Treatment Of Graft-versus-host Disease Research Articles

Human CD83-targeted chimeric antigen receptor T cells prevent and treat graft-versus-host disease.

Graft-versus-host disease (GVHD) remains an important cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). For decades, GVHD prophylaxis has included calcineurin inhibitors, despite their incomplete efficacy and impairment of graft-versus-leukemia (GVL). Distinct from pharmacologic immune suppression, we have developed what we believe is a novel, human CD83-targeted chimeric antigen receptor (CAR) T cell for GVHD prevention. CD83 is expressed on allo-activated conventional CD4+ T cells (Tconvs) and proinflammatory dendritic cells (DCs), which are both implicated in GVHD pathogenesis. Human CD83 CAR T cells eradicate pathogenic CD83+ target cells, substantially increase the ratio of regulatory T cells (Tregs) to allo-activated Tconvs, and provide durable prevention of xenogeneic GVHD. CD83 CAR T cells are also capable of treating xenogeneic GVHD. We show that human acute myeloid leukemia (AML) expresses CD83 and that myeloid leukemia cell lines are readily killed by CD83 CAR T cells. Human CD83 CAR T cells are a promising cell-based approach to preventing 2 critical complications of allo-HCT - GVHD and relapse. Thus, the use of human CD83 CAR T cells for GVHD prevention and treatment, as well as for targeting CD83+ AML, warrants clinical investigation.

The Butyrogenic and Lactic Bacteria of the Gut Microbiota Determine the Outcome of Allogenic Hematopoietic Cell Transplant.

Graft versus host disease (GVHD) is a post-transplant pathology in which donor-derived T cells present in the Peyer’s patches target the cell-surface alloantigens of the recipient, causing host tissue damages. Therefore, the GVHD has long been considered only a purely immunological process whose prevention requires an immunosuppressive treatment. However, since the early 2010s, the impact of gut microbiota on GVHD has received increased attention. Both a surprising fall in gut microbiota diversity and a shift toward Enterobacteriaceae were described in this disease. Recently, unexpected results were reported that further link GVHD with changes in bacterial composition in the gut and disruption of intestinal epithelial tight junctions leading to abnormal intestinal barrier permeability. Patients receiving allogenic hematopoietic stem cell transplant (allo-HCT) as treatment of hematologic malignancies showed a decrease of the overall diversity of the gut microbiota that affects Clostridia and Blautia spp. and a predominance of lactic acid bacteria (LAB) of the Enterococcus genus, in particular the lactose auxotroph Enterococcus faecium. The reduced microbiota diversity (likely including Actinobacteria, such as Bifidobacterium adolescentis that cross feed butyrogenic bacteria) deprives the butyrogenic bacteria (such as Roseburia intestinalis or Eubacterium) of their capacity to metabolize acetate to butyrate. Indeed, administration of butyrate protects against the GVHD. Here, we review the data highlighting the possible link between GVHD and lactase defect, accumulation of lactose in the gut lumen, reduction of Reg3 antimicrobial peptides, narrower enzyme equipment of bacteria that predominate post-transplant, proliferation of En. faecium that use lactose as metabolic fuels, induction of innate and adaptive immune response against these bacteria which maintains an inflammatory process, elevated expression of myosin light chain kinase 210 (MLCK210) and subsequent disruption of intestinal barrier, and translocation of microbial products (lactate) or transmigration of LAB within the liver. The analysis of data from the literature confirms that the gut microbiota plays a major role in the GVHD. Moreover, the most recent publications uncover that the LAB, butyrogenic bacteria and bacterial cross feeding were the missing pieces in the puzzle. This opens new bacteria-based strategies in the treatment of GVHD.

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.

The Prolyl Hydroxylase Inhibitor Dimethyl Oxalyl Glycine Decreases Early Gastrointestinal GVHD in Experimental Allogeneic Hematopoietic Cell Transplantation.

