Diagnosis Of GVHD Research Articles

Healthcare Resource Utilization and Costs of Steroid-Associated Complications in Patients With Graft-Versus-Host Disease

Acute and chronic graft-versus-host disease (aGVHD/cGVHD) are serious conditions occurring after allogeneic hematopoietic cell transplantation (HCT). Steroids are the most common first-line therapy; however, they are frequently associated with numerous morbid complications. To describe the healthcare resource utilization (HCRU) and costs of steroid-related complications in patients receiving systemic steroids for GVHD. This retrospective study used medical and pharmacy claims from the Optum Research database. Eligible patients were diagnosed with GVHD (aGVHD, cGVHD, or both) after HCT and were treated with systemic steroids between July 1, 2010, and August 31, 2019. The index date was the date of the first claim for systemic steroids after GVHD diagnosis. The baseline period was the 6 months before the index date, and the follow-up period was 2 years after the index date. Outcome variables included HCRU and costs associated with steroid complications, grouped into 4 categories: bone/muscle, gastrointestinal, infection, and metabolic/endocrine. A multivariate analysis was used to assess the cost ratio associated with the presence of each steroid complication; the linear model was adjusted for baseline patient characteristics and types of steroid conditions identified during follow-up. Another multivariate analysis assessed the hazard ratio for hospitalization associated with each steroid complication using a Cox proportional hazards regression model adjusted for the time-varying presence of each complication category. A total of 689 patients were studied (median age, 55 years; male, 60%); 22% had aGVHD only, 21% had cGVHD only, and 39% had both types of GVHD. After 2 years of follow-up, 97% had at least 1 steroid-associated complication. The most common complication category was infection (79.5%), followed by metabolic/endocrine (32.4%), gastrointestinal (29.2%), and bone/muscle conditions (19.7%). About two thirds (66%) of patients with any steroid complication had ≥1 hospitalization requiring a median (interquartile range [IQR]) of 20 (8-43) hospital days. Patients with an infection experienced the highest hospitalization rate (72%) and thus the highest associated costs. The total mean (median [IQR]) healthcare cost potentially related to steroid complications was $164,787 ($50,834 [$8865-$182,693]), and the largest expense was hospitalization (mean [median {IQR}], $140,637 [$26,782 {$0-$141,398}]). Of the different steroid complications, infections were associated with the highest cost (mean [median {IQR}], $167,473 [$57,680 {$16,261-$178,698}]). In addition, a significantly higher total adjusted cost was associated with the presence of an infection, gastrointestinal complication, or bone/muscle complication in patients with GVHD versus the absence of each complication (all P < .001). Complications occurring after steroid treatment for GVHD may add substantially to the HCRU and costs associated with GVHD management. Infections in particular required inpatient care and were associated with the highest economic burden.

Non-Invasive Diagnosis of Pediatric Intestinal Graft-Versus-Host Disease: A Case Series

Intestinal graft-versus-host disease (I-GvHD) represents a life-threatening complication in allogeneic stem cell transplantation (SCT). Unfortunately, non-invasive validated diagnostic tools to diagnose I-GvHD, evaluate treatment response, and guide the duration of immunosuppression are still lacking. We employed standard ultrasound and power Doppler to diagnose and follow up on pediatric intestinal GvHD. We herein report on three patients, prospectively evaluated among 24 pediatric patients referred to our center for allogeneic SCT. These three patients presented abdominal pain and diarrhea within the first 200 days after transplantation. In the reported cases, we performed small- and large-intestine ultrasound (US) at clinical onset of lower-intestinal symptoms and, when intestinal GvHD was confirmed, at GvHD flares, if any, and at follow-up. US constantly (3/3 patients) revealed increased bowel wall thickening (BWT) with different bowel segments’ involvement from patient to patient. Further, a moderate or strong increased Doppler signaling was seen in 2 out of 3 patients, according to clinical GVHD staging (e.g., the more the increase, the more the staging). Standard sonography corroborated GvHD diagnosis in all patients considered and was able to detect GvHD progression or complete normalization of findings, thus simplifying ensuing clinical decisions. Our report highlights the need to design clinical trials for the validation of non-invasive radiologic tools for diagnosis and follow-up of GvHD, especially in pediatric patients.

Transplant Associated Thrombotic Microangiopathy (TA-TMA) Commonly Occurs after Steroid-Refractory or Dependent Gastrointestinal (GI) Graft Versus Host Disease (GVHD) and Contributes to Post-Transplant Morbidity

