Outcomes of Etanercept Treatment for Steroid-Refractory Acute Graft-Versus-Host Disease in Adult and Pediatric Patients: A Retrospective Single-Center Cohort Study

Outcomes of Etanercept Treatment for Steroid-Refractory Acute Graft-Versus-Host Disease in Adult and Pediatric Patients: A Retrospective Single-Center Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Outcomes of Etanercept Treatment for Steroid-Refractory Acute Graft-Versus-Host Disease in Adult and Pediatric Patients: A Retrospective Single-Center Cohort Study Shlomo Elias, Or Gilad, Irina Zaidman, Ehud Even-Or, Eran zimran, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6528634/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Steroid-refractory acute graft-versus-host disease (SR-aGvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (alloHSCT), particularly in grade III–IV cases. While ruxolitinib is the only approved second-line therapy for patients aged 12 and older, its limited efficacy and lack of approval for younger children underscore the need for alternatives. Etanercept (ET), a TNF-alpha inhibitor, has been used off-label for SR-aGvHD, but age-stratified data are limited. In this retrospective single-center study, we analyzed outcomes of 103 patients with grade III–IV SR-aGvHD treated with either ET or best available therapy (BAT) at Hadassah Medical Center. Pediatric patients had significantly better overall survival (OS) and event-free survival (EFS) than adults (p < 0.0001). Among ET-treated patients, children had a 71% response rate versus 6.7% in adults. ET use in pediatric patients was associated with improved survival over BAT (p < 0.05), while adults showed a non-significant trend toward worse outcomes (p = 0.085). Infection was the leading cause of death across all groups, though ET was not linked to increased infection-related mortality. These findings support ET as a potentially effective and safe salvage therapy in pediatric SR-aGvHD, with limited benefit in adults. Prospective studies are needed to refine age-specific treatment strategies. Health sciences/Diseases/Haematological diseases Health sciences/Medical research/Clinical trial design Figures Figure 1 Figure 2 Figure 3 Introduction The success of allogeneic hematopoietic stem cell transplantation (alloHSCT) is limited by graft-versus-host disease (GvHD). High-dose corticosteroids are first-line therapy for moderate to severe acute GvHD (aGvHD), but about 50% of patients develop steroid-refractory aGvHD (SR-aGvHD), with poor outcomes in grade III-IV disease. 1 , 2 Ruxolitinib is currently the only second-line treatment approved by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for SR-aGvHD in adults and adolescents aged ≥ 12 years. 3 , 4 It has also been recently included in the 2024 European Society for Blood and Marrow Transplantation (EBMT) consensus guidelines. 5 Despite this, ruxolitinib demonstrates an overall response rate (ORR) of approximately 55%, with no significant reduction in non-relapse mortality (NRM) compared to best available therapy (BAT), and is not yet approved for children under 12 years of age. 6 , 7 Beyond second-line treatment, the standard of care remains undefined, underscoring the urgent need for additional effective therapies. 8 , 9 Etanercept (ET), a TNF-α inhibitor, is approved for autoimmune conditions in patients ≥ 2 years. 10 TNF-α is a key mediator in aGvHD, making ET a candidate for off-label use. 10 Studies show day-28 ORRs of 20–69% 11,12 for ET monotherapy, and up to 91% when combined with other agents, 13 , 14 but 2-year survival rates remain < 50%. One of the primary concerns associated with ET use is a high incidence of serious infections. 12 , 15 , 16 However, similar infection rates have been reported with other immunosuppressive regimens. 8 In pediatric patients, concerns have also been raised regarding a potential increased risk of malignancy. 17 Establishing a causal relationship, however, remains difficult due to confounding factors such as the underlying autoimmune condition and concurrent or previous oncogenic therapies. 18 Given the poor prognosis of SR-aGvHD, ET’s benefits may outweigh its risks. 15 Due to age-related differences in transplant characteristics and GvHD biology, 19 further investigation is warranted into the efficacy and safety of ET in distinct age groups. To date, the impact of age on ET outcomes in SR-aGvHD remains insufficiently characterized. Hadassah Medical Center’s integrated pediatric and adult alloHSCT program offers a unique setting to evaluate ET across age groups. This single-center retrospective study assessed the efficacy and safety of ET versus best available therapy (BAT) in pediatric and adult patients with grade III–IV SR-aGvHD. Methods Patient cohort This retrospective cohort study included adult and pediatric patients who underwent alloHSCT at the adult and pediatric BMT center at Hadassah Medical Center and were diagnosed with grade III-IV SR-aGvHD according to the published EBMT criteria, 20 between January 2010 and June 2019. Patient information is routinely recorded using a predefined case report form (CRF) and documented in electronic medical records (EMR) software. Patients were allocated to the ET arm if they received at least one dose of ET for SR-aGvHD (intervention). The rest of the patients were allocated to the BAT arm (control). ET was administered at a starting dose of 0.4 mg/kg/dose subcutaneously (SC) up to a maximum dose of 25 mg/dose SC, twice a week. There were no restrictions on the starting time or previous treatment lines. The institutional ET protocol was twice weekly for 4 weeks (≥ 72 hours between injections), followed by weekly for 4 more weeks, with clinical adjustments as needed for specific patietns. Further treatment lines were added as deemed necessary by the treating physicians. The choice of BAT was based on the physician's discretion, considering factors such as comorbidities, prior treatment and target organ involvement. Options for BAT included various therapies such as anti-thymocyte globulin (ATG), calcineurin inhibitors (CNI i.e., cyclosporine A or tacrolimus), extracorporeal photopheresis (ECP), intra-arterial corticosteroids, mesenchymal stromal cells (MSC), methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (sirolimus or everolimus), thalidomide, ruxolitinib, alemtuzumab, and vedolizumab. Conditioning regimens were classified as myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) according to the Center for International Blood and Marrow Transplant Research (CIBMTR). 21 Patients received standard institutional supportive care, including aGvHD prophylaxis, consisting of CNI with either MTX or MMF, and infection prophylaxis consisting of acyclovir and trimethoprim sulfamethoxazole. Blood count was monitored daily and engraftment was defined as per EBMT criteria. 22 The study was conducted in accordance with the Declaration of Helsinki, and the protocol was reviewed and approved by the institutional review board (IRB) (approval no. 0637-20-HMO). Outcomes The primary endpoint of the study was OS, defined as the time from aGvHD diagnosis to death due to any cause. Secondary endpoints were event-free survival (EFS), defined as the time from aGvHD diagnosis to the date of primary malignant disease relapse or death due to any cause; non-relapse mortality (NRM), defined as the time from aGvHD diagnosis to the date of death due to any cause except for primary disease relapse; rate of malignancy relapse (MR), calculated only for patients with primary malignant disease and defined as the time from aGvHD to the date of relapse; incidence of serious infections by day 30 after commencing ET, was defined according to the Common Terminology Criteria for Adverse Events (CTC-AE) version 5.0 as either grade 2 events requiring systemic treatment or grade 3 or higher. Additionally, response to treatment was evaluated and defined as complete response (CR) for stage 0 in all target organs, partial response (PR) for improvement of at least one stage in one affected organ without worsening or de novo aGvHD in other organs. Stable disease (SD) was defined as no change in stage in all affected organs, without de novo aGvHD in others. Progressive disease (PD) was defined as worsening of at least one affected organ or de novo aGvHD in any other organ. 23 Statistical Analysis Comparison between treatment groups was conducted based on variable features, as follows: Categorical variables were presented as numbers (%), and associations were tested using the χ2 test or Fisher's exact test, as appropriate. Continuous variables were described based on their distribution. For variables with a normal distribution the mean (± standard distribution; STD) was reported, and differences were tested using independent Student's t-test. For variables with a non-normal distribution the median and interquartile range (IQR) were reported, and differences were tested using Mann-Whitney U test. Survival analyses utilized Kaplan-Meier estimates, with curves compared using the Log-Rank test. Cox regression models were used to identify predictors of overall survival (OS) and assess the impact of treatment with ET and age group on OS, with analyses performed separately for adult and pediatric cohorts. To identify predictors of OS, variables preceding the alloHSCT were tested using a univariate and a multivariate Cox regression model. The analyses were performed for the total cohort and also separately for the adult and pediatric cohorts and for the ET arm. The statistical analyses were performed using SPSS, version 26.0 (IBM Corp., Armonk, NY, USA) and RStudio, version 4.3.3., and the figures were plotted using GraphPad Prism, version 9.0.0 (GraphPad Software, San Diego, California, USA). A two-tailed p-value < 0.05 was considered statistically significant. Results Patient characteristics A total of 123 patients who underwent alloHSCT were diagnosed with grade III-IV SR-aGvHD, comprising 74 adults (60.2%) and 49 pediatric patients (39.8%) (Fig. 1). Among them, 15 adults and 31 pediatric patients received ET for the treatment of grade III-IV SR-aGvHD. The median age at transplantation was 42 years (range 18–71) in adults and 7 