Prolyl hydroxylase inhibitors (PHI) promote stabilization of hypoxia-inducible factor-1 alpha and affect signaling cascades of inflammation and cell death. Their beneficial use in experimental models of ulcerative colitis and lung allograft rejection led us to test the effect of the PHI dimethyl oxalyl glycine (DMOG) in the pathophysiology of graft versus host disease (GVHD). Acute GVHD was induced in lethally irradiated BALB/c mice. DMOG was administered intraperitoneally on alternate days for the first 2-weeks posttransplant, and then twice a week till day +50, while controls received vehicle only. Animals were monitored for clinical GVHD and analyzed at day +7 and at day +50. DMOG treatment of allogeneic recipients improved survival by day +50, which was associated with decreased early gut injury and serum tumor necrosis factor-α compared with allogeneic controls. DMOG treatment of allogeneic recipients resulted in increased hypoxia-inducible factor-1 alpha expression and reduced apoptosis in the terminal ileum via Fas-associated protein with death domain protein repression along with decreased T-cell infiltration. Reduced pathology in colon after DMOG treatment associates with intestinal epithelium integrity and reduced damage caused by diminished recruitment of neutrophils. Taken together, we show protective effects of DMOG on early gut GVHD and improved survival in a model of allogeneic hematopoietic cell transplantation, providing the rationale for further evaluation of PHIs, in the prevention and treatment of acute GVHD.

Mesenchymal Stromal Cells for Graft Versus Host Disease: Mechanism-Based Biomarkers.

The immunosuppressive activity of mesenchymal stromal cells (MSCs) in graft versus host disease (GvHD) is well-documented, but their therapeutic benefit is rather unpredictable. Prospective randomized clinical trials remain the only means to address MSC clinical efficacy. However, the imperfect understanding of MSC biological mechanisms has undermined patients' stratification and the successful design of clinical studies. Furthermore, although MSC efficacy seems to be dependent on patient-associated factors, the role of patients' signature to predict and/or monitor clinical outcomes remains poorly elucidated. The analysis of GvHD patient serum has identified a set of molecules that are associated with high mortality. However, despite their importance in defining GvHD severity, their role in predicting or monitoring response to MSCs has not been confirmed. A new perspective on the use of MSCs for GvHD has been prompted by the recent findings that MSCs are actively induced to undergo apoptosis by recipient cytotoxic cells and that this process is essential to initiate MSC-induced immunosuppression. This discovery has not only reconciled the conundrum between MSC efficacy and their lack of engraftment, but also highlighted the determinant role of the patient in promoting and delivering MSC immunosuppression. In this review we will revisit the extensive use of MSCs for the treatment of GvHD and will elaborate on the need that future clinical trials must depend on mechanistic approaches that facilitate the development of robust and consistent assays to stratify patients and monitor clinical outcomes.

Pulmonary Complications After Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma: A Case Report

We present a case of a young patient with life-threatening pulmonary complications after allogeneic hematopoietic stem cell transplantation (HSCT). The 25-year-old woman, after HSCT for multiple myeloma, developed severe chronic graft-vs-host disease (GvHD), including bronchiolitis obliterans syndrome. During the treatment of chronic GvHD, 18 months after HSCT, she experienced sudden massive pulmonary hemorrhage with cardiac arrest. The computed tomography imaging revealed lesions suggestive of fungal etiology, with cavity adjacent to the pulmonary vessels. Disqualified from invasive treatment due to poor pulmonary performance, she was treated conservatively with broad-spectrum antibiotics and antifungals. The microbiological workup consistently revealed only Pseudomonas aeruginosa colonization. Her condition steadily improved on treatment. Over 18 months after the incident, she did not experience recurrent bleeding nor serious infection, her primary disease remains in remission, and GvHD symptoms are controlled. Allogeneic HSCT offers possibility of sustained immune-mediated disease control and sometimes even cure, but despite reduced transplant related mortality, GvHD and infections may be detrimental for transplant recipients. Our report illustrates atypical manifestation of pulmonary lesions and highlights the importance of infection control during GvHD treatment.