Background: Hematopoietic cell transplantation associated thrombotic microangiopathy (TA-TMA) shares common features with atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. TA-TMA affects multiple organ systems resulting in multi-organ failure and non-relapse mortality. Recently, complement activation has been shown to be associated with TA-TMA leading to utilization of complement blockade as a therapeutic intervention in TA-TMA. We sought to evaluate the incidence of TA-TMA in patients with GVHD. We hypothesized that patients with gastrointestinal (GI) GVHD with transfusion dependence and renal dysfunction have a concomitant diagnosis of TA-TMA and that this contributes to worse outcomes.Methods: We performed a retrospective review of 124 patients with grade 3/4 GI GVHD admitted October 2008-October 2016. Patients who did not achieve a response by 7 days of 2mg/kg steroids were defined as steroid-refractory and patients who had flare of GVHD symptoms requiring a second course of 2mg/kg steroids were defined as steroid-dependent GVHD. We collected transplant-related data, number of hospitalizations, infections, length of stay and number of platelet/ pRBC transfusions. We assigned patients to groups by likelihood of TA-TMA based on presence of two out of three criteria: (1) > 2 transfusions after first GI biopsy, (2) evidence of hemolysis (schistocytes or nucleated RBCs) with negative Coombs' test and (3) evidence of renal dysfunction. 29/124 patients had paired samples for measurement of complement activation at time of GVHD diagnosis and 2-6 weeks later. Markers of complement activation included C5a and C5b-9 (terminal complement pathway), C4d (Classical pathway), and BBPlus (Alternative pathway).Results: The median age at transplant was 54 years (19-72) and 40.3% were female. Reduced intensity or non-myeloablative conditioning was used in 66.1% of patients and all but 10 patients received tacrolimus. The median time to GVHD onset was 38 days (range: 12-273).TA-TMA and GVHD. A total of 84 (67.7%) subjects met at least 2 criteria for TA-TMA. TA-TMA typically occurred after GVHD at a median of 142 days post-transplant and 78 days post-GVHD. The median time to GVHD was 38 days (12-273). Patients with steroid-refractory GVHD received more platelet and pRBC transfusions than those with steroid-responsive GVHD (p = 0.0018 and 0.0068, respectively) at 2 and 4 weeks post GVHD diagnosis (Figure 1). Patients with steroid-refractory or dependent GVHD were more likely to develop TA-TMA than those with steroid-responsive GVHD. Regardless of responsiveness of GVHD to steroids and accounting for differences in follow-up, patients with TA-TMA had longer length of hospital stay (median: 53 v. 25.5 days, p < 0.001) than patients without TA-TMA.Post-transplant infections in all patients included CMV reactivation (46.8%), other viral infection (60.5%), fungal infection (12.1%), and bacterial infection (65.3%). Renovascular complications included new or worsening hypertension (18.6%), acute kidney injury (45.2%), need for hemodialysis (16.9%), and proteinuria >30mg/dL (75.8%). In multivariable analysis, the risk factors for developing TA-TMA from time of transplant included acute GVHD, viral infection other than CMV, and fungal infection (Table 1).At 2-4 weeks after GVHD diagnosis, differential upregulation of alternative pathway (BBPlus) was seen in patients who went on to develop TA-TMA. It is notable that no differences in complement activation were seen at initial GVHD diagnosis, suggesting that TA-TMA appears to be a secondary event that follows GVHD.Discussion: We show that GVHD is a risk factor for development of TA-TMA and that patients with steroid-refractory/dependent GVHD are more likely to have TA-TMA than steroid-responsive patients. Patients with both GVHD and TA-TMA receive more transfusions and have longer hospitalizations than those with GVHD alone. Our work suggests that the alternative complement pathway (BBPlus) is upregulated in patients with GVHD and TA-TMA, suggesting that complement blockade may be evaluated as a therapeutic strategy in these patients. Prospective study is warranted to understand the triggers of TA-TMA in patients with GVHD, particularly the role of viral and fungal infections and whether complement biomarkers could differentiate between steroid-responsive and steroid refractory/dependent GVHD. [Display omitted] DisclosuresWilliam:Miragen: Consultancy, Honoraria. Blum:Pfizer: Consultancy; Boerhinger Ingelheim: Research Funding; Astellas: Consultancy. Jaglowski:Pharmacyclics: Consultancy, Research Funding. Mims:Novartis: Honoraria. Brammer:Celgene: Research Funding. Hofmeister:Karyopharm: Research Funding; Roche: Research Funding; Janssen: Research Funding; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Research Funding. Walker:Gilead: Research Funding. Vasu:Stemline Therapeutics: Research Funding; Boehringer-Ingelheim: Research Funding.

Direct Costs in 4-Years Post Allogeneic Transplant Follow-up: A Comparative Analysis of 15 Matched Patients with and without GvHD