years (range 0.3–17) in pediatric patients. The majority of the patients received grafts from male, HLA-matched, ABO-matched and CMV seropositive donors (Table 1). Table 1 Baseline Demographics and Transplant Characteristics of Adult and Pediatric Cohorts. aGvHD, acute graft-versus-host disease; alloHSCT, allogeneic hematopoietic stem cell transplantation; ATG, anti-thymocyte globulin; BM, bone marrow; CB, cord blood; CMV, cytomegalovirus; CR, complete response; D/R, donor/recipient; ET, etanercept; GI, gastrointestinal; HLA, human leukocyte antigens; MA, myeloablative; MM, mismatch; PBSC, peripheral blood stem cells; SR-aGvHD, steroid refractory acute graft-versus-host disease; Trp, transplantation; yr, years. Variable Adults (N = 74) Pediatrics (N = 49) Total (N = 123) P value Age at Trp, yr – median (IQR) 42.1 (28.6–55.6) 7.2 (2.6–12.1) 25.75 (9.78–45.67) < 0.0001 Male sex – no. (%) 53 (71.6) 29 (59.2) 82 (66.67) 0.152 Primary malignant disease – no. (%) 70 (94.6) 21 (42.8) 91 (73.98) < 0.0001 CR of malignant disease at alloHSCT – no. (%) 39 (55.7) 16 (76.2) 55 (60.44) 0.197 Donor age, years – median (IQR) 33.3 (26.2–47) 25.1 (21.38–33.4) 30.0 (23.27–44.34) < 0.01 Gender (D/R) – no. (%) M/M 41 (55.4) 16 (32.6) 57 (46.34) 0.101 M/F 12 (16.2) 11 (22.4) 23 (18.70) F/F 9 (12.2) 9 (18.4) 18 (14.63) F/M 12 (16.2) 13 (17.6) 25 (20.32) HLA Match 58 (78.4) 25 (51.0) 84 (68.29) < 0.01 ABO match – no. (%) Match 35 (47.3) 19 (38.8) 54 (43.90) 0.748 Minor MM 17 (23.0) 11 (22.4) 28 (22.76) Major MM 13 (17.7) 11 (22.4) 24 (19.51) Bidirectional 9 (12.2) 8 (16.4) 17 (13.82) CMV serostatus (D/R) – no. (%) +/+ 52 (72.2) 23 (50.0) 76 (64.41) 0.061 -/+ 10 (13.9) 15 (32.6) 24 (20.34) +/- 4 (5.6) 4 (8.7) 8 (6.78) -/- 6 (8.3) 4 (8.7) 10 (8.47) MA conditioning regimen – no. (%) 50 (67.6) 47 (95.9) 97 (78.86) < 0.001 ATG – no. (%) 31 (41.9) 32 (65.3) 63 (51.22) < 0.05 Double GvHD prophylaxis – no. (%) 10 (13.5) 6 (12.2) 107 (86.99) 0.838 Source of graft – no. (%) PBSC 67 (90.5) 17 (34.7) 84 (68.29) < 0.0001 BM 5 (6.8) 30 (61.2) 35 (28.45) CB 2 (2.7) 2 (4.1) 4 (3.25) Time from alloHSCT to aGvHD, days – median (IQR) 33 (20–54) 20 (12–37) 28 (16-50.5) < 0.01 aGvHD grade at diagnosis – no. (%) I 2 (2.7) 1 (2.0) 3 (2.44) < 0.05 II 11 (14.9) 0 (0.0) 11 (8.94) III 41 (55.4) 26 (53.1) 67 (54.47) IV 20 (27.0) 22 (44.9) 42 (34.15) aGvHD organ involvement at diagnosis – no. (%) GI 68 (91.9) 43 (87.7) 111 (90.24) 0.449 Liver 17 (23.0) 16 (32.6) 33 (26.83) 0.235 Skin 41 (55.4) 43 (87.7) 84 (68.29) < 0.001 Treatment lines for SR-aGvHD – median (range) 4 (2–5) 3 (1–5) 3 (1–5) 0.447 In adults, malignant diseases were predominant (94.6%), whereas in pediatric patients, diagnoses were evenly distributed between malignant (42.8%) and non-malignant (57.2%) conditions. Peripheral blood stem cells (PBSC) were the primary choice for transplants in adults (90.5%) while bone marrow (BM) grafts were preferred in pediatric patients (61.2%). The myeloablative (MA) conditioning regimen was predominant in both groups, used in 95.9% of pediatric and 67.6% of adult patients. Most patients received dual aGVHD prophylaxis. Both age groups predominantly presented with grade III-IV aGvHD at diagnosis of aGVHD. Double organ involvement was common, observed in 51.2% of patients, with the gastrointestinal tract being the most commonly affected (90.2%). Skin involvement was significantly more frequent in pediatric patients (87.7% vs. 55.4% in adults). There were no significant differences in donor characteristics including age, donor/recipient sex, HLA compatibility, ABO compatibility and CMV serostatus between the ET and BAT arms in both age groups (Supplementary Tables 1, 2 ). In the pediatric cohort, patients in the ET arm had a higher probability of being diagnosed with a non-malignant primary disease (71.0% vs. 33.3%, p = 0.010), received bone marrow grafts (74.2% vs. 38.9%, p = 0.0495) and dual aGVHD prophylaxis more often than those in the BAT arm (100.0% vs. 66.7%, p = 0.001) ( Supplementary Tables 1, 2 ). In the adult cohort, there was a significant difference in aGvHD severity at diagnosis, with patients in the BAT arm presenting with a higher proportion of grade III-IV aGVHD (88.1% vs. 60.0%, p = 0.011). No significant differences were observed between adult and pediatric patients treated with ET, except from age-related baseline differences already described ( Supplementary Table 3 ). Notably, in the ET arm, pediatric patients presented with a higher grade of aGVHD (grade III-IV 96.8% vs. 60.0%, p = 0.003) and underwent fewer treatment lines prior to ET compared to adults (median 1.5 vs. 4, respectively, p = 0.001) ( Supplementary Table 3 ). Response to treatment The proportion of patients who achieved CR of aGvHD signs and symptoms was significantly higher in the pediatric cohort (57.1% vs. 17.6% in adults, p < 0.00001). Within the pediatric cohort, resolution of all SR-aGvHD-related signs and symptoms was more common in the ET arm compared to the BAT arm (71.0% vs. 33.3%, p = 0.016). In contrast, among adults, CR rates were comparable between the ET and BAT arms (6.7% vs. 20.3%, p = 0.282). A majority of pediatric patients achieved CR with ET (58.1%), whereas only 6.7% of adults did (p = 0.0009). Nearly two-thirds (64.5%) of pediatric patients in the ET arm did not require additional treatment, while a similar proportion of adults (60.0%) received one to three treatment lines after ET. Among those requiring further therapy, a significant majority of pediatric patients achieved CR (72.7% vs. 0.0% in adults, p = 0.001). Relapses In the entire cohort, 13 patients (14.2% of those with primary malignant disease) experienced relapse of their primary disease. The median interval from aGvHD diagnosis to relapse was 2.2 months. The 5-year relapse rate following aGvHD diagnosis was comparable in the adult and pediatric cohorts (28.7% vs. 13.4%, p = 0.233). Of those who relapsed, 11 patients (84.6%) died from relapse after a median of 6.1 months. The remaining two were lost to follow-up within 30 days but had active disease at last contact. Infections post-ET treatment Overall, within 30 days of ET administration, severe bloodstream infections occurred in 42 patients (91.3%), including 21 cases of bacteremia (45.6%), 34 of viremia (73.9%), and 5 of fungemia (10.9%). Bacteremia was significantly more common in adults compared to pediatric patients (60.0% vs. 38.7%, respectively, HR 2.6, 95% CI 0.9–7.2, p = 0.022, Fig. 2A). The median time to bacteremia was 10 days in adults and 16 days in pediatric patients (p = 0.596). Gram-negative bacteria predominated in adults (66.6%), while gram-positive species were more frequent in pediatric patients (91.7%, p = 0.076). Sixteen patients (34.8%) experienced bacterial infections in other sites, primarily in the urinary tract, with adults showing a borderline higher cumulative incidence of such infections at day + 30 compared to pediatric patients (55.1% vs. 29.0%, p = 0.052). Viremia was the most frequent infection in pediatric patients, but no significant age-related difference was observed (59.4% vs. 83.9% at day + 30 for adults vs. pediatric patients, p = 0.241; Fig. 2B). The median time to viremia was 4.5 days in adults and 6.5 in pediatric patients (p = 0.246). Twenty-one patients (45.6%) had viral infections elsewhere, mostly urinary BK virus. Fungemia incidence was low (11.6% at day + 30) and similar between adults and pediatric patients (6.7% vs. 12.9%, p = 0.612). Survival The median OS of the entire cohort was 6.9 months following aGvHD diagnosis. During the follow-up period, 75 patients died: 11 due to a relapse of primary malignant disease, 16 from infections, and 46 from aGvHD, 34 of whom also had concurrent infections contributing to their deaths. Among the two latter groups (death due to infection or aGVHD with infection), 33 patients had bacterial infections, seven had viral infections, and nine had uncontrolled fungal infections at the time of death. In the ET group, 11 infection-related deaths were recorded. Bacterial infections were the leading cause of death in the adult population (five out of seven cases), with one adult succumbing to a viral infection and three patients dying from fungal infections, two of whom were in the pediatric group. Additionally, one patient died from sinusoidal obstruction syndrome (SOS). The 12- and 24-month OS probabilities were significantly higher in the pediatric cohort compared with the adult cohort (p < 0.0001). Among pediatric patients, ET treatment was associated with a significant survival advantage compared to BAT (p < 0.05, Fig. 3D). Conversely, in the adult cohort, ET treatment was associated with a trend toward lower survival compared to BAT, although this difference did not reach statistical significance (Fig. 3A, p = 0.085). Similar trends were observed for event-free survival (EFS) (Fig. 3B, 3E ) , with the pediatric cohort demonstrating a significantly higher EFS compared to adults (median not reached versus 3 months, respectively, p < 0.0001). Additionally, the cumulative incidence of non-relapse mortality (NRM) (Fig. 3C, 3F) was significantly lower in pediatric patients compared to adults (p < 0.0001). In univariate analysis, several variables had a statistically significant impact on OS in the entire cohort (Table 2). These included: age category (adults versus pediatric), presence of primary malignant disease, donor type, conditioning intensity, ATG administration, graft source and time from diagnosis to transplant. In multivariate analysis, incorporating all significant variables occurring prior to aGvHD diagnosis, only age category and time from diagnosis to transplant retained significance (HR = 3.515, 95% CI: 2.056–6.007, p < 0.001; HR = 1.102, 95% CI: 1.039–1.17, p = 0.001). In univariate analysis of patients treated with ET, several variables were significantly associated with OS, including age category, ethnicity, presence of malignant disease, donor type, conditioning intensity, ATG administration, graft source, liver involvement at ET initiation, number of treatment lines before ET, and interval from aGvHD diagnosis to ET treatment (Table 3). In multivariate analysis of variables occurring prior to ET treatment, age category, primary malignant disease and liver involvement at ET initiation remained statistically significant predictors (HR = 12.05, 95% CI: 3.77–38.53, p < 0.001 HR = 3.76, 95% CI: 1.19–11.84, p = 0.024; HR = 3.65, 95% CI: 1.42–9.40, p = 0.007). Discussion Effective salvage treatments for steroid-refractory acute graft-versus-host disease (SR-aGvHD) resistant to ruxolitinib remain an unmet clinical need. 3 , 9 , 24 Several retrospective studies have evaluated ET in both adults and children, with sample sizes ranging from 13 to 124 patients. 