RARE DISEASE
Chronic graft versus host disease
Chronic graft versus host disease
Chronic graft versus host disease
Drug discovery
16
drugs
With orphan designations
Overview
Chronic graft-versus-host disease (cGVHD) is a systemic immune-mediated disorder occurring in 30–70% of allogeneic hematopoietic stem cell transplant (HSCT) recipients, typically emerging ≥100 days post-transplant. It manifests as autoimmune-like inflammation and fibrosis across multiple organs (e.g., skin, eyes, liver, lungs), driven by donor T-cells attacking host tissues. cGVHD is a leading cause of late non-relapse mortality and long-term morbidity due to organ dysfunction, infections, and immunosuppressive therapy toxicity [1][3][5][10].
Burden
Morbidity: 26–40% of patients with active cGVHD cannot work; high rates of pain, depression, and physical disability [2][9][14].
Mortality: Leading cause of non-relapse mortality (8–38%), driven by infections and organ failure [3][10][17].
Economic: Prolonged immunosuppression increases healthcare costs (e.g., $21,000 annual outpatient visits) and caregiver dependency [14][17][18].
Therapies
First-line: Systemic corticosteroids ± calcineurin inhibitors (tacrolimus, cyclosporine) [3][8][13].
Steroid-refractory options: JAK inhibitors (ruxolitinib), BTK inhibitors (ibrutinib), and ROCK2 inhibitors (belumosudil) [3][8][15].
Prophylaxis: Post-transplant cyclophosphamide, T-cell depletion (ATG, CD34+ selection), and graft engineering (naive T-cell depletion) [3][8][11].
Categories: rare immunological diseases, rare transplant-related disorders
Research Papers
2,397 drug discovery papers about Chronic graft versus host disease, with 1 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,397 drug discovery papers about Chronic graft versus host disease, with 1 first-in-class and 16 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-14 | Ruxolitinib-Associated Improvement in Post-transplant Air-Leak Syndrome Complicating Steroid-Dependent Organizing Pneumonia: A Case Report.
Air-leak syndrome (ALS), including pneumothorax, pneumomediastinum, and subcutaneous emphysema, is a rare but life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, no standard treatment has yet been established. Here, we report the case of a 60-year-old man with acute myeloid leukemia who underwent allogeneic HSCT. He developed chronic graft-versus-host disease (GVHD) and cryptogenic organizing pneumonia (COP) on day 126 after transplantation. Although initial corticosteroid therapy improved the COP, the relapse occurred during tapering, and repeated steroid treatment failed to achieve sustained disease control. The patient subsequently developed pneumomediastinum, consistent with ALS. Ruxolitinib treatment was initiated on day 265 for steroid-dependent chronic GVHD and organizing pneumonia. Following treatment, oxygenation improved, pneumomediastinum improved, and corticosteroids were successfully tapered and discontinued without COP recurrence. Serum Krebs von den Lungen-6 (KL-6) levels decreased in parallel with clinical and radiological improvement. The introduction of ruxolitinib is associated with improvements in ALS and enabled the discontinuation of steroids. Adverse events included cytopenia and mild liver dysfunction, consistent with known safety profiles. The patient died of acute respiratory failure after transfusion, which was not considered a direct complication of the ruxolitinib treatment. This case suggests that ruxolitinib may facilitate corticosteroid tapering and radiographic improvement of organizing pneumonia-associated ALS after allogeneic transplantation.
2026-08-10 | Reduced Cumulative Post-Transplant Cyclophosphamide Exposure Is Associated with Increased Acute and Chronic Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation.
