RARE DISEASE
Acute graft versus host disease
Acute graft versus host disease
Acute graft versus host disease
Drug discovery
28
drugs
With orphan designations
Overview
Acute graft-versus-host disease (aGVHD) is a life-threatening immune-mediated complication occurring post-allogeneic hematopoietic stem cell transplantation (HSCT), where donor T cells attack host tissues. It primarily affects the skin (rash), liver (jaundice), and gastrointestinal tract (diarrhea), typically emerging within 100 days post-transplant [1][2][5]. Incidence ranges from 35%–50%, with severity and prognosis influenced by HLA compatibility, conditioning intensity, and prophylaxis regimens [1][3][15]. First-line therapy involves corticosteroids, while refractory cases require salvage immunosuppression [2][8][16].
Burden
Healthcare utilization: Grade III/IV aGVHD doubles hospitalization duration (median 28 vs. 22 days) and ICU admission rates (13% vs. 6%) [4][7]
Economic impact: Mean 100-day costs reach $120,929 for severe cases, driven by prolonged hospital stays and readmissions [4]
Mortality: >50% non-relapse mortality in steroid-refractory cases, particularly with lower GI involvement [4][8][15]
Therapies
First-line: High-dose corticosteroids (e.g., methylprednisolone 2 mg/kg/day) [2][10][16]
Second-line: Anti-TNF agents (infliximab), JAK inhibitors (ruxolitinib), or interleukin-2 receptor antagonists [8][16][18]
Prophylaxis: Calcineurin inhibitors (tacrolimus) combined with methotrexate or mycophenolate mofetil [3][5][8]
Categories: rare immunological diseases, rare transplant-related disorders
Research Papers
3,410 drug discovery papers about Acute graft versus host disease, with 2 first-in-class and 23 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
3,410 drug discovery papers about Acute graft versus host disease, with 2 first-in-class and 23 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-11 | Phenotype-Specific Associations Between Graft‑Versus‑Host Disease and Post‑Transplant Outcomes.
Disease relapse remains the leading cause of failure following allogeneic hematopoietic cell transplantation (HCT). As novel prophylactic strategies increasingly aim to universally eliminate all forms of graft‑versus‑host disease (GVHD), how these approaches may inadvertently sacrifice graft‑versus‑leukemia (GVL) activity in the post‑transplant cyclophosphamide (PTCy) era is unclear. To evaluate the associations between time‑updated GVHD phenotypes and clinical outcomes, including relapse, non‑relapse mortality (NRM), and overall survival (OS), in patients undergoing PTCy‑based haploidentical or mismatched unrelated donor (MMUD) HCT. This was a retrospective cohort study using the Center for International Blood and Marrow Transplant Research registry. Participants included 7,055 patients with hematologic malignancies who received a first haploidentical or MMUD HCT with PTCy from 2013-2021. Associations with relapse, NRM and OS were evaluated using multi‑state time‑dependent Cox proportional hazards models and a multi‑state random survival forest (MS‑RSF). Time‑updated acute and chronic GVHD phenotypes included isolated grade II acute GVHD (aGVHD), grade III-IV aGVHD, mild chronic GVHD (cGVHD), and immunosuppressive therapy-requiring (IST‑requiring) cGVHD. IST‑requiring cGVHD without antecedent aGVHD was associated with a lower modeled relapse hazard compared with remaining GVHD‑free (Hazard Ratio [HR], 0.74; 95% confidence interval [CI], 0.62-0.89; False Discovery Rate (FDR)-adjusted p (q)=0.006) and lower overall mortality (HR 0.62; 95% CI, 0.53-0.73; q < 0.001). In contrast, grade III-IV aGVHD was associated with significantly higher modeled NRM (HR, 3.15; 95% CI, 2.57-3.84; q < 0.001). Mild cGVHD and isolated grade II aGVHD showed intermediate patterns without consistent associations. These associations were directionally consistent across multiple analytic approaches, including standard time‑dependent Cox regression, dynamic and fixed landmark analyses, and MS‑RSF. In this large PTCy‑treated mismatched donor cohort, IST‑requiring cGVHD was the GVHD phenotype most consistently associated with lower relapse incidence, whereas severe aGVHD was associated with higher NRM. These findings highlight heterogeneity in GVHD phenotypes and suggest that strategies distinguishing toxic acute GVHD from chronic alloreactivity patterns may better balance morbidity and long‑term disease control. Given that relapse remains the predominant cause of post‑transplant mortality, approaches aiming to universally eliminate all GVHD warrant careful reconsideration.
2026-08-06 | Recipient Endothelial IRF1 mediates IFNγ-driven tissue tolerance in mouse models of acute Graft-versus-Host Disease.
Recipient endothelial cells (ECs) actively respond to inflammation during allogeneic hematopoietic cell transplant (allo-HCT), yet mechanisms by which ECs influence acute graft-versus-host-disease (GVHD) pathology remain incompletely defined. Single cell RNA-sequencing of ECs isolated from a GVHD target organ, the liver, showed rapid, subset-specific transcriptional reprogramming after allo-HCT, with induction of canonical interferon-γ (IFNγ)-inducible genes including interferon regulatory factor 1 (IRF1), MHC II, and PD-L1 in lymphatic ECs (LECs). In allo-HCT recipients, circulating IFNγ peaked on day 4 (early), decreased but remained elevated at day 14 (late), and declined by day 21, with a concordant induction of IRF1+ LECs in the liver and GI tract. IFNγ neutralization with anti-IFNγ monoclonal antibody at either early or late time points attenuated IRF1⁺MHCII⁺PD-L1⁺ LEC activation. Notably, early donor T cell expansion was IFNγ-independent, whereas late IFNγ blockade selectively impaired donor Treg, but not Th1, expansion, leading to accelerated GVHD. Using in vitro LEC-CD4 T cell co-cultures and allo-HCT in Irf1-/- bone marrow chimera recipients, we show that recipient ECs that cannot mediate IFNγ-IRF1 signaling exhibit reduced activation and apoptosis, but also have impaired Treg expansion, increased donor Th1/Treg ratios, and worsened GVHD severity. Finally, pharmacological JAK inhibition in allo-HCT recipient mice spares IRF1+ LECs and Tregs while reducing pathogenic Th1 cells, correlating with reduced GVHD severity and improved survival. Our findings identify a role for the lymphatic endothelial IFNγ-IRF1 axis in regulating early vascular remodeling, donor T cell mediated tolerance, underscoring a potential "goldilocks" level of pathway activation required to improve post-transplant outcomes.
2026-07-29 | Immediate versus delayed short-course ruxolitinib for acute GVHD prophylaxis after myeloablative allogeneic hematopoietic stem cell transplantation.
The optimal timing of ruxolitinib initiation for acute graft-versus-host disease (aGVHD) prophylaxis after myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains undefined, particularly within anti-thymocyte globulin (ATG)-based platforms. This study compared immediate versus delayed short-course ruxolitinib initiation using a concurrent two-strategy design. This single-center, retrospective, concurrent two-strategy cohort study enrolled 39 consecutive patients aged 15-65 years with hematologic malignancies who received standard "Beijing Protocol" backbone plus a 14-day short-course ruxolitinib. Patients were non-randomly assigned to immediate (day +1; n = 19) or delayed (at confirmed neutrophil engraftment; median day +13; n = 20) initiation. Haploidentical transplantation and ATG use were perfectly collinear in this cohort, complicating attribution of outcome differences. Co-primary endpoints were 100-day cumulative incidence of grade II-IV aGVHD and 2-year overall survival (OS). A 1:1 propensity score matching (PSM) analysis (12 pairs) served as a sensitivity analysis. Given the limited sample size, multivariable models were constructed as exploratory analyses and should be interpreted with caution. Delayed initiation was associated with lower 100-day grade II-IV aGVHD (10.0% vs. 42.1%, P = 0.031), lower cytomegalovirus (CMV) reactivation (35.0% vs. 73.7%, P = 0.025), reduced grade ≥3 hematologic toxicity (35.0% vs. 68.4%, P = 0.043), and superior 2-year OS rate (90.0% vs. 57.9%, P = 0.012). PSM confirmed these findings (aGVHD: 8.3% vs. 41.7%, P = 0.039; OS: 91.7% vs. 58.3%, P = 0.028). In the exploratory haploidentical subgroup (n = 26), grade II-IV aGVHD was 11.8% vs. 55.6% (P = 0.028) and OS was 94.1% vs. 55.6% (P = 0.006). In exploratory multivariable models, immediate initiation was associated with higher aGVHD risk [adjusted subdistribution hazard ratio (sHR) 2.31, 95% CI 1.15-4.64, P = 0.019] and higher NRM (adjusted sHR 4.65, 95% CI 1.47-14.72, P = 0.009). Relapse risk was not significantly different (adjusted sHR 2.17, 95% CI 0.85-5.56, P = 0.095). Pre-transplant measurable residual disease (MRD) positivity was associated with inferior OS (adjusted hazard ratio [HR] 7.81, 95% CI 1.12-54.32, P = 0.038). Median follow-up was 42.1 months. Interpretation of the CMV reactivation difference is limited by the absence of donor and recipient CMV serostatus data. Delaying short-course ruxolitinib until neutrophil engraftment was associated with reduced aGVHD and NRM and improved survival after myeloablative allo-HSCT. No statistically significant difference in relapse risk was observed, although a clinically meaningful difference cannot be excluded. These findings warrant confirmation in a multicenter randomized trial with adequate sample size, stratified by donor type and pre-transplant MRD.
2026-07-28 | Inhibition of Fatty Acid Metabolism in Alloreactive T Cells Minimizes Acute Graft-versus-host Disease 2303327
Abstract Introduction Acute Graft-Versus-Host Disease (GVHD) is a complication of allogeneic blood and marrow transplantation in which alloreactive T cells destroy tissues in the liver, skin, and gastrointestinal tract. The dual energetic demands of activation and proliferation push alloreactive T cells into adopting fatty acid oxidation (FAO), a pathway that then becomes a therapeutic target for mitigating GVHD. Here we demonstrate the results of genetic deletion of FAO machinery in donor T cells, and administration of a novel FAO-targeting pharmaceutical as a GVHD treatment. Methods We utilized a C57BL/6 donor into B6D2F1/J recipient model of GVHD. Post-transplant, recipient clinical scores were calculated weekly and weight assessed twice weekly. Genetic FAO inhibition was achieved through a T cell-specific knockout (KO) of carnitine palmitoyltransferase 1a in C57BL/6 mice; recipient mice received either KO (n = 16) or wild-type (n = 16) splenic T cells in transplant. For compound testing, recipient mice with wild-type T cell transplants received either the drug (n = 12) or vehicle control (n = 13) intraperitoneally at days 3, 7, and 10 post-transplant. Results KO T cell recipients exhibited increased survival (Mantel-Cox p = 0.008). While the ongoing drug treatment experiment has not found a significant survival improvement, the drug-treated group exhibits a trend towards greater weights at day 21 post-transplant (Student’s t-test p = 0.06). Conclusion Our results find that genetic inhibition of FAO reduces GVHD; as such, pharmacological inhibition of mitochondrial FAO could theoretically produce the same effect. Although preliminary results do not reveal a survival benefit to drug treatment, optimization of dosing strategy and formulation is underway to clarify the drug’s potential therapeutic benefit. Further investigations will characterize its role in post-transplant weight recovery and impact on specific T cell subpopulations early after transplantation, and determine whether similar effects manifest in human T cells. Funding Source Department of Pediatrics, University of Minnesota Topic Categories Transplantation Immunology (TRAN)
2026-07-12 | Dietary stearic acid aggravates acute graft-versus-host disease by promoting oxidative stress and pro-inflammatory macrophage polarization.