12 – 14 , 25 – 32 Some focused exclusively on adults, with sample sizes between 30 and 58, reporting overall response rates (ORR) of 36–83% and overall survival (OS) of 0–69%. 12,13,16,27,30 Data in pediatrics are more limited but indicate high response rates, up to 68%. 33 This study retrospectively compared ET and best available therapy (BAT) in SR-aGvHD patients of all ages treated at Hadassah’s combined adult and pediatric center. ET was associated with significantly improved OS and event-free survival (EFS) in pediatric patients (p < 0.05 and p < 0.0001, respectively), along with lower non-relapse mortality (NRM) (p < 0.0001). In contrast, adults showed a trend toward inferior survival (p = 0.085), aligning with De Jong 30 and Park 12 , but differing from Busca et al. 27 Importantly, survival data in pediatrics remain scarce. Relapse remains the leading cause of death post-alloHSCT, accounting for approximately 40% of all deaths. 34 In our cohort, relapse incidence was 14.2% among patients with malignant disease. Notably, only one relapse occurred in the ET group. No pediatric patients with malignant disease treated with ET (n = 9) relapsed, suggesting ET may be safe in this population. Infection is a major cause of mortality following alloHSCT. 35 Treatment with methylprednisolone (MP) plus ET as initial aGvHD therapy has not been shown to increase the risk of bacterial, viral, or fungal infections compared to MP alone in mixed adult-pediatric cohorts. 36 In our study, infection was the most frequent cause of death in both treatment arms. Viremia predominated in pediatric patients, while bacteremia was more common in adults. Although high infection rates with ET have been reported, age-specific infection patterns are underexplored. 12 , 13 , 26 , 30 In our cohort, infection was the leading cause of death in both ET and BAT arms, with bacterial infections being the most common across all groups. Importantly, ET treatment was not associated with higher infection-related mortality. Age is a key factor in aGvHD outcomes., with better outcomes reported in pediatric patients with grade III-IV aGvHD than in adults. 9 , 37 – 39 In our study, the OS probability was significantly superior in the pediatric cohort compared with the adult cohort, supporting previous publications on the association between advanced age and dismal prognosis in these patients. Moreover, among patients treated with ET, pediatric patients had a markedly higher response rate compared to adults (71% vs 6.7%, respectively). Most pediatric patients did not require additional therapy after ET, whereas nearly two-thirds of adults received one to three additional treatment lines. When comparing ET to BAT, pediatric patients demonstrated a significantly better response rate, while the adult cohort showed a significant opposite effect. Several studies examining ET for SR-aGVHD in adults have shown variable outcomes with second-line response rates up to 60% with wide variation in complete response (CR) rates. 12 , 13 , 26 In our study, ET was administered later in the treatment course for adults (median fourth line) compared to earlier use in pediatric patients (median 1.5 lines), which may partially explain the observed lower response rates in adults. This study has limitations, including its retrospective design and variability in prior treatments, which complicate assessment of ET’s isolated effect. ET was also initiated later in adults, possibly contributing to poorer outcomes. The timing and dosing of ET remain undefined, leading to inconsistency in its use. Finally, the role of ET in the ruxolitinib era, now the standard second-line therapy, remains unclear and warrants prospective evaluation. In conclusion, ET showed benefit in pediatric patients but limited efficacy in adults. Further randomized trials are needed to clarify its optimal use, particularly regarding timing, age, and disease type (malignant vs. non-malignant). Declarations Acknowledgments SE is supported by Hadassah “OFEK” research fund, ASH global research award, ISF grant (2873/23), Israel Society of Hematology and Transfusion Medicine research grant, and a grant from the Ministry of Innovation, Science and Technology (0007868). Conflict of Interest SE received honoraria from Novartis and Gilead. Author Contributions OG was responsible for data collection, analysis, and writing the manuscript. SE, SG, and BA supervised the project and contributed to writing the manuscript. 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Hematopoietic cell transplantation and cellular therapy survey of the EBMT: monitoring of activities and trends over 30 years. Bone Marrow Transplant 2021; 56 : 1651–1664. Schoemans HM, Lee SJ, Ferrara JL, Wolff D, Levine JE, Schultz KR et al. EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment. Bone Marrow Transplant 2018; 53 : 1401–1415. Bacigalupo A, Ballen K, Rizzo D, Giralt S, Lazarus H, Ho V et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant 2009; 15 : 1628–1633. Sureda A, Carpenter PA, Bacigalupo A, Bhatt VR, de la Fuente J, Ho A et al. Harmonizing definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism in allogeneic hematopoietic cell transplantation: a report on behalf of the EBMT, ASTCT, CIBMTR, and APBMT. Bone Marrow Transplant 2024; 59 : 832–837. MacMillan ML, Robin M, Harris AC, DeFor TE, Martin PJ, Alousi A et al. A refined risk score for acute graft-versus-host disease that predicts response to initial therapy, survival, and transplant-related mortality. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant 2015; 21 : 761–767. Ciurea SO, Al Malki MM, Kongtim P, Zou J, Aung FM, Rondon G et al. Treatment of allosensitized patients receiving allogeneic transplantation. Blood Adv 2021; 5 : 4031–4043. Kennedy GA, Butler J, Western R, Morton J, Durrant S, Hill GR. Combination antithymocyte globulin and soluble TNFalpha inhibitor (etanercept) +/- mycophenolate mofetil for treatment of steroid refractory acute graft-versus-host disease. Bone Marrow Transplant 2006; 37 : 1143–1147. Wolff D, Roessler V, Steiner B, Wilhelm S, Weirich V, Brenmoehl J et al. Treatment of steroid-resistant acute graft-versus-host disease with daclizumab and etanercept. Bone Marrow Transplant 2005; 35 : 1003–1010. Busca A, Locatelli F, Marmont F, Ceretto C, Falda M. Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. Am J Hematol 2007; 82 : 45–52. Xhaard A, Rocha V, Bueno B, de Latour RP, Lenglet J, Petropoulou A et al. Steroid-refractory acute GVHD: lack of long-term improved survival using new generation anticytokine treatment. Biol Blood Marrow Transplant J Am Soc Blood Marrow Transplant 2012; 18 : 406–413. Jaiswal SR, Zaman S, Chakrabarti A, Sehrawat A, Bansal S, Gupta M et al. T cell costimulation blockade for hyperacute steroid refractory graft versus-host disease in children undergoing haploidentical transplantation. Transpl Immunol 2016; 39 : 46–51. De Jong CN, Saes L, Klerk CPW, Van der Klift M, Cornelissen JJ, Broers AEC. Etanercept for steroid-refractory acute graft-versus-host disease: A single center experience. PloS One 2017; 12 : e0187184. Zhao Y, Wu H, Shi J, Luo Y, Li X, Lan J et al. Ruxolitinib combined with etanercept induce a rapid response to corticosteroid-refractory severe acute graft vs host disease after allogeneic stem cell transplantation: Results of a multi-center prospective study. Am J Hematol 2020; 95 : 1075–1084. García-Cadenas I, Rivera I, Martino R, Esquirol A, Barba P, Novelli S et al. Patterns of infection and infection-related mortality in patients with steroid-refractory acute graft versus host disease. Bone Marrow Transplant 2017; 52 : 107–113. Han HY, Shin JH, Kim SY. Effect of Etanercept on Steroid Refractory Graft-versus-host Disease in Children. kjh 2009; 44 : 212–219. Styczyński J, Tridello G, Koster L, Iacobelli S, van Biezen A, van der Werf S et al. Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors. Bone Marrow Transplant 2020; 55 : 126–136. Lindsay J, Kerridge I, Wilcox L, Tran S, O’Brien TA, Greenwood M et al. Infection-Related Mortality in Adults and Children Undergoing Allogeneic Hematopoietic Cell Transplantation: An Australian Registry Report. Transplant Cell Ther 2021; 27 : 798.e1-798.e10. Levine JE, Paczesny S, Mineishi S, Braun T, Choi SW, Hutchinson RJ et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood 2008; 111 : 2470–2475. El Jurdi N, Rayes A, MacMillan ML, Holtan SG, DeFor TE, Witte J et al. Steroid-dependent acute GVHD after allogeneic hematopoietic cell transplantation: risk factors and clinical outcomes. Blood Adv 2021; 5 : 1352–1359. Uygun V, Uygun DFK, Daloğlu H, Öztürkmen SI, Karasu G, Hazar V et al. Outcomes of high-grade gastrointestinal graft-versus-host disease posthematopoietic stem cell transplantation in children. Medicine (Baltimore) 2016; 95 : e5242. Castilla-Llorente C, Martin PJ, McDonald GB, Storer BE, Appelbaum FR, Deeg HJ et al. Prognostic factors and outcomes of severe gastrointestinal GVHD after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2014; 49 : 966–971. Table 2 and 3 Table 2 and 3 are available in the Supplementary Files section. Additional Declarations The authors have declared there is NO conflict of interest to disclose. Supplementary Files SupplementaryData.docx Supplemental Material Table2and3.