% for the SAP and IAT cohorts, respectively (p = ns). The CI of acute GVHD grade II-IV (30% vs. 39%) at 100 days or chronic GVHD of any grade (50% vs. 45%) at 3 years did not differ significantly between the SAP and IAT groups. There was a tendency towards a higher CI of severe chronic GVHD in the SAP cohort (28% vs. 13%, p = 0.08). Our single center experience in conducting alloHSCT without antibiotic prophylaxis but with stringent guidelines for prompt antibiotic intervention demonstrated no disadvantages in terms of OS and NRM. IAT led to significantly reduced consumption of cefotaxime, carbapenem, and glycopeptide antibiotics. In conclusion, our findings suggest that replacing SAP with the proposed IAT procedure is both safe and feasible. [ABSTRACT FROM AUTHOR]

Chronic graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (HSCT). Chronic GVHD may have atypical manifestations affecting non-classical organs. The diagnosis in patients with atypical manifestations of chronic GVHD is particullarly challenging, and there is a lack of knowledge regarding their pathogenesis and treatment. We reported a case who developed post-HSCT nephrotic syndrome and portal hypertensive ascites, which are both rare and atypical manifestations of chronic GVHD. Kidney biopsy revealed membranous nephropathy and renal thrombotic microangiopathy with glomerular immune deposits, suggesting antibody-mediated kidney injury. Treatment with ruxolitinib resulted in remission of both nephrotic syndrome and ascites, suggesting a role of cytokines in the pathogenesis. This case highlighted the awareness of nephrotic syndrome and portal hypertensive ascites as atypical manifestations of chronic GVHD, and the efficacy of ruxolitinib for the two manifestations. [ABSTRACT FROM AUTHOR]

BackgroundAnti-Thymocyte Globulin (ATG) is commonly used to prevent graft-versus-host disease (GVHD), but the optimal dosage and type of ATG remains to be determined.ObjectiveWe compared retrospectively the safety and efficacy outcomes of allogeneic transplantation using low-dose ATG-Fresenius (15mg/kg) and ATG-Thymoglobulin (10mg/kg) for GVHD prevention.Study designNinety-eight patients were included, with 46 in the ATG-T group and 52 in the ATG-F group. The median age was 48 years in the ATG-T group (range 20-71) and 50 years in the ATG-F group (range 18-73). Baseline characteristics were similar, with slightly more HLA mismatched donors and single-agent cyclosporine GVHD prophylaxis use in the ATG-T group. Additionally, the ATG-F group had more myeloid leukemia and myelodysplastic syndrome patients, while the ATG-T group had more lymphoma patients.ResultsThe cumulative incidence of acute GVHD (aGVHD) grade II-IV and chronic GVHD (cGVHD) showed no significant differences. Multivariate analysis indicated that donor HLA mismatch influenced aGVHD risk significantly (p=0.005), and myeloablative conditioning increased cGVHD risk. Bacteremia and CMV reactivation rates were similar, but EBV DNA viremia was higher in the ATG-T group (22% vs. 8%, p=0.047), with one case of Post-Transplant Lymphoproliferative Disorder (PTLD) in the ATG-T group. Cumulative incidence of overall survival (OS), relapse incidence, non-relapse mortality (NRM) and GVHD free, Relapse free Survival (GRFS) did not significantly differ.ConclusionsThis study highlights the safety and efficacy of low-dose ATG-F compared to a relatively high dose ATG-T. Prospective studies are necessary to validate the safety and efficacy of low dose ATG-F for GVHD prevention.

Muhammad B Qureshi,1 Jose O Garcia,1 Jaxon Quillen,2 Carolyn Mead-Harvey,2 Christina Wentz,3 Cherie B Nau,4 Muriel Schornack,4 Keith Baratz,4 Sanjay V Patel,4 Joanne Shen5 1Mayo Clinic Alix School of Medicine, Scottsdale, AZ, USA; 2Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, AZ, USA; 3Illinois College of Optometry, Chicago, IL, USA; 4Department of Ophthalmology, Mayo Clinic, Rochester, MN, USA; 5Department of Ophthalmology, Mayo Clinic, Scottsdale, AZ, USACorrespondence: Joanne Shen, Department of Ophthalmology, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, USA, 85259, Tel +1 480-301-8085, Fax +1 480-301-7326, Email shen.joanne@mayo.eduPurpose: To compare baseline characteristics and treatment of chronic ocular graft-versus-host disease (oGVHD) patients in two treatment locations.Patients and Methods: Patients diagnosed with definite chronic oGVHD between September 1, 2014 and September 20, 2021 at two locations were identified. IRB-approved retrospective chart review was conducted for the following data: demographic information, ocular surface disease index (OSDI), corneal fluorescein staining (CFS), and treatment(s) used. Differences by site were assessed using Pearson’s Chi-Square tests and two-sample t-tests; differences by time were assessed using paired t-tests.Results: At baseline, Clinic 1 (C1) patients had a worse mean OSDI score (47.8 vs 36.3, p = 0.011) and CFS in both OD (1.3 vs 0.8, p = 0.005) and OS (1.3 vs 0.6, p < 0.001) compared to Clinic 2 (C2). Comparing baseline to endpoint, C1 patients experienced an improvement in OSDI (− 17.26, p < 0.001), CFS OD (− 0.50, p < 0.001), and CFS OS (− 0.51, p < 0.001) at C1. Change in OSDI, CFS OD, or CFS OS was not statistically significant at C2. Despite similar follow-up length, C1 demonstrated more clinic visits (10.4 vs 3.4, p < 0.001) and more treatment trials (4.9 vs 2.4, p < 0.001) compared to C2. Punctal plugs (85.5% vs 61.2%, p = 0.002), punctal cautery (69.7% vs 28.6%, p < 0.001), topical steroids (72.4% vs 22.4%, p < 0.001), and autologous serum tears (AST) (52.6% vs 8.2%, p < 0.001) were used more frequently at C1 than at C2.Conclusion: oGVHD patients at C1 experienced significant improvement in OSDI and corneal fluorescein staining and compared to patients at C2, had more frequent follow-up and use of punctal plugs, punctal cautery, topical steroids, and AST.Keywords: graft-versus-host disease, GVHD, chronic GVHD, dry eye disease, ocular GVHD, keratoconjunctivitis sicca, KCS

Abstract We evaluated the clinical impacts of the concurrent modification of post‐transplant cyclophosphamide (PTCy) dose and tacrolimus (Tac)‐initiation timing in 61 patients with human leukocyte antigen‐haploidentical transplantation. Reduced‐dose PTCy (80 mg/kg) was associated with a higher incidence of moderate‐to‐severe chronic graft‐versus‐host disease (GVHD) than standard‐dose PTCy (100 mg/kg) (35.0% vs. 26.6%, p = 0.053). Notably, early‐initiation Tac (day ‐1) increased moderate‐to‐severe chronic GVHD than standard‐initiation Tac (day 5) in the reduced‐dose PTCy group (p = 0.032), whereas Tac‐initiation timing did not impact chronic GVHD in the standard‐dose PTCy group. These data indicate that the combination of reduced‐dose PTCy and early‐initiation Tac can amplify chronic GVHD.

