Steroid Refractoriness Research Articles

Development and Clinical Validation of Liquid Chromatography-Tandem Mass Spectrometry for Measuring Ruxolitinib in Steroid-Refractory Graft-Versus-Host Disease: A First Step Towards Optimized Treatment.

This non-interventional, prospective, single-center study aimed to develop a technique to measure ruxolitinib (RUX) concentrations and provide preliminary data on the distribution of plasma drug levels in patients with steroid refractory (SR) GvHD. Between April 2023 and May 2024, we analyzed 48 blood samples from 29 patients with SR-GvHD. Median individual plasma concentrations varied across different RUX doses and largely overlapped: 39.2 ng/mL at 10 mg b.i.d (range: 0-73), 13.1 ng/mL at 10-5 mg (range, 6.1-35.6), and 31.6 ng/mL at 5 mg b.i.d (range: 0.7-99.9). Samples taken under non-optimal temperature conditions showed a lower median concentration of 0.77 ng/mL (range: 0-7.4 ng/mL). The four patients who did not respond at days +28 and +180 after RUX initiation (3 with lower gastrointestinal aGvHD, and 1 with ocular, hepatic, and pulmonary cGvHD) showed a median concentration of only (7.4 ng/mL (range, 0-29) ng/mL) with full dosing. The introduction and validation of a liquid chromatography-tandem mass spectrometry method for quantifying plasma RUX concentrations was feasible in our center. Administering predetermined and fixed doses of RUX in patients with SR-GvHD showed highly variable and overlapping plasma drug concentrations. This underscores the potential importance of RUX- pharmacokinetics (PK) monitoring.

Impact of cytopenias and early versus late treatment with ruxolitinib in patients with steroid-refractory acute or chronic graft-versus-host disease.

REACH2 and REACH3 were randomized, multicenter, open-label phase 3 studies comparing the selective Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib versus investigators' choice of best available therapy (BAT) in steroid-refractory (SR) acute (REACH2) or chronic (REACH3) graft-versus-host disease (aGVHD/cGVHD). Moderate-severe aGVHD/cGVHD can progress rapidly; thus, key clinical considerations driving management of patients with SR-aGVHD/SR-cGVHD are prompt treatment initiation and concomitant cytopenias. These posthoc analyses of REACH2/REACH3 describe the impact of timing of treatment initiation after SR-aGVHD/SR-cGVHD diagnosis and development of concomitant cytopenias on treatment outcomes. Ruxolitinib initiation within 3 days from SR-aGVHD diagnosis yielded an extended duration of response and higher Day 28 complete response rates compared with initiation ≥7 days after SR-aGVHD diagnosis (median 178 vs 167 days and 36.6% vs 25.0%, respectively). For patients with SR-cGVHD, Week 24 overall response was not impacted by time to treatment (54.5% vs 42.6% for <14 vs >28 days). Clinically relevant cytopenias were manageable, allowing for maintenance of dose intensity (median 20 mg/d), and did not impact the favorable efficacy outcomes from ruxolitinib treatment. This analysis highlights the practical importance of considering earlier ruxolitinib initiation after SR diagnosis in GVHD and the benefits of ruxolitinib treatment compared with BAT even for patients with cytopenias.

Current Approaches for the Prevention and Treatment of Acute and Chronic GVHD.

Whereas aGVHD has strong inflammatory components, cGVHD displays autoimmune and fibrotic features; incidence and risk factors are similar but not identical; indeed, the aGVHD is the main risk factor for cGVHD. Calcineurin Inhibitors (CNI) with either Methotrexate (MTX) or Mycophenolate (MMF) still represent the standard prophylaxis in HLA-matched allogeneic stem cell transplantation (HSCT); other strategies focused on ATG, Post-Transplant Cyclophosphamide (PTCy), Abatacept and graft manipulation. Despite the high rate, first-line treatment for aGVHD is represented by corticosteroids, and Ruxolitinib is the standard second-line therapy; investigational approaches include Microbiota transplant and the infusion of Mesenchymal stem cells. GVHD is a pleiotropic disease involving any anatomical district; also, Ruxolitinib represents the standard for steroid-refractory cGVHD in this setting. It is a pleiotropic disease involving any anatomical district; also, Ruxolitinib represents the standard for steroid-refractory cGVHD in this setting. Extracorporeal Photopheresis (ECP) is still an option used for steroid refractoriness or to achieve a steroid-sparing. For Ruxolitinib-refractory cGVHD, Belumosudil and Axatilimab represent the most promising agents. Bronchiolitis obliterans syndrome (BOS) still represents a challenge; among the compounds targeting non-immune effectors, Alvelestat, a Neutrophil elastase inhibitor, seems promising in BOS. Finally, in both aGVHD and cGVHD, the association of biological markers with specific disease manifestations could help refine risk stratification and the availability of reliable biomarkers for specific treatments.

Extracorporeal Photopheresis in Pediatric and Adult Patients with Graft-Versus-Host Disease.