Chinese Medicine Treatment on Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Graft-versus-host disease (GVHD) is the most common complication after allogeneic hematopoietic stem cell transplantation, and also an important factor affecting the survival and quality of life in patients after transplantation. Currently, immunosuppressive therapy is commonly used for GVHD, but the curative effect is not ideal. How to effectively prevent and treat GVHD is one of the difficulties to be solved urgently in the field of transplantation. In this paper, we summarize the latest progress in pathogenesis, prevention and treatment of GVHD with Chinese medicine (CM). We hope it will provide ideas and methods for exploring the mechanism and establishing a new comprehensive therapy for GVHD with CM.

Glutathione dynamics determine the therapeutic efficacy of mesenchymal stem cells for graft-versus-host disease via CREB1-NRF2 pathway.

Glutathione (GSH), the most abundant nonprotein thiol functioning as an antioxidant, plays critical roles in maintaining the core functions of mesenchymal stem cells (MSCs), which are used as a cellular immunotherapy for graft-versus-host disease (GVHD). However, the role of GSH dynamics in MSCs remains elusive. Genome-wide gene expression profiling and high-throughput live-cell imaging assays revealed that CREB1 enforced the GSH-recovering capacity (GRC) of MSCs through NRF2 by directly up-regulating NRF2 target genes responsible for GSH synthesis and redox cycling. MSCs with enhanced GSH levels and GRC mediated by CREB1-NRF2 have improved self-renewal, migratory, anti-inflammatory, and T cell suppression capacities. Administration of MSCs overexpressing CREB1-NRF2 target genes alleviated GVHD in a humanized mouse model, resulting in improved survival, decreased weight loss, and reduced histopathologic damages in GVHD target organs. Collectively, these findings demonstrate the molecular and functional importance of the CREB1-NRF2 pathway in maintaining MSC GSH dynamics, determining therapeutic outcomes for GVHD treatment.

Anti-Apoptotic Molecule BCL2 Is a Therapeutic Target in Steroid-Refractory Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) is the leading cause of mortality after hematopoietic stem cell transplantation and primarily affects barrier organs such as the skin. One-third of cases are refractory to steroid treatment resulting in poor outcomes and the need for novel therapies. Longitudinal analysis of T-cell transcriptomes in patients before the appearance of GVHD symptoms revealed the upregulation of anti-apoptotic regulator B-cell lymphoma 2 (BCL2) at GVHD initiation. To determine the potential of BCL2 inhibition in active GVHD, we analyzed tissues of 88 patients with acute or chronic GVHD. BCL2 RNA was elevated in multiple organs affected by GVHD and expression correlated with transplant-related mortality and steroid-refractory GVHD. BCL2-expressing lymphocytes were present in skin lesions and peripheral blood of patients with acute and chronic GVHD. Inhibition of BCL2 increased the CD4 to CD8 ratio in allogeneic T cells invitro and induced apoptosis of T cells from patients with steroid-pretreated chronic GVHD exvivo. In addition, the higher ratio of regulatory to nonregulatory T cells upon blockage of BCL2 could add to the anti-inflammatory effect of BCL2 blockage. Collectively, our results highlight BCL2 as an important factor for GVHD development and introduce BCL2 inhibition as previously unreported and urgently needed targeted therapy in the treatment of steroid-refractory GVHD.