Graft-versus-host disease (GVHD) is an expected and relatively common complication after allogeneic hematopoietic stem cell transplantation. It may affect different organs and typically involves the skin, liver, and gastrointestinal tract (GI-GVHD). GI-GVHD may show heterogeneous presentations with peculiar diagnostic implications. Although an endoscopic biopsy is considered the "gold standard" for the diagnosis of GI-GVHD, its broad application is limited due to the poor clinical conditions usually present in these patients, including thrombocytopenia. In the emergency department, enhanced computed tomography (CECT) has emerged as the best imaging modality for the evaluation of GI damage in frail patients. However, the role of CT in the context of either acute or chronic GI-GVHD has not been systematically investigated. Herein, we focus on the radiological features found on CECT in five patients with GI-GVHD confirmed on histology. CECT was performed for the persistence of GI symptoms in three cases (case 1, case 3, and case 4), for small bowel occlusion in one case (case 5), and for acute GI symptoms in one case (case 2). Serpiginous intestinal wall appearance with multisegmental parietal thickness and homogeneous, mucosal, or stratified small bowel enhancement were common features. Colic involvement with segmental or diffuse parietal thickness was also present. One patient (case 5) presented with inflammatory jejunal multisegmental stenosis with sub-occlusion as a chronic presentation of GI-GVHD. Regarding mesenterial findings, all five patients presented comb signs in the absence of lymphadenopathy. Extraintestinal findings included biliary tract dilatation in two cases (case 2 and case 4). These data support the utility of appropriate radiological investigation in GI-GVHD, paving the way for further serial and systematic investigations to track the appearance and evolution of GI damage in GVHD patients. [ABSTRACT FROM AUTHOR]

This is a consensus-based Canadian guideline whose primary purpose is to standardize and facilitate the management of chronic graft-versus-host disease (cGvHD) across the country. Creating uniform healthcare guidance in Canada is a challenge for a number of reasons including the differences in healthcare authority structure, funding and access to healthcare resources between provinces and territories, as well as the geographic size. These differences can lead to variable and unequal access to effective therapies for GvHD. This document will provide comprehensive and practical guidance that can be applied across Canada by healthcare professionals caring for patients with cGvHD. Hopefully, this guideline, based on input from GvHD treaters across the country, will aid in standardizing cGvHD care and facilitate access to much-needed novel therapies. This consensus paper aims to discuss the optimal approach to the initial assessment of cGvHD, review the severity scoring and global grading system, discuss systemic and topical treatments, as well as supportive therapies, and propose a therapeutic algorithm for frontline and subsequent lines of cGvHD treatment in adults and pediatric patients. Finally, we will make suggestions about the future direction of cGvHD treatment development such as (1) a mode-of-action-based cGvHD drug selection, according to the pathogenesis of cGvHD, (2) a combination strategy with the introduction of newer targeted drugs, (3) a steroid-free regimen, particularly for front line therapy for cGvHD treatment, and (4) a pre-emptive approach which can prevent the progression of cGvHD in high-risk patients destined to develop severe and highly morbid forms of cGvHD.

Abstract Graft-versus-host disease (GVHD) is a serious complication of otherwise curative allogeneic haematopoietic stem cell transplants. Chronic GVHD induces pathological changes in peripheral organs as well as the brain and is a frequent cause of late morbidity and death after bone-marrow transplantation. In the periphery, bone-marrow-derived macrophages are key drivers of pathology, but recent evidence suggests that these cells also infiltrate into cGVHD-affected brains. Microglia are also persistently activated in the cGVHD-affected brain. To understand the involvement of these myeloid cell populations in the development and/or progression of cGVHD pathology, we here utilized the blood–brain-barrier permeable colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (pexidartinib) at varying doses to pharmacologically deplete both cell types. We demonstrate that PLX3397 treatment during the development of cGVHD (i.e., 30 days post-transplant) improves disease symptoms, reducing both the clinical scores and histopathology of multiple cGVHD target organs, including the sequestration of T cells in cGVHD-affected skin tissue. Cognitive impairments associated with cGVHD and neuroinflammation were also attenuated by PLX3397 treatment. PLX3397 treatment prior to the onset of cGVHD (i.e., immediately post-transplant) did not change in clinical scores or histopathology. Overall, our data demonstrate significant benefits of using PLX3397 for the treatment of cGVHD and associated organ pathologies in both the periphery and brain, highlighting the therapeutic potential of pexidartinib for this condition.

This is a consensus-based Canadian guideline whose primary purpose is to standardize and facilitate the management of chronic graft-versus-host disease (cGvHD) across the country. Creating uniform healthcare guidance in Canada is a challenge for a number of reasons including the differences in healthcare authority structure, funding and access to healthcare resources between provinces and territories, as well as the geographic size. These differences can lead to variable and unequal access to effective therapies for GvHD. This document will provide comprehensive and practical guidance that can be applied across Canada by healthcare professionals caring for patients with cGvHD. Hopefully, this guideline, based on input from GvHD treaters across the country, will aid in standardizing cGvHD care and facilitate access to much-needed novel therapies. This consensus paper aims to discuss the optimal approach to the initial assessment of cGvHD, review the severity scoring and global grading system, discuss systemic and topical treatments, as well as supportive therapies, and propose a therapeutic algorithm for frontline and subsequent lines of cGvHD treatment in adults and pediatric patients. Finally, we will make suggestions about the future direction of cGvHD treatment development such as (1) a mode-of-action-based cGvHD drug selection, according to the pathogenesis of cGvHD, (2) a combination strategy with the introduction of newer targeted drugs, (3) a steroid-free regimen, particularly for front line therapy for cGvHD treatment, and (4) a pre-emptive approach which can prevent the progression of cGvHD in high-risk patients destined to develop severe and highly morbid forms of cGvHD. [ABSTRACT FROM AUTHOR]

Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). For many years, corticosteroids have been the mainstay treatment for GVHD, but cases of steroid-refractory GVHD and the severe adverse effects of high-dose corticosteroids have increased the need for preventative and therapeutic strategies for GVHD. Due to the nature of alloreactive T cells, GVHD is inherently linked to the graft-versus-leukemia (GVL) effect, the therapeutic driving force behind stem cell transplantation. A considerable clinical challenge is to preserve GVL while suppressing GVHD. The field of GVHD research has greatly expanded over the past decades, including advancements in T cell modulation and depletion, antibody therapies, chemotherapeutics, cellular therapies, and Janus kinase inhibition. In this review, we discuss current approaches and advances in the prophylaxis and treatment of GVHD with a focus on new emerging advancements in Janus kinase inhibitor therapy. [ABSTRACT FROM AUTHOR]

In the coronavirus disease 19 (COVID-19) pandemic era, the number of haploidentical hematopoietic cell transplantations (HCTs) with peripheral blood (PB) grafts increased significantly compared with HCTs with bone marrow (BM) grafts, which may be associated with adverse outcomes. We compared outcomes of HCT in BM graft and PB graft recipients age ≥18 years with hematologic malignancies who underwent T cell- replete haploidentical HCT and received graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Among the 264 patients, 180 (68%) received a BM graft and 84 (32%) received a PB graft. The median patient age was 50 years in both groups. The majority (n = 199; 75%) received reduced-intensity conditioning. The rate of acute leukemia or myelodysplastic syndrome was higher in the BM graft recipients compared with the PB graft recipients (85% [n = 152] versus 55% [n = 46]; P < .01). The median times to neutrophil and platelet engraftment and the incidence of grade II-IV and grade III-IV acute GVHD (aGVHD) were comparable in the 2 groups. Among the patients with grade II-IV aGVHD, the rate of steroid-refractory aGVHD was 9% (95% confidence interval [CI], 5% to 18%) in the BM group versus 32% (95% CI, 19% to 54%) in the PB group (hazard ratio [HR], 3.7, 95% CI, 1.5 to 9.3; P = .006). At 1 year post-HCT, the rate of chronic GVHD (cGVHD) was 8% (95% CI, 4% to 13%) in the BM group versus 22% (95% CI, 14% to 36%) in the PB group (HR, 3.0; 95% CI, 1.4-6.6; P = .005), and the rate of systemic therapy-requiring cGVHD was 2.5% (95% CI, 1% to 7%) versus 14% (95% CI, 7% to 27%), respectively (HR, 5.6; 95% CI, 1.7 to 18; P = .004). The PB group had a significantly higher risk of bacterial and viral infections, with no appreciable advantage in the duration of hospitalization, immune reconstitution, relapse, nonrelapse mortality, or survival. Our data suggest a benefit of the use of BM grafts over PB grafts for haplo-HCT.