Background/Objectives: Graft-versus-host disease (GVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) resulting from histocompatibility differences between donor and host cells leading to inflammation, tissue damage, and compromised patient outcome. Extracorporeal photopheresis (ECP) is considered as a second-line treatment administered to patients with GVHD who do not respond to corticosteroid treatment or who experience a relapse after an initial response and are therefore classified as steroid refractory (SR). The aim of this study is to evaluate the clinical response rates in both pediatric and adult patients with acute (a) or chronic (c) GVHD and to assess the effectiveness of ECP using the real-world data from a single center. Methods: We performed a retrospective study on 30 patients, including 11 pediatric and 19 adult patients who were treated with ECP as a second-, third-, or fourth-line therapy for (a) and (c) GVHD, alongside corticosteroids and other immunomodulatory medications. The median time from aGVHD onset to ECP was 11.5 days (range: 3 days-9 months), while for cGVHD, the median time was 90 days (range: 2 days-9 months). Results: The overall response rate (ORR) in the aGVHD patient population was 60% with a median of 9 procedures (range: 2-20). For cGVHD patients, the ORR was 70% after a median of 23.5 ECP procedures (range: 8-43). Most patients had skin involvement, with ECP achieving an ORR of 81.8% in aGVHD and 77.7% in cGVHD cases. Conclusions: ECP is a beneficial therapy for patients with (a) and (c) GVHD who have not responded to corticosteroids and other forms of immunosuppressive therapy. Specifically, ECP demonstrated efficacy in improving skin and oral symptoms and permitted reductions in or the elimination of their corticosteroid usage. The study found that extending the duration of ECP treatment was associated with better outcomes, and no detectable complications were observed over a 38-week period.

Rescue Therapies for Steroid-Refractory Acute Severe Ulcerative Colitis: A Systemic Review and Network Meta-analysis.

Approximately 40% of patients with steroid-refractory acute severe ulcerative colitis (steroid-refractory (SR) ASUC) requires colectomies. Advanced therapies may reduce the short-term colectomy rates in patients with SR ASUC. However, comparative clinical studies evaluating the effectiveness of these rescue therapies are lacking. Therefore, we conducted a network meta-analysis to study the effectiveness of rescue therapies for SR ASUC. Six randomized controlled trials and 15 cohort studies including 2,004 patients were analyzed. Rescue drugs included tofacitinib, infliximab with a 5 or 10mg/kg induction dose at 0, 2, and 6 weeks (IFX and IFX10, respectively), IFX with an accelerated regimen of three 5mg/kg induction doses timed according to clinical need (accelerated IFX), tacrolimus, cyclosporine (CyA), ustekinumab, and adalimumab. Treatments were compared with a placebo. Tofacitinib (odds ratio [OR]: 0.09 [95% confidence interval [CI]: 0.02-0.52]), accelerated IFX (OR: 0.16 [95% CI: 0.03-0.94]), IFX (OR: 0.2 [95% CI: 0.07-0.58]), and tacrolimus (OR: 0.24 [95% CI: 0.06-0.96]) significantly reduced the short-term colectomy rates compared with placebo. IFX10 and CyA tended to prevent colectomies. However, ustekinumab and adalimumab did not significantly affect the colectomy rates. This is the first network meta-analysis to investigate the efficacy of advanced therapies in reducing short-term colectomy rates in patients with SR ASUC. Tofacitinib, accelerated IFX, standard IFX, and tacrolimus significantly reduced the colectomy rates in SR ASUC patients compared with placebo. Thus, advanced therapies should be considered for rescue therapies in patients with SR ASUC.

Ruxolitinib Plus Basiliximab Therapy for Steroid-Refractory Acute Graft-Versus-Host Disease in Unrelated Cord Blood Transplantation: A Large-Scale Study

Steroid-refractory (SR) acute graft-versus-host disease (aGVHD) is a major cause of mortality after allogeneic hematopoietic stem cell transplantation. We aimed to evaluate the effectiveness and safety of ruxolitinib plus basiliximab for treating SR-aGVHD after unrelated cord blood transplantation (UCBT). Among the 1154 patients with hematological malignancies who underwent UCBT between February 2014 and May 2022, 198 patients with grade II to IV SR-aGVHD were enrolled, 112 of whom were treated with basiliximab alone (basiliximab group) and 86 of whom received basiliximab plus ruxolitinib (combined therapy group). The combined therapy group demonstrated a significantly higher complete response rate (CRR) on day 28 (36.0%) than did the basiliximab group (12.5%, P < .001). SR-aGVHD patients were further stratified into standard-risk and high-risk groups using the refined Minnesota aGVHD risk score. For standard-risk patients, combined therapy significantly improved the CRR (51.1% versus 13.6%, P < .001) and 3-year overall survival (74.5% versus 52.4%, P = .033). However, high-risk patients did not exhibit the same benefits. Compared with basiliximab monotherapy, ruxolitinib plus basiliximab therapy was an effective therapy for patients with standard-risk SR-aGVHD following UCBT. The effectiveness of combined therapy in high-risk patients was not apparent, indicating the need for other treatments.