BackgroundGraft versus Host Disease (GvHD) still represents a major complication in allogeneic hematopoietic cell transplantation (HSCT) and a primary cause of non-relapse mortality.GvHD, together with rejection and fungal infection, not only has been demonstrate to have a relevant impact in clinical outcome and quality of life but it is also associated with important direct costs during follow-up. Despite the relevance of this topic, so far there have been very few investigations and publications regarding the cost of HSCT in a long term perspective.MethodsTo address the evaluation of direct costs of GvHD, we retrospectively selected 15 patients who underwent HSCT in our Center for hematological diseases between 2009 and 2015. Patients were collected in 3 groups: no GvHD (Group A), chronic GvHD (Group B) and acute GvHD (Group C, 3/5 developed also chronic GvHD).Those three groups were matched for known risk factors for outcome: conditioning regimens, GvHD prophylaxis, anti-infective prophylaxis, source of graft and donor selection according to Institutional policy.We retrospectively collected parameters relevant for clinical course and direct costs: viral monitoring and reactivations, time of anti-infective prophylaxis and treatments, number of transfusions, days of hospitalization, number of outpatient clinical evaluations. GvHD treatment was also listed. All these parameters were monitored from discharge after HSCT procedure or after GvHD diagnosis, whichever occurred first. Finally all these parameters were compared between the three groups.ResultsDiagnosis at time of HSCT was acute myeloid leukemia (10 out of 15 cases); only one patient was transplanted for non-malignant disease. Five patients were transplanted from unrelated donor, four from matched siblings and six from haploidentical donors; peripheral blood was graft source in 14/15 and bone marrow in 1/15.Per group evaluation of relevant factors for direct cost of HSCT is reported in Table 1.In Group A (no GvHD) we documented lower re-hospitalization need, fewer out-patient clinical evaluations, shorter time of immunosuppressive treatment, lower incidence of infection and reduced need of anti-infective treatment.In Group B (chronic GvHD) and Group C (acute GvHD +/- chronic GvHD) we documented higher re-hospitalization need, more out-patient clinical evaluations, longer time of immunosuppressive treatment (4/9 pts still under active treatment at a median follow-up of 49 months), higher incidence of infection and higher need of anti-infective treatment.Differences are even more significant if patients from Group B and Group C are pooled and re-classified in Group D (complete GvHD resolution and withdrawal of immunosuppressive treatments) and Group E (pts with active GvHD still under immunosuppressive treatments at last FU).ConclusionsSignificant differences in events and direct costs are registered in 4-year follow-up period in patients with or without GvHD. Additionally, more relevant differences can also be documented in patients achieving a rapid response of GvHD and those requiring more than 2 lines of immunosuppressive treatments. These events computation represent the basis for direct costs calculation according to actual prices of drugs, examinations and procedures.Impact of new therapies for GvHD prevention and treatment should be balanced according to direct costs evaluation in patients experiencing severe acute and chronic GvHD. [Display omitted] DisclosuresMarktel:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Ciceri:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding.

Immune Reconstitution after Allogeneic Stem Cell Transplantation - a Systematic Single Center Survey

The renewal of the immune system after allogeneic hematopoietic stem cell transplantation (HSCT) is a complex process not fully understood. Recently, the use of reduced intensity conditioning (RIC) regimens, new anti-viral drugs and intensified GvHD treatment changed the landscape of allogeneic transplantation. Here, the influence of several parameters on the development of the cellular and humoral immunity of 136 patients consecutively transplanted in a single center was analyzed.All adult patients transplanted during a period of three years (September 2010 to August 2013), were analyzed in respect of immunoglobulin levels with the turbidimetric method, serum electrophoresis, immunofixation and lymphocyte subset counts by flow cytometry. Also the occurrence of a monoclonal/biclonal gammopathy was reported. In addition, we looked for donor chimerism, B and T cell receptor repertoire of peripheral blood samples. Most patients received a reduced conditioning regimen; nearly all patients received either anti-thymoglobulin (ATG) or alemtuzumab (25/136 matched related donors) leading to a relatively low rate of chronic GvHD (40%). The immune parameters obtained one year after stem cell transplantation were correlated with relevant factors of stem cell transplantation, namely the conditioning regimen, diagnosis, relapse rate, age, sex and history of CMV infection, acute and chronic GvHD using Pearson correlation, t-test and regression analysis (SPSS).A normal CD4/CD8 ratio at day 360 after HSCT was only seen in 14% of evaluable patients, while it was reduced in 83%. This was mainly due by an impaired CD4 cell count while the CD8 cell count was even increased in 42%. The CD8 cell count was significantly higher in patients after CMV infection (p<0.001) and in those not receiving alemtuzumab as part of the conditioning regimen (p=0.003). The IgG level was normal in 51%, reduced in 31% and increased in 17 % of tested patients. The IgG level correlated with a history of CMV infection, NK, CD4, and CD8 cell count (all p≤0.025); but age, sex, diagnosis, relapse, use of RIC, acute and chronic GvHD had no significant impact. The development of a new clonal gammopathy was found in 18 patients after undergoing a HSCT and was in nearly all cases reversible. Interestingly, this was associated with chronic GvHD (p=0.034), but not any of the other parameters.Almost all patients show a compromised immune system one year after allogeneic stem cell transplantation mainly characterized by an inverted CD4/CD8 ratio. Whether an increased CD8 cell count may not only reflect the response to viral infections but in some cases improved immunosurveillance, is hard to document. Interestingly, the immunoglobulin levels are highly variable ranging from antibody deficiency to hypergammaglobulinemia positively correlating with CMV reactivation. Continuous disbalanced immunoreactivity indicated by clonal gammopathy was associated with chronic GvHD. The systematic evaluation of these basic immune parameters may lead to better therapeutic guidance in patients after allogeneic HSCT. DisclosuresNo relevant conflicts of interest to declare.