Graft-versus-host disease (GVHD) is an expected and relatively common complication after allogeneic hematopoietic stem cell transplantation. It may affect different organs and typically involves the skin, liver, and gastrointestinal tract (GI-GVHD). GI-GVHD may show heterogeneous presentations with peculiar diagnostic implications. Although an endoscopic biopsy is considered the “gold standard” for the diagnosis of GI-GVHD, its broad application is limited due to the poor clinical conditions usually present in these patients, including thrombocytopenia. In the emergency department, enhanced computed tomography (CECT) has emerged as the best imaging modality for the evaluation of GI damage in frail patients. However, the role of CT in the context of either acute or chronic GI-GVHD has not been systematically investigated. Herein, we focus on the radiological features found on CECT in five patients with GI-GVHD confirmed on histology. CECT was performed for the persistence of GI symptoms in three cases (case 1, case 3, and case 4), for small bowel occlusion in one case (case 5), and for acute GI symptoms in one case (case 2). Serpiginous intestinal wall appearance with multisegmental parietal thickness and homogeneous, mucosal, or stratified small bowel enhancement were common features. Colic involvement with segmental or diffuse parietal thickness was also present. One patient (case 5) presented with inflammatory jejunal multisegmental stenosis with sub-occlusion as a chronic presentation of GI-GVHD. Regarding mesenterial findings, all five patients presented comb signs in the absence of lymphadenopathy. Extraintestinal findings included biliary tract dilatation in two cases (case 2 and case 4). These data support the utility of appropriate radiological investigation in GI-GVHD, paving the way for further serial and systematic investigations to track the appearance and evolution of GI damage in GVHD patients.

Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). For many years, corticosteroids have been the mainstay treatment for GVHD, but cases of steroid-refractory GVHD and the severe adverse effects of high-dose corticosteroids have increased the need for preventative and therapeutic strategies for GVHD. Due to the nature of alloreactive T cells, GVHD is inherently linked to the graft-versus-leukemia (GVL) effect, the therapeutic driving force behind stem cell transplantation. A considerable clinical challenge is to preserve GVL while suppressing GVHD. The field of GVHD research has greatly expanded over the past decades, including advancements in T cell modulation and depletion, antibody therapies, chemotherapeutics, cellular therapies, and Janus kinase inhibition. In this review, we discuss current approaches and advances in the prophylaxis and treatment of GVHD with a focus on new emerging advancements in Janus kinase inhibitor therapy.

Graft-versus-host disease (GVHD) is a serious complication of otherwise curative allogeneic haematopoietic stem cell transplants. Chronic GVHD induces pathological changes in peripheral organs as well as the brain and is a frequent cause of late morbidity and death after bone-marrow transplantation. In the periphery, bone-marrow-derived macrophages are key drivers of pathology, but recent evidence suggests that these cells also infiltrate into cGVHD-affected brains. Microglia are also persistently activated in the cGVHD-affected brain. To understand the involvement of these myeloid cell populations in the development and/or progression of cGVHD pathology, we here utilized the blood–brain-barrier permeable colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (pexidartinib) at varying doses to pharmacologically deplete both cell types. We demonstrate that PLX3397 treatment during the development of cGVHD (i.e., 30 days post-transplant) improves disease symptoms, reducing both the clinical scores and histopathology of multiple cGVHD target organs, including the sequestration of T cells in cGVHD-affected skin tissue. Cognitive impairments associated with cGVHD and neuroinflammation were also attenuated by PLX3397 treatment. PLX3397 treatment prior to the onset of cGVHD (i.e., immediately post-transplant) did not change in clinical scores or histopathology. Overall, our data demonstrate significant benefits of using PLX3397 for the treatment of cGVHD and associated organ pathologies in both the periphery and brain, highlighting the therapeutic potential of pexidartinib for this condition. Key points: PLX3397 treatment during the progression phase of chronic graft-versus-host disease (cGVHD) attenuates pathology in multiple organ systems and reduces T-cell infiltration into the skin. PLX3397 treatment during cGVHD progression attenuates microglia/macrophage reactivity and major histocompatibility complex class II (MHCII) expression in the brain. PLX3397 treatment during cGVHD progression alleviates cognitive impairment. [ABSTRACT FROM AUTHOR]

Introduction:Chronic graft-versus host disease (GVHD) is a serious complication that develops in 35-50% of patients in the late period after allogeneic hematopoetic stem cell transplantation. About half of the patients are resistant to corticosteroids, which is the first-line treatment of chronic GVHD, and therefore new treatment options that can be effective in chronic GVHD are needed. In the present study, we aimed to share our experience with the use of ibrutinib therapy in patients with steroid-resistant chronic GVHD who have previously received multiple lines of systemic therapy.Methods:The characteristics and clinical outcomes of steroid-resistant chronic patients with GVHD receiving ibrutinib were retrospectively reviewed.Results:A total of 10 steroid resi-stant chronic patients with GVHD who received ibrutinib was included. While 50% of the patients had more than one organ involvement, 50% had a single organ involvement. The most commonly affected organs were the skin and liver. The patients received a median of three lines of systemic therapy before ibrutinib. After a median of 210 days of ibrutinib usage, the complete response rate of patients was 40% and the partial response rate was 40%. Corticosteroids were completely discontinued in 30% of patients after ibrutinib were initiated. Before ibrutinib, patients were given a median of 0.3 mg/kg methylprednisolone. The median methylprednisolone dose after ibrutinib was 0.03 mg/kg.Conclusion:Ibrutinib therapy causes a quite high overall response in steroid resistant chronic patients with GVHD and appears to be a good option in these patients.

Purpose: The current study was carried out to evaluate the clinical features and management outcomes of dry eye disease (DED) in chronic ocular GvHD following allogenic hematopoietic stem cell transplantation (HSCT). Methods: A retrospective review of consecutive patients diagnosed with chronic ocular GvHD between 2011 and 2020 was performed at a tertiary eye care network. Multi-variate regression analysis was carried out for identifying risk factors associated with progressive disease. Results: A total of 34 patients (68 eyes) with a median age of 33 years [inter-quartile range (IQR) 23–40.5] were studied. The most common indication for HSCT was acute lymphocytic leukemia (26%). Ocular GvHD developed at a median of 2 years (IQR 1–5.5 years) after HSCT. Aqueous tear deficiency was present in 71% of the eyes, of which 84% had a Schirmer value of

Background. Chronic graft-versus-host disease (cGvHD) is a complex disorder that typically manifests after allogeneic hematopoietic stem cell transplantation (HSCT). It is a major cause of non-relapse mortality, which makes finding biomarkers associated with its occurrence a priority. Recent studies increasingly indicate that microRNAs (miRNAs, short regulatory RNA molecules) can be used as biomarkers of various disorders. They can circulate in patients' bodies encapsulated within extracellular vesicles (EVs). Objectives. To identify miRNAs associated with the occurrence of cGvHD in EVs isolated from the plasma of patients after allogeneic HSCT. Materials and methods. We performed global miRNA expression profiling in a pilot cohort of 3 cGvHD cases and 4 non-cGvHD patients without disease symptoms 90 days after the transplantation (control group). Results. The 2 groups were naturally clustered according to their miRNA profiles using unsupervised hierarchical clustering analysis. We identified 3 miRNAs that were differentially expressed in the cGvHD patients compared to the non-cGvHD patients. The levels of hsa-miR-630 and hsa-miR-374b-5p were lower in the cGvHD patients: 4.1-fold (p = 0.002) and 2.7-fold (p = 0.044), respectively. In contrast, the levels of hsa-miR-29c-3p were 5.8-fold higher (p = 0.004). Conclusions. Our results suggest that miRNA profiles from plasma EVs may act as markers of cGvHD onset. [ABSTRACT FROM AUTHOR]