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6528634","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":449281248,"identity":"dc9aface-9247-4c7b-a146-9e48976dbc72","order_by":0,"name":"Shlomo Elias","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYDACdsYGEJXAByI/ADEbOyEtzFAtbECCcQZICzNBLRAKrIWZB0kEJ+BnZm78+IOhLo+NvTvxsc2vbfJ8zAyMHz7m4NYi2czYLM3DcLiYjefsZuPcvtuGbcwMzJIzt+HWYnCYsUGageFAYptE7jbp3J7bjEAtbMy8eLTYH2Zs/gl0GESLZc9te4JaDJgZ2yR4GJghWhh+3E4kqEXiMGObNY/B4cQ2oF8MextuJ7cxMzbj9Qt/e/vjmz8q6hL72Xs3Pvjx57bt/Pbmgx8+4tECdR6UZmwDkw2E1CODP6QoHgWjYBSMgpECAMZZSckdvgLYAAAAAElFTkSuQmCC","orcid":"","institution":"Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem Israel","correspondingAuthor":true,"prefix":"","firstName":"Shlomo","middleName":"","lastName":"Elias","suffix":""},{"id":449281249,"identity":"7458901a-889a-4a6b-ab7c-e5e54c00d574","order_by":1,"name":"Or Gilad","email":"","orcid":"","institution":"The Hebrew University, Jerusalem, Israel","correspondingAuthor":false,"prefix":"","firstName":"Or","middleName":"","lastName":"Gilad","suffix":""},{"id":449281250,"identity":"a56407e2-773b-4561-9dbd-bd7b7b622de0","order_by":2,"name":"Irina Zaidman","email":"","orcid":"","institution":"Hadassah-Hebrew University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Irina","middleName":"","lastName":"Zaidman","suffix":""},{"id":449281251,"identity":"8005a762-918a-4551-8ce7-c0aedffa7d1a","order_by":3,"name":"Ehud Even-Or","email":"","orcid":"https://orcid.org/0000-0002-4292-6376","institution":"Hadassah-Hebrew University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Ehud","middleName":"","lastName":"Even-Or","suffix":""},{"id":449281252,"identity":"bf818c61-9732-46af-b85a-aaf944d421d5","order_by":4,"name":"Eran zimran","email":"","orcid":"","institution":"Faculty of Medicine, Hebrew University of Jerusalem","correspondingAuthor":false,"prefix":"","firstName":"Eran","middleName":"","lastName":"zimran","suffix":""},{"id":449281253,"identity":"4fe20fdd-76f9-4e42-92e2-061808c9bfaa","order_by":5,"name":"Adir Shaulov","email":"","orcid":"","institution":"Hadassah Medical Center and Faculty of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Adir","middleName":"","lastName":"Shaulov","suffix":""},{"id":449281254,"identity":"00f3f5a3-6139-4691-9119-111ed7173a37","order_by":6,"name":"Polina Stepensky","email":"","orcid":"","institution":"Hadassah-Hebrew University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Polina","middleName":"","lastName":"Stepensky","suffix":""},{"id":449281255,"identity":"1d925907-b2f5-45c6-969a-29ff38f7ba05","order_by":7,"name":"Sigal Grisariu","email":"","orcid":"","institution":"Hadassah University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sigal","middleName":"","lastName":"Grisariu","suffix":""},{"id":449281256,"identity":"82324d6e-688f-43b9-8329-f8a405ea55e7","order_by":8,"name":"Batia Avni","email":"","orcid":"","institution":"Faculty of Medicine, Hebrew University of Jerusalem","correspondingAuthor":false,"prefix":"","firstName":"Batia","middleName":"","lastName":"Avni","suffix":""}],"badges":[],"createdAt":"2025-04-25 11:46:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6528634/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6528634/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82142361,"identity":"222fb505-0281-469f-b808-c8ceb309b624","added_by":"auto","created_at":"2025-05-07 06:37:58","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":193709,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart illustrating the patient cohorts included in the study. \u003c/strong\u003eAbbreviations: ET, etanercept; BAT, best available treatment; SR-aGVHD, steroid-refractory acute graft-versus-host disease.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6528634/v1/15831b4c00e4e53e5552f366.jpg"},{"id":82146012,"identity":"3b7a558a-54b6-4e09-8163-8ba62191aeca","added_by":"auto","created_at":"2025-05-07 06:53:58","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":233767,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCumulative incidences of infections post-ET, stratified by age groups. (\u003c/strong\u003eA) bacteremia and (B) viremia. Abbreviations: ET, etanercept.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6528634/v1/fb455fb1ebc23a3e64f5007a.jpg"},{"id":82142369,"identity":"fecc641d-2596-48cc-876e-5ba76bd04108","added_by":"auto","created_at":"2025-05-07 06:37:58","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":488332,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePatient outcomes stratified by age group and treatment. \u003c/strong\u003epanels A–C show outcomes for adults and panels D–F for pediatric patients. (A, D) Overall survival, (B, E) event-free survival, and (C, F) non-relapse mortality.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6528634/v1/32671dca4f8b77ff8aefb077.jpg"},{"id":83665626,"identity":"5ae6a100-aa09-4d92-a597-99bc9f9de95a","added_by":"auto","created_at":"2025-05-30 11:35:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2045897,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6528634/v1/6255ba0d-5079-48f8-a3fe-b07849aa0b23.pdf"},{"id":82144493,"identity":"fed7851c-3ed8-430a-a173-46150c3aedb4","added_by":"auto","created_at":"2025-05-07 06:45:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":29121,"visible":true,"origin":"","legend":"Supplemental Material","description":"","filename":"SupplementaryData.docx","url":"https://assets-eu.researchsquare.com/files/rs-6528634/v1/7060e913ba5734231a7a1622.docx"},{"id":82142362,"identity":"b46e15fd-3f74-44eb-a6ad-e5d8e4ca2a68","added_by":"auto","created_at":"2025-05-07 06:37:58","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":42139,"visible":true,"origin":"","legend":"","description":"","filename":"Table2and3.docx","url":"https://assets-eu.researchsquare.com/files/rs-6528634/v1/b8d83f99eaa45c5eff569278.docx"}],"financialInterests":"The authors have declared there is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"Outcomes of Etanercept Treatment for Steroid-Refractory Acute Graft-Versus-Host Disease in Adult and Pediatric Patients: A Retrospective Single-Center Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe success of allogeneic hematopoietic stem cell transplantation (alloHSCT) is limited by graft-versus-host disease (GvHD). High-dose corticosteroids are first-line therapy for moderate to severe acute GvHD (aGvHD), but about 50% of patients develop steroid-refractory aGvHD (SR-aGvHD), with poor outcomes in grade III-IV disease.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eRuxolitinib is currently the only second-line treatment approved by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for SR-aGvHD in adults and adolescents aged\u0026thinsp;\u0026ge;\u0026thinsp;12 years.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e It has also been recently included in the 2024 European Society for Blood and Marrow Transplantation (EBMT) consensus guidelines.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Despite this, ruxolitinib demonstrates an overall response rate (ORR) of approximately 55%, with no significant reduction in non-relapse mortality (NRM) compared to best available therapy (BAT), and is not yet approved for children under 12 years of age.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Beyond second-line treatment, the standard of care remains undefined, underscoring the urgent need for additional effective therapies.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eEtanercept (ET), a TNF-α inhibitor, is approved for autoimmune conditions in patients\u0026thinsp;\u0026ge;\u0026thinsp;2 years.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e TNF-α is a key mediator in aGvHD, making ET a candidate for off-label use.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Studies show day-28 ORRs of 20\u0026ndash;69%\u003csup\u003e11,12\u003c/sup\u003e for ET monotherapy, and up to 91% when combined with other agents,\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e but 2-year survival rates remain\u0026thinsp;\u0026lt;\u0026thinsp;50%.\u003c/p\u003e \u003cp\u003eOne of the primary concerns associated with ET use is a high incidence of serious infections.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e However, similar infection rates have been reported with other immunosuppressive regimens.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn pediatric patients, concerns have also been raised regarding a potential increased risk of malignancy.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e Establishing a causal relationship, however, remains difficult due to confounding factors such as the underlying autoimmune condition and concurrent or previous oncogenic therapies.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Given the poor prognosis of SR-aGvHD, ET\u0026rsquo;s benefits may outweigh its risks.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eDue to age-related differences in transplant characteristics and GvHD biology,\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e further investigation is warranted into the efficacy and safety of ET in distinct age groups. To date, the impact of age on ET outcomes in SR-aGvHD remains insufficiently characterized.\u003c/p\u003e \u003cp\u003eHadassah Medical Center\u0026rsquo;s integrated pediatric and adult alloHSCT program offers a unique setting to evaluate ET across age groups. This single-center retrospective study assessed the efficacy and safety of ET versus best available therapy (BAT) in pediatric and adult patients with grade III\u0026ndash;IV SR-aGvHD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient cohort\u003c/h2\u003e \u003cp\u003eThis retrospective cohort study included adult and pediatric patients who underwent alloHSCT at the adult and pediatric BMT center at Hadassah Medical Center and were diagnosed with grade III-IV SR-aGvHD according to the published EBMT criteria,\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e between January 2010 and June 2019. Patient information is routinely recorded using a predefined case report form (CRF) and documented in electronic medical records (EMR) software. Patients were allocated to the ET arm if they received at least one dose of ET for SR-aGvHD (intervention). The rest of the patients were allocated to the BAT arm (control). ET was administered at a starting dose of 0.4 mg/kg/dose subcutaneously (SC) up to a maximum dose of 25 mg/dose SC, twice a week. There were no restrictions on the starting time or previous treatment lines. The institutional ET protocol was twice weekly for 4 weeks (\u0026ge;\u0026thinsp;72 hours between injections), followed by weekly for 4 more weeks, with clinical adjustments as needed for specific patietns. Further treatment lines were added as deemed necessary by the treating physicians. The choice of BAT was based on the physician's discretion, considering factors such as comorbidities, prior treatment and target organ involvement. Options for BAT included various therapies such as anti-thymocyte globulin (ATG), calcineurin inhibitors (CNI i.e., cyclosporine A or tacrolimus), extracorporeal photopheresis (ECP), intra-arterial corticosteroids, mesenchymal stromal cells (MSC), methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (sirolimus or everolimus), thalidomide, ruxolitinib, alemtuzumab, and vedolizumab.