Ruxolitinib for the treatment of graft-versus-host disease

ABSTRACTIntroduction: Ruxolitinib is an oral selective JAK1/JAK2 inhibitor, initially approved by the FDA for the treatment of intermediate-2 or high-risk myelofibrosis and patients with polycythemia vera who have had an inadequate response or are intolerant to hydroxyurea.Areas covered: Accumulating evidence supports the role of JAK1/JAK2 pathways in the pathogenesis of graft-versus-host disease (GVHD), and preclinical studies have demonstrated promising efficacy of ruxolitinib in treatment/prevention of GVHD. Early clinical observations that ruxolitinib was effective in treatment of steroid-refractory (SR) acute and chronic GVHD led to the development of prospective clinical trials; Phase II REACH1 (NCT02953678), Phase III REACH2 (NCT02913261), and REACH3 (NCT03112603). Based on the data from the REACH1 trial, ruxolitinib was approved by the FDA in May 2019 for SR acute GVHD in adult and pediatric patients 12 years and older.Expert opinion: Ruxolitinib and other JAK1/JAK2 inhibitors hold promise in other treatment settings such as GVHD prevention and/or first-line therapy.

In Vivo Analysis of Human Immune Responses in Immunodeficient Rats.

Humanized immune system immunodeficient mice have been extremely useful for the in vivo analyses of immune responses in a variety of models, including organ transplantation and graft versus host disease (GVHD) but they have limitations. Rat models are interesting complementary alternatives presenting advantages over mice, such as their size and their active complement compartment. Immunodeficient rats have been generated but human immune responses have not yet been described. We generated immunodeficient Rat Rag-/- Gamma chain-/- human signal regulatory protein alpha-positive (RRGS) rats combining Rag1 and Il2rg deficiency with the expression of human signal regulatory protein alpha, a negative regulator of macrophage phagocytosis allowing repression of rat macrophages by human CD47-positive cells. We then immune humanized RRGS animals with human peripheral blood mononuclear cells (hPBMCs) to set up a human acute GVHD model. Treatment of GVHD was done with a new porcine antihuman lymphocyte serum active through complement-dependent cytotoxicity. We also established a tumor xenograft rejection model in these hPBMCs immune system RRGS animals by subcutaneous implantation of a human tumor cell line. RRGS animals receiving hPBMCs showed robust and reproducible reconstitution, mainly by T and B cells. A dose-dependent acute GVHD process was observed with progressive weight loss, tissue damage, and death censoring. Antihuman lymphocyte serum (L1S1) antibody completely prevented acute GVHD. In the human tumor xenograft model, detectable tumors were rejected upon hPBMCs injection. hPBMC can be implanted in RRGS animals and elicit acute GVHD or rejection of human tumor cells and these are useful models to test new immunotherapies.

Comparative efficacy of 20 graft-versus-host disease prophylaxis therapies for patients after hematopoietic stem-cell transplantation: A multiple-treatments network meta-analysis.

Graft-versus-host disease (GVHD) is a leading cause of death in patients after hematopoietic stem-cell transplantation (HSCT). Previous studies have shown different efficacy of GVHD prophylaxis therapies. We reviewed 46 randomized controlled trials (including 8050 participants) systematically from Jun 20, 2004 to Aug 20, 2019. These investigations compared the following drugs or their combination at therapeutic dose range for GVHD after HSCT. The main results were based on the proportion of patients who respond to these therapies. Cyclosporine + methotrexate + Anti-T cell globulin (ATG), tacrolimus + methotrexate + ATG, tacrolimus + bortezomib + sirolimus and cyclosporine + marrow mesenchymal stem cells (MMSCs) were significantly more efficacious than corticosteroids alone (OR: 12.15, 6.71, 6.25, 3.73). corticosteroids alone were less efficacious than all the other GVHD prophylaxis therapies tested. Cyclosporine + methotrexate + ATG may be the best choice when starting treatment for GVHD.

Infusion of Mesenchymal Stem Cells to Treat Graft Versus Host Disease: the Role of HLA-G and the Impact of its Polymorphisms.