Purpose: The current study was carried out to evaluate the clinical features and management outcomes of dry eye disease (DED) in chronic ocular GvHD following allogenic hematopoietic stem cell transplantation (HSCT). Methods: A retrospective review of consecutive patients diagnosed with chronic ocular GvHD between 2011 and 2020 was performed at a tertiary eye care network. Multi‐variate regression analysis was carried out for identifying risk factors associated with progressive disease. Results: A total of 34 patients (68 eyes) with a median age of 33 years [inter‐quartile range (IQR) 23–40.5] were studied. The most common indication for HSCT was acute lymphocytic leukemia (26%). Ocular GvHD developed at a median of 2 years (IQR 1–5.5 years) after HSCT. Aqueous tear deficiency was present in 71% of the eyes, of which 84% had a Schirmer value of <5 mm. The median visual acuity at presentation and that after a median follow‐ up of 6.9 months were comparable at 0.1 log minimum angle of resolution (logMAR) (P = 0.97). Topical immunosuppression was required in 88% of cases, and with this, improvement in corneal (53%, P = 0.003) and conjunctival staining scores (45%, P = 0.43) was noted. A progressive disease was present in 32% with persistent epithelial defects being the most common complication. Grade 2 conjunctival hyperemia [odds ratio (OR): 2.6; P = 0.01] and Schirmer’s value <5 mm (OR: 2.7; P = 0.03) were found to be associated with progressive disease. Conclusion: Aqueous deficient DED is the most common ocular manifestation of chronic ocular GvHD, and the risk of the disease progression is greater in eyes with conjunctival hyperemia and severe aqueous deficiency. Awareness among ophthalmologists of this entity is essential for its timely detection and optimal management. [ABSTRACT FROM AUTHOR]

Haematopoietic stem cell transplantation (HSCT) is the treatment of choice for malignant haematological diseases. Despite continuous improvements in pre- and post-transplantation procedures, the applicability of allo-HSCT is limited by lifethreatening complications such as graft-versus-host disease (GvHD), engraftment failure, and opportunistic infections. Extracorporeal photopheresis (ECP) is used to treat steroid resistant GvHD with significant success. However, the molecular mechanisms driving its immunomodulatory action, whilst preserving immune function, require further understanding. As ECP is safe to administer with few significant adverse effects, it has the potential for earlier use in the post-HSCT treatment of GvHD. Thus, further understanding the immunomodulatory mechanisms of ECP action may justify more timely use in clinical practice, as well as identify biomarkers for using ECP as first line or pre-emptive GvHD therapy. This review aims to discuss technical aspects and response to ECP, review ECP as an immunomodulatory treatment modality for chronic GvHD including the effect on regulatory T cells and circulating vs. tissue-resident immune cells and consider the importance of emerging biomarkers for ECP response. [ABSTRACT FROM AUTHOR]

Haematopoietic stem cell transplantation (HSCT) is the treatment of choice for malignant haematological diseases. Despite continuous improvements in pre- and post-transplantation procedures, the applicability of allo-HSCT is limited by life-threatening complications such as graft-versus-host disease (GvHD), engraftment failure, and opportunistic infections. Extracorporeal photopheresis (ECP) is used to treat steroid resistant GvHD with significant success. However, the molecular mechanisms driving its immunomodulatory action, whilst preserving immune function, require further understanding. As ECP is safe to administer with few significant adverse effects, it has the potential for earlier use in the post-HSCT treatment of GvHD. Thus, further understanding the immunomodulatory mechanisms of ECP action may justify more timely use in clinical practice, as well as identify biomarkers for using ECP as first line or pre-emptive GvHD therapy. This review aims to discuss technical aspects and response to ECP, review ECP as an immunomodulatory treatment modality for chronic GvHD including the effect on regulatory T cells and circulating vs. tissue-resident immune cells and consider the importance of emerging biomarkers for ECP response.

Hematopoietic allogeneic stem cell transplantation (allo-SCT) is a curative option for patients with hematological malignancies. However, due to disparities in major and minor histocompatibility antigens between donor and recipient, severe inflammatory complications can occur, among which chronic graft-versus-host disease (cGVHD) can be life-threatening. A classical therapeutic approach to the prevention and treatment of cGVHD has been broad immunosuppression, but more recently adjuvant immunotherapies have been tested. This review summarizes and discusses immunomodulatory approaches with T cells, including chimeric antigen receptor (CAR) and regulatory T cells, with natural killer (NK) cells and innate lymphoid cells (ILCs), and finally with mesenchymal stromal cells (MSC) and extracellular vesicles thereof. Clinical studies and pre-clinical research results are presented likewise. [ABSTRACT FROM AUTHOR]

Hematopoietic allogeneic stem cell transplantation (allo-SCT) is a curative option for patients with hematological malignancies. However, due to disparities in major and minor histocompatibility antigens between donor and recipient, severe inflammatory complications can occur, among which chronic graft-versus-host disease (cGVHD) can be life-threatening. A classical therapeutic approach to the prevention and treatment of cGVHD has been broad immunosuppression, but more recently adjuvant immunotherapies have been tested. This review summarizes and discusses immunomodulatory approaches with T cells, including chimeric antigen receptor (CAR) and regulatory T cells, with natural killer (NK) cells and innate lymphoid cells (ILCs), and finally with mesenchymal stromal cells (MSC) and extracellular vesicles thereof. Clinical studies and pre-clinical research results are presented likewise.

Graft-versus Host Disease (GvHD) is a major complication of hematopoietic stem cell transplant. GvHD is characterized by the chronic activation of immune cells leading to the development of systemic inflammation, autoimmunity, fibrosis and eventually death. Arsenic trioxide (ATO) is a therapeutic agent under clinical trial for the treatment of patients with systemic lupus erythematosus (SLE) and chronic GvHD (cGvHD). This therapy is admittedly rather safe although adverse effects can occur and may necessitate short interruptions of the treatment. The aim of this study was to combine ATO with a divalent cation, to generate a Fenton or Fenton-like reaction in order to potentiate the deletion of activated immune cells through the reactive oxygen species (ROS)-mediated effects of ATO in a mouse model, and thereby enabling the use of lower and safer ATO concentrations to treat patients with cGvHD. In vitro, among the various combinations of divalent cations tested, we observed that the combination of ATO and CuCl2 (copper chloride) induced a high level of oxidative stress in HL-60 and A20 cells. In addition, this co-treatment also decreased the proliferation of CD4+ T lymphocytes during a mixed lymphocyte reaction (MLR). In vivo, in a cGvHD mouse model, daily injections of ATO 2.5 μg/g + CuCl2 0.5 μg/g induce a decrease in lymphocyte activation and fibrosis that was equivalent to that induced by ATO 5 μg/g. Our results show that the addition of CuCl2 improved the effects of ATO and significantly limited the development of the disease. This co-treatment could be a real benefit in human patients to substantially decrease the known ATO side effects and optimize ATO treatment in pathologies characterized by activated cells sensitive to an increase in oxidative stress. [ABSTRACT FROM AUTHOR]

Background: There are currently few data on the outcome of acute myeloid leukemia (AML) in adolescents after allogeneic HSCT. The aim of this study is to describe the outcome and its specific risk factors for children, adolescents and young adults after a first allogeneic HSCT for AML. Methods: In this retrospective study, we compared the outcome of AML patients receiving a first allogeneic HSCT between 2005 and 2017 according to their age at transplantation's time: children (< 15 years, n = 564), adolescent and post-adolescent (APA) patients (15–25 years, n = 647) and young adults (26–40 years; n = 1434). Results: With a median follow-up of 4.37 years (min–max 0.18–14.73 years), the probability of 2-year overall survival (OS) was 71.4% in children, 61.1% in APA patients and 62.9% in young adults (p = 0.0009 for intergroup difference). Both relapse and non-relapse mortality (NRM) Cumulative Incidence (CI) estimated at 2 years were different between the age groups (30.8% for children, 35.2% for APA patients and 29.4% for young adults—p = 0.0254, and 7.0% for children, 10.6% for APA patients and 14.2% for young adults, p < 0.0001; respectively). Whilst there was no difference between the three groups for grade I to IV acute GVHD CI at 3 months, the chronic GVHD CI at 2 years was higher in APA patients and young adults (31.4% and 36.4%, respectively) in comparison to the children (17.5%) (p < 0.0001). In multivariable analysis, factors associated with death were AML cytogenetics (HR1.73 [1.29–2.32] for intermediate risk 1, HR 1.50 [1.13–2.01] for intermediate risk 2, HR 2.22 [1.70–2.89] for high cytogenetics risk compared to low risk), use of TBI ≥ 8 Grays (HR 1.33 [1.09–1.61]), disease status at transplant (HR 1.40 [1.10–1.78] for second Complete Remission (CR), HR 2.26 [1.02–4.98] for third CR and HR 3.07 [2.44–3.85] for active disease, compared to first CR), graft source (HR 1.26 [1.05–1.50] for Peripheral Blood Stem Cells compared to Bone Marrow) and donor age (HR 1.01 (1–1.02] by increase of 1 year). Conclusion: Age is an independent risk factor for NRM and extensive chronic GVHD. This study suggests that APA patients with AML could be beneficially treated with a chemotherapy-based MAC regimen and bone marrow as a stem cells source. [ABSTRACT FROM AUTHOR]