\u003c/p\u003e \u003cp\u003eConditioning regimens were classified as myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) according to the Center for International Blood and Marrow Transplant Research (CIBMTR).\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e Patients received standard institutional supportive care, including aGvHD prophylaxis, consisting of CNI with either MTX or MMF, and infection prophylaxis consisting of acyclovir and trimethoprim sulfamethoxazole. Blood count was monitored daily and engraftment was defined as per EBMT criteria.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e The study was conducted in accordance with the Declaration of Helsinki, and the protocol was reviewed and approved by the institutional review board (IRB) (approval no. 0637-20-HMO).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOutcomes\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint of the study was OS, defined as the time from aGvHD diagnosis to death due to any cause. Secondary endpoints were event-free survival (EFS), defined as the time from aGvHD diagnosis to the date of primary malignant disease relapse or death due to any cause; non-relapse mortality (NRM), defined as the time from aGvHD diagnosis to the date of death due to any cause except for primary disease relapse; rate of malignancy relapse (MR), calculated only for patients with primary malignant disease and defined as the time from aGvHD to the date of relapse; incidence of serious infections by day 30 after commencing ET, was defined according to the Common Terminology Criteria for Adverse Events (CTC-AE) version 5.0 as either grade 2 events requiring systemic treatment or grade 3 or higher. Additionally, response to treatment was evaluated and defined as complete response (CR) for stage 0 in all target organs, partial response (PR) for improvement of at least one stage in one affected organ without worsening or de novo aGvHD in other organs. Stable disease (SD) was defined as no change in stage in all affected organs, without de novo aGvHD in others. Progressive disease (PD) was defined as worsening of at least one affected organ or de novo aGvHD in any other organ.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eComparison between treatment groups was conducted based on variable features, as follows: Categorical variables were presented as numbers (%), and associations were tested using the χ2 test or Fisher's exact test, as appropriate. Continuous variables were described based on their distribution. For variables with a normal distribution the mean (\u0026plusmn;\u0026thinsp;standard distribution; STD) was reported, and differences were tested using independent Student's t-test. For variables with a non-normal distribution the median and interquartile range (IQR) were reported, and differences were tested using Mann-Whitney U test. Survival analyses utilized Kaplan-Meier estimates, with curves compared using the Log-Rank test. Cox regression models were used to identify predictors of overall survival (OS) and assess the impact of treatment with ET and age group on OS, with analyses performed separately for adult and pediatric cohorts. To identify predictors of OS, variables preceding the alloHSCT were tested using a univariate and a multivariate Cox regression model. The analyses were performed for the total cohort and also separately for the adult and pediatric cohorts and for the ET arm. The statistical analyses were performed using SPSS, version 26.0 (IBM Corp., Armonk, NY, USA) and RStudio, version 4.3.3., and the figures were plotted using GraphPad Prism, version 9.0.0 (GraphPad Software, San Diego, California, USA). A two-tailed p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\"\u003e\n \u003ch2\u003ePatient characteristics\u003c/h2\u003e\n \u003cp\u003eA total of 123 patients who underwent alloHSCT were diagnosed with grade III-IV SR-aGvHD, comprising 74 adults (60.2%) and 49 pediatric patients (39.8%) (Fig.\u0026nbsp;1). Among them, 15 adults and 31 pediatric patients received ET for the treatment of grade III-IV SR-aGvHD. The median age at transplantation was 42 years (range 18\u0026ndash;71) in adults and 7 years (range 0.3\u0026ndash;17) in pediatric patients. The majority of the patients received grafts from male, HLA-matched, ABO-matched and CMV seropositive donors (Table\u0026nbsp;1).\u003c/p\u003e\n \u003cdiv\u003e\n \u003ctable id=\"Tab1\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 1\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003e\u003cstrong\u003eBaseline Demographics and Transplant Characteristics of Adult and Pediatric Cohorts.\u003c/strong\u003e aGvHD, acute graft-versus-host disease; alloHSCT, allogeneic hematopoietic stem cell transplantation; ATG, anti-thymocyte globulin; BM, bone marrow; CB, cord blood; CMV, cytomegalovirus; CR, complete response; D/R, donor/recipient; ET, etanercept; GI, gastrointestinal; HLA, human leukocyte antigens; MA, myeloablative; MM, mismatch; PBSC, peripheral blood stem cells; SR-aGvHD, steroid refractory acute graft-versus-host disease; Trp, transplantation; yr, years.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAdults\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;74)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePediatrics\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;123)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at Trp, yr \u0026ndash; median (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42.1 (28.6\u0026ndash;55.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.2 (2.6\u0026ndash;12.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.75 (9.78\u0026ndash;45.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMale sex \u0026ndash; no. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e53 (71.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29 (59.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e82 (66.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.152\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary malignant disease \u0026ndash; no. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e70 (94.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e21 (42.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e91 (73.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eCR of malignant disease at alloHSCT \u0026ndash; no. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e39 (55.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (76.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55 (60.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.197\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDonor age, years \u0026ndash; median (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33.3 (26.2\u0026ndash;47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.1 (21.38\u0026ndash;33.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30.0 (23.27\u0026ndash;44.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender (D/R) \u0026ndash; no. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eM/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41 (55.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (32.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e57 (46.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003e0.101\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eM/F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (16.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (22.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (18.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF/F\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (18.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18 (14.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eF/M\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12 (16.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (17.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (20.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHLA Match\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e58 (78.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (51.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84 (68.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eABO match \u0026ndash; no. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMatch\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (47.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19 (38.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e54 (43.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003e0.748\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMinor MM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (23.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (22.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (22.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMajor MM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (17.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (22.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (19.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBidirectional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9 (12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (16.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (13.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eCMV serostatus (D/R) \u0026ndash; no. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+/+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e52 (72.