Mucosal Foxp3+ Regulatory T Cells Show Significant Numerical Differences in Patients with Intestinal Graft-Versus-Host Disease Compared to Infectious Diseases of the Gut.

Objectives: The clinical diagnosis of intestinal GvHD is often complicated, even if bioptical material is present. So far, it is difficult to separate between GvHD and infectious complications, since distinguishing immunological features are not established. In a multicenter study, we quantified Foxp3+ immunoregulatory T cells (Treg) and effector T cells in the intestinal mucosa of patients with acute or chronic GvHD, and infectious diseases of the gut.Methods: 95 paraffin-embedded tissue samples (44 with acute GvHD, 18 with chronic GvHD and 33 without histological GvHD) derived from intestinal biopsies from 49 patients undergoing allogeneic stem cell transplantation, and 12 inflammatory controls (6 patients with CMV-colitis and 6 with diverticulitis) were analysed by double immunoenzymatic labeling. Serial sections were stained for CD4, CD8 and co-stained for CD3/Foxp3 and CD25/Foxp3. In addition, lamina propria lymphocytes were isolated from intestinal biopsies by collagenase digestion and further characterized by flow-cytometry in comparison to peripheral blood lymphocytes in 24 patients with suspected GvHD after allogeneic stem cell transplantation and healthy controls.Results: The number of CD3+ T cells was extensively increased in intestinal GvHD, CMV colitis and diverticulitis. Though the number of CD8+ cells was similar, we saw striking differences in the frequency of Foxp3+ Treg in relation to CD8+ effector T cells. The number of Foxp3+ T cells per 100 CD8+ T cells was significantly lower in GvHD samples (1.7 ± 0.2) than in CMV colitis (27.4 ± 2.5) or diverticulitis (50.0 ± 4.4). Within the allogeneic transplanted patients, samples without histological signs of GvHD had also significantly elevated numbers of Foxp3+/100 CD8+ T cells (14.1 ± 2.0) compared to acute (1.7 ± 0.2) and chronic GvHD (2.9 ± 0.8) and healthy controls (2.0 ± 0.3).Conclusion: In contrast to infectious diseases of the gut, GvHD is characterized by a considerable decrease of mucosal Treg cells. Together with recent experimental data, our results give new insights in the pathophysiology of intestinal GvHD and can be helpful for the precise diagnosis of intestinal complications after allogeneic stem cell transplantation.

Prospective longitudinal evaluation of microbiome diversity in patients with hematological malignancy undergoing allogeneic hematopoietic stem cell transplantation (HSCT).

7005 Background: Studies suggest that decreased microbial diversity due to chemotherapeutic and antibiotic exposure may be associated with acute graft vs host disease (aGvHD) and mortality in patients undergoing allogeneic HSCT. In addition, disruption of the microbiome by antibiotics may lead to intestinal domination by pro-inflammatory bacteria, resulting in increased risk of aGvHD. This relationship has been described in settings with prophylactic antibiotic use, a standard of care in most transplant centers. Here we assessed how the microbiome and GvHD outcomes differ when prophylactic use of antibiotics is avoided. Methods: We collaborated on an observational study (COLLECT) to evaluate changes in microbial diversity over time in subjects undergoing allogeneic HSCT. According to protocol at the University Hospital of Cologne, antibiotics were administered only as empiric treatment for febrile neutropenia or as targeted treatment. Stool was collected weekly from 65 subjects at baseline (pre-HSCT) to day 28 with additional time points taken at day 56, day 90, day 365, and upon diagnosis of intestinal GvHD (GvHD-day 0 and GvHD-day 7). Patients were monitored for incidence of GvHD, including acute GvHD of the liver, intestine, and skin. Microbiome 16SV4 profiles were generated from 381 stool samples. Linear effects models were developed to evaluate the association between Shannon diversity, intestinal domination, and the incidence of intestinal GvHD and mortality. Results: Of the 65 subjects, 28 subjects (42%) went on to develop intestinal GvHD, and 16 subjects (25%) did not survive to day 365. A decline in Shannon diversity was observed during the neutropenic period following HSCT. Subjects who went on to develop intestinal GvHD had significantly lower Shannon diversity at the time of stem cell engraftment (p &lt; 0.0468). Furthermore, lower diversity was observed throughout the study period in subjects experiencing intestinal GvHD. We developed a linear model evaluating the association between mortality and Shannon diversity and found a significant relationship at days 28 and 90 post HSCT (p &lt; 0.0001 and 0.0121, resp). Intestinal domination by Enterobacteriaceae or Enterococcus was significantly associated with the incidence of intestinal GvHD (p &lt; 0.0082) or mortality (p &lt; 0.001), respectively. Conclusions: Data from this observational study (COLLECT) suggests decreases in microbial diversity over time occur in subjects undergoing allogeneic HSCT despite the lack of prophylactic antibiotics. Investigation of whether administration of microbiome therapeutic drugs prior to transplant and/or at the time of engraftment can reduce morbidity and mortality in this high-risk patient population is warranted. Clinical trial information: NCT03148197.