Acute graft-versus-host disease (aGVHD) remains a major life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although immune activation and tissue inflammation are central to aGVHD pathogenesis, how dietary fatty acid exposure shapes inflammatory responses after transplantation remains insufficiently defined. Building on our previous finding that a high stearic acid diet (HSAD) alters the gut microbiota and aggravates aGVHD, we hypothesized that stearic acid (SA), a major saturated fatty acid, further exacerbates aGVHD by inducing oxidative stress and promoting pro-inflammatory macrophage polarization. Using a murine aGVHD model, we found that HSAD significantly increased serum SA levels and aggravated disease severity. Mechanistically, HSAD enhanced reactive oxygen species (ROS) production in splenocytes and disrupted glutathione redox homeostasis, indicating increased systemic oxidative stress. SA promoted M1-like macrophage polarization both in vivo and in vitro, without directly altering Th1 or Th17 differentiation. Pharmacological ROS scavenging with N-acetylcysteine (NAC) attenuated SA-induced ROS accumulation and M1 polarization. Additionally, SA activated mTOR signaling and promoted NLRP3 inflammasome activation in macrophages, as evidenced by increased NLRP3 expression, caspase-1 cleavage, and IL-1β maturation, which were attenuated by rapamycin. Collectively, these findings identify dietary SA as a modifiable factor that aggravates aGVHD by linking lipid metabolic stress to oxidative injury and M1 macrophage polarization. This work provides a rationale for targeting SA intake or its downstream signaling pathways as a strategy to mitigate aGVHD severity.
cell therapies
2026-07-22 | GZMK-expressing tissue-resident memory CD8+ T cells participate in human intestinal acute graft-versus-host disease.
Intestinal acute graft-versus-host disease (aGVHD) is a common life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although tissue-resident memory T (TRM) cells are thought to play a pathophysiological role in animal models of aGVHD, little is known about the role of distinct subsets of TRM cells in human intestinal aGVHD. Herein, we combined multiplex immunohistochemical staining with single-cell RNA sequencing to elucidate the differentiation trajectory, lineage commitment, clonal expansion, and functional properties of distinct CD8+ TRM cell subsets in human intestinal aGVHD. We identified a predominant GZMK+CD8+ TRM subset, characterized by the GZMK and CD49A markers. Intestinal aGVHD was associated with infiltration of GZMK+CD8+ T cells with TRM features, which showed enhanced clonal expansion, IFN signaling pathway-associated proinflammatory pathway expression, and lineage bifurcation differentiation properties. High GZMK+CD8+ TRM subset infiltration was associated with greater human intestinal aGVHD severity and poor prognosis. Together, our studies highlight the importance of the GZMK+CD8+ TRM subset in human intestinal aGVHD, and interest for designing GZMK+CD8+ TRM cell-targeted therapies.
2026-07-02 | Fecal microbiota transplantation promotes gut microbiome recovery in pediatric hematopoietic stem cell transplant recipients.
Hematopoietic stem cell transplantation (HSCT) profoundly disrupts the gut microbiome and may contribute to adverse post-transplant outcomes. Fecal microbiota transplantation (FMT) has emerged as a strategy to restore microbial diversity; however, data in pediatric HSCT recipients remain limited. We conducted a longitudinal analysis of 17 pediatric HSCT recipients who received FMT. Fecal samples were collected before FMT and at days 7, 14, and 30 after treatment. Gut microbiome composition was analyzed using 16S rRNA gene sequencing. Baseline samples showed reduced microbial diversity and a dysbiotic microbial profile. Following FMT, microbial diversity increased progressively, with recovery evident from day 7 and stabilization by day 30. Taxonomic analyses demonstrated depletion of dysbiosis-associated genera and enrichment of beneficial short-chain fatty acid-producing taxa, including Faecalibacterium, Blautia, Subdoligranulum, and Akkermansia. Distinct microbial configurations were observed according to gastrointestinal involvement by acute graft-versus-host disease. FMT was associated with progressive restoration of gut microbiome diversity and structure in pediatric HSCT recipients, supporting its potential role as a microbiota-based strategy to promote ecological recovery after HSCT.
2026-06-30 | Endothelial cell damage in patients with acute graft versus host disease receiving treatment with extracorporeal photopheresis.
Extracorporeal photopheresis (ECP) is a safe, effective treatment for steroid-refractory acute GVHD (SR-aGVHD). Endothelial damage is a pathological substrate of aGVHD. Endothelial damage biomarkers were measured in SR-aGVHD patients' plasma before (PRE) and 1-month after initiating ECP as second-line therapy to explore differences by treatment response. ECP-treated SR-aGVHD patients (n=35) were classified into good (GR; n=18) and poor (PR; n=17) responders. Endothelial activation biomarkers (soluble Vascular Cell Adhesion Molecule-1, sVCAM-1; von Willebrand Factor, VWF; thrombomodulin, TM; soluble TNF receptor 1, sTNFR1; angiopoietin 2; ANG2); GVHD markers (suppression tumorigenicity 2, ST2; regenerating islet-derived 3-alpha, REG3alpha; T-cell immunoglobulinmucin-3, TIM3); soluble C5b9 (sC5b9), for complement activation; and circulating dsDNA, for neutrophil extracellular traps (NETs), were analyzed. The endothelial activation and stress index (EASIX) and C-reactive protein were evaluated. Before ECP, endothelial damage biomarkers were elevated in all patients, with no significant differences between GR and PR. After 1-month, increased levels of REG3alpha and sC5b9, and decreased levels of TIM3, were observed in samples from PR. A panel combining 5 biomarkers (ST2, VWF, NETs, TIM3, ANG2) could identify GR after 1-month on ECP (likelihood ratio 2.0) and predict ECP response. We propose a simplified endothelial damage biomarker panel capturing early biological signals associated with response to ECP in SR-aGVHD patients.
2026-06-10 | Gut Microbiome-Immune Interactions During Pediatric Hematopoietic Cell Transplantation: From Conditioning to GvHD Prevention.
Hematopoietic stem cell transplantation (HCT) offers curative potential for children with high-risk hematologic malignancies. However, this treatment carries significant risks, particularly acute graft-versus-host disease (aGvHD), which affects 30%-60% of pediatric recipients and causes 15%-20% of post-transplant deaths. The gut microbiome has emerged as a critical factor in aGvHD development, yet pediatric microbiome dynamics differ substantially from adult patterns. This review seeks to evaluate the current state of knowledge of how the gut microbiome impacts aGvHD pathogenesis and the methods of microbiome modulation that may lead to aGvHD prevention and treatment. Children's microbiomes undergo more rapid compositional shifts and contain distinct bacterial compositions enriched in taxa like Bifidobacterium and Lactobacillus. During transplant, conditioning regimens and antibiotics cause dramatic microbiome disruption in children. This eliminates beneficial bacteria that normally maintain intestinal barrier integrity and produce immunomodulatory metabolites. Consequently, this disruption triggers inflammatory cascades through bacterial translocation, impaired immune education, and altered metabolite production. Unlike adults, where low diversity consistently predicts poor outcomes, pediatric studies show inconsistent diversity-outcome relationships, with only pre-transplant microbiome patterns reliably predicting aGvHD risk. Several promising interventions have emerged from this research. These include enteral nutrition to preserve beneficial bacteria, targeted antibiotic strategies, and fecal microbiota transplantation. Fecal microbiota transplantation has shown remarkable response rates in pediatric steroid-resistant aGvHD cases. Nevertheless, significant knowledge gaps remain regarding pediatric-specific mechanisms, optimal biomarkers, and age-appropriate therapeutic approaches for microbiome-directed aGvHD prevention.
2026-06-08 | Safety and efficacy of fecal microbial transplantation for the prevention and treatment of acute graft-versus-host disease: a meta-analysis.
In recent years, fecal microbiota transplantation (FMT) has been increasingly investigated for the prevention and treatment of acute graft-versus-host disease (aGVHD). Nevertheless, its clinical efficacy remains uncertain. Therefore, this study aims to systematically evaluate the clinical efficacy of FMT in preventing and treating aGVHD. We systematically searched Cochrane Library, PubMed, Embase, and Web of Science from inception to October 2025 for studies comparing FMT with conventional regimens (corticosteroids and/or immunosuppressants) for aGVHD prevention and treatment. All statistical analyses were performed using RevMan 5.4.1 and Stata 16. Six studies involving 262 patients were included. Among them, 85 patients received FMT for aGVHD prevention, 65 received conventional prophylaxis, 68 received FMT for Gastrointestinal aGVHD (GI-aGVHD) treatment, and 44 received conventional treatment for GI-aGVHD. Meta-analysis showed no significant difference in the incidence of aGVHD between the FMT and conventional groups [odds ratio (OR) = 1.30, 95% confidence interval (CI) = 0.10-16.72, p = 0.84]. However, the FMT group demonstrated significantly higher 14-day and 30-day complete response (CR) rates, as well as 14-day clinical response rates, in patients with GI-aGVHD compared to the conventional group (OR = 8.54, 95% CI = 2.49-29.29, p = 0.0007; OR = 8.44, 95% CI = 2.98-23.96, p < 0.0001; OR = 4.66, 95% CI = 1.73-12.55, p = 0.002). No significant differences were observed in the incidence of bacteremia or sepsis between the two groups (OR = 0.37, 95% CI = 0.13-1.01, p = 0.05; OR = 0.38, 95% CI = 0.11-1.33, p = 0.13). Additionally, the abundances of Bacteroides and Bifidobacterium were significantly higher in the FMT group than in the conventional group [standardized mean difference (SMD) = 1.59, 95% CI = 0.15-3.03, p = 0.03; SMD = 1.01, 95% CI = 0.41-1.60, p = 0.0009]. FMT showed favorable effects in improving clinical symptoms of GI-aGVHD and increasing the abundance of beneficial gut bacteria, and no increased risk of bloodstream infection was observed. These findings suggest that, for patients with established GI-aGVHD who may respond poorly to conventional regimens, FMT can serve as an effective adjunctive or salvage treatment. However, no significant advantage was observed for FMT in preventing aGVHD.
antibodies
2026-07-28 | IL-39/IL-39R Signaling Drives Acute Graft-versus-Host Disease by Promoting Pathogenic T-Cell Responses 2259690
Abstract Introduction Acute graft-versus-host disease (aGVHD) remains a life-threatening complication of allogeneic hematopoietic cell transplantation. Among IL-12 family cytokines, the newly identified IL-39, composed of IL-23p19 and EBI3, ligands IL-39 receptor, a complex of IL-23Rα and gp130. IL-39 has been implicated in inflammatory disorders, but its contribution to aGVHD and graft-versus-leukemia (GVL) remains undefined. Methods Murine and human T cells were stimulated with allogeneic APCs in the presence of recombinant human IL-39 (rhIL-39) to test the effect of IL-39 in T-cell response in vitro. Proximity ligation assay (PLA) was used to detect IL-23Rα/GP130 heterodimerization. T-cell pathogenicity in GVHD was measured in murine allogeneic bone marrow transplantion (BMT). The GVL activity was assessed using MLL-AF9 leukemia challenge. A xenogeneic GVHD (xeno-GVHD) model with human PBMCs was used to evaluate IL-39’s effect on human T-celll responses. Results rhIL-39 enhanced proliferation and production of IFN-γ, TNF-α, and GM-CSF, promoted Th1/Th17 polarization, and suppressed Foxp3+Treg differentiation in murine and human T cells. It induced robust STAT1/3 phosphorylation in IL-23Rαhigh Th17 cells and PLA assay confirmed IL-23Rα/gp130 heterodimerization. In murine BMT models, recipients receiving IL-23Rα-/- or DKO donor cells exhibited less GVHD compared to those of WT or IL-12Rβ1-/- cells while preserving GVL activity. rhIL-39 markedly increased GVHD scores, decreased survival, and expanded IFN-γ+, TNF-α+, and IL-17+CD4+ T cells while reducing Foxp3+ Tregs in the recipients of WT but not IL-23Rα-/- T cells. In the xeno-GVHD model, rhIL-39 aggravated GVHD with reduced survival and elevated human T-cell infiltration and inflammatory cytokines. Taken together, IL-39 enhances T-cell pathogenicity in GVHD through IL-23Rα. Conclusion IL-39/IL-39R signaling drives aGVHD pathogenesis and represents a promising therapeutic target for aGVHD while preserving GVL responses. Funding Source NIH, Advancing A Healthier Wisconsin Endowment Topic Categories Transplantation Immunology (TRAN)
2026-07-06 | The application of rituximab during the conditioning regimen prevents Epstein - Barr virus infection following rATG-based haploidentical hematopoietic stem cell transplantation in the era of letermovir for cytomegalovirus prophylaxis.