Current and Recent Advances in the Treatment of Steroid Refractory Acute Graft versus Host Disease

Acute Graft versus Host Disease (aGVHD) is a life-threatening complication that occurs within the first 100 days after an allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to treat aGVHD, corticosteroids are commonly used as first-line therapy. Nevertheless, their complete response rate is only around 50%. The rest of the patients became steroid-refractory (SR), and the death rate of steroid-refractory aGVHD (SR-aGVHD) patients was more than 90%, which shows that there is a pressing need for a cure for this condition. Hence, this review aims to highlight the currently available and recent advancements in the field of treatments for SR-aGVHD. Despite the deaths, relapses and infections caused by SR-aGVHD, there are significant innovations, specifically in the area of using stem cells as a treatment. Ultimately, this literature has reflected on the development of SR-aGVHD treatments over the years, indicated by the rise in the number and the quality of ongoing and completed trials.

NOD2 and Crohn's Disease Clinical Practice: From Epidemiology to Diagnosis and Therapy, Rewired.

Crohn's disease (CD) is a chronic inflammatory bowel disease with a multifactorial pathogenesis involving environmental and genetic factors. Since the late 20th century, the discovery of the first susceptibility gene (NOD2, previously referred to as CARD15) for CD has paved the way for further investigations into the correlations between clinical features and genetics, and its potential impact on clinical practice has fueled the research in the last 2 decades. Recent therapeutic advancements involving novel biologic drugs and small molecules have shifted inflammatory bowel disease management from a disease-centered to a patient-centric approach. To date, the role of NOD2 has not been fully understood yet. Recent data suggest that its clinical impact may be greater than currently recognized. This review overviews the most common NOD2 variants' role in real-life clinical practice. These genetic variants increase the risk of developing the disease and can aid in tailoring diagnosis and treatment. They are associated with the stricturing phenotype and ileal involvement and increase the risk of steroid refractoriness. In the meantime, limited and inconclusive evidence exists regarding their predictive role in response to azathioprine, biologic drugs, and small molecules. Eventually, their role in increasing the risk for surgery is evident, especially in those with the L1007fs variant. If further trials will support the initial evidence reported so far, NOD2 genetic variants will emerge as possible candidates for developing precision medicine in CD.

P366 Risk factors and outcomes of chronic antibiotic-refractory pouchitis in Korean ulcerative colitis patients: a single center retrospective study

Abstract Background Chronic inflammation of the pouch after total proctocolectomy with ileal pouch-anal anastomosis (IPAA) remains a morbid complication in ulcerative colitis (UC). The goal of this study was to investigate risk factors and clinical outcomes of chronic antibiotic-refractory pouchitis (CARP) in Korean patients with UC. Methods This was a single center retrospective study on patients with UC who underwent total proctocolectomy with IPAA at Asan Medical Center in Korea between January 1987 and December 2022. CARP was defined as failure to respond to a 4-week course of a single antibiotic, needing more than 4 weeks of therapy with 5-aminosalicylates, steroids, immunomodulators or biologics/small molecules, while chronic antibiotic-dependent pouchitis (CADP) was defined as more than 3 episodes of pouchitis per year or persistent symptoms requiring long-term antibiotics to maintain disease remission. Primary outcomes were endoscopic remission defined as complete mucosal healing of chronic pouchitis and pouch failure defined as the requirement of diverting loop ileostomy or pouch excision. Univariable and multivariable logistic regression analysis were used to identify risk factors of CARP. Results A total of 251 patients were included and 232 were analyzed (Male, 57.3%; Current smoker, 13.4%; Median age at surgery, 44 years; Disease duration at surgery, 4 years; Previous exposure to biologics/small molecules, 23.7%; Extra-intestinal manifestations, 8.2%; Preoperative cytomegalovirus infection, 19.4%). The most common cause of surgery was steroid refractoriness (50.9%), followed by dysplasia/colorectal cancer (26.7%). The median time from surgery to chronic pouchitis was 48 months (interquartile range 23.5–100.0). Among 74 patients (31.9%) with chronic pouchitis, 31 patients (13.4%) were CARP and 43 patients (18.5%) were CADP. The most frequent endoscopic phenotype according to Chicago classification was focal inflammation of the pouch in all groups (chronic pouchitis, 47.3%; CARP, 35.5%; CADP, 55.8%). Patients with CARP were less likely to have concomitant probiotics compared with CADP (29.0% vs 72.1%; p&amp;lt;0.01). Endoscopic remission rate in chronic pouchitis, CARP, and CADP were 14.9% (11/74), 9.7% (3/31), and 18.6% (8/43), respectively (Table 1). Pouch failure rate in chronic pouchitis, CARP, and CADP were 13.5% (10/74), 16.1% (5/31), and 11.6% (5/43), respectively (Table 1). In a multivariable analysis, current smoking status was positively associated with CARP development (OR: 3.56; 95% confidence interval 1.33–9.52; p=0.01). Conclusion Current smoker with UC who underwent IPAA had a higher risk of CARP. Concomitant use of probiotics was less likely to be associated with developing CARP.