Utility of capsule endoscopy in the diagnosis of gastrointestinal graft-versus-host disease

Introduction and aimGraft-versus-host disease (GvHD) is a complication of hematopoietic cell transplantation, and the small bowel is one of the main targets in the gastrointestinal tract. Capsule endoscopy is a safe procedure and can be useful in the diagnosis of GvHD. The aim of the present study was to compare the diagnostic yield of capsule endoscopy with the histopathologic findings in GvHD. Materials and methodsA retrospective diagnostic test study included all the patients with suspected GvHD that underwent gastroscopy and colonoscopy, with histopathologic evaluation of the biopsies taken, and capsule endoscopy, within the time frame of July 2015 and July 2019. Capsule endoscopy findings were compared with the histopathologic diagnosis, considered the gold standard. ResultsTwenty-one patients with GvHD (7 [33%] women; 37 ± 11.9 years of age) were included, 20 (95%) of whom had acute GvHD. The median gastric transit time of the capsule was 55 minutes (20-113) and the median small bowel transit time was 261 minutes (238-434). The entire small bowel was visualized through capsule endoscopy in 17 cases (80.95%). The histopathologic findings and capsule endoscopy findings resulted in the diagnosis of GvHD in 17 and 16 cases, respectively. There was agreement between the histopathologic and capsule endoscopy findings in 18 cases (15 positive and 3 negative). Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic yield of capsule endoscopy were 88%, 75%, 94%, 60%, and 85%, respectively. ConclusionsCapsule endoscopy is a safe tool for the diagnosis of GvHD, with high sensitivity and positive predictive value, as well as moderate agreement with histopathologic findings.

Unusual presentation of toxoplasmosis with gastro‐intestinal involvement in HLA non‐identical stem cell transplantation

Toxoplasmosis is a life-threatening infection in allogenic stem cell recipients usually involving the brain or retina and more rarely lungs or bone marrow. Digestive involvement has only been reported in AIDS patient. We report about a 38-year-old man who received a haploidentical allograft for acute myeloid leukemia and developed an unusual digestive presentation with severe protein-losing enteropathy following grade III acute digestive GvHD treated with steroids and ruxolitinib. Diagnosis was brought up because of concomitant brain involvement. Digestive symptoms fully recovered after treatment with sulfamethoxazole-trimethoprim. Digestive toxoplasmosis could be considered as a differential diagnosis or complication of severe digestive GvHD.

α4β7 Integrin expression and blockade in pediatric and young adult gastrointestinal graft-versus-host disease.

We hypothesized that α4β7 integrin expression on effector memory T cells (TEMs) would be elevated in pediatric hematopoietic stem cell transplant (HSCT) patients before and at diagnosis of acute gastrointestinal graft-versus-host disease (GI GVHD) symptoms compared to patients without GVHD, and that clinical blockade of α4β7 integrin with vedolizumab would be effective in pediatric GI GVHD. We analyzed surface expression of α4β7 integrin on T cells from 48 pediatric allogeneic HSCT recipients from our biorepository with known clinical outcomes as follows: acute GI GVHD (n=22), isolated skin GVHD (n=12), and no GVHD (n=14). T-cell analyses were performed 1week before and at GVHD diagnosis in patients with GVHD, and day +30 after HSCT in patients without GVHD. We describe clinical outcomes of seven additional patients, different from above-described 48 patients, who received vedolizumab (anti-α4β7 integrin antibody) for the treatment of steroid-refractory acute GI GVHD. Expression of α4β7 integrin on CD8+ TEMs was upregulated in patients with GI GVHD compared to the no GI GVHD (skin GVHD + no GVHD) group 1week prior to clinical symptoms (p=.02) and at acute GI GVHD diagnosis (p=.05). Four of seven treated patients with clinical steroid-refractory acute GI GVHD were evaluable for response to vedolizumab. One patient had a complete response at day +28, while two had a partial response, and one had no response. No adverse effects directly attributable to vedolizumab were observed. Our data suggest a rationale for the blockade of α4β7 integrin for acute GI GVHD management in children.