In the era of letermovir for cytomegalovirus (CMV) prophylaxis, several centers reported that the incidence of Epstein-Barr virus (EBV) infection were significantly increased. To investigate the efficacy and safety of rituximab administration during conditioning regimen following haploidentical hematopoietic stem cell transplantation(haplo-HSCT)in the prevention of post-transplant EBV infection. We conducted a retrospective analysis of 100 patients with acute leukemia or myelodysplastic syndrome who underwent haplo-HSCT. Patients in observation group(R group) received rituximab (375 mg/m²) on day -3 before transplantation due to the presence of donor-specific antibody (MFI ≥ 2000) (n = 25) and patients in control group (C group) did not receive rituximab (n = 75) and donor-specific antibody was low (MFI < 2000). The primary objectives were the incidence of EBV-DNA viremia and PTLD within one-year post-transplantation. Secondary objectives included the incidence of CMV infection, cumulative incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD, 100-day non-relapse mortality (NRM), progression-free survival (PFS), and overall survival (OS). No significant differences were observed in baseline characteristics between the two groups except for primary disease. When compared with the C group, patients in R group exhibited a lower cumulative incidence of EBV viremia within one-year post - transplantation (4.00% vs. 22.67%, P = 0.049) and a lower incidence of aGVHD (28% vs. 50.67%, P = 0.048). There was a trend toward reduction of PTLD in the R group compared with C group (0% vs. 10.67%, P = 0.089).There were no significant differences of the incidence of CMV viremia (24% vs. 13.33%, P = 0.208), cGVHD (16% vs. 12%, P = 0.607), and 100 - day NRM (4.0% vs. 10.67%, P = 0.313) between two groups. The 2-year OS rates in the R group and C group were 83.8% ± 0.086% and 81.9% ± 0.050% respectively (P = 0.360). The 2-year PFS rates in the R group and C group were 83.8% ± 0.086% and 72.6% ± 0.068% respectively (P = 0.360). The combined use of rituximab during the conditioning regimen may be regarded as an effective strategy for preventing EBV reactivation after rATG - based haplo - HSCT in the era of letermovir for CMV prophylaxis.Prospective randomized controlled trials are still required to further validate the reliability of the results.
2026-06-15 | Pre-transplant Clostridioides difficile infection predicts subsequent gastrointestinal GVHD and non-relapse mortality after allogeneic hematopoietic stem cell transplantation.
This study aimed to define the incidence of Clostridioides difficile infection (CDI), identify its risk factors, and evaluate its association with early post-transplant complications and overall clinical outcomes. To characterize CDI in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) setting, we retrospectively analyzed a cohort of 539 recipients who experienced diarrhea in the peri-transplant period (from conditioning to discharge from laminar flow). Among these diarrheic recipients, 64 patients developed CDI, the cumulative incidence of CDI was 12.1%, with a median onset of day -1 (range, -7 to +26) relative to HSCT. In a multivariate analysis, older age was independently associated with a lower risk of CDI (HR, 0.97; P = 0.008) among diarrheic recipients. The incidence of CDI stratified by the median onset time revealed that pre-transplant CDI was an independent risk factor for grade 1-4 lower gastrointestinal acute graft-versus-host disease (lower-GI aGVHD) (HR, 2.43; P=0.024). Furthermore, pre-transplant CDI was associated with a markedly increased risk of severe fungal infection (HR,6.97; P=0.026) and 100-day non-relapse mortality (NRM) (HR, 3.13; P=0.046). In conclusion, this study highlights a critical, timing-dependent distinction in CDI-associated severe complications and mortality in allo-HSCT recipients with diarrhea.
2026-06-12 | Begelomab (BEGESAND®) Salvages Steroid-Resistant Acute GVHD in Pediatric Patients.
Background: Acute graft-versus-host disease (aGVHD) is a leading cause of morbidity and mortality following pediatric hematopoietic stem cell transplantation (HSCT). Approximately half of children achieve complete response (CR) to corticosteroids, whereas steroid-refractory (SR) disease carries a 1-2-year mortality of 41-44%. Mortality risk is 2.6-fold higher in children > 13.9 years, and respiratory failure accounts for 26% of deaths. Existing second-line agents-ruxolitinib, tocilizumab, or extracorporeal photopheresis-have delayed onset or high toxicity. Begelomab (BEGESAND®), a monoclonal antibody targeting CD26/dipeptidyl peptidase-4 (DPP4), inhibits CD26-mediated T-cell activation and has demonstrated 75% response in adults with minimal toxicity. However, pediatric data are lacking. Methods: We retrospectively reviewed five consecutive pediatric patients (ages 3-20 years) treated with Begelomab (BEGESAND®) for SR (n = 4) or steroid-dependent (SD; n = 1) aGVHD between 2017-2021 under emergency IND authorization. Begelomab (BEGESAND®) was administered intravenously at 2.7 mg/m2/day on days 1-5, 10, 14, 17, 21, 24, and 28. GVHD was graded by MAGIC criteria; flow cytometry and immunohistochemistry (IHC) assessed CD26 expression and immune effects. Results: All patients had grade IV disease after ≥2 prior agents. Two with pre-existing sepsis died early, before treatment response could be assessed. Of three evaluable patients, two (67%) achieved CR within 21 days and one achieved durable control by 6 months. All three remain alive; no Begelomab (BEGESAND®)-related toxicity, cytopenia, or new infections occurred. Flow cytometry showed preserved T-cell subsets, and IHC demonstrated CD26 localization at sites of epithelial injury. Conclusions: Begelomab (BEGESAND®) showed promising timely and durable responses with excellent safety in pediatric SR/SD-aGVHD, supporting further evaluation in multicenter pediatric trials.
2026-04-24 | Xenopax from a real-world and economic perspective: The future of second-line treatment and prophylaxis for SR-aGVHD.
Steroid-refractory acute graft-versus-host disease (SR-aGVHD) remains a major therapeutic challenge after allogeneic hematopoietic stem cell transplantation. Although ruxolitinib and basiliximab are widely used, their limitations highlight the need for safer, more effective, and scalable biologic strategies. Xenopax, a humanized anti-CD25 monoclonal antibody, has demonstrated encouraging results across real-world and clinical studies. The multicenter RELAX study reported a 28-day overall response rate of 64.5% and a 2-year overall survival of 68.0%, with reduced corticosteroid exposure and infection rates compared with historical basiliximab cohorts. Importantly, RELAX incorporated an economic assessment, showing a lower incremental cost per responder and reinforcing xenopax as a cost-efficient option for SR-aGVHD. Beyond salvage therapy, xenopax is gaining momentum in prophylactic settings, including as a potential replacement for methotrexate in haploidentical transplantation. Looking ahead, integration with autonomous decision-support systems-most notably daGOAT, the first AI platform validated to prescribe risk-adapted GVHD prophylaxis-may further strengthen CD25-targeted approaches. Together, these developments position xenopax as a versatile biologic with the potential to reshape both treatment and prevention paradigms in GVHD management.
proteins
2026-08-09 | Pegtarazimod limits acute graft-versus-host disease mortality and severity in mice and is tolerated in patients.
The success of allogeneic hematopoietic cell transplantation (allo-HCT) is limited by acute graft-versus-host disease (aGVHD). We have previously reported that neutrophils can exacerbate tissue damage caused by conditioning regimens. Pegtarazimod is a synthetic peptide, derived from the capsid protein of human astrovirus serotype 1, that was shown to reduce neutrophil effector functions. Therefore, we evaluated the therapeutic activity of pegtarazimod against aGVHD. Pegtarazimod significantly reduced aGVHD-related mortality, histological aGVHD severity, and pro-inflammatory cytokines in multiple in vivo mouse models, while maintaining the anti-leukemia effect. Mechanistically, pegtarazimod reduced inflammation by decreasing ROS production as investigated using allo-HCT recipient mice with genetic inactivation of NADPH oxidase (NOX2) in the bone marrow. In addition to the anti-inflammatory effect, pegtarazimod protected intestinal organoids against TNF-induced toxicity and oxidative DNA damage. In the phase-2 clinical trial AURORA, pegtarazimod treatment was well-tolerated in patients with corticosteroid-refractory (SR) aGVHD (NCT06343792) with an overall response rate (ORR) of 4/7 patients at day 28. In summary, pegtarazimod reduced aGVHD in mice by suppressing pro inflammatory neutrophil effector functions and preserving enterocyte integrity. The clinical trial data support tolerability of pegtarazimod in aGVHD patients and further studies are needed to determine efficacy.
2026-07-31 | Gastrointestinal acute graft versus host disease: a translational perspective from pathogenesis to precision prevention and treatment.
Allo-HSCT represents a curative option for various hematological disorders. However, aGVHD remains the leading cause of non-relapse mortality following transplantation. The gastrointestinal tract is the most severely affected and prognostically unfavorable target organ in aGVHD, driven by donor T-cell-mediated epithelial damage, microbiota dysbiosis-driven immune amplification, and a self-perpetuating cycle of barrier disruption. Recent multi-omics studies have identified key pathogenic mechanisms, including microbiota-driven MHC-II expression and immunomodulation by microbial metabolites. Biomarker-driven risk stratification using the MAGIC algorithm has shifted management toward precision medicine, while targeted agents such as ruxolitinib, vedolizumab, and microbiota-directed interventions are reshaping therapeutic strategies. Novel interventional modalities, including FMT, recombinant LCN2, and specific bile acids, have forged innovative avenues that synergize microbiota-directed approaches with immunomodulation for the prevention and treatment of GI-aGVHD. This review systematically delineates the latest advances in the pathogenesis, risk stratification, and therapeutic strategies for GI-aGVHD, and envisions future directions for precision medicine centered on personalized microbiota-immune interventions.
2026-06-29 | ATG Exposure in T Replete Transplant for Hematological Malignancies: Real World Analysis from BMT CTN 1202.
Traditional weight-based dosing results in variable rabbit anti-thymocyte globulin (rATG) clearance, delaying CD4 + Tcell-immune-reconstitution (CD4 + IR) and impacting outcomes. In a retrospective pharmacokinetic/pharmacodynamic analysis of patients undergoing first T-replete hematopoietic cell transplantation (HCT), enrolled on BMT CTN 1202, we estimated post-HCT rATG-exposures as area under the curve (arbitrary unit per day/milliliter [AUxd/mL]) using a validated pharmacokinetic-model. Results were compared to patients who did not receive rATG. Previously defined post-HCT rATG-exposure groups: A:<30, B:30-55 and C:≥55 AUxd/mL were correlated with outcomes of interest using cox-proportional-hazard and cause-specific-hazards models. 325 patients (median age 51 years) were included: 228 received rATG. Median post-HCT rATG-exposure was 44.1 (Range 6.2-125.0). Among patients who received rATG, higher exposure correlated with worse five-year overall survival (OS) (no-ATG:51%; group A:67%; B:49%; C:34%, p = 0.01), higher five-year relapse incidence (no-ATG:31%; A:27%; B: 42%; C: 58%, p < 0.001) and lower CD4 + IR (no-ATG:64%; A:73%; B:51%; C:19%, p = 0.001). Grade 2-4 acute graft versus host disease (GVHD) rates were: no-ATG:40%; A:26%, B:39%, C:35%, (p = 0.44). Any rATG-exposure was associated with lower moderate/severe chronic GVHD (HR:0.63, p = 0.025). Low post-HCT rATG-exposure (< 30AUxd/mL) but not absent correlated with higher OS, lower relapse, and lower GVHD related deaths. Model-based-dosing could be used to target optimal post-HCT rATG-exposure and improve HCT outcomes.
2026-06-02 | A Phase 1b Study of Efmarodocokin Alfa, an Interleukin-22 Agonist, in Combination with Standard of Care, in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.
Acute graft-versus-host disease (aGVHD) remains a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT), and no nonimmunosuppressive pharmacologic therapies are currently available for prophylaxis. We conducted a Phase 1b, open-label, dose-escalation study to evaluate the safety, pharmacokinetics (PK), and preliminary activity of efmarodocokin alfa, an interleukin-22 agonist, administered with standard-of-care prophylaxis in patients undergoing matched unrelated and matched related donor allogeneic HSCT following myeloablative conditioning. Eighteen patients were enrolled across 3 dose cohorts receiving efmarodocokin alfa at 30 µg/kg every 4 weeks, 30 µg/kg every 2 weeks, or 60 µg/kg every 2 weeks. Efmarodocokin alfa was well-tolerated and demonstrated an acceptable safety and PK profile, characterized by predominantly Grades 1 to 2 adverse events and linear PK across all dose levels. All patients achieved neutrophil engraftment by Day 30. By Day 100 post-transplant, 5 patients (27.8%) developed Grade 2 aGVHD, 2 (11.1%) of which had Stage 1 lower GI aGVHD. No patients developed Grades 3 to 4 aGVHD. Exploratory analysis demonstrated a lower gastrointestinal aGVHD-free survival rate of 83.3% at Day 180 and overall survival of 77.8% at Day 365. Although conclusions regarding efficacy are limited by the small sample size and exploratory design, these results demonstrate favorable safety and PK characteristics and provide initial observations regarding the potential role of efmarodocokin alfa in the prevention of lower gastrointestinal aGVHD as a nonimmunosuppressive prophylactic strategy.