Vedolizumab for second-line treatment of steroid-refractory gastrointestinal late acute graft-versus-host disease.

Late acute graft-versus-host disease (aGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with little data regarding treatment and outcomes. There is no standard treatment for gastrointestinal (GI) late aGVHD, especially for steroid-refractory (SR) GI late aGVHD. Vedolizumab, a monoclonal antibody inhibiting the migration of both naive and activated lymphocytes into the GI endothelium, has been verified to be effective for SR GI aGVHD. We retrospectively analyzed the clinical efficacy and safety of vedolizumab as the second line for SR GI late aGVHD in seven patients after allo-HSCT. Four patients received two doses of vedolizumab infusion, while three patients received only one dose of vedolizumab infusion. The complete response and partial response rates were 57.1% (4/7) and 42.9% (3/7), respectively. No patient progressed to chronic GVHD during the period of follow-up. There was no severe adverse event related to vedolizumab. Our data suggest that vedolizumab is expected to ameliorate SR GI late aGVHD. Further data on the treatment timing, efficacy, and safety of vedolizumab are warranted in prospective clinical trials.

Cytomegalovirus Infection: An Underrated Target in Inflammatory Bowel Disease Treatment.

CMV infection is still a matter of concern in IBD patients, especially regarding the disease's relapse management. Why IBD patients, particularly those affected by ulcerative colitis, are more susceptible to CMV reactivation is not totally explained, although a weakened immune system could be the reason. Various techniques, ranging from serology to histology, can be employed to detect intestinal CMV infection; however, there is currently disagreement in the literature regarding the most effective diagnostic test. Furthermore, CMV involvement in steroid resistance has been broadly discussed, but whether CMV infection is a cause or consequence of the disease severity and, consequently, steroid refractoriness is still debated. Its potential contribution to the lack of response to advanced therapy and small molecules must be more valued and wholly explored. In this review, we look at the actual literature on CMV in IBD patients, and we suggest a pragmatic algorithm for clinical practice management of CMV infection.

Update on the Use of Mesenchymal Stem Cells and their Products in Hematopoietic Stem Cell Transplantation

Graft Versus Host Disease (GVHD) is a major limitation to the success of allogeneic Hematopoietic Stem Cell Transplantation (HSCT) as Steroid-Refractory (SR) acute GVHD carries poor prognosis due to the absence of an efficacious second-line therapy. Mesenchymal Stem Cells (MSCs) which have immunosuppressive, immunomodulatory, and regenerative properties may become a highly effective therapeutic modality for SR-GVHD in the near future. MSCs have already been approved to treat childhood SR-GVHD in Japan, and they have been conditionally licensed in New Zealand and Canada. It is expected that MSCs will be approved for the treatment of SR-GVHD in adults in Europe, North America, and other parts of the world within a few years. Utilization of the recently introduced techniques including the use of MSC products such as exosomes and Extracellular Vesicles (ECVs) instead of the parent MSCs, robotic manufacturing technology, and genetic engineering of MSCs will ultimately overcome the remaining obstacles facing the widespread utilization of MSCs and their products as therapeutics not only in HSCT but also in other medical fields. The aim of this review is to provide an update on the remarkable progress achieved in the use of MSCs and their products in the field of HSCT.

Use of a Tissue-Targeting Recombinant Human Interleukin-22 Fusion Molecule (F-652) for the Treatment of Advanced Refractory Lower GI Acute Gvhd