DIAGNOSIS AND TREATMENT OF GVHD

THE BRAZILIAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION (SBTMO) PRESENTS THE BRAZILIAN GUIDELINES ON HEMATOPOIETIC STEM CELL TRANSPLANTATION

Glycolytic metabolism of pathogenic T cells enables early detection of GVHD by 13C-MRI

AbstractGraft-versus-host disease (GVHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (AHSCT). Definitive diagnosis of GVHD is invasive, and biopsies of involved tissues pose a high risk of bleeding and infection. T cells are central to GVHD pathogenesis, and our previous studies in a chronic GVHD mouse model showed that alloreactive CD4+ T cells traffic to the target organs ahead of overt symptoms. Because increased glycolysis is an early feature of T-cell activation, we hypothesized that in vivo metabolic imaging of glycolysis would allow noninvasive detection of liver GVHD as activated CD4+ T cells traffic into the organ. Indeed, hyperpolarized 13C-pyruvate magnetic resonance imaging detected high rates of conversion of pyruvate to lactate in the liver ahead of animals becoming symptomatic, but not during subsequent overt chronic GVHD. Concomitantly, CD4+ T effector memory cells, the predominant pathogenic CD4+ T-cell subset, were confirmed to be highly glycolytic by transcriptomic, protein, metabolite, and ex vivo metabolic activity analyses. Preliminary data from single-cell sequencing of circulating T cells in patients undergoing AHSCT also suggested that increased glycolysis may be a feature of incipient acute GVHD. Metabolic imaging is being increasingly used in the clinic and may be useful in the post-AHSCT setting for noninvasive early detection of GVHD.

Epidemiology and Treatment of Chronic Graft-versus-Host Disease Post-Allogeneic Hematopoietic Cell Transplantation: A US Claims Analysis

Chronic graft-versus-host disease (cGVHD) is a complication of hematopoietic cell transplantation (HCT). Although the clinical outcomes of cGVHD are well documented, few studies have assessed treatment practices outside of clinical trials. The present study aimed to quantify the prevalence of cGVHD, examine provider prescribing patterns, and evaluate the healthcare cost and resource utilization (HCRU) in a US cGVHD population. We analyzed anonymized claims from the Medicare Fee-for-Service (FFS) 5% sample for beneficiaries enrolled between 2013 and 2016 and PharMetrics commercial 2013 to 2018 databases to identify cGVHD in allogeneic HCT recipients. cGVHD was identified based on International Classification of Diseases Ninth/Tenth Revision diagnosis codes for cGVHD or unspecified GVHD with a first diagnosis >180 days post-HCT or a maintained unspecified GVHD diagnosis for >12 months postindex of unspecified GVHD diagnosis. Longitudinal and line of therapy (LOT) analyses were based on the PharMetrics dataset for 2013 to 2018. Healthcare costs were calculated by adding the inpatient, outpatient, and pharmacy insurer and beneficiary paid amounts for the commercially insured population. Total HCRU was assessed using the number of inpatient and outpatient visits following the initial cGVHD diagnosis. In 2016, the projected prevalence of cGVHD in the United States based on the Medicare FFS and PharMetrics commercial databases was 14,017 individual patients. Within 3 years after undergoing allogeneic HCT, 42% of patients developed cGVHD; 66% of the cGVHD patients had a prior diagnosis of acute GVHD. The majority of cGVHD patients received at least one systemic therapy; 71% and 47% of cGVHD patients progressed to a second and third LOT, respectively. A total of 24 unique therapeutic agents and more than 150 combinations were used in the second and third LOTs. Corticosteroids and corticosteroid combination therapy were the most common forms of treatment across all examined LOTs. Furthermore, the most commonly used agents in the first LOT, second LOT, and third LOT were corticosteroids only, calcineurin inhibitors only, and corticosteroids only, respectively. In the 12 months postdiagnosis, cGVHD patients had an average of 21.0 cGVHD-related inpatient and outpatient visits (2.8 inpatient and 18.2 outpatient visits). A significant proportion of allogeneic HCT recipients continue to develop cGVHD, and despite advances in the understanding of cGVHD, corticosteroids remain the mainstay of therapy. Patients often progress beyond the first LOT, at which time the utilization of systemic therapies is highly variable, demonstrating the need for evidence-based treatment approaches.

Vedolizumab for Steroid Refractory Lower Gastrointestinal Tract Graft Versus Host Disease

Vedolizumab for Steroid Refractory Lower Gastrointestinal Tract Graft Versus Host Disease

Efficacy and Toxicity Profile of Investigational Monoclonal Antibodies for the Treatment of Acute Gvhd