2026-04-27 | Differential impact of allogeneic stem-cell transplantation on large B-cell lymphomas and peripheral T-cell lymphomas.
Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is one of the standard treatments for relapsed/refractory (r/r) non-Hodgkin lymphoma, but benefits across large B-cell lymphoma (LBCL) and nodal peripheral T-cell lymphoma (PTCL) subtypes remain unclear. This single-center retrospective study evaluated outcomes after the first allo-HSCT in 92 adults with r/r aggressive lymphoma (59 and 33 patients with LBCLs and PTCLs, respectively) treated during 2011–2023. The patients’ median age was 51 years; 58.7% had active disease at transplant, and 77.2% received cord blood grafts. With a median follow-up of 7.6 years among survivors, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 31.6% and 27.9%, respectively. Furthermore, the non-relapse mortality (NRM) and relapse/progression rates were 30.8% and 41.3%, respectively. Compared with patients with LBCLs, those with PTCLs showed superior 5-year outcomes (OS: 47.7% vs. 22.4%, P = 0.03; PFS: 39.7% vs. 21.0%, P = 0.04) and lower relapse rates (26.9% vs. 49.5%, P = 0.02), with similar NRM and acute graft-versus-host disease rates. Multivariable models showed that PTCL histology was an independent predictor of improved OS and PFS. These findings suggest that allo-HSCT confers greater long-term benefits in patients with PTCL, supporting its role as an effective option in this subgroup.
other
2026-03-04 | IL1B rs1143627 and IL17A rs8193036 in the risk of Acute Graft Versus Host Disease in pediatric HSCT.
Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). While HLA compatibility is a key determinant, increasing evidence suggests that non-HLA immune gene polymorphisms, particularly those in cytokine genes, contribute to GVHD risk. This study seeks to validate in a pediatric population, cytokine-related single nucleotide polymorphisms (SNPs) associated with acute GVHD (aGVHD) and analyze them in combination with the previously identified HLA risk alleles. Pediatric HSCT recipients were recruited from the CHU Sainte-Justine biobank and a prior European Society for Blood and Marrow Transplantation (EBMT) multicenter study. Twenty-five SNPs in 12 cytokine genes were selected based on published associations with aGVHD. Genotypes were obtained for discovery (n = 87) and replication (n = 154) cohorts and association analyses were conducted in each cohort and in the combined dataset. Two SNPs, IL1B rs1143627 and IL17A rs8193036, were significantly associated with increased risk of aGVHD II-IV (p = 0.019 and p < 0.001, respectively). These associations were strongest in HLA-matched unrelated-donor-recipient pairs for IL1B rs1143627 (p = 0.015) and in all HLA-matched pairs for IL17A rs8193036 (p = 0.004). Notably, carriers of one or both risk alleles combined with HLA-B*15:01 had a markedly elevated risk (HR: 2.14 CI:1.41-3.25, p = 6 ×10⁻⁶). These findings highlight the relevance of non-HLA genetic variants in aGVHD pathogenesis. Incorporating cytokine SNP profiles, especially IL1B rs1143627 and IL17A rs8193036, alongside HLA typing may improve donor selection and guide individualized aGVHD prophylaxis.
2025-08-01 | NK Alloreactivity Evaluation According to KIR-HLA Interaction Models Influences the Outcome of Haploidentical Haematopoietic Stem-Cell Transplantation Based on Post-Transplant Cyclophosphamide.
Haploidentical haematopoietic stem-cell transplantation (haplo-HSCT) is characterised by a high degree of HLA mismatching. Therefore, NK alloreactivity driven by the interactions between KIR and HLA mismatched molecules could benefit its outcome. However, the influence of NK alloreactivity in haplo-HSCT with post-transplant Cyclophosphamide (PTCy) remains controversial. The aim of this work was to investigate the clinical utility of predicting NK alloreactivity according to previously described models in the context of haplo-HSCT with PTCy. We studied 145 patients who underwent this procedure, evaluating the influence of NK alloreactivity in transplant outcomes. Models that disregard the interactions between KIR and HLA evidenced an unsuccessful prediction of the outcomes. On the contrary, approaches based on KIR-HLA interaction were the most accurate to predict transplant outcomes. The analysis of inhibitory KIRs (iKIRs) based on the missing-ligand model showed that the presence of at least two iKIR mismatches (iKIRmm) among the donor-recipient pair was an independent risk factor for acute graft-versus-host disease (aGvHD) grade III‑IV (HR: 3.21, p = 0.021), relapse rate (HR: 2.46, p = 0.046), relapse-free survival (RFS) (HR: 1.96, p = 0.039) and GvHD/relapse-free survival (GRFS) (HR = 2.16, p = 0.008). The analysis of the missing-licensing model showed that the existence of the mismatch KIR2DL1/C2 associated to relapse rate (HR: 4.34, p = 0.002) and more than one iKIRmm correlated to poorer RFS (HR: 2.31, p = 0.038) and GRFS (HR: 2.26, p = 0.022). These results suggest that NK alloreactivity influences the outcome of haplo-HSCT with PTCy and should be incorporated into the donor selection algorithm for this procedure.
2025-05-28 | [Effects of donor T cell stat3 deficiency on acute intestinal graft-versus-host disease in mice].
Objective: To investigate the effects and underlying mechanisms of Stat3 knockout in donor T cells on acute gastrointestinal graft-versus-host disease (GI-aGVHD) . Methods: BALB/c mice were exposed to lethal irradiation and transplanted with bone marrow and spleen cells from BALB/c mice (syngeneic control group), C57BL/6 mice (wild-type T cell group, WT group), or C57BL/6J-Stat3(em1cyagen) mice (Stat3 gene knockout T cell group, Stat3-KO group) via tail vein injection to establish the aGVHD model. The survival rate, body weight changes, and clinical scores of mice were monitored. Cytometric bead array (CBA) was used to detect the concentrations of serum cytokines. Lymphocytes were isolated from tissues for flow cytometric analysis. H&E staining was performed to observe intestinal pathological changes. FITC-dextran assay was conducted to assess intestinal permeability. Immunohistochemistry was used to evaluate the expression of Ki67 and Muc2. Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) was employed to analyze the gene expression levels of Olfm4, Lysozyme, and Muc2 in the small intestine. Metabolomics was conducted to detect metabolites in serum and intestinal tissues. An in vitro GI-aGVHD organoid model was established by coculturing intestinal organoids with allogeneic T cells, where the number and area of small intestinal organoids were recorded. The GVL effect was assessed using luciferase-transfected ALL cells (ALL/Luc) and bioluminescent imaging. Results: Compared with the WT group, Stat3 knockout T cells alleviated body weight loss, reduced symptoms-such as hunchback and diarrhea-in mice, improved survival rate (P<0.05), and reduced serum interleukin (IL) -2, IL-6, interferon-γ, tumor necrosis factor-α, IL-17A, and IL-10 levels (all P<0.05), intestinal inflammatory cell infiltration (P<0.05), and intestinal mucosal permeability. Further, Muc2 and Ki67 expression levels in the small intestine of the Stat3 knockout group were markedly increased, and Olfm4, Lysozyme, and Muc2 gene expression levels were significantly increased (all P<0.05). In vitro, the Stat3 knockout group demonstrated better organoid development than the WT group. Metabolomic analyses indicated that Stat3 knockout in T cells may affect the pathways associated with bile acid secretion and unsaturated fatty acids. ALL/Luc cells in the GVL mouse model proliferated rapidly in the TCD-BM group; however, 80% of the mice in the Stat3-KO group survived tumor-free for >100 days (P<0.05) . Conclusion: Knocking out Stat3 in graft T cells reduces T cell damage to intestinal stem cells, thereby ultimately alleviating GI-aGVHD while maintaining a stable GVL effect.
2025-03-22 | Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy.
Previous data indicated that the leucine-rich α-2 glycoprotein 1 (LRG1) pathway contributes to vascular dysfunction during cancer growth. Therapeutic targeting of LRG1 normalized tumor vessel dysfunction and enhanced the efficacy of anti-cancer adoptive T cell therapy. A major clinical problem after allogeneic hematopoietic stem cell transplantation (alloHSCT) and after chimeric antigen receptor (CAR) T-cell therapy is the induction of hyperinflammatory side effects, which are typically associated with severe endothelial dysfunction. We investigated LRG1 in preclinical models and in patient samples. In prospective studies, we found elevated LRG1 serum levels in patients with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome after CAR-T-cell therapy as well as in patients with acute graft-versus-host disease (aGVHD) after alloHSCT.In preclinical models of aGVHD, we found vasculature-associated LRG1 upregulation as well as LRG1 pathway gene upregulation. The genetic deletion of LRG1 in alloHSCT donors and in alloHSCT recipients led to reduced clinical and histological aGVHD. In line with this, LRG1 deletion led to clinically and histologically reduced disease severity in experimental inflammatory models of colitis (dextran sulfate sodium colitis) and paw edema. LRG1 deletion reduced inflammation-related vascular leakiness, endothelial cell proliferation, and migration. The current data support the hypothesis that LRG1 is an attractive therapeutic target after alloHSCT and after CAR-T cell therapy for cancer because of its role in dysfunctional tumor vessels as well as in inflammatory complications.
2024-09-18 | mRNA-delivery of IDO1 suppresses T cell-mediated autoimmunity.
Indoleamine-2,3-dioxygenase (IDO)1 degrades tryptophan, obtained through dietary intake, into immunoregulatory metabolites of the kynurenine pathway. Deficiency or blockade of IDO1 results in the enhancement of autoimmune severity in rodent models and increased susceptibility to developing autoimmunity in humans. Despite this, therapeutic modalities that leverage IDO1 for the treatment of autoimmunity remain limited. Here, we use messenger (m)RNA formulated in lipid nanoparticles (LNPs) to deliver a human IDO1 variant containing the myristoylation site of Src to anchor the protein to the inner face of the plasma membrane. This membrane-anchored IDO1 has increased protein production, leading to increased metabolite changes, and ultimately ameliorates disease in three models of T cell-mediated autoimmunity: experimental autoimmune encephalomyelitis (EAE), rat collagen-induced arthritis (CIA), and acute graft-versus-host disease (aGVHD). The efficacy of IDO1 is correlated with hepatic expression and systemic tryptophan depletion. Thus, the delivery of membrane-anchored IDO1 by mRNA suppresses the immune response in several well-characterized models of autoimmunity.
small molecules
2026-08-11 | Phenotype-Specific Associations Between Graft‑Versus‑Host Disease and Post‑Transplant Outcomes.