Background: Steroid-refractory (SR) gastrointestinal acute GVHD (GI aGVHD) is a serious complication after allogeneic hematopoietic transplantation (allo-HCT), and subsequent lines of treatment following steroid failure are often ineffective. The JAK 1/2 inhibitor ruxolitinib is the only FDA-approved treatment for SR aGVHD, and patients for whom ruxolitinib is not effective or not tolerated have limited therapeutic options and high mortality. Interleukin-22 (IL-22) is a tissue-protective IL-10-family cytokine that has been shown to support intestinal mucosa after damage, directly signaling to the intestinal epithelium and promoting its survival, regeneration, and production of innate antimicrobial molecules. F-652, a recombinant human (rh)IL-22 fusion protein composed of an IL-22 dimer and IgG2 Fc fragment, has recently been studied in a phase 2 trial for patients with newly diagnosed lower GI aGVHD, demonstrating a promising day 28 treatment response rate and improved gut microbial health. Given this, we examined F-652 administration in 3 patients with severe SR GI aGVHD. Methods: Three patients with hematologic malignancies underwent MUD allo-HCT with tacrolimus and methotrexate GVHD prophylaxis ( Table). The patients were initially treated for GI aGVHD with methylprednisolone at a dose of 2 mg/kg/day without response. All patients presented with or progressed to stage 4 gut aGVHD and failed several lines of therapy, including ruxolitinib. All patients also had multiple episodes of bacteremia and at least some degree of GVHD-associated GI bleeding. F-652 treatment was initiated under single-patient-use authorization as the 5 th-7 th line of therapy and was administered at a dose of 45 mcg/kg IV weekly. In vitro cultures suggested that rho kinase inhibition did not interfere with trophic effects of IL-22 on intestinal epithelium, so patients were permitted to continue belumosidil upon F-652 initiation. While there was concern that JAK inhibition could compromise the activity of IL-22, continuation of ruxolitinib was considered on a case-by-case basis. C-reactive protein (CRP) is an acute phase reactant induced by IL-22, and circulating CRP levels served as a pharmacodynamic marker of in vivo biologic activity of F-652. Results: Consistent CRP elevations were observed 3 days after F-652 dosing in patients A and C, both of whom demonstrated a reduction in GVHD symptoms following F-652 treatment. These CRP elevations occurred despite concurrent use of belumosidil in Patient A and ruxolitinib in Patient C. CRP levels increased in Patient B after the first two doses, but not the third ( Figure). By day 28 following F-652 initiation, 2-of-3 patients (A and C) achieved a partial response, with decreased stool output and resolution of GI bleeding. Patient A had experienced 21 episodes of bacteremia prior to initiating rhIL-22 therapy but continued to demonstrate a partial response at day 56 and resolutiuon of bacteremias. Further improvement during the continued treatment (12 total doses) allowed for hospital discharge after 14 months of hospitalization. Patient B received 4 failed lines of therapy beyond ruxolitinib and was experiencing GI bleeding necessitating frequent transfusions prior to F-652 initiation. The symptoms persisted following F-652 treatment, and the patient passed at day 149 post-HCT. Patient C continues on active F-652 treatment and remains in a partial response as of this submission (&amp;gt; 50 days after treatment initiation). Overall, F-652 treatment has been well tolerated, and no significant adverse events attributable to the drug were observed. Conclusions: This is the first report of IL-22 therapy in SR aGVHD. Treatment was well tolerated, and 2-of-3 patients achieved a response following rhIL-22 administration after failing multiple previous therapies. Whereas most treatments for GVHD target immune cells and deepen immunosuppression, IL-22 is understood to act directly upon epithelial cells where it can support tissue recovery, improve barrier function, and promote innate antimicrobial immunity. CRP elevations post-treatment suggest that IL-22 administration may be able to exert these effects even with concurrent use of a JAK inhibitor. Our findings support further development of this approach and provide proof-of-concept for the use of tissue-supportive strategies to enhance the recovery of damaged gastrointestinal mucosa in advanced lower GI aGVHD.

Graft-Versus-Host Disease (GvHD) and Steroid-Refractory GvHD after Allogeneic Hematopoietic Stem Cell Transplantation: A Large Real-World EBMT-Based Epidemiology and Treatment Pattern Study

Introduction: Graft-versus-host disease (GvHD) is a multi-systemic disorder affecting patients who undergo allogenic hematopoietic stem cell transplantation (allo-HSCT) and is associated with considerable morbidity and mortality both in its acute (a) and chronic (c) forms, particularly in patients with steroid-refractory (SR)-GvHD (Flinn AM and Gennery AR. Fac Rev 2023).Given the lack of real-life data on GvHD, this study was conducted using a large European database with the objective to provide evidence on the epidemiology and treatment patterns in patients with aGvHD, cGvHD, and SR-GvHD. Methods: This retrospective, observational cohort study was conducted between July 1, 2014 and December 31, 2020 in allo-HSCT patients registered to the European Society for Blood and Marrow Transplantation (EBMT) database. Male or female patients aged ≥12 years at index (≥18 years for SR-GvHD and ruxolitinib [RUX] cohorts) who had received ≥1 allo-HSCT during this study period (January 1, 2017 to July 1, 2019 for SR-GvHD and RUX cohorts) were included in the study population. The EBMT cohort included all allo-HSCT patients, irrespective of GvHD development post-transplant (Tx). The primary objective was to assess the cumulative incidence of aGvHD and cGvHD in patients from the EBMT cohort who met the inclusion criteria. Overall survival of patients up to 60 months was also assessed in the EBMT cohort. The SR-GvHD cohort comprised a sub-selection of GvHD patients (from selected EBMT centers) who were diagnosed with SR-aGvHD, SR-cGvHD, or both, some receiving RUX as treatment; from the SR-GvHD cohort, a sub-selection of patients who had been treated with RUX for aGvHD and/or cGvHD, irrespective of treatment line, were included in the RUX cohort. Results:In the EBMT database, 60,140 patients had received an allo-HSCT. Most patients (94.5%) underwent 1 allo-HSCT, the remaining had &amp;gt;1 procedure. The EBMT cohort included a higher proportion of male patients between 50 and 69 years (Table 1). The main indication for allo-HSCT was acute leukemia. At the time of Tx, most patients were in their early disease stage and had unrelated donors(Table 1). The cumulative incidence of aGvHD was 27.9% and 27.6%, 4 months after first and second Tx, respectively. The cumulative incidence of cGvHD was 37.4% and 29.7%, 60 months after first and second Tx, respectively. aGvHD was of grade 2-4 in 27.1% of patients, and the most affected organ was skin (33.6%, grade 2-4: 19.5%) followed by liver (4.0%, grade 2-4: 2.3%) and gut (4.6%, grade 2-4: 2.8%); however, organ involvement was not collected in many patients. The cGvHD was limited (13.6%), extensive (14.7%) or of unknown grade (3.1%). Graft failure occurred in 5.9% of patients. The overall survival of EBMT cohort patients at 60 months was 53.1% with a median follow-up time of 32.9 months. The most frequent cause of death was relapse/progression (30.6%) followed by infection (27.1%) and GvHD (19.1%). The EBMT registry contains more SR-GvHD patients but only for subset of 292 SR-GvHD patients, additional information was obtained, of which 37 (34.6%) patients were treated with RUX and 70 (65.4%) with other second-line (2L) treatment for SR-aGvHD. For SR-cGvHD, 59 (31.9%) received RUX and 126 (68.1%) other 2L treatment. Baseline characteristics were comparable between SR-GvHD and the EBMT cohort (Table 1). Within SR-GvHD treatment groups, overall, the baseline characteristics were comparable across RUX and other 2L, and consistent with the EBMT and SR-GvHD cohorts. Compared with other 2L treatment, a slightly higher proportion of RUX-treated patients were females in SR-aGvHD cohort and males in SR-cGvHD cohort. While the most common first-line treatment for aGvHD in both RUX and the other group was methylprednisolone, for SR-cGvHD, it was prednisone+cyclosporine in RUX and prednisone in the other group. Conclusion:This large retrospective real-world evidence study from the EBMT reports on patients with GvHD after allo-HSCT. The cumulative incidence of aGvHD at 4 months post-Tx and cGvHD at 60 months was similar after the first or the second Tx. Though this study provides valuable insights on the epidemiology and treatment patterns of SR-GvHD patients, interpretation of these data is limited due to the small sample size of RUX and other treatment groups compared with the EBMT cohort.