Introduction: Acute graft versus host disease (aGVHD) carries high morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Corticosteroids remain the mainstay treatment approach for aGVHD, with limited efficacy (≤50%). Different treatment modalities have been studied to improve outcomes. Monoclonal antibodies (mAb) are currently being tested, especially for steroid-refractory (SR) aGVHD. Methods: A comprehensive literature search, from 2015 to 2020, was performed using Medline, Embase, and Cochrane. MeSH terms and keywords were HSCT, acute GVHD, and monoclonal antibodies. PRISMA guideline was used for study selection. Results: A total of 11 studies were identified, including 241 patients. Extracted outcomes were depicted in Table 1. Ten studies included patients with SR aGVHD (n=221), with most of them having GI involvement. Most of the patients had ≥grade III-IV aGVHD and concomitant organ involvement. Most of the studies continued systemic steroids and gradually tapered based on the therapy responses. Natalizumab: In a phase II trial, 20 patients with newly diagnosed lower GI aGVHD received natalizumab along with methylprednisone. 55% of the patients had grade III-IV. The overall response rate (ORR) was 62% at day 56, and overall survival (OS) was 52% at six months. GVHD free survival was 37.5% on day 56, and two patients died from GVHD. Vedolizumab: Four studies evaluated vedolizumab in SR GI aGVHD patients (grade ≥III-IV). In a study of 29 patients, durable responses were reported; ORR and complete response (CR) were 64% and 28% at day 56, respectively. Overall survival (OS)was 47% at 12 months. In this study, patients received vedolizumab as a 2nd line. Another study, n= 29 patients, also showed positive results with ORR of 79% with CR 28%. OS at 12 months was 27.5%. The other two small studies, however, reported low response rates with high mortality. Remarkably, in these studies, vedolizumab was given as a 4th or 5th line. Brentuximab vedotin: Ina phase I study, n= 34 SR aGVHD patients (70% grade ≥III-IV) demonstrated ORR of 38% at day 28. OS was 41% at six months, and 38% at 12 months. In this study, dose revision was made (from 0.6 mg/kg weekly to 0.6-0.8 mg/kg every-2-weekly) after deaths due to neutropenic sepsis. Begelomab: A phase I/II study evaluated 28 patients with SR aGVHD. All patients had gut, skin, and liver involvement before the therapy (75% grade III-IV).ORR at day 28 was 75%, CR 11%, and OS was 50% at 12 months. Patients received begelomab within the 13 days from the diagnosis of GVHD after failing one previous line. A compassionate use study including 41 patients demonstrated ORR of 61% on day 28 and CR of 12%. OS at 12 months was 33%. For this group, begelomab was given after 1-4 lines of previous therapies. Tocilizumab: A study of 16 patients with GI aGVHD (94% of grade ≥III-IV) demonstrated ORR of 69%, CR rate of 62.5%, and median OS of 7.6 months. However, only three patients remained GVHD-free after discontinuation of tocilizumab. In a small retrospective study of 15 patients, 40% of patients achieved CR with a resolution of aGVHD. Patients with liver aGVHD did not respond. A durable response was not achieved for nine patients. Conclusion: Monoclonal antibodies for the treatment of aGVHD show encouraging results. Responses appear to be related to the duration and timing of the therapy, GVHD severity, organ involvement, and the number of previous lines of therapy received. Large prospective clinical trials are needed to further solidify the role of monoclonal antibodies in aGVHD treatment. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Visualization of Activated T Cells by OX40-ImmunoPET as a Strategy for Diagnosis of Acute Graft-versus-Host Disease.

Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT), mediated primarily by donor T cells that become activated and attack host tissues. Noninvasive strategies detecting T-cell activation would allow for early diagnosis and possibly more effective management of HCT recipients. PET imaging is a sensitive and clinically relevant modality ideal for GvHD diagnosis, and there is a strong rationale for the use of PET tracers that can monitor T-cell activation and expansion with high specificity. The TNF receptor superfamily member OX40 (CD134) is a cell surface marker that is highly specific for activated T cells, is upregulated during GvHD, and mediates disease pathogenesis. We recently reported the development of an antibody-based activated T-cell imaging agent targeting OX40. In the present study, we visualize the dynamics of OX40 expression in an MHC-mismatch mouse model of acute GvHD using OX40-immunoPET. This approach enabled visualization of T-cell activation at early stages of disease, prior to overt clinical symptoms with high sensitivity and specificity. This study highlights the potential utility of the OX40 PET imaging as a new strategy for GvHD diagnosis and therapy monitoring. SIGNIFICANCE: OX40-immunoPET imaging is a promising noninvasive strategy for early detection of GvHD, capable of detecting signs of GvHD pathology even prior to the development of overt clinical symptoms.

A Review on Therapeutic Management for Oral Chronic Graft-versus-Host Disease

Chronic graft-versus-host disease (cGVHD) is one of the main complications of transplantation in allogeneic hematopoietic cells which results in reduced quality of life. cGVHD mostly affects the oral cavity, producing various symptoms and manifestations. It can lead to both short- and long-term complications such as limited oral intake, mucosal sensitivity, secondary malignancy and even early death. GVHD is an alloimmune and autoimmune disorder with a variable clinical course that commonly involves various tissues and organs. It can occur in both the acute and chronic forms. In the case of cGVHD, a large number of organs are affected including the oral cavity. However, in some cases of cGVHD only the oral cavity gets affected. The clinical indications of chronic oral GVHD may include sclerosis, hyperkeratotic plaques, lichenoid lesions, and limited oral aperture. The level of oral involvement is commonly mild, but medium to high severity erosive as well as ulcerated lesions may also be occurred. Although diagnosed through clinical examination, its confirmation is usually done by biopsy study. The first treatment option is using local corticosteroids with the potency to treat half of patients. Extracorporeal photopheresis and systemic corticosteroids are in the next ranks. Patient survival after diagnosis of oral chronic GVHD is within 4.5 years in 50% of the cases, thus it is not regarded as a determinant factor in patient survival. This study attempted to provide a detailed approach for clinical diagnosis and management of patients suffered from oral cGVHD. It is particularly considered the factors such as differential diagnosis, symptom control, screening for and prevention of secondary complications. It has been tried to provide practical and relevant considerations and recommendations for all clinicians who dealswith oral cGVHD patients in order to achieve improved care and outcomes.