Disease relapse remains the leading cause of failure following allogeneic hematopoietic cell transplantation (HCT). As novel prophylactic strategies increasingly aim to universally eliminate all forms of graft‑versus‑host disease (GVHD), how these approaches may inadvertently sacrifice graft‑versus‑leukemia (GVL) activity in the post‑transplant cyclophosphamide (PTCy) era is unclear. To evaluate the associations between time‑updated GVHD phenotypes and clinical outcomes, including relapse, non‑relapse mortality (NRM), and overall survival (OS), in patients undergoing PTCy‑based haploidentical or mismatched unrelated donor (MMUD) HCT. This was a retrospective cohort study using the Center for International Blood and Marrow Transplant Research registry. Participants included 7,055 patients with hematologic malignancies who received a first haploidentical or MMUD HCT with PTCy from 2013-2021. Associations with relapse, NRM and OS were evaluated using multi‑state time‑dependent Cox proportional hazards models and a multi‑state random survival forest (MS‑RSF). Time‑updated acute and chronic GVHD phenotypes included isolated grade II acute GVHD (aGVHD), grade III-IV aGVHD, mild chronic GVHD (cGVHD), and immunosuppressive therapy-requiring (IST‑requiring) cGVHD. IST‑requiring cGVHD without antecedent aGVHD was associated with a lower modeled relapse hazard compared with remaining GVHD‑free (Hazard Ratio [HR], 0.74; 95% confidence interval [CI], 0.62-0.89; False Discovery Rate (FDR)-adjusted p (q)=0.006) and lower overall mortality (HR 0.62; 95% CI, 0.53-0.73; q < 0.001). In contrast, grade III-IV aGVHD was associated with significantly higher modeled NRM (HR, 3.15; 95% CI, 2.57-3.84; q < 0.001). Mild cGVHD and isolated grade II aGVHD showed intermediate patterns without consistent associations. These associations were directionally consistent across multiple analytic approaches, including standard time‑dependent Cox regression, dynamic and fixed landmark analyses, and MS‑RSF. In this large PTCy‑treated mismatched donor cohort, IST‑requiring cGVHD was the GVHD phenotype most consistently associated with lower relapse incidence, whereas severe aGVHD was associated with higher NRM. These findings highlight heterogeneity in GVHD phenotypes and suggest that strategies distinguishing toxic acute GVHD from chronic alloreactivity patterns may better balance morbidity and long‑term disease control. Given that relapse remains the predominant cause of post‑transplant mortality, approaches aiming to universally eliminate all GVHD warrant careful reconsideration.
2026-08-06 | Recipient Endothelial IRF1 mediates IFNγ-driven tissue tolerance in mouse models of acute Graft-versus-Host Disease.
Recipient endothelial cells (ECs) actively respond to inflammation during allogeneic hematopoietic cell transplant (allo-HCT), yet mechanisms by which ECs influence acute graft-versus-host-disease (GVHD) pathology remain incompletely defined. Single cell RNA-sequencing of ECs isolated from a GVHD target organ, the liver, showed rapid, subset-specific transcriptional reprogramming after allo-HCT, with induction of canonical interferon-γ (IFNγ)-inducible genes including interferon regulatory factor 1 (IRF1), MHC II, and PD-L1 in lymphatic ECs (LECs). In allo-HCT recipients, circulating IFNγ peaked on day 4 (early), decreased but remained elevated at day 14 (late), and declined by day 21, with a concordant induction of IRF1+ LECs in the liver and GI tract. IFNγ neutralization with anti-IFNγ monoclonal antibody at either early or late time points attenuated IRF1⁺MHCII⁺PD-L1⁺ LEC activation. Notably, early donor T cell expansion was IFNγ-independent, whereas late IFNγ blockade selectively impaired donor Treg, but not Th1, expansion, leading to accelerated GVHD. Using in vitro LEC-CD4 T cell co-cultures and allo-HCT in Irf1-/- bone marrow chimera recipients, we show that recipient ECs that cannot mediate IFNγ-IRF1 signaling exhibit reduced activation and apoptosis, but also have impaired Treg expansion, increased donor Th1/Treg ratios, and worsened GVHD severity. Finally, pharmacological JAK inhibition in allo-HCT recipient mice spares IRF1+ LECs and Tregs while reducing pathogenic Th1 cells, correlating with reduced GVHD severity and improved survival. Our findings identify a role for the lymphatic endothelial IFNγ-IRF1 axis in regulating early vascular remodeling, donor T cell mediated tolerance, underscoring a potential "goldilocks" level of pathway activation required to improve post-transplant outcomes.
2026-07-29 | Immediate versus delayed short-course ruxolitinib for acute GVHD prophylaxis after myeloablative allogeneic hematopoietic stem cell transplantation.
The optimal timing of ruxolitinib initiation for acute graft-versus-host disease (aGVHD) prophylaxis after myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains undefined, particularly within anti-thymocyte globulin (ATG)-based platforms. This study compared immediate versus delayed short-course ruxolitinib initiation using a concurrent two-strategy design. This single-center, retrospective, concurrent two-strategy cohort study enrolled 39 consecutive patients aged 15-65 years with hematologic malignancies who received standard "Beijing Protocol" backbone plus a 14-day short-course ruxolitinib. Patients were non-randomly assigned to immediate (day +1; n = 19) or delayed (at confirmed neutrophil engraftment; median day +13; n = 20) initiation. Haploidentical transplantation and ATG use were perfectly collinear in this cohort, complicating attribution of outcome differences. Co-primary endpoints were 100-day cumulative incidence of grade II-IV aGVHD and 2-year overall survival (OS). A 1:1 propensity score matching (PSM) analysis (12 pairs) served as a sensitivity analysis. Given the limited sample size, multivariable models were constructed as exploratory analyses and should be interpreted with caution. Delayed initiation was associated with lower 100-day grade II-IV aGVHD (10.0% vs. 42.1%, P = 0.031), lower cytomegalovirus (CMV) reactivation (35.0% vs. 73.7%, P = 0.025), reduced grade ≥3 hematologic toxicity (35.0% vs. 68.4%, P = 0.043), and superior 2-year OS rate (90.0% vs. 57.9%, P = 0.012). PSM confirmed these findings (aGVHD: 8.3% vs. 41.7%, P = 0.039; OS: 91.7% vs. 58.3%, P = 0.028). In the exploratory haploidentical subgroup (n = 26), grade II-IV aGVHD was 11.8% vs. 55.6% (P = 0.028) and OS was 94.1% vs. 55.6% (P = 0.006). In exploratory multivariable models, immediate initiation was associated with higher aGVHD risk [adjusted subdistribution hazard ratio (sHR) 2.31, 95% CI 1.15-4.64, P = 0.019] and higher NRM (adjusted sHR 4.65, 95% CI 1.47-14.72, P = 0.009). Relapse risk was not significantly different (adjusted sHR 2.17, 95% CI 0.85-5.56, P = 0.095). Pre-transplant measurable residual disease (MRD) positivity was associated with inferior OS (adjusted hazard ratio [HR] 7.81, 95% CI 1.12-54.32, P = 0.038). Median follow-up was 42.1 months. Interpretation of the CMV reactivation difference is limited by the absence of donor and recipient CMV serostatus data. Delaying short-course ruxolitinib until neutrophil engraftment was associated with reduced aGVHD and NRM and improved survival after myeloablative allo-HSCT. No statistically significant difference in relapse risk was observed, although a clinically meaningful difference cannot be excluded. These findings warrant confirmation in a multicenter randomized trial with adequate sample size, stratified by donor type and pre-transplant MRD.
2026-07-28 | Inhibition of Fatty Acid Metabolism in Alloreactive T Cells Minimizes Acute Graft-versus-host Disease 2303327
Abstract Introduction Acute Graft-Versus-Host Disease (GVHD) is a complication of allogeneic blood and marrow transplantation in which alloreactive T cells destroy tissues in the liver, skin, and gastrointestinal tract. The dual energetic demands of activation and proliferation push alloreactive T cells into adopting fatty acid oxidation (FAO), a pathway that then becomes a therapeutic target for mitigating GVHD. Here we demonstrate the results of genetic deletion of FAO machinery in donor T cells, and administration of a novel FAO-targeting pharmaceutical as a GVHD treatment. Methods We utilized a C57BL/6 donor into B6D2F1/J recipient model of GVHD. Post-transplant, recipient clinical scores were calculated weekly and weight assessed twice weekly. Genetic FAO inhibition was achieved through a T cell-specific knockout (KO) of carnitine palmitoyltransferase 1a in C57BL/6 mice; recipient mice received either KO (n = 16) or wild-type (n = 16) splenic T cells in transplant. For compound testing, recipient mice with wild-type T cell transplants received either the drug (n = 12) or vehicle control (n = 13) intraperitoneally at days 3, 7, and 10 post-transplant. Results KO T cell recipients exhibited increased survival (Mantel-Cox p = 0.008). While the ongoing drug treatment experiment has not found a significant survival improvement, the drug-treated group exhibits a trend towards greater weights at day 21 post-transplant (Student’s t-test p = 0.06). Conclusion Our results find that genetic inhibition of FAO reduces GVHD; as such, pharmacological inhibition of mitochondrial FAO could theoretically produce the same effect. Although preliminary results do not reveal a survival benefit to drug treatment, optimization of dosing strategy and formulation is underway to clarify the drug’s potential therapeutic benefit. Further investigations will characterize its role in post-transplant weight recovery and impact on specific T cell subpopulations early after transplantation, and determine whether similar effects manifest in human T cells. Funding Source Department of Pediatrics, University of Minnesota Topic Categories Transplantation Immunology (TRAN)
2026-07-12 | Dietary stearic acid aggravates acute graft-versus-host disease by promoting oxidative stress and pro-inflammatory macrophage polarization.
Acute graft-versus-host disease (aGVHD) remains a major life-threatening complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although immune activation and tissue inflammation are central to aGVHD pathogenesis, how dietary fatty acid exposure shapes inflammatory responses after transplantation remains insufficiently defined. Building on our previous finding that a high stearic acid diet (HSAD) alters the gut microbiota and aggravates aGVHD, we hypothesized that stearic acid (SA), a major saturated fatty acid, further exacerbates aGVHD by inducing oxidative stress and promoting pro-inflammatory macrophage polarization. Using a murine aGVHD model, we found that HSAD significantly increased serum SA levels and aggravated disease severity. Mechanistically, HSAD enhanced reactive oxygen species (ROS) production in splenocytes and disrupted glutathione redox homeostasis, indicating increased systemic oxidative stress. SA promoted M1-like macrophage polarization both in vivo and in vitro, without directly altering Th1 or Th17 differentiation. Pharmacological ROS scavenging with N-acetylcysteine (NAC) attenuated SA-induced ROS accumulation and M1 polarization. Additionally, SA activated mTOR signaling and promoted NLRP3 inflammasome activation in macrophages, as evidenced by increased NLRP3 expression, caspase-1 cleavage, and IL-1β maturation, which were attenuated by rapamycin. Collectively, these findings identify dietary SA as a modifiable factor that aggravates aGVHD by linking lipid metabolic stress to oxidative injury and M1 macrophage polarization. This work provides a rationale for targeting SA intake or its downstream signaling pathways as a strategy to mitigate aGVHD severity.
cell therapies
2026-07-22 | GZMK-expressing tissue-resident memory CD8+ T cells participate in human intestinal acute graft-versus-host disease.
Intestinal acute graft-versus-host disease (aGVHD) is a common life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although tissue-resident memory T (TRM) cells are thought to play a pathophysiological role in animal models of aGVHD, little is known about the role of distinct subsets of TRM cells in human intestinal aGVHD. Herein, we combined multiplex immunohistochemical staining with single-cell RNA sequencing to elucidate the differentiation trajectory, lineage commitment, clonal expansion, and functional properties of distinct CD8+ TRM cell subsets in human intestinal aGVHD. We identified a predominant GZMK+CD8+ TRM subset, characterized by the GZMK and CD49A markers. Intestinal aGVHD was associated with infiltration of GZMK+CD8+ T cells with TRM features, which showed enhanced clonal expansion, IFN signaling pathway-associated proinflammatory pathway expression, and lineage bifurcation differentiation properties. High GZMK+CD8+ TRM subset infiltration was associated with greater human intestinal aGVHD severity and poor prognosis. Together, our studies highlight the importance of the GZMK+CD8+ TRM subset in human intestinal aGVHD, and interest for designing GZMK+CD8+ TRM cell-targeted therapies.
2026-07-02 | Fecal microbiota transplantation promotes gut microbiome recovery in pediatric hematopoietic stem cell transplant recipients.
Hematopoietic stem cell transplantation (HSCT) profoundly disrupts the gut microbiome and may contribute to adverse post-transplant outcomes. Fecal microbiota transplantation (FMT) has emerged as a strategy to restore microbial diversity; however, data in pediatric HSCT recipients remain limited. We conducted a longitudinal analysis of 17 pediatric HSCT recipients who received FMT. Fecal samples were collected before FMT and at days 7, 14, and 30 after treatment. Gut microbiome composition was analyzed using 16S rRNA gene sequencing. Baseline samples showed reduced microbial diversity and a dysbiotic microbial profile. Following FMT, microbial diversity increased progressively, with recovery evident from day 7 and stabilization by day 30. Taxonomic analyses demonstrated depletion of dysbiosis-associated genera and enrichment of beneficial short-chain fatty acid-producing taxa, including Faecalibacterium, Blautia, Subdoligranulum, and Akkermansia. Distinct microbial configurations were observed according to gastrointestinal involvement by acute graft-versus-host disease. FMT was associated with progressive restoration of gut microbiome diversity and structure in pediatric HSCT recipients, supporting its potential role as a microbiota-based strategy to promote ecological recovery after HSCT.