Hematopoietic stem-cell transplantation is widely performed for the treatment of hematologic diseases and is increasingly being used for the experimental treatment of various autoimmune diseases. Despite the rapid evolution of this therapy, the mortality rate of patients undergoing this procedure is still high, mainly due to the development of graft versus host disease (GvHD). Even with the administration of immunosuppressive therapy, some patients manifest the chronic form of the disease. For these cases, infusion of mesenchymal stem cells (MSCs) was proposed as a therapeutic strategy, considering the immunosuppressive potential of these cells. This review describes the main results obtained in cell therapy with MSCs for the treatment of GvHD. Despite the encouraging results found, some points differed among the studies. Although the factors that influence the different results are uncertain, some investigators have suggested that variations in immunosuppressive molecules are responsible for these divergences. We highlight the key role of the HLA-G gene in modulating the immune response, and the importance of the polymorphisms and alleles of this gene associated with the outcome of the transplants. We suggest that the HLA-G gene and its polymorphisms be analyzed as a factor in selecting the MSCs to be used in treating GvHD, given its strong immunosuppressive role.

Efficacy of BMMSCs on aGVHD and Its Correlation with SerumInflammatory Cytokines in Pediatric Patients with Severe Refractory Acute Graft-Versus-Host Disease

To investigate the efficacy of bone marrow mesenchymal stem cells (BMMSC) on children with refractory graft-versus-host disease (GVHD) and to judge the efficacy of BMMSC by dynamically monitoring the changes of cytokines in children with GVHD before and after infusion of BMMSC, so as to provide a theoretical basis for clarifying the mechanism of BMMSC. 17 children with refractory aGVHD including 7 of grade II, 6 cases of grade III and 4 cases of grade IV after allo-HSCT were enrolled. All the children with aGVHD, who received routine immunosuppressive therapy, but the state of disease not improved, were treated with immunosuppressive drugs combined with BMMSC infusion. Study endpoints included safety of BMMSC infusion, response to BMMSC, and overall response of aGVHD. The serum levels of IL-2α, IL-6, IL-10, IL-8 and TNF-α in aGVHD patients were measured by chemiluminescence before infusion of BMMSCs and Day 7, Day 14 after infusion of BMMSCs. The cumulative median dose of BMMSCs was 5.5 (3.4-11.1) × 106/kg for average of 3.7 times, and the median time of 16.5 (4-95) days for the first infusion of MSCs. In 17 cases of refractory GVHD, 14 responded to treatment, whereas 3 patients failed. The total effective rate was 82.4% and no adverse reactions occurred. Of the 14 survived cases (82.4%), the median follow-up time was 944 (559-1245) days from the first infusion of MSCs. The levels of TNF-α in children with grade II, III and IV GVHD before treatment were 9.5±4.3 pg/ml, 16.3±10.9 pg/ml and 35.8±21.2 pg/ml respectively. The difference between grade II and IV, III and IV was statistically significant (P<0.05). Compared with the ineffective group of BMMSC infusion, the serum TNF-αlevel in the BMMSCs treatment effective group was 10.8±5.6 pg/ml vs 40.6±14.8 pg/ml (t=-3.901, P<0.05) before treatment. In the effective group of BMMSCs infusion, IL-10 20±17.4 pg/ml of day 14 was significantly higher than that 7.3±3.1 pg/ml before the treatment (t=-2.850, P<0.05), while , the serum levels of IL-2α, IL-6, IL-8, TNF-α were not statistically significantly different (P＞0.05). The infusion of BMMSC is safe and effective in the treatment of refractory GVHD in children. TNF-αlevel relates with the severity of GVHD. BMMSC may play an anti-GVHD role by up regulating the level of cytokine IL-10 in vivo.