Post-transplant cyclophosphamide (PTCy) is conventionally administered at a cumulative dose of 100 mg/kg for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation (allo-HCT). In clinical practice, cumulative PTCy exposure may be reduced because of institutional protocols, physician-directed dose modifications, or body weight-adjusted dosing strategies. However, the clinical consequences of receiving cumulative PTCy doses below the standard 100 mg/kg remain poorly defined. We retrospectively evaluated 251 consecutive allo-HCT recipients transplanted between 2015 and 2025. Among them, 180 patients receiving PTCy-based GVHD prophylaxis were stratified according to cumulative PTCy exposure (<100 vs. ≥100 mg/kg), irrespective of the reason for dose reduction. Acute GVHD, chronic GVHD, relapse, non-relapse mortality (NRM), and overall survival (OS) were analyzed using logistic regression, Cox proportional hazards models, and competing-risk methods. Among the 180 PTCy recipients, 71 received <100 mg/kg and 109 received ≥100 mg/kg; the median cumulative dose in the reduced-exposure group was approximately 80 mg/kg. Reduced cumulative PTCy exposure (<100 mg/kg) was associated with a significantly increased incidence of acute GVHD compared with standard exposure (57.7% vs. 37.0%; OR 2.31, 95% CI 1.21-4.49; p=0.009). Patients receiving <100 mg/kg also experienced a higher burden of clinically significant GVHD, including grade II-IV acute GVHD (25.4% vs. 12.8%; OR 2.30, 95% CI 1.07-5.08; p=0.035), moderate-to-severe chronic GVHD (21.1% vs. 7.3%; OR 3.48, 95% CI 1.29-10.12; p=0.010), and greater use of second-line GVHD-directed therapy with ruxolitinib and/or extracorporeal photopheresis (34.4% vs. 19.8%; OR 2.12, 95% CI 1.05-4.31; p=0.036). In multivariable analyses, reduced cumulative PTCy exposure remained independently associated with acute GVHD (OR 2.29, 95% CI 1.18-4.53; p=0.016) and moderate-to-severe chronic GVHD (OR 4.07, 95% CI 1.52-11.63; p=0.005). Competing-risk analysis confirmed a higher cumulative incidence of acute GVHD (SHR 1.83, 95% CI 1.18-2.83; p=0.007). No significant differences were observed in relapse, non-relapse mortality, or overall survival. In this cohort, cumulative PTCy exposure below 100 mg/kg was associated with increased acute GVHD, a greater burden of clinically significant chronic GVHD, and increased use of second-line GVHD-directed therapies, without significant differences in relapse, non-relapse mortality, or overall survival. These findings suggest that effective GVHD prophylaxis with PTCy may depend on achieving adequate cumulative drug exposure and support prospective studies to define the optimal cumulative PTCy dose for GVHD prophylaxis.
2026-08-09 | Loss of MGAT3 Amplifies TGF-β Signaling to Promote Bronchiolitis Obliterans Progression.
Bronchiolitis obliterans syndrome (BOS), a severe complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), presents as chronic graft-versus-host disease characterized by inflammation and fibrosis of the small airway epithelium. This progressive fibrosis obstructs bronchiolar airways, leading to respiratory distress in patients. Due to the lack of effective treatments, a deeper understanding of the underlying mechanisms is crucial. This study explored the molecular mechanisms underlying the abnormal glycosylation regulation in BOS, aiming to provide new insights for early diagnosis and treatment of this disease. Bronchoalveolar lavage fluid (BALF) was collected from patients with and without BOS following allo-HSCT. N-glycans from the BALF were enriched using a solid-phase extraction method. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF-MS) was used to detect N-glycosylation characteristics in the BALF of BOS patients. This phenomenon was validated using a graft-versus-host disease (GVHD) mouse model. The impact of MGAT3 knockdown on the biological functions of airway epithelial cells (BEAS-2B) was then examined using lentivirus transfection. The molecular mechanism by which the loss of MGAT3 enhances TGF-β signaling was explored using western blotting, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence (IF). Our study investigated N-glycosylation changes in BALF of BOS patients and identified a strong correlation between the loss of bisecting-GlcNAc N-glycans and BOS progression. We found a novel mechanism where MGAT3, the enzyme synthesizing bisecting-GlcNAc structures, critically regulates TGF-β signaling. MGAT3 and bisecting-GlcNAc deficiency significantly enhance TGF-β signaling by increasing TGF-β storage through upregu-lation of latent TGF-β binding protein 1 (LTBP1) and by increasing the availability of TGF-β receptors. Our discovery highlights the crucial role of aberrant glycosylation in BOS progression and holds significant promise for developing novel biomarkers for early diagnosis, identifying new therapeutic targets, and ultimately improving the quality of life for BOS patients.
2026-08-06 | Novel highly selective ROCK2 inhibitor (TDI01) for the treatment of chronic graft-versus-host disease: a multicenter, open-label phase Ib/II study.
Chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic hematopoietic stem cell transplantation for long-term survival. Emerging evidence highlights Rho-associated coiled-coil kinase 2 (ROCK2) as a promising therapeutic target for cGVHD, which can modulate immune responses and profibrotic reactions. TDI01, a potent and highly selective ROCK2 inhibitor, represents a potential breakthrough in cGVHD treatment. This was the dose-finding, phase Ib portion of a multicenter, open-label phase Ib/II study (NCT06169722) designed to evaluate the safety and preliminary efficacy of TDI01 in patients with moderate-to-severe cGVHD after failure of 1 to 5 prior therapies. Sixty patients were enrolled in two once-daily dosing cohorts: 200 mg (n = 30) and 400 mg (n = 30). The primary endpoints were the 24-week best overall response rate (BORR) and safety. As of January 17, 2025, 57 patients were evaluated for efficacy. The 24-week BORRs were 67.9% (200 mg cohort) and 86.2% (400 mg cohort), with an overall BORR of 77.2%. The median times to response were 44.5 days (200 mg cohort) and 30.0 days (400 mg cohort). Neither the median duration of response nor the median failure-free survival (FFS) was achieved. The probability of FFS at 24 weeks was 83.9%. The most common adverse events ( ≥ 20% of patients) were transient bilirubin elevation (total bilirubin elevation 81.7%, unconjugated 56.7%, conjugated 45.0%) and headache (23.3%), without significant increases in liver enzymes. Thus, TDI01, particularly at the 400 mg QD dose, demonstrated promising efficacy and safety in moderate-to-severe cGVHD, which will be confirmed in a forthcoming phase III randomized controlled trial.
2026-08-06 | Long-term follow-up of ruxolitinib pre-approval use in acute and chronic graft-versus-host disease.
Steroid-refractory (SR) acute and chronic graft-versus-host disease (aGVHD/cGVHD) are frequent and serious complications after allogeneic hematopoietic stem cell transplantation. Ruxolitinib (RUX) is approved for the treatment of both conditions. Real world evidence may provide valuable complementary information beyond prospective trials because of significant divergences in study populations, endpoints, treatment strategies, and observation time. We report long-term outcomes of 118 patients with acute (n = 61), classic chronic (n = 43) and overlap chronic GVHD (n = 14) who received RUX within a named-patient-program in the pre-approval era as second-line treatment or beyond. In 22 patients, GVHD occurred after donor lymphocyte infusion (DLI). The cohort included heavily pretreated patients, with 26.2% of aGVHD in 3rd -line or beyond, and 29.8% of cGVHD in 4th -line or beyond. Only 22 patients (18.6%) met all in-/exclusion criteria of the respective pivotal phase III studies. The most frequent incompatibilities were unmet SR criteria, excessive pretreatment, previous DLI, overlap chronic GVHD, and medical/hematological criteria. Overall response rate to RUX was 68.9% in aGVHD, and 66.7% in cGVHD. In all three GVHD types, > 50% of patients were able to discontinue systemic steroids. With a survivors' median follow up of 60.3 months (range, 25.5-99.3) from RUX initiation, 4-year survival probability was 57.4% in aGVHD, 81.1% in classic cGVHD, and 78.6% in overlap cGVHD. Our findings reveal favorable survival probabilities associated with a long-term steroid-sparing/replacing potential of RUX in treatment-refractory aGVHD and cGVHD, including overlap syndrome and DLI-associated GVHD.
antibodies
2026-08-11 | Comorbid conditions after allogeneic haematopoietic stem cell transplantation in young adults in Germany-A prospective, multicentre trial.
Young adults (YA) are particularly affected by comorbid conditions following allogeneic haematopoietic stem cell transplantation (alloHSCT), as they have to live with them for many years. This is the first multicentre prospective study investigating sequelae after alloHSCT in YA in Germany. In total, 107 patients who survived relapse-free until day 100 after alloHSCT were enrolled. Median patient age was 29.3 years. Chronic graft-versus-host disease (cGvHD) occurred in 40.2%. Comorbidities were captured at days 100, 180, 365 and 910 by applying the post-transplant multimorbidity index (PTMI). Considering all time points, 12.5%-23.5% of patients had no comorbidity, while 39.2%-49.5% had 1-3, 26.3%-33.0% had 4-6 and 5.7%-8.4% had >6 PTMI-defined comorbidities respectively. The most prevalent PTMI-based comorbidities were iron overload, hypogonadism, arterial hypertension, infections, hepatic dysfunction and osteopenia/osteoporosis. However, the spectrum of PTMI-recorded comorbidities and those concurrently self-reported by patients differed substantially. Factors linked to a higher PTMI were total body irradiation and active cGvHD. Investigating single PTMI-defined comorbidities, we found significant associations of osteopenia/osteoporosis with cGvHD, ongoing immunosuppression and hypogonadism, which was more common among female survivors. These results provide a detailed analysis of the occurrence of a vast spectrum of PTMI-defined comorbidities in YA after alloHSCT.