2026-06-30 | Endothelial cell damage in patients with acute graft versus host disease receiving treatment with extracorporeal photopheresis.
Extracorporeal photopheresis (ECP) is a safe, effective treatment for steroid-refractory acute GVHD (SR-aGVHD). Endothelial damage is a pathological substrate of aGVHD. Endothelial damage biomarkers were measured in SR-aGVHD patients' plasma before (PRE) and 1-month after initiating ECP as second-line therapy to explore differences by treatment response. ECP-treated SR-aGVHD patients (n=35) were classified into good (GR; n=18) and poor (PR; n=17) responders. Endothelial activation biomarkers (soluble Vascular Cell Adhesion Molecule-1, sVCAM-1; von Willebrand Factor, VWF; thrombomodulin, TM; soluble TNF receptor 1, sTNFR1; angiopoietin 2; ANG2); GVHD markers (suppression tumorigenicity 2, ST2; regenerating islet-derived 3-alpha, REG3alpha; T-cell immunoglobulinmucin-3, TIM3); soluble C5b9 (sC5b9), for complement activation; and circulating dsDNA, for neutrophil extracellular traps (NETs), were analyzed. The endothelial activation and stress index (EASIX) and C-reactive protein were evaluated. Before ECP, endothelial damage biomarkers were elevated in all patients, with no significant differences between GR and PR. After 1-month, increased levels of REG3alpha and sC5b9, and decreased levels of TIM3, were observed in samples from PR. A panel combining 5 biomarkers (ST2, VWF, NETs, TIM3, ANG2) could identify GR after 1-month on ECP (likelihood ratio 2.0) and predict ECP response. We propose a simplified endothelial damage biomarker panel capturing early biological signals associated with response to ECP in SR-aGVHD patients.
2026-06-10 | Gut Microbiome-Immune Interactions During Pediatric Hematopoietic Cell Transplantation: From Conditioning to GvHD Prevention.
Hematopoietic stem cell transplantation (HCT) offers curative potential for children with high-risk hematologic malignancies. However, this treatment carries significant risks, particularly acute graft-versus-host disease (aGvHD), which affects 30%-60% of pediatric recipients and causes 15%-20% of post-transplant deaths. The gut microbiome has emerged as a critical factor in aGvHD development, yet pediatric microbiome dynamics differ substantially from adult patterns. This review seeks to evaluate the current state of knowledge of how the gut microbiome impacts aGvHD pathogenesis and the methods of microbiome modulation that may lead to aGvHD prevention and treatment. Children's microbiomes undergo more rapid compositional shifts and contain distinct bacterial compositions enriched in taxa like Bifidobacterium and Lactobacillus. During transplant, conditioning regimens and antibiotics cause dramatic microbiome disruption in children. This eliminates beneficial bacteria that normally maintain intestinal barrier integrity and produce immunomodulatory metabolites. Consequently, this disruption triggers inflammatory cascades through bacterial translocation, impaired immune education, and altered metabolite production. Unlike adults, where low diversity consistently predicts poor outcomes, pediatric studies show inconsistent diversity-outcome relationships, with only pre-transplant microbiome patterns reliably predicting aGvHD risk. Several promising interventions have emerged from this research. These include enteral nutrition to preserve beneficial bacteria, targeted antibiotic strategies, and fecal microbiota transplantation. Fecal microbiota transplantation has shown remarkable response rates in pediatric steroid-resistant aGvHD cases. Nevertheless, significant knowledge gaps remain regarding pediatric-specific mechanisms, optimal biomarkers, and age-appropriate therapeutic approaches for microbiome-directed aGvHD prevention.
2026-06-08 | Safety and efficacy of fecal microbial transplantation for the prevention and treatment of acute graft-versus-host disease: a meta-analysis.
In recent years, fecal microbiota transplantation (FMT) has been increasingly investigated for the prevention and treatment of acute graft-versus-host disease (aGVHD). Nevertheless, its clinical efficacy remains uncertain. Therefore, this study aims to systematically evaluate the clinical efficacy of FMT in preventing and treating aGVHD. We systematically searched Cochrane Library, PubMed, Embase, and Web of Science from inception to October 2025 for studies comparing FMT with conventional regimens (corticosteroids and/or immunosuppressants) for aGVHD prevention and treatment. All statistical analyses were performed using RevMan 5.4.1 and Stata 16. Six studies involving 262 patients were included. Among them, 85 patients received FMT for aGVHD prevention, 65 received conventional prophylaxis, 68 received FMT for Gastrointestinal aGVHD (GI-aGVHD) treatment, and 44 received conventional treatment for GI-aGVHD. Meta-analysis showed no significant difference in the incidence of aGVHD between the FMT and conventional groups [odds ratio (OR) = 1.30, 95% confidence interval (CI) = 0.10-16.72, p = 0.84]. However, the FMT group demonstrated significantly higher 14-day and 30-day complete response (CR) rates, as well as 14-day clinical response rates, in patients with GI-aGVHD compared to the conventional group (OR = 8.54, 95% CI = 2.49-29.29, p = 0.0007; OR = 8.44, 95% CI = 2.98-23.96, p < 0.0001; OR = 4.66, 95% CI = 1.73-12.55, p = 0.002). No significant differences were observed in the incidence of bacteremia or sepsis between the two groups (OR = 0.37, 95% CI = 0.13-1.01, p = 0.05; OR = 0.38, 95% CI = 0.11-1.33, p = 0.13). Additionally, the abundances of Bacteroides and Bifidobacterium were significantly higher in the FMT group than in the conventional group [standardized mean difference (SMD) = 1.59, 95% CI = 0.15-3.03, p = 0.03; SMD = 1.01, 95% CI = 0.41-1.60, p = 0.0009]. FMT showed favorable effects in improving clinical symptoms of GI-aGVHD and increasing the abundance of beneficial gut bacteria, and no increased risk of bloodstream infection was observed. These findings suggest that, for patients with established GI-aGVHD who may respond poorly to conventional regimens, FMT can serve as an effective adjunctive or salvage treatment. However, no significant advantage was observed for FMT in preventing aGVHD.
antibodies
2026-07-28 | IL-39/IL-39R Signaling Drives Acute Graft-versus-Host Disease by Promoting Pathogenic T-Cell Responses 2259690
Abstract Introduction Acute graft-versus-host disease (aGVHD) remains a life-threatening complication of allogeneic hematopoietic cell transplantation. Among IL-12 family cytokines, the newly identified IL-39, composed of IL-23p19 and EBI3, ligands IL-39 receptor, a complex of IL-23Rα and gp130. IL-39 has been implicated in inflammatory disorders, but its contribution to aGVHD and graft-versus-leukemia (GVL) remains undefined. Methods Murine and human T cells were stimulated with allogeneic APCs in the presence of recombinant human IL-39 (rhIL-39) to test the effect of IL-39 in T-cell response in vitro. Proximity ligation assay (PLA) was used to detect IL-23Rα/GP130 heterodimerization. T-cell pathogenicity in GVHD was measured in murine allogeneic bone marrow transplantion (BMT). The GVL activity was assessed using MLL-AF9 leukemia challenge. A xenogeneic GVHD (xeno-GVHD) model with human PBMCs was used to evaluate IL-39’s effect on human T-celll responses. Results rhIL-39 enhanced proliferation and production of IFN-γ, TNF-α, and GM-CSF, promoted Th1/Th17 polarization, and suppressed Foxp3+Treg differentiation in murine and human T cells. It induced robust STAT1/3 phosphorylation in IL-23Rαhigh Th17 cells and PLA assay confirmed IL-23Rα/gp130 heterodimerization. In murine BMT models, recipients receiving IL-23Rα-/- or DKO donor cells exhibited less GVHD compared to those of WT or IL-12Rβ1-/- cells while preserving GVL activity. rhIL-39 markedly increased GVHD scores, decreased survival, and expanded IFN-γ+, TNF-α+, and IL-17+CD4+ T cells while reducing Foxp3+ Tregs in the recipients of WT but not IL-23Rα-/- T cells. In the xeno-GVHD model, rhIL-39 aggravated GVHD with reduced survival and elevated human T-cell infiltration and inflammatory cytokines. Taken together, IL-39 enhances T-cell pathogenicity in GVHD through IL-23Rα. Conclusion IL-39/IL-39R signaling drives aGVHD pathogenesis and represents a promising therapeutic target for aGVHD while preserving GVL responses. Funding Source NIH, Advancing A Healthier Wisconsin Endowment Topic Categories Transplantation Immunology (TRAN)
2026-07-06 | The application of rituximab during the conditioning regimen prevents Epstein - Barr virus infection following rATG-based haploidentical hematopoietic stem cell transplantation in the era of letermovir for cytomegalovirus prophylaxis.
In the era of letermovir for cytomegalovirus (CMV) prophylaxis, several centers reported that the incidence of Epstein-Barr virus (EBV) infection were significantly increased. To investigate the efficacy and safety of rituximab administration during conditioning regimen following haploidentical hematopoietic stem cell transplantation(haplo-HSCT)in the prevention of post-transplant EBV infection. We conducted a retrospective analysis of 100 patients with acute leukemia or myelodysplastic syndrome who underwent haplo-HSCT. Patients in observation group(R group) received rituximab (375 mg/m²) on day -3 before transplantation due to the presence of donor-specific antibody (MFI ≥ 2000) (n = 25) and patients in control group (C group) did not receive rituximab (n = 75) and donor-specific antibody was low (MFI < 2000). The primary objectives were the incidence of EBV-DNA viremia and PTLD within one-year post-transplantation. Secondary objectives included the incidence of CMV infection, cumulative incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD, 100-day non-relapse mortality (NRM), progression-free survival (PFS), and overall survival (OS). No significant differences were observed in baseline characteristics between the two groups except for primary disease. When compared with the C group, patients in R group exhibited a lower cumulative incidence of EBV viremia within one-year post - transplantation (4.00% vs. 22.67%, P = 0.049) and a lower incidence of aGVHD (28% vs. 50.67%, P = 0.048). There was a trend toward reduction of PTLD in the R group compared with C group (0% vs. 10.67%, P = 0.089).There were no significant differences of the incidence of CMV viremia (24% vs. 13.33%, P = 0.208), cGVHD (16% vs. 12%, P = 0.607), and 100 - day NRM (4.0% vs. 10.67%, P = 0.313) between two groups. The 2-year OS rates in the R group and C group were 83.8% ± 0.086% and 81.9% ± 0.050% respectively (P = 0.360). The 2-year PFS rates in the R group and C group were 83.8% ± 0.086% and 72.6% ± 0.068% respectively (P = 0.360). The combined use of rituximab during the conditioning regimen may be regarded as an effective strategy for preventing EBV reactivation after rATG - based haplo - HSCT in the era of letermovir for CMV prophylaxis.Prospective randomized controlled trials are still required to further validate the reliability of the results.
2026-06-15 | Pre-transplant Clostridioides difficile infection predicts subsequent gastrointestinal GVHD and non-relapse mortality after allogeneic hematopoietic stem cell transplantation.
This study aimed to define the incidence of Clostridioides difficile infection (CDI), identify its risk factors, and evaluate its association with early post-transplant complications and overall clinical outcomes. To characterize CDI in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) setting, we retrospectively analyzed a cohort of 539 recipients who experienced diarrhea in the peri-transplant period (from conditioning to discharge from laminar flow). Among these diarrheic recipients, 64 patients developed CDI, the cumulative incidence of CDI was 12.1%, with a median onset of day -1 (range, -7 to +26) relative to HSCT. In a multivariate analysis, older age was independently associated with a lower risk of CDI (HR, 0.97; P = 0.008) among diarrheic recipients. The incidence of CDI stratified by the median onset time revealed that pre-transplant CDI was an independent risk factor for grade 1-4 lower gastrointestinal acute graft-versus-host disease (lower-GI aGVHD) (HR, 2.43; P=0.024). Furthermore, pre-transplant CDI was associated with a markedly increased risk of severe fungal infection (HR,6.97; P=0.026) and 100-day non-relapse mortality (NRM) (HR, 3.13; P=0.046). In conclusion, this study highlights a critical, timing-dependent distinction in CDI-associated severe complications and mortality in allo-HSCT recipients with diarrhea.