The MAGIC Algorithm Probability (MAP) Is a Validated Response Biomarker of Treatment for Acute Graft-Versus-Host Disease

There are no validated biomarkers that measure a patient's response to therapy for acute graft-versus-host disease (GVHD), the leading cause of non-relapse mortality (NRM) after allogeneic hematopoietic cell transplant (HCT). Recent studies from the Mount Sinai Acute GVHD International Consortium (MAGIC) have validated an algorithm probability (MAP) that combines serum concentrations of two biomarkers of GVHD (REG3α and ST2) to generate an estimated probability of 6 month NRM for individual patients. The MAP estimates GVHD-mediated damage to crypts throughout the lower GI tract at single time points (Hartwell et al., JCI Insight, 2017; Major- Monfried et al., Blood, 2018). We hypothesized that the change in MAP between start of treatment and 28 days later could serve as a response biomarker and would compare favorably to clinical response, the gold standard which is widely used as a surrogate for long term survival and is the primary endpoint in most GVHD treatment trials (Martin et al., BBMT, 2009; MacMillan et al., Blood, 2010). We prospectively collected serum samples and clinical staging from 368 sequential HCT patients who received systemic treatment for acute GVHD in one of 20 MAGIC centers between January 2016 and February 2018. We computed MAPs and clinical responses for each patient. MAPs of patients who experienced 6 month NRM increased significantly compared to MAPs of patients who survived (p=0.0004). In patients whose initial MAPs were low (Ann Arbor 1, MAP 0.290), those who survived tended to have the largest decreases in MAP (Fig 1C). We found that patients whose MAPs rose above the previously determined high-risk threshold MAP of 0.290 had significantly worse survival compared to those who remained below it, whereas the large number patients with initially high MAPs that remained above the threshold had a large increase in mortality (Fig 2). When measured at day 28, MAPs predicted NRM more accurately than clinical responses, with areas under the receiver operating characteristic curve (AUC) of 0.86 and 0.70, respectively (p We conclude that the MAP is, to our knowledge, the first laboratory test validated as a response biomarker for acute GVHD treatment and more accurately predicts survival than clinical response after 28 days of treatment. The MAP may serve as a novel endpoint in future trials of GVHD treatment.

An Educational Initiative to Increase Bone Marrow Transplant Staff Knowledge of Steroid Induced Hyperglycemia Secondary to Graft Versus Host Disease Treatment

Topic Significance & Study Purpose/Background/Rationale Patients status post allogeneic hematopoietic stem cell transplant (HSCT) are at increased risk of developing graft versus host disease (GVHD). First-line treatment of GVHD is systemic high-dose steroids. Although effective, a major side effect of this treatment is hyperglycemia. Detection is often delayed, especially when treatment occurs in the outpatient setting. Methods, Intervention, & Analysis This educational study included baseline assessment of staff knowledge of recognition and treatment of steroid induced hyperglycemia, staff education on steroid induced hyperglycemia, and re-assessment of effectiveness of education and knowledge retention following education. Approximately 30 registered nurses (RNs) and nurse practitioners (NPs) were included in the survey. The baseline and post-education assessment contained 14 questions. Prior to education, the average overall score of the baseline assessment was 65.88%. The lowest scoring concepts included dosage of high-dose steroids, resolution of steroid induced hyperglycemia, testing for steroid induced hyperglycemia, effects of hyperglycemia related to steroid use, and incidence of steroid induced hyperglycemia. The overall average score on the post-test was 75.5%, with areas of most improvement including when to test for steroid induced hyperglycemia, steroid dosage considered high-dose, steroid peak times with associated increase in blood glucose, and steroid preparations most likely to cause increase in blood glucose. Findings & Interpretation and Discussion & Implications A 1-month post educational assessment to determine educational effectiveness and staff retention concluded that education was effective. A knowledge deficit in the recognition and treatment among RNs and NPs was identified that will likely improve with continued staff education. Now that the knowledge deficit has been identified, additional education regarding steroid induced hyperglycemia will be implemented to include updates for patient education.