Graft-versus Host Disease (GvHD) is a major complication of hematopoietic stem cell transplant. GvHD is characterized by the chronic activation of immune cells leading to the development of systemic inflammation, autoimmunity, fibrosis and eventually death. Arsenic trioxide (ATO) is a therapeutic agent under clinical trial for the treatment of patients with systemic lupus erythematosus (SLE) and chronic GvHD (cGvHD). This therapy is admittedly rather safe although adverse effects can occur and may necessitate short interruptions of the treatment. The aim of this study was to combine ATO with a divalent cation, to generate a Fenton or Fenton-like reaction in order to potentiate the deletion of activated immune cells through the reactive oxygen species (ROS)-mediated effects of ATO in a mouse model, and thereby enabling the use of lower and safer ATO concentrations to treat patients with cGvHD. In vitro, among the various combinations of divalent cations tested, we observed that the combination of ATO and CuCl2 (copper chloride) induced a high level of oxidative stress in HL-60 and A20 cells. In addition, this co-treatment also decreased the proliferation of CD4+ T lymphocytes during a mixed lymphocyte reaction (MLR). In vivo, in a cGvHD mouse model, daily injections of ATO 2.5 µg/g + CuCl2 0.5 µg/g induce a decrease in lymphocyte activation and fibrosis that was equivalent to that induced by ATO 5 µg/g. Our results show that the addition of CuCl2 improved the effects of ATO and significantly limited the development of the disease. This co-treatment could be a real benefit in human patients to substantially decrease the known ATO side effects and optimize ATO treatment in pathologies characterized by activated cells sensitive to an increase in oxidative stress.

Long-term follow-up studies are crucial to ensure surveillance and intervention for late complications after allogeneic stem cell transplantation, but they are scarce on the pediatric population. This study aims to analyze risk factors for long-term transplant outcomes. We report a landmark analysis of 162 pediatric patients who underwent allogeneic transplantation between 1991 and 2016, and survived for at least 12 months after the transplant. With a median follow-up time of 10 years for the survivors, the probability of disease-free survival (DFS) and overall survival (OS) is 81 ± 3 and 88 ± 2%, respectively. Variables that influenced DFS in the univariate analysis were: disease phase (early phase 87 ± 3% vs. advanced phase 74 ± 5%; p = 0.04), acute graft vs. host disease (aGvHD; yes 73 ± 5% vs. no 87 ± 3%; p = 0.038), severe chronic GvHD (cGvHD; yes 41 ± 13% vs. no 85 ± 3%; p = 0.0001), and CD4+ lymphocytes 2 years after the transplant (above the median of 837/μl 98 ± 2% vs. below the median 82 ± 6%, p = 0.026). However, in the multivariate analysis, the only variable that influenced DFS was presence of severe chronic GvHD (yes vs. no, HR 6.25; 95% CI, 1.35–34.48; p = 0.02). Transplant strategies should aim to reduce the risk of severe cGvHD. Immune reconstitution surveillance may help clinicians to better deal with late transplant complications.

Background: Graft-versus-host disease (GVHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD in the female genital tract can cause sinusorrhagia, dyspareunia, synechia, and even complete vagina occlusion.Purpose: This prospective study aimed to evaluate the clinical characteristics and effects of preventive and prompt treatment for genital GVHD in females undergoing HSCT (n = 40).Results: Genital GVHD was diagnosed in 11 of 40 patients (27.5%), and the most common complaint was vaginal dryness (54.6%). The majority of patients (63.6%) presented mild genital GVHD (clinical score 1), with interlabial fissures and lichen-like lesions, while a minority of patients (9.1%) presented advanced genital GVHD (clinical score 3) with the fusion of the small and large lips. The median time of onset of genital GVHD signs was 10 months after HSCT, concomitant with GVHD in the skin and oral cavity. Personalized and topical therapy was effective in most cases (81.8%), and no patient required surgical intervention.Conclusion: We confirmed that female genital GVHD affects approximately one-third of females undergoing HSCT, highlighting the importance of periodic gynecological monitoring for early detection and treatment to improve care for these females. [ABSTRACT FROM AUTHOR]

Chronic oral graft-versus-host disease (cGVHD) is a complex, frequent, and highly impactful complication of allogeneic hematopoietic cell transplantation (alloHCT). It represents the leading cause of morbidity and mortality in long-term alloHCT survivors. cGVHD can affect almost any visceral organ system and commonly affects the skin, eyes and mouth, manifesting with signs and symptoms similar to other known immune-mediated and autoimmune diseases. Oral manifestations of GVHD include inflammation, thinning, and ulceration of oral mucosal tissues (similar to lichen planus), lymphocyte-mediated salivary gland dysfunction (similar to Sjögren/Sicca Syndrome), and decreased oral opening (trismus) secondary to sclerosis of oral and perioral tissues (analogous to limitation in scleroderma). Potential sequelae include severe mucosal pain, compromised nutrition, weight loss, limitation in opening, and sometimes irreversible fibrosis of the salivary glands. While some cases can be managed with topical therapies, management may also require long-term targeted immunosuppressive and/or corticosteroid therapy with associated risk of local and systemic infection, hyperglycemia, kidney dysfunction, osteopenia/osteoporosis, and possibly secondary malignancies. The aim of this mini-review is to provide an up-to-date review of literature related to the diagnosis and management of oral cGVHD to aid dental and medical clinicians in optimizing oral cGVHD therapy while minimizing potential adverse effects.

Chronic graft-versus-host disease (cGVHD) represents a common long-term complication after allogeneic hematopoietic stem cell transplantation (HSCT). It imposes a significant morbidity burden and is the leading cause of non-relapse mortality among long-term HSCT survivors. cGVHD can manifest in nearly any organ, severely affecting the quality of life of a transplant survivor. While the mainstay of treatment has remained systemic immunosuppression with glucocorticoids, progress has been made within the last few years with approvals of three oral agents to treat steroid-refractory cGVHD: ibrutinib, ruxolitinib, and belumosudil. Iatrogenesis contributes a significant portion of the morbidity experienced by patients with cGVHD, primarily from glucocorticoids. This review highlights the myriad impacts of cGVHD, including and beyond the traditional organ systems captured by the National Institutes of Health Consensus Criteria, including iatrogenic complications of long-term immunosuppression. It presents the implications of cGVHD and its treatment on cardiovascular and metabolic health, bone density, endocrine function, sexual health, and ocular and pulmonary disease and outlines a framework around the comprehensive multidisciplinary approach for its evaluation and management., Competing Interests: Andrew Jallouk: Consulting for Kite/Gilead. Tae K. Kim: Consulting for Agenus and Immunobiome. Carrie Kitko: Advisory board for Incyte Therapeutics. Bipin Savani: Editor-in-Chief of Clinical Hematology International. Bhagirathbhai Dholaria: Institutional research funding from Janssen, Angiocrine, Pfizer, Poseida, MEI, Orcabio, Wugen, Allovir Adicet, BMS, Molecular Templates; Consultancy/Advisor for MJH BioScience, Arivan Research, BEAM therapeutics, Janssen, ADC therapeutics, Roche. Rahul Shah, Danielle Murphy, Melissa Logue, Kassim Adetola, Olalekan Oluwole, Reena Jayani, Eden Biltibo, Salyka Sengsayadeth, Wichai Chinratanalab report no pertinent competing interests.

Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapeutic procedure to treat hematological malignancies. However, the benefit of allo-HCT is limited by a major complication, chronic graft-versus-host disease (cGVHD). Since transmembrane and secretory proteins are generated and modified in the endoplasmic reticulum (ER), the ER stress response is of great importance to secretory cells including B cells. By using conditional knock-out (KO) of XBP-1, IRE-1α or both specifically on B cells, we demonstrated that the IRE-1α/XBP-1 pathway, one of the major ER stress response mediators, plays a critical role in B cell pathogenicity on the induction of cGVHD in murine models of allo-HCT. Endoribonuclease activity of IRE-1α activates XBP-1 signaling by converting unspliced XBP-1 (XBP-1u) mRNA into spliced XBP-1 (XBP-1s) mRNA but also cleaves other ER-associated mRNAs through regulated IRE-1α-dependent decay (RIDD). Further, ablation of XBP-1s production leads to unleashed activation of RIDD. Therefore, we hypothesized that RIDD plays an important role in B cells during cGVHD development. In this study, we found that the reduced pathogenicity of XBP-1 deficient B cells in cGVHD was reversed by RIDD restriction in IRE-1α kinase domain KO mice. Restraining RIDD activity per se in B cells resulted in an increased severity of cGVHD. Besides, inhibition of RIDD activity compromised B cell differentiation and led to dysregulated expression of MHC II and costimulatory molecules such as CD86, CD40, and ICOSL in B cells. Furthermore, restraining the RIDD activity without affecting XBP-1 splicing increased B cell ability to induce cGVHD after allo-HCT. These results suggest that RIDD is an important mediator for reducing cGVHD pathogenesis through targeting XBP-1s.

Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapeutic procedure to treat hematological malignancies. However, the benefit of allo-HCT is limited by a major complication, chronic graft-versus-host disease (cGVHD). Since transmembrane and secretory proteins are generated and modified in the endoplasmic reticulum (ER), the ER stress response is of great importance to secretory cells including B cells. By using conditional knock-out (KO) of XBP-1, IRE-1α or both specifically on B cells, we demonstrated that the IRE-1α/XBP-1 pathway, one of the major ER stress response mediators, plays a critical role in B cell pathogenicity on the induction of cGVHD in murine models of allo-HCT. Endoribonuclease activity of IRE-1α activates XBP-1 signaling by converting unspliced XBP-1 (XBP-1u) mRNA into spliced XBP-1 (XBP-1s) mRNA but also cleaves other ER-associated mRNAs through regulated IRE-1α-dependent decay (RIDD). Further, ablation of XBP-1s production leads to unleashed activation of RIDD. Therefore, we hypothesized that RIDD plays an important role in B cells during cGVHD development. In this study, we found that the reduced pathogenicity of XBP-1 deficient B cells in cGVHD was reversed by RIDD restriction in IRE-1α kinase domain KO mice. Restraining RIDD activity per se in B cells resulted in an increased severity of cGVHD. Besides, inhibition of RIDD activity compromised B cell differentiation and led to dysregulated expression of MHC II and costimulatory molecules such as CD86, CD40, and ICOSL in B cells. Furthermore, restraining the RIDD activity without affecting XBP-1 splicing increased B cell ability to induce cGVHD after allo-HCT. These results suggest that RIDD is an important mediator for reducing cGVHD pathogenesis through targeting XBP-1s. [ABSTRACT FROM AUTHOR]

IntroductionAllogeneic stem cell transplantation survivors are at a relevant risk of developing chronic GvHD (cGvHD), which importantly affects quality of life and increases morbidity and mortality. Early identification of patients at risk of cGvHD-related morbidity could represent a relevant tool to tailor preventive strategies. The aim of this study was to evaluate the prognostic power of immune reconstitution (IR) at cGvHD onset through an IR-based score.MethodsWe analyzed data from 411 adult patients consecutively transplanted between January 2011 and December 2016 at our Institution: 151 patients developed cGvHD (median follow-up 4 years). A first set of 111 consecutive patients with cGvHD entered the test cohort while an additional consecutive 40 patients represented the validation cohort. A Cox multivariate model for OS (overall survival) in patients with cGvHD of any severity allowed the identification of six variables independently predicting OS and TRM (transplant-related mortality). A formula for a prognostic risk index using the β coefficients derived from the model was designed. Each patient was assigned a score defining three groups of risk (low, intermediate, and high).ResultsOur multivariate model defined the variables independently predicting OS at cGvHD onset: CD4+ >233 cells/mm3, NK 3.09 and ≤6.9, and high-risk patients >6.9. By ROC analysis, we identified a cut-off of 6.310 for both TRM and overall mortality.In the training cohort, the 6-year OS and TRM from cGvHD occurrence were 85% (95% CI, 70-92) and 13% (95% CI, 5-25) for low-risk, 64% (95% CI, 44-89) and 30% (95% CI, 15-47) for intermediate-risk, 26% (95% CI, 10-47), and 42% (95% CI, 19-63) for high-risk patients (OS p

Introduction: Allogeneic stem cell transplantation survivors are at a relevant risk of developing chronic GvHD (cGvHD), which importantly affects quality of life and increases morbidity and mortality. Early identification of patients at risk of cGvHD-related morbidity could represent a relevant tool to tailor preventive strategies. The aim of this study was to evaluate the prognostic power of immune reconstitution (IR) at cGvHD onset through an IR-based score. Methods: We analyzed data from 411 adult patients consecutively transplanted between January 2011 and December 2016 at our Institution: 151 patients developed cGvHD (median follow-up 4 years). A first set of 111 consecutive patients with cGvHD entered the test cohort while an additional consecutive 40 patients represented the validation cohort. A Cox multivariate model for OS (overall survival) in patients with cGvHD of any severity allowed the identification of six variables independently predicting OS and TRM (transplant-related mortality). A formula for a prognostic risk index using the β coefficients derived from the model was designed. Each patient was assigned a score defining three groups of risk (low, intermediate, and high). Results: Our multivariate model defined the variables independently predicting OS at cGvHD onset: CD4+ >233 cells/mm3, NK <115 cells/mm3, IgA <0.43g/L, IgM <0.45g/L, Karnofsky PS <80%, platelets <100x103/mm3. Low-risk patients were defined as having a score ≤3.09, intermediate-risk patients >3.09 and ≤6.9, and high-risk patients >6.9. By ROC analysis, we identified a cut-off of 6.310 for both TRM and overall mortality. In the training cohort, the 6-year OS and TRM from cGvHD occurrence were 85% (95% CI, 70-92) and 13% (95% CI, 5-25) for low-risk, 64% (95% CI, 44-89) and 30% (95% CI, 15-47) for intermediate-risk, 26% (95% CI, 10-47), and 42% (95% CI, 19-63) for high-risk patients (OS p<0.0001; TRM p = 0.015). The validation cohort confirmed the model with a 6-year OS and TRM of 83% (95% CI, 48-96) and 8% (95% CI, 1-32) for low-risk, 78% (95% CI, 37-94) and 11% (95% CI, 1-41) for intermediate-risk, 37% (95% CI, 17-58), and 63% (95% CI, 36-81) for high-risk patients (OS p = 0.0075; TRM p = 0.0009). Conclusions: IR score at diagnosis of cGvHD predicts GvHD severity and overall survival. IR score may contribute to the risk stratification of patients. If confirmed in a larger and multicenter-based study, IR score could be adopted to identify patients at high risk and modulate cGvHD treatments accordingly in the context of clinical trial. [ABSTRACT FROM AUTHOR]