Pooled Fecal Allogenic Microbiotherapy for Refractory Gastrointestinal Acute Graft-Versus-Host Disease : Results from Early Access Program in Europe

Introduction Acute Graft-versus-host disease (aGvHD) is a major source of mortality following allogeneic hematopoietic cell transplantation (allo-HCT). Fecal microbiotherapy has shown promising results in several pilot studies in patients with refractory gastrointestinal (GI)-aGvHD. Here we report clinical outcomes from 111 patients diagnosed with steroid-refractory (SR) or dependent (SD) GI-aGvHD treated with the pooled allogeneic microbiotherapy MaaT013 as part of the Early Access Program (EAP) in Europe. Patients and methods One hundred and eleven patients (including 1 pediatric patient aged 15 years) with SR/SD GI-aGvHD (Classical n=70, late onset n=12, overlap syndrome n=16, hyper-acute n=13) were treated with MaaT013 therapy as part of Early Access Program in Europe (France and Germany). These patients had previously failed 1 to 6 systemic GvHD treatment lines (median 3; 94/111 received ruxolitinib). Most patients had grade III to IV aGvHD (9% grade II, 49% grade III aGvHD, 42% grade IV). For each patient, a total of 3 MaaT013 administrations were planned every 7 +/- 2 days (median dose administered 3). Each dose is composed of 30 g of feces in 150 mL of suspension from 4 to 8 healthy donors administered by enema (except for 1 patient by nasogastric tube). Treatment response was calculated among all treated patients based on aGvHD staging and grading at day 28 (D28) at the time of the EAP request. Results At D28, the GI-ORR was 53%: 39 CR (35%), 15 VGPR (14%), 5 PR (5%). GI-ORR was higher in patients with lower grade aGvHD (100% in grade II, 63% in grade III, 32% in grade IV) and higher in SD versus SR (88% versus 47%). Overall response considering all organs (n=108 with 3 missing data) was 50%, including 34 CR, 16 VGPR and 4 PR. Administration of MaaT013 in the pediatric patient was well tolerated and led to complete response of GI and skin symptoms (the patient had stage 3 skin and stage 4 GI aGvHD) up to 12 months. Symptoms of the liver were not resolved at D28 (stage 2 liver, stable disease) but improved from month 6 without additional therapy. Overall survival (OS) was 56% at 6 months (M6) and 47% at M12 . The median follow-up among surviving patients was 355 days (range, 27-731).OS was significantly higher in patients achieving at least GI-PR at D28 (Responder, R; n=59) compared to patients in treatment failure (Non-responder, NR; n=52): 74% versus 36% at M6, 67% versus 24% at M12 (p&amp;lt;0.0001 log-rank test) . Median survival duration in R was 293 days versus 56 days in NR. Interestingly, in the subgroup of 38 patients previously treated with ruxolitinib as 2 nd line and MaaT013 as 3 rd line GI-ORR was improved being 61% D28, with 58% CR. OS at M6 was 55% and 52% at M12. OS was significantly higher in R patients, when compared to NR patients (81% versus 16% at M6 and 81% versus 8% at M12 for R and NR respectively, p&amp;lt;0.0001 log-rank test). MaaT013 displays a good overall safety profile in EAP population: 29 pharmacovigilance cases were reported in 27 patients, including 18 cases that could be possibly considered related to MaaT013 either by the physician or the company: sepsis in 5 patients, bacteremia in 7 patients, rectal bleeding/ anorectal disorder in 3, C. difficile colitis in 1, E. coli osteoarthritis in 1, detection of G. silvicola in stools in 1. No pathogen transmission has been reported. In 2 patients, non-pathogenic commensal bacteria isolated following infectious events were detected in the administered MaaT013 batch. Causality could not be formally excluded in these cases. 56 deaths have been reported. The cause of death was GvHD in 23 patients, severe infection in 15, relapse of underlying malignancy in 9, COVID-19 in 5, hemorrhage during surgery in 1, neurological complications post allo-HCT in 1, and cardiac arrest in 2 patients. No causality link with MaaT013 administration has been identified. Conclusion Overall, EAP clinical data showed that MaaT013 was safe and effective for the treatment of SR/SD-GI-aGvHD especially in patients having previously received ruxolitinib. Interestingly, response of GI-aGvHD correlates with increased overall survival, suggesting a strong favorable benefit-risk profile for MaaT013. A Phase 3 trial is currently ongoing to confirm these results in ruxolitinib-refractory patients (NCT04769895).