A Case Report of the Benefit of Cannabidiol (Cannabidiol (CBD)-Predominant Medical Cannabis Preparation) in the Management of Refractory Skin Graft Vshost Disease (GVHD)

Cannabis sativa contains numerous cannabinoids, with D9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the primary cannabinoids. Both possess potent anti-inflammatory and immunosuppressive properties, but THC has significant psychoactive properties. Yeshuron's phase 2 study of CBD plus standard GVHD prophylaxis found low rates of grade 2-4 acute(A-) GVHD, and compared with 101 historical controls given standard GVHD prophylaxis, the hazard ratio of developing grades 2-4 A-GVHD was .3 (P =.0002). Kalytera Therapeutics announced a Phase 2a study of CBD for treatment of Grade 3 - 4 A-GVHD, including 9/ 10 responses, of which 7 were complete remission (CR). We report a case of steroid refractory eczematous GVHD successfully treated with a CBD predominant medical cannabis product. A 35 year old woman with T-cell Acute Lymphoblastic Leukemia with CNS involvement in complete remission underwent matched related donor stem cell transplant (SCT) conditioned with Etoposide, TBI 1200 cGy. GvHD prophylaxis was Alemtuzumab, Tacrolimus. A rash developed on day 126 post transplant involving face and scalp and within 1 week involved 100% BSA with itching, facial and orbital swelling, ankle/feet swelling. Skin biopsy revealed an eczematous variant of GvHD known to be very aggressive, difficult to control with immunosuppression , and carries a poor prognosis. Phototherapy and steroid ointment provided initial benefit and regression of rash but it recurred within 6 months. Ruxolitinib provided no benefit. Systemic steroids were restarted at 1mg/kg/ day with minimal benefit. Photopheresis offered only minimal response. Ibrutinib was added. With steroids, photopheresis and ibrutinib she had only marginal response . Numerous infectious complications including soft tissue skin infections required multiple admissions. At 16 months post SCT, she began a medical cannabis product manufactured by VIREO HEALTH, consisting of a high CBD:THC ratio (19:1) oral solution containing CBD 47.5mg/ml and THC 2.5mg/ml. A daily dose of 6 ml provided 285 mg CBD and 15mg THC daily comparable to the 300 mg CBD Kalytera product. Toxicity was sleepiness; thus it was dosed in the evening. There was a definite response within 3 months, allowing discontinuation of ibrutinib and photopheresis. By 2 years post SCT, her GVHD had resolved with only mild itching and flakiness. Her response is sustained 1 year after starting CBD. She remains on 6 ml daily. This adds to the evidence of the anti- inflammatory and immunosuppressive effects of medical cannabis and its activity for the treatment of active GVHD. THC and CBD are anti-inflammatory via CB2 receptors. THC inhibits T-lymphocyte expansion in a murine BMT model. The THC component may have both therapeutic benefit and dose limiting toxicity. Further studies are warranted to explore the role, optimal dose of medical cannabis, in the management of GVHD.

Pediatric Acute Gvhd: Transcriptome Analysis of Gastrointestinal Biopsies Reveal a Unique Signature in Pediatric Acute GI Gvhd with Involvement of the ERK Pathway and Similarities with Pediatric Inflammatory Bowel Disease