• Disability as defined by progressive chronic graft-versus-host disease (GVHD) impairments are associated with decline in human activity profile scores and performance status at 18 months. • Worse oral scores and patient-reported eye and skin scores are significantly associated with progressive chronic GVHD impairment at 18 months. Chronic graft-versus-host disease (cGVHD) is a heterogenous syndrome whose symptoms and treatment are often associated with decreases in functional status and quality of life among survivors of transplantation. We explored definitions of cGVHD-related disability and factors associated with disability in cGVHD. We analyzed 371 patients with cGVHD requiring a new systemic therapy with enrollment and 18-month assessments through the Chronic GVHD Consortium, evaluating disability as a composite endpoint including any 1 of 5 impairments previously defined by Fatobene et al [1] (score 2 or 3 keratoconjunctivitis sicca, score 2 or 3 scleroderma, any diagnosis of bronchiolitis obliterans, score 2 or 3 joint/fasciae involvement, or score 3 esophageal stricture requiring dilation). We also evaluated disability, defined as an ≥8-point decline in a human activity profile (HAP) score or a ≥20% decline in Karnofsky Performance Status (KPS) from enrollment to 18 months. At enrollment, 47% of patients had at least 1 of the 5 Flowers disability features, with 50% of this group acquiring additional impairments at 18 months. Of the 197 patients (53%) with no Flowers disability at enrollment, 50% progressed with disability features at 18 months. We found that any progressive Flowers impairment was associated with a decline in HAP/KPS as well as with increased National Institutes of Health severity scores at 18 months. Enrollment mouth scores and patient-reported eye and skin scores were significantly associated with progressive impairment at 18 months. Progressive disability at 18 months did not predict subsequent nonrelapse mortality. Additional studies to define chronic GVHD related-disability and risk factors are needed to develop this important patient-centered outcome. [ABSTRACT FROM AUTHOR]

Background: Advances of allogeneic hematopoietic cell transplantation (allo-HCT) have brought long-term survival to the patients with hematologic malignancies. Chronic graft-versus-host disease (GVHD) is one of major problems for the long-survivors after allo-HCT. Dysregulation of immune reconstitution has been reported to be involved in the pathogenesis of chronic GVHD. Differences of immune reconstitution between cord blood transplantation (CBT) and unrelated bone marrow transplantation (uBMT) remain unclear in long-term survivors. We investigated immune reconstitution in patients who survive for more than 2 years after CBT (n=21) or uBMT (n=20) without relapse of underlying disease. Materials and Methods: Using flowcytomeric analysis of peripheral blood, we investigated immune reconstitution of T cells, B cells, and NK cells between CBT and uBMT patients. We collected clinical data regarding allo-HCT and examined the relation of immune reconstitution to the development of chronic GVHD. Results: Between CBT and uBMT patients, we found significant differences in absolute cell number of CD8+ as well as CD19+ cell and CD4/CD8 ratio even more than 2 years after allo-HCT. Among uBMT patients, absolute cell number of naïve CD4+ cell was significantly lower in patients with chronic GVHD. In addition, we found significant differences in absolute cell number of CD19+ cell, especially naïve B cell between patients with and without chronic GVHD in both CBT and uBMT patients. Conclusion: These results suggest that differences of immune recovery between CBT and uBMT patients may exist even in patients who survive for more than 2 years and might be related to the development of chronic GVHD.

• The incidences of late acute and chronic graft-versus-host disease (GVHD) were lower in Japanese than in whites. • Organ manifestations and risk factors were similar to previous reports. • Global severity was not associated with overall survival, nonrelapse mortality, or GVHD-specific survival. • Severe patients showed a significantly lower rate of treatment termination. To prospectively validate the incidence, manifestations, and outcomes of graft-versus-host disease (GVHD) by National Institutes of Health criteria, we recruited 406 hematopoietic stem cell transplantation recipients at 16 transplant centers in Japan from May 2012 to June 2014. The 2-year cumulative incidence of late acute and chronic GVHD was 3.2% (n = 13) and 35.4% (n = 145), with a median onset of 3.6 and 4.7 months after transplant, respectively. The global severity at onset was mild in 30.3%, moderate in 43.5%, and severe in 26.2%. Eighty-two patients were followed up for 2 years, with 79.3% still manifesting GVHD symptoms, and 80.6% (n = 117) of the patients received systemic immunosuppressive treatment (IST), with a 2-year cumulative incidence of IST termination of 33.1%. Severe patients showed a significantly lower rate of IST termination than those with mild and moderate severities (mild, 38.5%; moderate, 40.9%; and severe, 17.2%). The 2-year incidence of nonrelapse mortality (NRM) and relapse was not significantly different according to the severity at onset (NRM: mild [16.6%] versus moderate [8.7%] versus severe [16.1%]; relapse: mild [14.9%] versus moderate [14.7%] versus severe [5.3%]). As a result, 2-year overall survival (OS) and GVHD-specific survival (GSS) were equivalent according to the severity at onset (mild: OS = 81.0%, GSS = 85.7%; moderate: OS = 84.2%, GSS = 92.5%; severe: OS = 83.9%, GSS = 89.2%). Our study helped identify the characteristics of late acute and chronic GVHD in Japanese patients. Further investigation is needed to identify an optimal endpoint for survival prediction. [ABSTRACT FROM AUTHOR]

• One third of patients with chronic graft-versus-host disease (GVHD) had clinically significant depression or anxiety. • Mood was associated with symptom burden, coping, and physical functioning. • Coping, symptoms, physical functioning, and social support related to quality of life (QOL) over time. • Studies should explore psychosocial interventions to improve mood and QOL in GVHD. Chronic graft-versus-host disease (GVHD) is one of most common complications following allogeneic hematopoietic cell transplantation (HCT) and the most significant contributor to morbidity and nonrelapse mortality. The physical burdens and psychosocial difficulties of these patients have not been described systematically. An exploration into the rates and correlates of mood and quality of life (QOL) in patients with chronic GVHD is necessary to develop a clinically relevant, evidence-based intervention to promote well-being. From July 2015 to July 2017, adult allogeneic HCT survivors with established moderate to severe chronic GVHD (N = 52) enrolled in a prospective, longitudinal study at a tertiary academic center. We examined the rates and correlates of depression and anxiety symptoms (Hospital Anxiety and Depression Scale) and explored whether constructs including coping strategies (Coping Inventory for Stressful Situations), symptom burden (Lee Symptom Assessment Scale), physical functioning (Human Activity Profile), and perceived social support (Medical Outcomes Study Social Support Survey) predicted QOL trajectory over time (Functional Assessment of Cancer Therapy–Bone Marrow Transplant) at the baseline, 3-month, and 6-month follow-up. Analyses adjusted for age, sex, chronic GVHD severity, and time since chronic GVHD diagnosis. At the baseline, 3-month, and 6-month follow-up, 32.7%, 31.1%, and 37.8% of patients reported clinically significant depression symptoms, and 30.8%, 20.0%, and 36.4% reported clinically elevated anxiety symptoms, respectively. Adjusting for covariates, greater use of negative emotion-oriented coping (β = 0.20, P =.002), less use of task-oriented coping (β = –0.10, P =.021), worse physical functioning (β = –0.07, P =.004), and higher symptom burden (β = 0.07, P =.002) were independently associated with depression symptoms at baseline. Greater use of negative emotion-oriented coping (β = 0.28, P <. 001) and worse physical functioning (β = –0.05, P =.034) were independently associated with anxiety at baseline. Patients who used more negative emotion-oriented coping (β = –0.58, P =.035), had less task-oriented (β = 0.40, P =.028) and social diversion-oriented coping (β = 0.35, P =.039), and had higher symptom burden (β = –0.30, P =.001), worse physical functioning (β = 0.32, P <. 001), and lower perceived social support (β = 6.47, P =.003) at baseline reported poorer QOL over time. The unmet physical and psychosocial needs of patients with chronic GVHD are substantial and warrant investigation into evidence-based interventions that may improve QOL and mood by targeting modifiable psychosocial constructs identified in this study. [ABSTRACT FROM AUTHOR]