2026-07-23 | Chronic GVHD Consortium CATCH Study: Incidence, initial presentation and risk factors for chronic GVHD development.
The incidence of chronic graft-versus-host disease (GVHD) is declining but up to 30% of survivors are still diagnosed with chronic GVHD. We conducted a prospective, multi-center, observational study to understand the incidence and earliest presenting signs and symptoms of chronic graft vs. host disease (GVHD) in the current era to inform trials testing early therapy. Patients were enrolled and assessed prior to allogeneic transplantation (HCT), and approximately every 2 months through the first year post-HCT, and at time of chronic GVHD diagnosis. Clinician assessments, patient-reported measures (Lee Symptom Score (LSS), PROMIS), and biologic samples were collected at each time point. A total of 208 subjects were enrolled across 7 HCT centers. The cumulative incidence of any chronic GVHD was 54% by 24 months post-HCT, while chronic GVHD requiring systemic immune suppressive therapy (IST) was 38%. At onset, organ involvement included skin (32%), eye (41%), mouth (42%), liver (17%), GI (9%), lung (11%), and joint/fascia (5%) with overall severity of mild (or less) in 55%, moderate in 37%, or severe in 8%. Management practices were heterogeneous. Subsequent chronic GVHD requiring IST was significantly associated with baseline donor/recipient CMV positivity and non-PTCY-based acute GVHD prophylaxis, as well as serial changes in skin/mouth/joint (PROM) organ scores and LSS summary score. These data provide current estimates of chronic GVHD incidence and presenting features, new data on risk predictors, and a data resource for future overall and organ-specific biomarker studies.
2026-07-22 | Chronic graft-versus-host disease: Update on pathobiology, biomarkers, and evolving treatment algorithms.
Chronic graft-versus-host disease (cGVHD) remains the leading cause of late non-relapse mortality and long-term disability after allogeneic hematopoietic cell transplantation (allo-HCT), affecting 30-70% of long-term survivors. Despite its substantial morbidity and the toxicities associated with prolonged corticosteroid use, therapeutic advances have accelerated considerably. This review synthesizes current mechanistic insights and clinical evidence within the framework of the well-established three-phase pathogenesis model of cGVHD. Phase 1 (early inflammation) involves tissue injury and innate immune activation; Phase 2 (months 2-12) is characterized by impaired central and peripheral tolerance with aberrant B- and T-cell responses; Phase 3 (>1 year) features macrophage-driven fibrosis and end-organ damage. Recognizing that these phases are conceptual and frequently overlap in clinical practice, we explore the alignment of contemporary biomarkers with each phase-ST2/CXCL9 (Phase 1), BAFF/autoantibodies (Phase 2), and MMP3/TGF-β (Phase 3)-and discuss how FDA-approved agents (ibrutinib, ruxolitinib, belumosudil, axatilimab) may target phase-specific pathways. A conceptual, risk-stratified treatment algorithm is proposed to link pathobiology to clinical decision-making, with the important caveat that biomarker-guided selection remains investigational and currently complements, rather than replaces, comprehensive clinical assessment. Notably, the adoption of prophylaxis and upfront strategies to prevent cGVHD has substantially reduced cGVHD incidence in modern cohorts.
2026-07-07 | Short-course blinatumomab as a bridge-to-transplantation improves the survival of Ph-negative MRD-positive B-ALL.
Post-transplant relapse remains the chief therapeutic challenge in Ph-negative B cell acute lymphoblastic leukemia (Ph- B-ALL). This retrospective study evaluated whether short-course blinatumomab for measurable resident disease (MRD) eradication could improve transplant outcomes. We compared 23 patients receiving pre-transplant short-course blinatumomab (2-week) for MRD eradication with 46 chemotherapy-only controls. All achieved MRD-negative before allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Only two patients developed grade 2 cytokine release syndrome with blinatumomab. The neutrophil and platelet engraftment times were similar between the two groups. The blinatumomab cohort had a significantly lower 18-month cumulative incidence (CI) of relapse (p = 0.05) and chronic graft-versus-host disease (GVHD) (14.8% vs. 41.8%; p = 0.05), with comparable non-relapse mortality (NRM) (p = 0.98) and 180-day grade II-IV acute GVHD rates (p = 0.93). Consequently, this cohort showed superior 18-month relapse-free survival (RFS) (90.9% vs. 65.2%; HR 0.30, 95% CI 0.09-1.04; p = 0.04), improved 18-month overall survival (OS) (95.7% vs. 81.9%; HR 0.20, 95% CI 0.03-1.71), and a trend toward better GVHD-free and relapse-free survival (GRFS) (74.71% vs. 63.71%; HR 0.64, 95% CI 0.23-1.78). Multivariate analysis confirmed blinatumomab as an independent favorable factor for RFS. In conclusion, short-course blinatumomab as a bridge-to-transplantation could reduce the risk of relapse and improve survival for Ph- B-ALL patients undergoing allo-PBSCT.