S2765 Autologous Graft vs Host Disease: An Unusual and Unexpected Cause of Bowel Obstruction

INTRODUCTION: Autologous-graft versus host disease (auto-GVHD) is an extremely rare entity comprising only 0.9% of cases of lymphoma patients undergoing autologous hematopoietic stem cell transplantation (HSCT). Although very uncommon, it can lead to serious complications including abdominal pain, rectal bleeding, and profuse diarrhea. We present a very rare case of auto-GVHD leading to small bowel obstruction. CASE DESCRIPTION/METHODS: A 39 year-old man with history of large B cell lymphoma underwent autologous-HSCT after treatment with R-CHOP and cyclophosphamide plus dexamethasone following a relapse. Days later developed fever, nausea, vomiting, abdominal pain and diarrhea. Laboratories showed leukopenia, thrombocytopenia, elevated liver enzymes and bilirubin. Tests for infectious diarrhea were negative. Colonoscopy showed elevated whitish lesions and diffuse loss of vascular pattern up to mid transverse and biopsies revealed marked crypt loss, regenerative atypia with rare apoptotic bodies. A diagnosis of auto-GVHD was entertained. Steroids were started and tapered off after clinical improvement. Months later there was worsening of symptoms associated with distended and tender abdomen with diminished bowel sounds. Abdominal CT scan showed ileal inflammation associated with small bowel dilatation. Colonoscopy showed a stricture at ileum with associated friable mucosa. Biopsy revealed chronic active ileitis and necrotic purulent material with associated ulcer, negative for CMV. Resection of ileal segment was performed and steroids given for 6 weeks. DISCUSSION: The differential diagnosis included auto-GVHD, lymphoma recurrence and Crohn's disease (CD). Lymphoma was unlikely given negative immunohistochemistry and PET scan. No classic endoscopic or histologic features of CD were observed. This led to a diagnosis of GVHD, a multisystem disorder that commonly complicates allogeneic-HSCT but is exceedingly rare in autologous-HSCT. The pathophysiology is unknown and establishing the diagnosis is a challenging task. The clinical presentation of Auto-GVHD is similar to allogeneic GVHD, with the skin, gastrointestinal tract and liver the principal target organs. It commonly begins with a maculopapular rash, diarrhea, hematochezia, abdominal pain, vomiting, and elevated liver tests. The diagnosis of auto-GVHD can be made on the basis of ongoing GI symptoms, endoscopic evidence of mucosal abnormalities, and histological findings of apoptotic epithelial cells or crypt cell dropout with lymphocytic infiltrate.Figure 1.: Elevated whitish lesions, loss of vascular pattern diffusely.Figure 2.: Glandular apoptosis and crypt cell drop out.

Acute and chronic graft versus host disease after hematopoietic stem cell transplant

Graft versus host disease is one of the main complications of Hematopoietic stem cell, in­volving about 50% to 80% of the patients. Acute GVHD clinical manifestations and therapy is discussed, as well as new NIH criteria for the diagnosis and classification of chronic GVHD. Therapy for both refractory chronic and acute GVHD is an important field of discussion once there is no superiority for the majority of the agents after primary therapy has failed. Hence, this review is meant to be a useful tool of consultation for clinicians who are dealing with this complex complication.

Graft-versus-host disease as an unusual complication following autologous stem cell transplantation

AbstractIntroductionGraft-versus-host disease (GVHD) is a common and serious complication after allogeneic stem cell transplantation (allo-SCT). However, a similar syndrome has been reported after autologous stem cell transplantation (ASCT) as well.Case reportA 61-year-old female diagnosed with immunoglobulin (Ig) G lambda multiple myeloma completed 10 cycles of bortezomib, thalidomide, and dexamethasone (VTD) and 2 cycles of cyclophosphamide, thalidomide, and dexamethasone (CTD). High-dose of melphalan (200 mg/kg) was given as conditioning, followed by an infusion of 2.5 × 106 CD34+ cells/kg. Three months later, she received her second ASCT. On Day +25 after tandem ASCT, the patient developed a maculopapular, itchy skin rash, which covered her face, trunk, and limbs. A skin biopsy was in line with the diagnosis of GVHD. The other organs were not involved. Treatment with systemic and local corticosteroids (CSs) resulted in the improvement of skin lesions, but the CSs were slowly tapered due to toxicity. In the following weeks, she developed symptoms of liver and gut involvement, which were resistant to steroids. The introduction of other immunosuppressive agents failed to achieve a response. As a consequence, she had cytomegalovirus (CMV) reactivation, as well as pancytopenia, and eventually, she died of infectious complications.ConclusionsGVHD after ASCT remains a rare but life-threatening complication with poor prognosis.