Highlights • A significant proportion of allogeneic hematopoietic cell transplantation patients with chronic graft-versus-host disease experience financial burden despite being insured. Nonwhite race, lower mental functioning, and lower activity score are associated with a higher likelihood of financial burden. • Patients with financial burden had poor psychosocial outcomes, such as greater depression/anxiety and difficulty sleeping. ABSTRACT Understanding the socioeconomic impact of chronic graft-versus-host disease (GVHD) on affected patients is essential to help improve their overall well-being. Using data from the Chronic GVHD Consortium, we describe the insurance, employment, and financial challenges faced by these patients and the factors associated with the ability to work/attend school and associated financial burdens. A 15-item cross-sectional questionnaire designed to measure financial concerns, income, employment, and insurance was completed by 190 patients (response rate, 68%; 10 centers) enrolled on a multicenter Chronic GVHD Consortium Response Measures Validation Study. Multivariable logistic regression models examined the factors associated with financial burden and ability to work/attend school. The median age of respondents was 56years, and 87% of the patients were white. A higher proportion of nonrespondents had lower income before hematopoietic cell transplantation and less than a college degree. All but 1 patient had insurance, 34% had faced delayed/denied insurance coverage for chronic GVHD treatments, and 66% reported a financial burden. Patients with a financial burden had greater depression/anxiety and difficulty sleeping. Nonwhite race, lower mental functioning, and lower activity score were associated with a greater likelihood of financial burden. Younger age, early risk disease, and higher mental functioning were associated with a greater likelihood of being able to work/attend school. In this multicenter cohort of patients with chronic GVHD, significant negative effects on finances were observed even with health insurance coverage. Future research should investigate potential interventions to provide optimal and affordable care to at-risk patients and prevent long-term adverse financial outcomes in this vulnerable group. [ABSTRACT FROM AUTHOR]

Highlights • Ruxolitinib use was associated with a reduction in prednisone dose. • The rate of infectious/bacterial infections was high and contributed to the overall mortality. • Ruxolitinib as salvage therapy is promising for chronic graft-versus-host disease refractory to steroids. Abstract Chronic graft-versus-host disease (cGVHD) continues to be a major complication after allogeneic hematopoietic cell transplantation, significantly affecting patients' quality of life. A regimen of systemic corticosteroids is considered first-line therapy but is often associated with inadequate responses and multiple side effects. In patients with refractory disease, an evidenced-based consensus is lacking as to the single best approach to managing symptoms. Ruxolitinib, a selective JAK1/2 inhibitor, has recently gained favor as a second-line approach in patients with steroid-refractory cGVHD. In this retrospective study, we evaluated the outcomes of 46 patients who received ruxolitinib for cGVHD between March 2016 and December 2017 at our institution, and evaluated ruxolitinib's impact at 6 and 12 months, based on the National Institutes of Health Severity Scale, including organ-specific responses, and mean prednisone dose. Furthermore, we present the first reported probability of ruxolitinib's treatment failure-free survival (FFS) in patients with cGVHD. After 12 months of ruxolitinib therapy, complete response, partial response, and stable disease was observed in 13% (n = 6), 30.4% (n = 14), and 10.9% (n = 5) of patients, respectively. The 1-year probability of FFS was 54.2% (95% confidence interval,.388 to.673), and ruxolitinib use was associated with a reduction in prednisone dose. In conclusion, our data, which represent the largest cohort of patients with cGVHD reported to date, support the use of ruxolitinib for cGVHD refractory to steroids and currently available salvage therapies, discontinued due to lack of response and high cost. [ABSTRACT FROM AUTHOR]

Highlights • Human cord blood (hCB) can be a source of immunosuppressive MDSCs. • Administration of hCB-MDSCs attenuates cGVHD in preclinical models. • hCB-MDSCs reduce thymic damage with less donor-derived T cell expansion. • cGVHD protection by hCB-MDSCs correlate with reversal of Th 17 skewing. • hCB-MDSCs modulate helper T cell subset and expand FoxP3 Treg. Abstract Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with anti-inflammatory activity, and expanded murine MDSCs are capable of attenuating preclinical acute graft-versus-host disease (aGVHD) severity. Two murine cGVHD models were used to evaluate the effectiveness of ex vivo cultured human cord blood (hCB) MDSCs in chronic GVHD (cGVHD). First, GVHD recipients surviving in a classic C57BL/6 into MHC-mismatched BALB/c aGVHD model developed cGVHD. Second, donor pretreatment with granulocyte colony-stimulating factor (G-CSF) induced cGVHD. hCB-MDSCs (1 × 106) were intravenously injected to determine their preventive effects (on days 5, 7, 10, and 21) or therapeutic effects (on days 21, 28, and 35). In the first model the onset of clinical cutaneous cGVHD was significantly delayed in preventive hCB-MDSCs–treated allogeneic recipients. Pathologic scoring of target organs confirmed these clinical results. Importantly, thymic tissues of GVHD mice treated with hCB-MDSCs were less severely damaged, showing higher numbers of double (CD4 and CD8) positive T cells with reduced expansion of donor-type CD4 and CD8 T cells. Moreover, late infusion of hCB-MDSCs controlled the severity of established cGVHD that had occurred in control recipients. In the second model, cGVHD induced by G-CSF–mobilized stem cell graft was associated with promotion of Th 17 and Th 2 differentiation. hCB-MDSCs attenuated clinical and pathologic cGVHD severity. Increased production of IL-17 and more infiltration of T cells and macrophages in cGVHD mice were markedly reduced after hCB-MDSCs treatment. Importantly, Foxp3+ regulatory T cells and IFN-γ–producing T cells were expanded, whereas IL-17– and IL-4–producing T cells were decreased in allogeneic recipients of hCB-MDSCs. Taken together, these results showed that hCB-MDSCs have preclinical capability of attenuating cGVHD by preserving thymus function and regulating Th 17 signaling, suggesting a possible therapeutic strategy for clinical application. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop a new composite endpoint that accurately reflects the long-term success of allogeneic hematopoietic stem cell transplantation (allo-HSCT), as the conventional graft-versus-host disease (GVHD)–free, relapse-free survival (GRFS) overestimates the impact of GVHD. First, we validated current GRFS (cGRFS), which recently was proposed as a more accurate endpoint of long-term transplant success. cGRFS was defined as survival without disease relapse/progression or active chronic GVHD at a given time after allo-HSCT, calculated using 2 distinct methods: a linear combination of a Kaplan-Meier estimates approach and a multistate modelling approach. Next, we developed a new composite endpoint, refractory GRFS (rGRFS). rGRFS was calculated similarly to conventional GRFS treating grade III to IV acute GVHD, chronic GVHD requiring systemic treatment, and disease relapse/progression as events, except that GVHD that resolved and did not require systemic treatment at the last evaluation was excluded as an event in rGRFS. The 2 cGRFS curves obtained using 2 different approaches were superimposed and both were superior to that of conventional GRFS, reflecting the proportion of patients with resolved chronic GVHD. Finally, the curves of cGRFS and rGRFS overlapped after the first 2 years of post-transplant follow-up. These results suggest that cGRFS and rGRFS more accurately reflect transplant success than conventional GRFS. Especially, rGRFS can be more easily calculated than cGRFS and analyzed with widely used statistical approaches, whereas cGRFS more accurately represents the burden of GVHD-related morbidity in the first 2 years after transplantation. [ABSTRACT FROM AUTHOR]

Mice with lupus-like autoimmune glomerulonephritis induced by chronic graft-versus-host reaction, have been treated with irradiation at lethal doses, followed by injection of bone marrow cells from syngeneic donors. Following such treatment, the autoimmune process was interrupted, as judged by disappearance of anti-DNA autoantibodies in peripheral blood. A drop in urine protein to normal values was also observed in the marrow recipients, thus being a characteristic sign of recovery from glomerulonephritis. Correction of the disease was confirmed by morphological data: the signs of oedema were diminished, and inflammatory reaction was found to be decreased in the kidneys of animals with lupus-like disorder after marrow transplantation.

Abstract. Induction of chronic GVHD in the DBA/2→(C57Bl/6xDBA/2) F1 semi-allogeneic murine model results into development of Th1- and Th2-dependent immunopathological conditions that are characterized by different cytokine profiles. Chronic GVHD is accompanied by a sharp increase in IgE levels, thus presuming considerable IL-4 production. In recipients with Th2-dependent GvHD variant, elevated contents of serum IL-6, IL-7 and TNFα were also observed, which, along with other effects, may support polyclonal activation of B cells, thus leading to development of autoimmune pathology.