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76 (64.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003e0.061\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-/+\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (13.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15 (32.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24 (20.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+/-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (5.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8 (6.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-/-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (8.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (8.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (8.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMA conditioning regimen \u0026ndash; no. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e50 (67.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47 (95.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97 (78.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eATG \u0026ndash; no. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31 (41.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e32 (65.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e63 (51.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.05\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eDouble GvHD prophylaxis \u0026ndash; no. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10 (13.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6 (12.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e107 (86.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.838\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eSource of graft \u0026ndash; no. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePBSC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (90.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (34.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84 (68.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"3\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.0001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5 (6.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30 (61.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e35 (28.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (3.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime from alloHSCT to aGvHD, days \u0026ndash; median (IQR)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (20\u0026ndash;54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (12\u0026ndash;37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28 (16-50.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eaGvHD grade at diagnosis \u0026ndash; no. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2 (2.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1 (2.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (2.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\" rowspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.05\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (14.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0 (0.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11 (8.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41 (55.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26 (53.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67 (54.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e20 (27.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22 (44.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42 (34.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"5\"\u003e\n \u003cp\u003e\u003cstrong\u003eaGvHD organ involvement at diagnosis \u0026ndash; no. (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e68 (91.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 (87.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e111 (90.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.449\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLiver\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17 (23.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16 (32.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e33 (26.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.235\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSkin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e41 (55.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e43 (87.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e84 (68.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;\u0026thinsp;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTreatment lines for SR-aGvHD \u0026ndash; median (range)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4 (2\u0026ndash;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (1\u0026ndash;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3 (1\u0026ndash;5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.447\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eIn adults, malignant diseases were predominant (94.6%), whereas in pediatric patients, diagnoses were evenly distributed between malignant (42.8%) and non-malignant (57.2%) conditions. Peripheral blood stem cells (PBSC) were the primary choice for transplants in adults (90.5%) while bone marrow (BM) grafts were preferred in pediatric patients (61.2%). The myeloablative (MA) conditioning regimen was predominant in both groups, used in 95.9% of pediatric and 67.6% of adult patients. Most patients received dual aGVHD prophylaxis. Both age groups predominantly presented with grade III-IV aGvHD at diagnosis of aGVHD. Double organ involvement was common, observed in 51.2% of patients, with the gastrointestinal tract being the most commonly affected (90.2%). Skin involvement was significantly more frequent in pediatric patients (87.7% vs. 55.4% in adults).\u003c/p\u003e\n \u003cp\u003eThere were no significant differences in donor characteristics including age, donor/recipient sex, HLA compatibility, ABO compatibility and CMV serostatus between the ET and BAT arms in both age groups \u003cstrong\u003e(Supplementary Tables\u0026nbsp;1, 2\u003c/strong\u003e). In the pediatric cohort, patients in the ET arm had a higher probability of being diagnosed with a non-malignant primary disease (71.0% vs. 33.3%, p\u0026thinsp;=\u0026thinsp;0.010), received bone marrow grafts (74.2% vs. 38.9%, p\u0026thinsp;=\u0026thinsp;0.0495) and dual aGVHD prophylaxis more often than those in the BAT arm (100.0% vs. 66.7%, p\u0026thinsp;=\u0026thinsp;0.001) (\u003cstrong\u003eSupplementary Tables\u0026nbsp;1, 2\u003c/strong\u003e). In the adult cohort, there was a significant difference in aGvHD severity at diagnosis, with patients in the BAT arm presenting with a higher proportion of grade III-IV aGVHD (88.1% vs. 60.0%, p\u0026thinsp;=\u0026thinsp;0.011). No significant differences were observed between adult and pediatric patients treated with ET, except from age-related baseline differences already described (\u003cstrong\u003eSupplementary Table\u0026nbsp;3\u003c/strong\u003e). Notably, in the ET arm, pediatric patients presented with a higher grade of aGVHD (grade III-IV 96.8% vs. 60.0%, p\u0026thinsp;=\u0026thinsp;0.003) and underwent fewer treatment lines prior to ET compared to adults (median 1.5 vs. 4, respectively, p\u0026thinsp;=\u0026thinsp;0.001) (\u003cstrong\u003eSupplementary Table\u0026nbsp;3\u003c/strong\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003eResponse to treatment\u003c/h2\u003e\n \u003cp\u003eThe proportion of patients who achieved CR of aGvHD signs and symptoms was significantly higher in the pediatric cohort (57.1% vs. 17.6% in adults, p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001). Within the pediatric cohort, resolution of all SR-aGvHD-related signs and symptoms was more common in the ET arm compared to the BAT arm (71.0% vs. 33.3%, p\u0026thinsp;=\u0026thinsp;0.016). In contrast, among adults, CR rates were comparable between the ET and BAT arms (6.7% vs. 20.3%, p\u0026thinsp;=\u0026thinsp;0.282). A majority of pediatric patients achieved CR with ET (58.1%), whereas only 6.7% of adults did (p\u0026thinsp;=\u0026thinsp;0.0009). Nearly two-thirds (64.5%) of pediatric patients in the ET arm did not require additional treatment, while a similar proportion of adults (60.0%) received one to three treatment lines after ET. Among those requiring further therapy, a significant majority of pediatric patients achieved CR (72.7% vs. 0.0% in adults, p\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eRelapses\u003c/h3\u003e\n\u003cp\u003eIn the entire cohort, 13 patients (14.2% of those with primary malignant disease) experienced relapse of their primary disease. The median interval from aGvHD diagnosis to relapse was 2.2 months. The 5-year relapse rate following aGvHD diagnosis was comparable in the adult and pediatric cohorts (28.7% vs. 13.4%, p\u0026thinsp;=\u0026thinsp;0.233). Of those who relapsed, 11 patients (84.6%) died from relapse after a median of 6.1 months. The remaining two were lost to follow-up within 30 days but had active disease at last contact.\u003c/p\u003e\n\u003ch3\u003eInfections post-ET treatment\u003c/h3\u003e\n\u003cp\u003eOverall, within 30 days of ET administration, severe bloodstream infections occurred in 42 patients (91.3%), including 21 cases of bacteremia (45.6%), 34 of viremia (73.9%), and 5 of fungemia (10.9%). Bacteremia was significantly more common in adults compared to pediatric patients (60.0% vs. 38.7%, respectively, HR 2.6, 95% CI 0.9\u0026ndash;7.2, p\u0026thinsp;=\u0026thinsp;0.022, Fig.\u0026nbsp;2A). The median time to bacteremia was 10 days in adults and 16 days in pediatric patients (p\u0026thinsp;=\u0026thinsp;0.596). Gram-negative bacteria predominated in adults (66.6%), while gram-positive species were more frequent in pediatric patients (91.7%, p\u0026thinsp;=\u0026thinsp;0.076). Sixteen patients (34.8%) experienced bacterial infections in other sites, primarily in the urinary tract, with adults showing a borderline higher cumulative incidence of such infections at day\u0026thinsp;+\u0026thinsp;30 compared to pediatric patients (55.1% vs. 29.0%, p\u0026thinsp;=\u0026thinsp;0.052). Viremia was the most frequent infection in pediatric patients, but no significant age-related difference was observed (59.4% vs. 83.9% at day\u0026thinsp;+\u0026thinsp;30 for adults vs. pediatric patients, p\u0026thinsp;=\u0026thinsp;0.241; Fig.