Treatment and Nursing for Steroid-Refractory Acute Graft-Versus-Host Disease.

Acute graft-versus-host disease (aGVHD) is a significant complication for patients who receive allogeneic stem cell transplantation. Patients whose aGVHD is refractory to corticosteroids face additional complications. This article provides foundational knowledge on steroid-refractory (SR) aGVHD, current treatment options, and related supportive care. Therapies for patients with SR aGVHD are summarized, along with supportive care recommendations and a review of related nursing considerations. Current treatment and research on SR aGVHD offer opportunities for improved clinical outcomes for these patients. Nursing knowledge of the pathophysiology, treatment, and supportive care for patients with SR aGVHD is integral to the provision of optimal nursing care for a complex population of patients.

A cost-effectiveness analysis of ruxolitinib versus best alternative therapy for patients with steroid-refractory chronic graft-versus-host disease aged > 12 years in Singapore

BackgroundApproximately 30–70% of patients who have undergone allogeneic (allo) hematopoietic stem cell transplantation (HSCT) eventually experience chronic graft-versus-host disease (cGVHD). Patients who develop steroid-refractory (SR)-cGVHD are the most severely impacted due to significant disease and financial burden. There remains an unmet need for safe, efficacious, and accessible treatments for these patients. The objective of this study was to determine the cost effectiveness of ruxolitinib for treatment of SR-cGvHD from the Singapore healthcare system perspective.MethodsBased on data from the REACH3 randomized open-label trial, a semi-Markov model was developed to evaluate cost-effectiveness of ruxolitinib compared with investigators' choice of best alternative therapy (BAT) for treatment of patients > 12 years of age with SR-cGVHD in Singapore over a 40-year time horizon. The model only considered direct medical-care costs related to the treatment of SR-cGVHD and reported them in Singapore Dollars (SGD). Half-cycle correction was applied to all costs and outcomes, which were discounted at 3%. Probabilistic sensitivity analysis (PSA), one-way sensitivity analysis (OWSA), and scenario analysis were conducted to explore the drivers of uncertainty in the model.ResultsIn the deterministic base case, more life years (LY; 10.28 vs. 9.42) and quality-adjusted life years (QALYs; 7.31 vs. 6.51) were gained with ruxolitinib than BAT at higher costs (SGD 303,214 vs. SGD 302,673) leading to an incremental cost-effectiveness ratio (ICER) of SGD 677/QALY. At a willingness-to-pay threshold of SGD 75,000/QALY gained, PSA found that ruxolitinib had a 78.52% probability of being cost-effective. Findings were sensitive to variations in non-responder utilities in the BAT arm and duration of BAT treatment in the OWSA, or comparison to either methotrexate (MTX) or mycophenolic acid as a single comparator in the scenario analysis. ICERs remained lower than SGD 75,000/QALY in all other tested variations and scenarios.ConclusionRuxolitinib is likely to be cost-effective from Singapore healthcare system’s perspective for patients with SR-cGVHD, which is promising in the management of patients with unmet clinical needs.