2026-07-06 | Targeting CD162 for Life-Threatening Cutaneous Chronic Graft-Versus-Host Disease: A Case Report.
Steroid-refractory chronic cutaneous graft-versus-host disease (GVHD) causes substantial morbidity, prolonged hospitalization, and non-relapse mortality after allogeneic hematopoietic cell transplantation. We report a young adult with multisystem chronic GVHD and recurrent life-threatening inflammatory skin flares refractory to multiple standard therapies, with cumulative inpatient care exceeding 1 year. Under an institutional review board-approved compassionate-use protocol, he received a non-cytotoxic monoclonal antibody targeting CD162 (P-selectin glycoprotein ligand-1). Treatment was associated with durable resolution of active cutaneous GVHD, corticosteroid reduction, improved mobility, and meaningful recovery in daily function and quality of life. The author has confirmed clinical trial registration is not needed for this submission.
proteins
2026-06-05 | Growth hormone therapy after hematopoietic cell transplantation in childhood: a nationwide survey and longitudinal cohort study.
Growth impairment is a major late effect in survivors of childhood hematopoietic cell transplantation (HCT); however, the long-term effectiveness and response patterns of growth hormone (GH) therapy after HCT remain unclear. Thus, this study aimed to evaluate the effectiveness of GH therapy and clinical factors associated with GH response in patients who underwent HCT during childhood and were diagnosed with short stature and to further examine long-term response patterns among those receiving GH therapy. We conducted a nationwide, multicenter retrospective cohort study of childhood HCT survivors with post-transplant short stature. Height outcomes were evaluated using final adult height standard deviation scores (SDS) and changes in SDS (ΔSDS). Factors associated with height outcomes and GH responsiveness were analyzed using multivariable regression models, and longitudinal growth trajectories after GH initiation were assessed at 1 year, 5 years, and final height. Among 171 patients with available final height data, 58 received GH therapy. GH-treated patients showed significantly greater improvement in final height SDS and ΔSDS than untreated patients, although growth responses were heterogeneous. Total body irradiation (TBI), HCT before 5 years of age, and chronic graft-versus-host disease were independently associated with poorer height outcomes. Factors associated with GH responsiveness differed by transplant type: absence of TBI and female sex were favorable in allogeneic HCT. Regarding complications, GH therapy was not associated with an increased risk of slipped capital femoral epiphysis, secondary malignancies, or relapse of the primary disease. GH therapy improves height outcomes after childhood HCT, but responses vary and are strongly influenced by transplant-related toxicity and long-term complications. To improve height outcomes, optimizing GH therapy and developing strategies for patients expected to respond poorly remain important challenges.
2026-03-28 | Alpha 1 Antitrypsin Suppresses Autoantibody Production and Cellular Autoimmunity in Chronic Graft-Versus-Host Disease (cGVHD) in a Lupus Mouse Model.
Systemic lupus erythematosus (SLE) is a severe autoimmune disease that is challenging to treat due to poor understanding of its pathogenesis and etiology. Clearly understanding and dissecting the therapeutic effects of potential treatment in animal models are important. It has been shown that human alpha-1 antitrypsin (hAAT) holds therapeutic potential for the treatment of autoimmune diseases including lupus. However, the mechanism underlying its protective effect requires further investigation. In the present study, we used a chronic graft-versus-host disease-induced lupus mouse model to test the effect of hAAT on lupus development. We performed adoptive transfer of MHC I-aβ mismatched bm12 splenocytes into hAAT transgenic mice and showed that hAAT significantly blocked the production of anti-dsDNA IgG autoantibodies. Mechanistically, hAAT inhibited T cell activation and proliferation, including that of effector memory T (Tem) and T follicular helper (Tfh) cells. In addition, hAAT suppressed germinal center formation and functions. These results advanced the current understanding of hAAT functions and provide a new insight for the treatment of SLE.