\u0026nbsp;2B). The median time to viremia was 4.5 days in adults and 6.5 in pediatric patients (p\u0026thinsp;=\u0026thinsp;0.246). Twenty-one patients (45.6%) had viral infections elsewhere, mostly urinary BK virus. Fungemia incidence was low (11.6% at day\u0026thinsp;+\u0026thinsp;30) and similar between adults and pediatric patients (6.7% vs. 12.9%, p\u0026thinsp;=\u0026thinsp;0.612).\u003c/p\u003e\n\u003cdiv id=\"Sec11\"\u003e\n \u003ch2\u003eSurvival\u003c/h2\u003e\n \u003cp\u003eThe median OS of the entire cohort was 6.9 months following aGvHD diagnosis. During the follow-up period, 75 patients died: 11 due to a relapse of primary malignant disease, 16 from infections, and 46 from aGvHD, 34 of whom also had concurrent infections contributing to their deaths. Among the two latter groups (death due to infection or aGVHD with infection), 33 patients had bacterial infections, seven had viral infections, and nine had uncontrolled fungal infections at the time of death. In the ET group, 11 infection-related deaths were recorded. Bacterial infections were the leading cause of death in the adult population (five out of seven cases), with one adult succumbing to a viral infection and three patients dying from fungal infections, two of whom were in the pediatric group. Additionally, one patient died from sinusoidal obstruction syndrome (SOS). The 12- and 24-month OS probabilities were significantly higher in the pediatric cohort compared with the adult cohort (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Among pediatric patients, ET treatment was associated with a significant survival advantage compared to BAT (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05, Fig.\u0026nbsp;3D). Conversely, in the adult cohort, ET treatment was associated with a trend toward lower survival compared to BAT, although this difference did not reach statistical significance (Fig.\u0026nbsp;3A, p\u0026thinsp;=\u0026thinsp;0.085). Similar trends were observed for event-free survival (EFS) (Fig.\u0026nbsp;3B, 3E\u003cstrong\u003e)\u003c/strong\u003e, with the pediatric cohort demonstrating a significantly higher EFS compared to adults (median not reached versus 3 months, respectively, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Additionally, the cumulative incidence of non-relapse mortality (NRM) (Fig.\u0026nbsp;3C, 3F) was significantly lower in pediatric patients compared to adults (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e\n \u003cp\u003eIn univariate analysis, several variables had a statistically significant impact on OS in the entire cohort (Table 2). These included: age category (adults versus pediatric), presence of primary malignant disease, donor type, conditioning intensity, ATG administration, graft source and time from diagnosis to transplant. In multivariate analysis, incorporating all significant variables occurring prior to aGvHD diagnosis, only age category and time from diagnosis to transplant retained significance (HR\u0026thinsp;=\u0026thinsp;3.515, 95% CI: 2.056\u0026ndash;6.007, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; HR\u0026thinsp;=\u0026thinsp;1.102, 95% CI: 1.039\u0026ndash;1.17, p\u0026thinsp;=\u0026thinsp;0.001). In univariate analysis of patients treated with ET, several variables were significantly associated with OS, including age category, ethnicity, presence of malignant disease, donor type, conditioning intensity, ATG administration, graft source, liver involvement at ET initiation, number of treatment lines before ET, and interval from aGvHD diagnosis to ET treatment (Table 3). In multivariate analysis of variables occurring prior to ET treatment, age category, primary malignant disease and liver involvement at ET initiation remained statistically significant predictors (HR\u0026thinsp;=\u0026thinsp;12.05, 95% CI: 3.77\u0026ndash;38.53, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 HR\u0026thinsp;=\u0026thinsp;3.76, 95% CI: 1.19\u0026ndash;11.84, p\u0026thinsp;=\u0026thinsp;0.024; HR\u0026thinsp;=\u0026thinsp;3.65, 95% CI: 1.42\u0026ndash;9.40, p\u0026thinsp;=\u0026thinsp;0.007).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eEffective salvage treatments for steroid-refractory acute graft-versus-host disease (SR-aGvHD) resistant to ruxolitinib remain an unmet clinical need.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Several retrospective studies have evaluated ET in both adults and children, with sample sizes ranging from 13 to 124 patients.\u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan additionalcitationids=\"CR26 CR27 CR28 CR29 CR30 CR31\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e Some focused exclusively on adults, with sample sizes between 30 and 58, reporting overall response rates (ORR) of 36\u0026ndash;83% and overall survival (OS) of 0\u0026ndash;69%.\u003csup\u003e12,13,16,27,30\u003c/sup\u003e Data in pediatrics are more limited but indicate high response rates, up to 68%.\u003csup\u003e33\u003c/sup\u003e This study retrospectively compared ET and best available therapy (BAT) in SR-aGvHD patients of all ages treated at Hadassah\u0026rsquo;s combined adult and pediatric center.\u003c/p\u003e \u003cp\u003eET was associated with significantly improved OS and event-free survival (EFS) in pediatric patients (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001, respectively), along with lower non-relapse mortality (NRM) (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). In contrast, adults showed a trend toward inferior survival (p\u0026thinsp;=\u0026thinsp;0.085), aligning with De Jong\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e and Park\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, but differing from Busca et al.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e Importantly, survival data in pediatrics remain scarce.\u003c/p\u003e \u003cp\u003eRelapse remains the leading cause of death post-alloHSCT, accounting for approximately 40% of all deaths.\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e In our cohort, relapse incidence was 14.2% among patients with malignant disease. Notably, only one relapse occurred in the ET group. No pediatric patients with malignant disease treated with ET (n\u0026thinsp;=\u0026thinsp;9) relapsed, suggesting ET may be safe in this population.\u003c/p\u003e \u003cp\u003eInfection is a major cause of mortality following alloHSCT.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e Treatment with methylprednisolone (MP) plus ET as initial aGvHD therapy has not been shown to increase the risk of bacterial, viral, or fungal infections compared to MP alone in mixed adult-pediatric cohorts.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e In our study, infection was the most frequent cause of death in both treatment arms. Viremia predominated in pediatric patients, while bacteremia was more common in adults. Although high infection rates with ET have been reported, age-specific infection patterns are underexplored.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e In our cohort, infection was the leading cause of death in both ET and BAT arms, with bacterial infections being the most common across all groups. Importantly, ET treatment was not associated with higher infection-related mortality.\u003c/p\u003e \u003cp\u003eAge is a key factor in aGvHD outcomes., with better outcomes reported in pediatric patients with grade III-IV aGvHD than in adults.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan additionalcitationids=\"CR38\" citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e In our study, the OS probability was significantly superior in the pediatric cohort compared with the adult cohort, supporting previous publications on the association between advanced age and dismal prognosis in these patients. Moreover, among patients treated with ET, pediatric patients had a markedly higher response rate compared to adults (71% vs 6.7%, respectively). Most pediatric patients did not require additional therapy after ET, whereas nearly two-thirds of adults received one to three additional treatment lines. When comparing ET to BAT, pediatric patients demonstrated a significantly better response rate, while the adult cohort showed a significant opposite effect. Several studies examining ET for SR-aGVHD in adults have shown variable outcomes with second-line response rates up to 60% with wide variation in complete response (CR) rates.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e In our study, ET was administered later in the treatment course for adults (median fourth line) compared to earlier use in pediatric patients (median 1.5 lines), which may partially explain the observed lower response rates in adults.\u003c/p\u003e \u003cp\u003eThis study has limitations, including its retrospective design and variability in prior treatments, which complicate assessment of ET\u0026rsquo;s isolated effect. ET was also initiated later in adults, possibly contributing to poorer outcomes. The timing and dosing of ET remain undefined, leading to inconsistency in its use. Finally, the role of ET in the ruxolitinib era, now the standard second-line therapy, remains unclear and warrants prospective evaluation.\u003c/p\u003e \u003cp\u003eIn conclusion, ET showed benefit in pediatric patients but limited efficacy in adults. Further randomized trials are needed to clarify its optimal use, particularly regarding timing, age, and disease type (malignant vs. non-malignant).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSE is supported by Hadassah \u0026ldquo;OFEK\u0026rdquo; research fund, ASH global research award, ISF grant (2873/23), Israel Society of Hematology and Transfusion Medicine\u003cspan dir=\"RTL\"\u003e \u003c/span\u003eresearch grant, and a grant from the Ministry of Innovation, Science and Technology (0007868).