2026-06-12 | Begelomab (BEGESAND®) Salvages Steroid-Resistant Acute GVHD in Pediatric Patients.
Background: Acute graft-versus-host disease (aGVHD) is a leading cause of morbidity and mortality following pediatric hematopoietic stem cell transplantation (HSCT). Approximately half of children achieve complete response (CR) to corticosteroids, whereas steroid-refractory (SR) disease carries a 1-2-year mortality of 41-44%. Mortality risk is 2.6-fold higher in children > 13.9 years, and respiratory failure accounts for 26% of deaths. Existing second-line agents-ruxolitinib, tocilizumab, or extracorporeal photopheresis-have delayed onset or high toxicity. Begelomab (BEGESAND®), a monoclonal antibody targeting CD26/dipeptidyl peptidase-4 (DPP4), inhibits CD26-mediated T-cell activation and has demonstrated 75% response in adults with minimal toxicity. However, pediatric data are lacking. Methods: We retrospectively reviewed five consecutive pediatric patients (ages 3-20 years) treated with Begelomab (BEGESAND®) for SR (n = 4) or steroid-dependent (SD; n = 1) aGVHD between 2017-2021 under emergency IND authorization. Begelomab (BEGESAND®) was administered intravenously at 2.7 mg/m2/day on days 1-5, 10, 14, 17, 21, 24, and 28. GVHD was graded by MAGIC criteria; flow cytometry and immunohistochemistry (IHC) assessed CD26 expression and immune effects. Results: All patients had grade IV disease after ≥2 prior agents. Two with pre-existing sepsis died early, before treatment response could be assessed. Of three evaluable patients, two (67%) achieved CR within 21 days and one achieved durable control by 6 months. All three remain alive; no Begelomab (BEGESAND®)-related toxicity, cytopenia, or new infections occurred. Flow cytometry showed preserved T-cell subsets, and IHC demonstrated CD26 localization at sites of epithelial injury. Conclusions: Begelomab (BEGESAND®) showed promising timely and durable responses with excellent safety in pediatric SR/SD-aGVHD, supporting further evaluation in multicenter pediatric trials.
2026-04-24 | Xenopax from a real-world and economic perspective: The future of second-line treatment and prophylaxis for SR-aGVHD.
Steroid-refractory acute graft-versus-host disease (SR-aGVHD) remains a major therapeutic challenge after allogeneic hematopoietic stem cell transplantation. Although ruxolitinib and basiliximab are widely used, their limitations highlight the need for safer, more effective, and scalable biologic strategies. Xenopax, a humanized anti-CD25 monoclonal antibody, has demonstrated encouraging results across real-world and clinical studies. The multicenter RELAX study reported a 28-day overall response rate of 64.5% and a 2-year overall survival of 68.0%, with reduced corticosteroid exposure and infection rates compared with historical basiliximab cohorts. Importantly, RELAX incorporated an economic assessment, showing a lower incremental cost per responder and reinforcing xenopax as a cost-efficient option for SR-aGVHD. Beyond salvage therapy, xenopax is gaining momentum in prophylactic settings, including as a potential replacement for methotrexate in haploidentical transplantation. Looking ahead, integration with autonomous decision-support systems-most notably daGOAT, the first AI platform validated to prescribe risk-adapted GVHD prophylaxis-may further strengthen CD25-targeted approaches. Together, these developments position xenopax as a versatile biologic with the potential to reshape both treatment and prevention paradigms in GVHD management.
proteins
2026-08-09 | Pegtarazimod limits acute graft-versus-host disease mortality and severity in mice and is tolerated in patients.
The success of allogeneic hematopoietic cell transplantation (allo-HCT) is limited by acute graft-versus-host disease (aGVHD). We have previously reported that neutrophils can exacerbate tissue damage caused by conditioning regimens. Pegtarazimod is a synthetic peptide, derived from the capsid protein of human astrovirus serotype 1, that was shown to reduce neutrophil effector functions. Therefore, we evaluated the therapeutic activity of pegtarazimod against aGVHD. Pegtarazimod significantly reduced aGVHD-related mortality, histological aGVHD severity, and pro-inflammatory cytokines in multiple in vivo mouse models, while maintaining the anti-leukemia effect. Mechanistically, pegtarazimod reduced inflammation by decreasing ROS production as investigated using allo-HCT recipient mice with genetic inactivation of NADPH oxidase (NOX2) in the bone marrow. In addition to the anti-inflammatory effect, pegtarazimod protected intestinal organoids against TNF-induced toxicity and oxidative DNA damage. In the phase-2 clinical trial AURORA, pegtarazimod treatment was well-tolerated in patients with corticosteroid-refractory (SR) aGVHD (NCT06343792) with an overall response rate (ORR) of 4/7 patients at day 28. In summary, pegtarazimod reduced aGVHD in mice by suppressing pro inflammatory neutrophil effector functions and preserving enterocyte integrity. The clinical trial data support tolerability of pegtarazimod in aGVHD patients and further studies are needed to determine efficacy.
2026-07-31 | Gastrointestinal acute graft versus host disease: a translational perspective from pathogenesis to precision prevention and treatment.
Allo-HSCT represents a curative option for various hematological disorders. However, aGVHD remains the leading cause of non-relapse mortality following transplantation. The gastrointestinal tract is the most severely affected and prognostically unfavorable target organ in aGVHD, driven by donor T-cell-mediated epithelial damage, microbiota dysbiosis-driven immune amplification, and a self-perpetuating cycle of barrier disruption. Recent multi-omics studies have identified key pathogenic mechanisms, including microbiota-driven MHC-II expression and immunomodulation by microbial metabolites. Biomarker-driven risk stratification using the MAGIC algorithm has shifted management toward precision medicine, while targeted agents such as ruxolitinib, vedolizumab, and microbiota-directed interventions are reshaping therapeutic strategies. Novel interventional modalities, including FMT, recombinant LCN2, and specific bile acids, have forged innovative avenues that synergize microbiota-directed approaches with immunomodulation for the prevention and treatment of GI-aGVHD. This review systematically delineates the latest advances in the pathogenesis, risk stratification, and therapeutic strategies for GI-aGVHD, and envisions future directions for precision medicine centered on personalized microbiota-immune interventions.
2026-06-29 | ATG Exposure in T Replete Transplant for Hematological Malignancies: Real World Analysis from BMT CTN 1202.
Traditional weight-based dosing results in variable rabbit anti-thymocyte globulin (rATG) clearance, delaying CD4 + Tcell-immune-reconstitution (CD4 + IR) and impacting outcomes. In a retrospective pharmacokinetic/pharmacodynamic analysis of patients undergoing first T-replete hematopoietic cell transplantation (HCT), enrolled on BMT CTN 1202, we estimated post-HCT rATG-exposures as area under the curve (arbitrary unit per day/milliliter [AUxd/mL]) using a validated pharmacokinetic-model. Results were compared to patients who did not receive rATG. Previously defined post-HCT rATG-exposure groups: A:<30, B:30-55 and C:≥55 AUxd/mL were correlated with outcomes of interest using cox-proportional-hazard and cause-specific-hazards models. 325 patients (median age 51 years) were included: 228 received rATG. Median post-HCT rATG-exposure was 44.1 (Range 6.2-125.0). Among patients who received rATG, higher exposure correlated with worse five-year overall survival (OS) (no-ATG:51%; group A:67%; B:49%; C:34%, p = 0.01), higher five-year relapse incidence (no-ATG:31%; A:27%; B: 42%; C: 58%, p < 0.001) and lower CD4 + IR (no-ATG:64%; A:73%; B:51%; C:19%, p = 0.001). Grade 2-4 acute graft versus host disease (GVHD) rates were: no-ATG:40%; A:26%, B:39%, C:35%, (p = 0.44). Any rATG-exposure was associated with lower moderate/severe chronic GVHD (HR:0.63, p = 0.025). Low post-HCT rATG-exposure (< 30AUxd/mL) but not absent correlated with higher OS, lower relapse, and lower GVHD related deaths. Model-based-dosing could be used to target optimal post-HCT rATG-exposure and improve HCT outcomes.
2026-06-02 | A Phase 1b Study of Efmarodocokin Alfa, an Interleukin-22 Agonist, in Combination with Standard of Care, in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.
Acute graft-versus-host disease (aGVHD) remains a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT), and no nonimmunosuppressive pharmacologic therapies are currently available for prophylaxis. We conducted a Phase 1b, open-label, dose-escalation study to evaluate the safety, pharmacokinetics (PK), and preliminary activity of efmarodocokin alfa, an interleukin-22 agonist, administered with standard-of-care prophylaxis in patients undergoing matched unrelated and matched related donor allogeneic HSCT following myeloablative conditioning. Eighteen patients were enrolled across 3 dose cohorts receiving efmarodocokin alfa at 30 µg/kg every 4 weeks, 30 µg/kg every 2 weeks, or 60 µg/kg every 2 weeks. Efmarodocokin alfa was well-tolerated and demonstrated an acceptable safety and PK profile, characterized by predominantly Grades 1 to 2 adverse events and linear PK across all dose levels. All patients achieved neutrophil engraftment by Day 30. By Day 100 post-transplant, 5 patients (27.8%) developed Grade 2 aGVHD, 2 (11.1%) of which had Stage 1 lower GI aGVHD. No patients developed Grades 3 to 4 aGVHD. Exploratory analysis demonstrated a lower gastrointestinal aGVHD-free survival rate of 83.3% at Day 180 and overall survival of 77.8% at Day 365. Although conclusions regarding efficacy are limited by the small sample size and exploratory design, these results demonstrate favorable safety and PK characteristics and provide initial observations regarding the potential role of efmarodocokin alfa in the prevention of lower gastrointestinal aGVHD as a nonimmunosuppressive prophylactic strategy.
2026-04-27 | Differential impact of allogeneic stem-cell transplantation on large B-cell lymphomas and peripheral T-cell lymphomas.
Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) is one of the standard treatments for relapsed/refractory (r/r) non-Hodgkin lymphoma, but benefits across large B-cell lymphoma (LBCL) and nodal peripheral T-cell lymphoma (PTCL) subtypes remain unclear. This single-center retrospective study evaluated outcomes after the first allo-HSCT in 92 adults with r/r aggressive lymphoma (59 and 33 patients with LBCLs and PTCLs, respectively) treated during 2011–2023. The patients’ median age was 51 years; 58.7% had active disease at transplant, and 77.2% received cord blood grafts. With a median follow-up of 7.6 years among survivors, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 31.6% and 27.9%, respectively. Furthermore, the non-relapse mortality (NRM) and relapse/progression rates were 30.8% and 41.3%, respectively. Compared with patients with LBCLs, those with PTCLs showed superior 5-year outcomes (OS: 47.7% vs. 22.4%, P = 0.03; PFS: 39.7% vs. 21.0%, P = 0.04) and lower relapse rates (26.9% vs. 49.5%, P = 0.02), with similar NRM and acute graft-versus-host disease rates. Multivariable models showed that PTCL histology was an independent predictor of improved OS and PFS. These findings suggest that allo-HSCT confers greater long-term benefits in patients with PTCL, supporting its role as an effective option in this subgroup.
other
2026-03-04 | IL1B rs1143627 and IL17A rs8193036 in the risk of Acute Graft Versus Host Disease in pediatric HSCT.
Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). While HLA compatibility is a key determinant, increasing evidence suggests that non-HLA immune gene polymorphisms, particularly those in cytokine genes, contribute to GVHD risk. This study seeks to validate in a pediatric population, cytokine-related single nucleotide polymorphisms (SNPs) associated with acute GVHD (aGVHD) and analyze them in combination with the previously identified HLA risk alleles. Pediatric HSCT recipients were recruited from the CHU Sainte-Justine biobank and a prior European Society for Blood and Marrow Transplantation (EBMT) multicenter study. Twenty-five SNPs in 12 cytokine genes were selected based on published associations with aGVHD. Genotypes were obtained for discovery (n = 87) and replication (n = 154) cohorts and association analyses were conducted in each cohort and in the combined dataset. Two SNPs, IL1B rs1143627 and IL17A rs8193036, were significantly associated with increased risk of aGVHD II-IV (p = 0.019 and p < 0.001, respectively). These associations were strongest in HLA-matched unrelated-donor-recipient pairs for IL1B rs1143627 (p = 0.015) and in all HLA-matched pairs for IL17A rs8193036 (p = 0.004). Notably, carriers of one or both risk alleles combined with HLA-B*15:01 had a markedly elevated risk (HR: 2.14 CI:1.41-3.25, p = 6 ×10⁻⁶). These findings highlight the relevance of non-HLA genetic variants in aGVHD pathogenesis. Incorporating cytokine SNP profiles, especially IL1B rs1143627 and IL17A rs8193036, alongside HLA typing may improve donor selection and guide individualized aGVHD prophylaxis.
2025-08-01 | NK Alloreactivity Evaluation According to KIR-HLA Interaction Models Influences the Outcome of Haploidentical Haematopoietic Stem-Cell Transplantation Based on Post-Transplant Cyclophosphamide.
Haploidentical haematopoietic stem-cell transplantation (haplo-HSCT) is characterised by a high degree of HLA mismatching. Therefore, NK alloreactivity driven by the interactions between KIR and HLA mismatched molecules could benefit its outcome. However, the influence of NK alloreactivity in haplo-HSCT with post-transplant Cyclophosphamide (PTCy) remains controversial. The aim of this work was to investigate the clinical utility of predicting NK alloreactivity according to previously described models in the context of haplo-HSCT with PTCy. We studied 145 patients who underwent this procedure, evaluating the influence of NK alloreactivity in transplant outcomes. Models that disregard the interactions between KIR and HLA evidenced an unsuccessful prediction of the outcomes. On the contrary, approaches based on KIR-HLA interaction were the most accurate to predict transplant outcomes. The analysis of inhibitory KIRs (iKIRs) based on the missing-ligand model showed that the presence of at least two iKIR mismatches (iKIRmm) among the donor-recipient pair was an independent risk factor for acute graft-versus-host disease (aGvHD) grade III‑IV (HR: 3.21, p = 0.021), relapse rate (HR: 2.46, p = 0.046), relapse-free survival (RFS) (HR: 1.96, p = 0.039) and GvHD/relapse-free survival (GRFS) (HR = 2.16, p = 0.008). The analysis of the missing-licensing model showed that the existence of the mismatch KIR2DL1/C2 associated to relapse rate (HR: 4.34, p = 0.002) and more than one iKIRmm correlated to poorer RFS (HR: 2.31, p = 0.038) and GRFS (HR: 2.26, p = 0.022). These results suggest that NK alloreactivity influences the outcome of haplo-HSCT with PTCy and should be incorporated into the donor selection algorithm for this procedure.
2025-05-28 | [Effects of donor T cell stat3 deficiency on acute intestinal graft-versus-host disease in mice].
Objective: To investigate the effects and underlying mechanisms of Stat3 knockout in donor T cells on acute gastrointestinal graft-versus-host disease (GI-aGVHD) . Methods: BALB/c mice were exposed to lethal irradiation and transplanted with bone marrow and spleen cells from BALB/c mice (syngeneic control group), C57BL/6 mice (wild-type T cell group, WT group), or C57BL/6J-Stat3(em1cyagen) mice (Stat3 gene knockout T cell group, Stat3-KO group) via tail vein injection to establish the aGVHD model. The survival rate, body weight changes, and clinical scores of mice were monitored. Cytometric bead array (CBA) was used to detect the concentrations of serum cytokines. Lymphocytes were isolated from tissues for flow cytometric analysis. H&E staining was performed to observe intestinal pathological changes. FITC-dextran assay was conducted to assess intestinal permeability. Immunohistochemistry was used to evaluate the expression of Ki67 and Muc2. Real-Time Quantitative Reverse Transcription PCR (qRT-PCR) was employed to analyze the gene expression levels of Olfm4, Lysozyme, and Muc2 in the small intestine. Metabolomics was conducted to detect metabolites in serum and intestinal tissues. An in vitro GI-aGVHD organoid model was established by coculturing intestinal organoids with allogeneic T cells, where the number and area of small intestinal organoids were recorded. The GVL effect was assessed using luciferase-transfected ALL cells (ALL/Luc) and bioluminescent imaging. Results: Compared with the WT group, Stat3 knockout T cells alleviated body weight loss, reduced symptoms-such as hunchback and diarrhea-in mice, improved survival rate (P<0.05), and reduced serum interleukin (IL) -2, IL-6, interferon-γ, tumor necrosis factor-α, IL-17A, and IL-10 levels (all P<0.05), intestinal inflammatory cell infiltration (P<0.05), and intestinal mucosal permeability. Further, Muc2 and Ki67 expression levels in the small intestine of the Stat3 knockout group were markedly increased, and Olfm4, Lysozyme, and Muc2 gene expression levels were significantly increased (all P<0.05). In vitro, the Stat3 knockout group demonstrated better organoid development than the WT group. Metabolomic analyses indicated that Stat3 knockout in T cells may affect the pathways associated with bile acid secretion and unsaturated fatty acids. ALL/Luc cells in the GVL mouse model proliferated rapidly in the TCD-BM group; however, 80% of the mice in the Stat3-KO group survived tumor-free for >100 days (P<0.05) . Conclusion: Knocking out Stat3 in graft T cells reduces T cell damage to intestinal stem cells, thereby ultimately alleviating GI-aGVHD while maintaining a stable GVL effect.
2025-03-22 | Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy.
Previous data indicated that the leucine-rich α-2 glycoprotein 1 (LRG1) pathway contributes to vascular dysfunction during cancer growth. Therapeutic targeting of LRG1 normalized tumor vessel dysfunction and enhanced the efficacy of anti-cancer adoptive T cell therapy. A major clinical problem after allogeneic hematopoietic stem cell transplantation (alloHSCT) and after chimeric antigen receptor (CAR) T-cell therapy is the induction of hyperinflammatory side effects, which are typically associated with severe endothelial dysfunction. We investigated LRG1 in preclinical models and in patient samples. In prospective studies, we found elevated LRG1 serum levels in patients with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome after CAR-T-cell therapy as well as in patients with acute graft-versus-host disease (aGVHD) after alloHSCT.In preclinical models of aGVHD, we found vasculature-associated LRG1 upregulation as well as LRG1 pathway gene upregulation. The genetic deletion of LRG1 in alloHSCT donors and in alloHSCT recipients led to reduced clinical and histological aGVHD. In line with this, LRG1 deletion led to clinically and histologically reduced disease severity in experimental inflammatory models of colitis (dextran sulfate sodium colitis) and paw edema. LRG1 deletion reduced inflammation-related vascular leakiness, endothelial cell proliferation, and migration. The current data support the hypothesis that LRG1 is an attractive therapeutic target after alloHSCT and after CAR-T cell therapy for cancer because of its role in dysfunctional tumor vessels as well as in inflammatory complications.
2024-09-18 | mRNA-delivery of IDO1 suppresses T cell-mediated autoimmunity.
Indoleamine-2,3-dioxygenase (IDO)1 degrades tryptophan, obtained through dietary intake, into immunoregulatory metabolites of the kynurenine pathway. Deficiency or blockade of IDO1 results in the enhancement of autoimmune severity in rodent models and increased susceptibility to developing autoimmunity in humans. Despite this, therapeutic modalities that leverage IDO1 for the treatment of autoimmunity remain limited. Here, we use messenger (m)RNA formulated in lipid nanoparticles (LNPs) to deliver a human IDO1 variant containing the myristoylation site of Src to anchor the protein to the inner face of the plasma membrane. This membrane-anchored IDO1 has increased protein production, leading to increased metabolite changes, and ultimately ameliorates disease in three models of T cell-mediated autoimmunity: experimental autoimmune encephalomyelitis (EAE), rat collagen-induced arthritis (CIA), and acute graft-versus-host disease (aGVHD). The efficacy of IDO1 is correlated with hepatic expression and systemic tryptophan depletion. Thus, the delivery of membrane-anchored IDO1 by mRNA suppresses the immune response in several well-characterized models of autoimmunity.
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Drug Discovery Landscape
28 orphan drug designations for Acute graft versus host disease, including 2 approved therapies.
28 orphan drug designations for Acute graft versus host disease, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
allogeneic-unrelated, CD4+ T cells transduced with lentiviral vector encoding full-length human interleukin-10 gene and a truncated (non-signaling) form of the human nerve growth factor receptor | cell therapies | FDA | 2025-09-30 | — | Tr1X, Inc. |
universal CAR-T cell injection targeting NKG2D ligands/OX40/CD70/BCMA | cell therapies | FDA | 2025-09-12 | — | ST Phi Therapeutics Co.,Ltd. |
human umbilical cord-derived mesenchymal stem cells | cell therapies | FDA | 2024-12-10 | — | Wuhan Optics Valley Vcanbiopharma Co., Ltd. |
xempritolimod | RNAs | FDA | 2024-08-23 | — | CONNEXT Co., Ltd. |
pegtarazimod | small molecules | FDA | 2024-07-31 | — | ReAlta Life Sciences, Inc. |
Tetrahydro-2H-pyran-4-yl 7-(2-(cyclopropanecarboxamido)- imidazo[1,2-a]pyridin-6-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate hydrochloride | small molecules | FDA | 2023-12-11 | — | Accropeutics Inc. |
tregalizumab | antibodies | FDA | 2023-08-31 | — | T-Balance Therapeutics GmbH |
Mesenchymal stem cells (MSCs) primed with interferon gamma (IFNgamma) | cell therapies | FDA | 2022-07-25 | — | Ossium Health, Inc. |
Mesenchymal stem cells | cell therapies | FDA | 2022-05-12 | — | Ossium Health, Inc. |
apraglutide | peptides | FDA | 2021-05-25 | — | Ironwood Pharmaceuticals, Inc. |
Teduglutide | peptides | FDA | 2020-12-08 | — | 9 Meters Biopharma Inc. |
Urinary-derived human chorionic gonadotropin and epidermal growth factor | proteins | FDA | 2020-08-12 | — | University of Minnesota |
defibrotide | oligonucleotides | FDA | 2020-05-14 | — | Jazz Pharmaceuticals Ireland Limited |
acazicolcept | antibodies | FDA | 2020-03-16 | — | Alpine Immune Sciences |
acazicolcept | small molecules | FDA | 2020-03-16 | — | Alpine Immune Sciences |
recombinant human interleukin 22-human immunoglobulin Fc fusion protein | proteins | FDA | 2019-10-21 | — | Evive Biotechnology (Shanghai) Ltd. |
itolizumab | antibodies | FDA | 2019-02-05 | — | Biocon Limited |
itolizumab | antibodies | FDA | 2019-02-01 | — | Biocon Limited |
Allogeneic mesenchymoangioblast-derived mesenchymal stem cells | cell therapies | FDA | 2018-03-26 | — | Cynata Therapeutics Limited |
neihulizumab | antibodies | FDA | 2018-01-25 | — | AltruBio Inc. (formerly AbGenomics International, Inc.) |
Human alpha-1-antitrypsin | proteins | FDA | 2017-06-12 | — | Paul Maher, MD |
ruxolitinib [Jakafi XR] | small molecules | FDA | 2016-11-03 | 2026-05-01 | Incyte Corporation |
Recombinant human monoclonal antibody against human complement component C5a | antibodies | FDA | 2016-10-06 | — | Alexion Pharmaceuticals, Inc. |
remestemcel-L-rknd [Ryoncil] | cell therapies | FDA | 2005-12-14 | 2024-12-18 | Mesoblast, Inc. |
Gavilimomab | small molecules | FDA | 2000-11-20 | — | Amgen |
Dimerizing drug that binds to mutated Fas protein/drug-binding domain fusion protein (FKBP) | small molecules | FDA | 1999-11-24 | — | Bellicum Pharmaceuticals, Inc. |
Humanized anti-tac | antibodies | FDA | 1993-03-05 | — | Hoffmann-La Roche, Inc. |
ST1-RTA immunotoxin (SR 44163) | antibodies | FDA | 1987-08-12 | — | Sanofi Winthrop, Inc. |
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