<h3>Introduction</h3> Studies of target organs at the time of acute graft versus host disease (GVHD) are needed to identify novel inflammatory and regulatory pathways. <h3>Methods</h3> We performed a prospective transcriptome analysis of gastrointestinal (GI) biopsies at diagnosis of acute GI GVHD and compared these to bone marrow transplant (BMT) patients without GVHD. Allogeneic BMT patients ≥2 years old undergoing endoscopy for clinical indications had 2 additional rectosigmoid mucosal biopsies for transcriptome analysis. Transcriptome data from 211 ulcerative colitis (UC) patients were included to uncover genes and pathways shared between GVHD and UC. Rectal biopsies from 20 children without inflammatory bowel disease (IBD) served as controls. <h3>Results</h3> Twenty-one patients underwent endoscopy pre (n=5) or post BMT (n=16). Median age of patients was 13.5 years (range 4.5 -25 years). Four patients were excluded from analyses (pre BMT colitis n=3, no lower GI biopsy n=1). Nine patients had acute GI GVHD, while 8 patients did not (Table 1). Principal component analysis shows patient clustering of those with and without GVHD, suggesting distinct transcriptomic mechanisms driving disease (Figure 1A). We identified 1310 significant genes, 144 of which were downregulated and 1266 upregulated in acute GVHD compared to no GVHD (Figure 1B). Top upregulated biological processes in GVHD revealed an innate antimicrobial response and associated cytokine signaling, notable for interferons. Top 20 differentially expressed genes in acute GVHD (Table 2), include CXCL9, CXCL10 and CXCL11, which are chemokines involved in GVHD, and IDO1 which regulates tryptophan metabolism. Four hundred and ninety shared genes were upregulated, and 126 genes were downregulated in GVHD and UC. Notable shared downregulated pathways involved butyrate metabolism (Table 3). DUOXA2, a gene involved in regulating innate antimicrobial responses in IBD, was the top upregulated genes in pediatric IBD and was the second highest differentially expressed gene in the acute GVHD, providing additional rationale for intestinal microbiome modulation in both diseases. Genes involving the ERK1/2 cascade (Table 4) were upregulated in acute GVHD (p=1.67 × 10 ⁻³) providing rationale for exploring ERK1/2 inhibition as novel acute GVHD treatment. <h3>Conclusions</h3> Acute GI GVHD has a distinct transcriptome signature which includes pathways of innate antimicrobial responses highlighting the role for microbiome modulation. The ERK1/2 cascade pathway is upregulated, suggesting a novel target in acute GI GVHD. Acute GI GVHD has important similarities with the UC transcriptome, including upregulation of DUOXA2 and downregulation in butyrate metabolism in both.

Prevention and Treatment of Acute Graft-versus-Host Disease in Children, Adolescents, and Young Adults.

Acute graft-versus-host disease (GVHD) continues to be a major cause of morbidity and mortality after allogeneic hematopoietic cell transplant (HCT) in pediatric patients (ie, children and adolescent and young adults) and limits broader application of the therapy. Pediatric HCT patients have faced major obstacles to access clinical trials that test new agents for GVHD prevention and treatment. According to a recent search, only 6 clinical trials of interventions for prevention or treatment of acute GVHD were conducted specifically in pediatric patients in the United States over the past decade, with 8 internationally. In this review, we summarize the studies that were performed and specifically enrolled and reported on pediatric patients after allogeneic HCT and provide a listing of studies currently under way.

The CELLEX is comparable to the UVAR-XTS for the treatment of acute and chronic graft versus host disease (GVHD).

Two extracorporeal photopheresis (ECP) instruments, the CELLEX and the UVARXTS are currently being used "off-label" in the US for treatment of graft versus host disease (GVHD). Our study compared the performance of the two instruments in the setting of acute and chronic GVHD. We retrospectively analyzed the outcomes of patients with steroid refractory or steroid resistant GVHD undergoing ECP at Barnes Jewish Hospital. Multivariate logistic regression was used to evaluate the comparative efficacy of the two instruments with respect to steroid dose reduction (≥50% from baseline) and clinical improvement in GVHD. Chi-square/Fisher exact tests were used to compare the incidence of adverse events, while multivariate Cox regression was employed to assess a potential difference in mortality between the two instrument treatment cohorts. After adjusting for potential confounders, there was no significant difference in the odds of steroid dose reduction (OR = 1.41, 95% confidence interval [CI]: 0.51-3.90, p = 0.50) or clinical improvement (OR 2.0, 95% CI: 0.63-6.41, p = 0.24) between the two instrument treatment cohorts. The frequency of adverse events (CELLEX 45.4%; UVAR XTS 40.5%, p = 0.55) was also comparable between the cohorts. There was no significant difference in mortality of either acute or chronic GVHD patients when treated by the CELLEX as compared to the UVAR-XTS (aHR 0.66, 95% CI: 0.35-1.25, p = 0.20). The efficacy and safety of the two ECP instruments, the CELLEX and the UVAR-XTS, are comparable for the treatment of acute and chronic GVHD.