\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eConflict of Interest \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSE received honoraria from Novartis and Gilead. \u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOG was responsible for data collection, analysis, and writing the manuscript. SE, SG, and BA supervised the project and contributed to writing the manuscript. IZ, EEO, EZ, AS, and PS contributed to the manuscript and participated in its critical revision. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing financial interests related to the work described in this manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHoltan SG, Yu J, Paranagama D, Tang J, Choe HK, Naim A \u003cem\u003eet al.\u003c/em\u003e Disease progression, hospital readmissions, and clinical outcomes for patients with steroid-refractory acute graft-versus-host disease: A multicenter, retrospective study. \u003cem\u003eBone Marrow Transplant\u003c/em\u003e 2022; \u003cstrong\u003e57\u003c/strong\u003e: 1399\u0026ndash;1404.\u003c/li\u003e\n\u003cli\u003eWestin JR, Saliba RM, De Lima M, Alousi A, Hosing C, Qazilbash MH \u003cem\u003eet al.\u003c/em\u003e Steroid-Refractory Acute GVHD: Predictors and Outcomes. \u003cem\u003eAdv Hematol\u003c/em\u003e 2011; \u003cstrong\u003e2011\u003c/strong\u003e: 601953.\u003c/li\u003e\n\u003cli\u003eJagasia M, Perales M-A, Schroeder MA, Ali H, Shah NN, Chen Y-B \u003cem\u003eet al.\u003c/em\u003e Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial. \u003cem\u003eBlood\u003c/em\u003e 2020; \u003cstrong\u003e135\u003c/strong\u003e: 1739\u0026ndash;1749.\u003c/li\u003e\n\u003cli\u003eZeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R \u003cem\u003eet al.\u003c/em\u003e Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. \u003cem\u003eN Engl J Med\u003c/em\u003e 2020; \u003cstrong\u003e382\u003c/strong\u003e: 1800\u0026ndash;1810.\u003c/li\u003e\n\u003cli\u003ePenack O, Marchetti M, Aljurf M, Arat M, Bonifazi F, Duarte RF \u003cem\u003eet al.\u003c/em\u003e Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. \u003cem\u003eLancet Haematol\u003c/em\u003e 2024; \u003cstrong\u003e11\u003c/strong\u003e: e147\u0026ndash;e159.\u003c/li\u003e\n\u003cli\u003eMurray A, Linn SM, Yu B, Novitzky-Basso I, Mattsson J, Kennah M \u003cem\u003eet al.\u003c/em\u003e Real-world experience with ruxolitinib therapy for steroid-refractory acute graft versus host disease. \u003cem\u003eBone Marrow Transplant\u003c/em\u003e 2024; \u003cstrong\u003e59\u003c/strong\u003e: 759\u0026ndash;764.\u003c/li\u003e\n\u003cli\u003eKurtzberg J, Abdel-Azim H, Carpenter P, Chaudhury S, Horn B, Mahadeo K \u003cem\u003eet al.\u003c/em\u003e A Phase 3, Single-Arm, Prospective Study of Remestemcel-L, Ex Vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells for the Treatment of Pediatric Patients Who Failed to Respond to Steroid Treatment for Acute Graft-versus-Host Disease. \u003cem\u003eBiol Blood Marrow Transplant J Am Soc Blood Marrow Transplant\u003c/em\u003e 2020; \u003cstrong\u003e26\u003c/strong\u003e: 845\u0026ndash;854.\u003c/li\u003e\n\u003cli\u003eMalard F, Huang X-J, Sim JPY. 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Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. \u003cem\u003eAm J Hematol\u003c/em\u003e 2007; \u003cstrong\u003e82\u003c/strong\u003e: 45\u0026ndash;52.\u003c/li\u003e\n\u003cli\u003eXhaard A, Rocha V, Bueno B, de Latour RP, Lenglet J, Petropoulou A \u003cem\u003eet al.\u003c/em\u003e Steroid-refractory acute GVHD: lack of long-term improved survival using new generation anticytokine treatment. \u003cem\u003eBiol Blood Marrow Transplant J Am Soc Blood Marrow Transplant\u003c/em\u003e 2012; \u003cstrong\u003e18\u003c/strong\u003e: 406\u0026ndash;413.\u003c/li\u003e\n\u003cli\u003eJaiswal SR, Zaman S, Chakrabarti A, Sehrawat A, Bansal S, Gupta M \u003cem\u003eet al.\u003c/em\u003e T cell costimulation blockade for hyperacute steroid refractory graft versus-host disease in children undergoing haploidentical transplantation. \u003cem\u003eTranspl Immunol\u003c/em\u003e 2016; \u003cstrong\u003e39\u003c/strong\u003e: 46\u0026ndash;51.\u003c/li\u003e\n\u003cli\u003eDe Jong CN, Saes L, Klerk CPW, Van der Klift M, Cornelissen JJ, Broers AEC. Etanercept for steroid-refractory acute graft-versus-host disease: A single center experience. \u003cem\u003ePloS One\u003c/em\u003e 2017; \u003cstrong\u003e12\u003c/strong\u003e: e0187184.\u003c/li\u003e\n\u003cli\u003eZhao Y, Wu H, Shi J, Luo Y, Li X, Lan J \u003cem\u003eet al.\u003c/em\u003e Ruxolitinib combined with etanercept induce a rapid response to corticosteroid-refractory severe acute graft vs host disease after allogeneic stem cell transplantation: Results of a multi-center prospective study. \u003cem\u003eAm J Hematol\u003c/em\u003e 2020; \u003cstrong\u003e95\u003c/strong\u003e: 1075\u0026ndash;1084.\u003c/li\u003e\n\u003cli\u003eGarc\u0026iacute;a-Cadenas I, Rivera I, Martino R, Esquirol A, Barba P, Novelli S \u003cem\u003eet al.\u003c/em\u003e Patterns of infection and infection-related mortality in patients with steroid-refractory acute graft versus host disease. \u003cem\u003eBone Marrow Transplant\u003c/em\u003e 2017; \u003cstrong\u003e52\u003c/strong\u003e: 107\u0026ndash;113.\u003c/li\u003e\n\u003cli\u003eHan HY, Shin JH, Kim SY. Effect of Etanercept on Steroid Refractory Graft-versus-host Disease in Children. \u003cem\u003ekjh\u003c/em\u003e 2009; \u003cstrong\u003e44\u003c/strong\u003e: 212\u0026ndash;219.\u003c/li\u003e\n\u003cli\u003eStyczyński J, Tridello G, Koster L, Iacobelli S, van Biezen A, van der Werf S \u003cem\u003eet al.\u003c/em\u003e Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors. \u003cem\u003eBone Marrow Transplant\u003c/em\u003e 2020; \u003cstrong\u003e55\u003c/strong\u003e: 126\u0026ndash;136.\u003c/li\u003e\n\u003cli\u003eLindsay J, Kerridge I, Wilcox L, Tran S, O\u0026rsquo;Brien TA, Greenwood M \u003cem\u003eet al.\u003c/em\u003e Infection-Related Mortality in Adults and Children Undergoing Allogeneic Hematopoietic Cell Transplantation: An Australian Registry Report. \u003cem\u003eTransplant Cell Ther\u003c/em\u003e 2021; \u003cstrong\u003e27\u003c/strong\u003e: 798.e1-798.e10.\u003c/li\u003e\n\u003cli\u003eLevine JE, Paczesny S, Mineishi S, Braun T, Choi SW, Hutchinson RJ \u003cem\u003eet al.\u003c/em\u003e Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. \u003cem\u003eBlood\u003c/em\u003e 2008; \u003cstrong\u003e111\u003c/strong\u003e: 2470\u0026ndash;2475.\u003c/li\u003e\n\u003cli\u003eEl Jurdi N, Rayes A, MacMillan ML, Holtan SG, DeFor TE, Witte J \u003cem\u003eet al.\u003c/em\u003e Steroid-dependent acute GVHD after allogeneic hematopoietic cell transplantation: risk factors and clinical outcomes. \u003cem\u003eBlood Adv\u003c/em\u003e 2021; \u003cstrong\u003e5\u003c/strong\u003e: 1352\u0026ndash;1359.\u003c/li\u003e\n\u003cli\u003eUygun V, Uygun DFK, Daloğlu H, \u0026Ouml;zt\u0026uuml;rkmen SI, Karasu G, Hazar V \u003cem\u003eet al.\u003c/em\u003e Outcomes of high-grade gastrointestinal graft-versus-host disease posthematopoietic stem cell transplantation in children. \u003cem\u003eMedicine (Baltimore)\u003c/em\u003e 2016; \u003cstrong\u003e95\u003c/strong\u003e: e5242.\u003c/li\u003e\n\u003cli\u003eCastilla-Llorente C, Martin PJ, McDonald GB, Storer BE, Appelbaum FR, Deeg HJ \u003cem\u003eet al.\u003c/em\u003e Prognostic factors and outcomes of severe gastrointestinal GVHD after allogeneic hematopoietic cell transplantation. \u003cem\u003eBone Marrow Transplant\u003c/em\u003e 2014; \u003cstrong\u003e49\u003c/strong\u003e: 966\u0026ndash;971.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 2 and 3","content":"\u003cp\u003eTable 2 and 3 are available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6528634/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6528634/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSteroid-refractory acute graft-versus-host disease (SR-aGvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (alloHSCT), particularly in grade III\u0026ndash;IV cases. While ruxolitinib is the only approved second-line therapy for patients aged 12 and older, its limited efficacy and lack of approval for younger children underscore the need for alternatives. Etanercept (ET), a TNF-alpha inhibitor, has been used off-label for SR-aGvHD, but age-stratified data are limited.\u003c/p\u003e \u003cp\u003eIn this retrospective single-center study, we analyzed outcomes of 103 patients with grade III\u0026ndash;IV SR-aGvHD treated with either ET or best available therapy (BAT) at Hadassah Medical Center. Pediatric patients had significantly better overall survival (OS) and event-free survival (EFS) than adults (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). Among ET-treated patients, children had a 71% response rate versus 6.7% in adults. ET use in pediatric patients was associated with improved survival over BAT (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), while adults showed a non-significant trend toward worse outcomes (p\u0026thinsp;=\u0026thinsp;0.085). Infection was the leading cause of death across all groups, though ET was not linked to increased infection-related mortality.\u003c/p\u003e \u003cp\u003eThese findings support ET as a potentially effective and safe salvage therapy in pediatric SR-aGvHD, with limited benefit in adults. Prospective studies are needed to refine age-specific treatment strategies.\u003c/p\u003e","manuscriptTitle":"Outcomes of Etanercept Treatment for Steroid-Refractory Acute Graft-Versus-Host Disease in Adult and Pediatric Patients: A Retrospective Single-Center Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-07 06:37:53","doi":"10.21203/rs.3.rs-6528634/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2324b852-f7c8-41d4-b422-2d4c883b5d83","owner":[],"postedDate":"May 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":47810794,"name":"Health sciences/Diseases/Haematological diseases"},{"id":47810795,"name":"Health sciences/Medical research/Clinical trial design"}],"tags":[],"updatedAt":"2025-05-30T11:27:27+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-07 06:37:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6528634","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6528634","identity":"rs-6528634","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}