Real-world experience with low-dose IL-2 for children and young adults with refractory chronic graft-versus-host disease

AbstractThe majority of patients with chronic graft-versus-host disease (cGVHD) are steroid refractory (SR), creating a need for safe and effective therapies. Subcutaneous low-dose interleukin-2 (LD IL-2), which preferentially expands CD4+ regulatory T cells (Tregs), has been evaluated in 5 clinical trials at our center with partial responses (PR) in ∼50% of adults and 82% of children by week 8. We now report additional real-world experience with LD IL-2 in 15 children and young adults. We conducted a retrospective chart review of patients with SR-cGVHD at our center who received LD IL-2 from August 2016 to July 2022 not on a research trial. The median age at start of LD IL-2 was 10.4 years (range, 1.2-23.2 years) at a median of 234 days from cGVHD diagnosis (range, 11-542 days). Patients had a median of 2.5 (range, 1-3) active organs at LD IL-2 start and received a median of 3 (range, 1-5) prior therapies. The median duration of LD IL-2 therapy was 462 days (range, 8-1489 days). Most patients received 1 × 106 IU/m2 per day. There were no serious adverse effects. The overall response rate in 13 patients who received >4 weeks of therapy was 85% (complete response, n = 5; PR, n = 6) with responses in diverse organs. Most patients significantly weaned corticosteroids. Tregs preferentially expanded with a median peak fold increase of 2.8 in the ratio of Tregs to CD4+ conventional T cells (range, 2.0-19.8) by 8 weeks on therapy. LD IL-2 is a well-tolerated, steroid-sparing agent with a high response rate in children and young adults with SR-cGVHD.

Pathophysiology of gastrointestinal acute graft-versus-host disease and the potential role of glucagon-like peptide 2.

Acute graft-versus-host disease (aGVHD) is a life-threatening complication after allogeneic haematopoietic cell transplantation, with gastrointestinal (GI) tract involvement (GI aGVHD) being one of the leading causes of morbidity and mortality. Whilst systemic steroids are the standard first-line treatment for aGVHD, approximately 50% of patients become steroid refractory (SR), which is associated with poor outcomes. Existing options for SR-GVHD are limited, and there is a significant unmet need for new non-immunosuppressive treatment approaches in patients with GI aGVHD. Here, we review newer concepts in the pathogenesis of GI aGVHD and present the evidence for the role of glucagon-like peptide 2 (GLP-2) in maintaining and protecting GI epithelial cells, including the enterocytes, intestinal stem cells and Paneth cells, which are direct targets of aGVHD. Finally, we discuss the therapeutic rationale for GLP-2 treatment as a tissue regeneration approach and the potential use of the novel GLP-2 analogue apraglutide as an adjunctive treatment for GI aGVHD.

P566 Colitis due to immunotherapy with anti-PD-1: a case series

Abstract Background Anti-programmed death-1 (PD-1) drugs have been associated with immune-mediated gastrointestinal adverse events in 0.5-9% of the cases. The aim of this study was to investigate the characteristics of colitis occurring in oncological patients treated with anti-PD-1 drugs. Methods This is a prospective cohort study including patients referred for new onset colitis at Azienda Ospedaliera of Padua between 2020 and 2022. All patients were treated with anti-PD-1 drugs at Istituto Oncologico Veneto due to oncological disease [n=2 melanoma, n=1 colorectal cancer, n=1 pleural mesothelioma, n=14 non-small-cell lung cancer (NSCLC)]. Median duration of follow up was 10 months. Results Eighteen patients who developed diarrhea (≥G2, CTCAE) following treatment with anti-PD-1 were included (n=12 males, median age 70 years). The diarrhea began after a mean of seven months of therapy and after two to six months its discontinuation in 3/18 patients. The mean fecal calprotectin values at diarrhea onset was 1063 ug/g. Most of the patients (14/18) had their immunotherapy suspended, among them four required hospitalization. All patients were initially treated with systemic steroids (1 mg/kg). Seven patients had ulcerative colitis (UC)-like colitis (n=5 pancolitis, n=2 left colitis) while the others (60%) had microscopic colitis (MC, n=9 collagenous, n=1 lymphocytic) with unspecific inflammatory mucosal abnormalities in half of the cases. Among patients with UC-like colitis, two were hospitalized and treated with anti-TNFα because of steroid refractoriness; all remaining patients with UC-like colitis are maintaining remission with oral mesalamine or with budesonide non-MMX or low-dose systemic steroid (0.1 mg/kg). Two patients restarted anti-PD-1 drugs with no colitis relapse in the following three months, with mesalamine as maintenance therapy. Among patients who developed a MC, one required Vedolizumab as maintenance therapy, while 8/10 achieved partial or complete remission with oral budesonide non-MMX or low-dose systemic steroid. Three patients restarted anti-PD-1 drugs with no colitis relapse in the following three months, taking budesonide non-MMX as maintenance therapy. In our cohort of study all patients with MC were previously treated with anti-PD-1 drugs for NSCLC, while those with UC-like colitis were treated for NSCLC (n=4), melanoma (n=2) and colorectal cancer (n=1). Conclusion We observed a significant proportion of microscopic colitis in patients with NSCLC, while UC-like colitis was equally distributed in the other forms of neoplasia. Men are at higher risk to develop anti-PD-1 induced MC in NSCLC, rather than women. Anti-PD-1 induced microscopic colitis presents more frequently endoscopic signs of inflammation.