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.
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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.
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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.
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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.
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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.
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