2026-01-01 | Increasing safety of pediatric hematopoietic stem cell transplantation by targeted approaches to chronic graft-versus-host disease
Hematopoietic stem cell transplant (HSCT) is a critical medical procedure used to treat various blood and bone marrow diseases. However, it is often associated with severe complications, including chronic graft-versus-host disease (cGVHD), a systemic condition that occurs when donor immune cells attack the recipient's tissues, leading to significant morbidity, with an incidence of 42% within three years and a non-relapse mortality rate of 30%. To date, most studies on cGvHD biomarkers have focused on adults, and the scientific mechanisms underlying the onset of cGvHD in the pediatric population remain poorly understood. Building on previous work that identified sCD13, an aminopeptidase, and the key intermediate metabolite in the TCA cycle, α-KG, as potential biomarkers, this thesis investigated their roles in cGvHD. Using two independent pediatric cohorts, I validated the elevation of α-KG at cGvHD onset. In vitro, recombinant sCD13 suppressed CD4⁺ and CD8⁺ T cell proliferation in a dose-dependent manner with minimal effects on cell survival, indicating an immunomodulatory role. Although no truncation of CXCL9, CXCL10, or CXCL11 was observed, sCD13 levels correlated with increased CD26, suggesting possible cooperative regulation of chemokines. Complementary experiments showed that α-KG enhanced NK cell cytotoxicity against K562 targets, slightly increased perforin expression, and exhibited trends towards improved metabolic fitness, while not significantly altering T cell proliferation. Together, these findings validate α-KG as a reproducible biomarker in children, establish sCD13 as an immune regulator of T cell responses, and reveal α-KG as a modulator of NK cell function. By uncovering mechanisms of biomarker activity, this work advances understanding of cGvHD pathogenesis and supports biomarker-driven strategies to improve diagnosis and treatment in pediatric HSCT.
2025-12-13 | Recombinant human soluble thrombomodulin prevents murine sclerodermatous chronic graft-versus-host disease.
Chronic graft-versus-host disease (cGVHD) develops with complex interactions between immune cells and cytokines, leading to irreversible fibrosis. Severe cGVHD impairs quality of life and is associated with nonrelapse mortality; however, effective treatments are limited. Recombinant human soluble thrombomodulin (rTM), a novel anticoagulant consisting of the extracellular domains of thrombomodulin, has shown efficacy in patients with transplantation-associated coagulation disorders and, recently, anti-inflammatory properties in animal studies. Here, we investigated the effects of rTM on cGVHD using a sclerodermatous cGVHD (Scl-cGVHD) mouse model. Prophylactic rTM administration suppressed the development of Scl-cGVHD skin lesions both clinically and histopathologically, prolonging event-free and overall survival. The rTM significantly reduced the infiltration of inflammatory cells, including activated T cells and transforming growth factor β1 (TGFβ1)-producing macrophages into the skin, while inflammation in the draining lymph nodes during priming phase and in spleen during chronic phase was unaffected. TGFβ1 expression in keratinocytes also decreased with rTM. Domain analysis suggested that these effects were mainly attributed to the N-terminal lectin-like domain (domain 1) of rTM, whose functions, including inhibition of inflammatory cell activation and recruitment related to interactions with endothelial cells, has recently been recognized in a limited number of preclinical studies. In conclusion, rTM prevented Scl-cGVHD development, likely by inhibiting the recruitment of inflammatory cells to the skin and subsequent TGFβ1 production by keratinocytes. The rTM may represent a novel prophylactic agent for cGVHD.
2025-10-01 | MON-682 Acquired Generalized Lipodystrophy Treated With Metreleptin in a Patient With Total Body Irradiation and Chronic Graft-Versus-Host Disease
Abstract Disclosure: T. Moazezi: None. B. Salehian: None. Background: Acquired lipodystrophy, both partial and generalized, is a rare disease that can be seen in patients with a history of total-body irradiation (TBI) and hematopoietic stem cell transplantation (HSCT). The widespread metabolic complications that arise from this disorder warrant attention and treatment. Clinical Case: A 25-year-old female with a history of Non-Hodgkin Lymphoma status post TBI and HSCT in 2000 and 2004 complicated by chronic graft-versus-host disease (GVHD) presented with multiple endocrinopathies to the endocrinology clinic. She presented with type 2 diabetes mellitus with severe insulin resistance, severe hypertriglyceridemia, and non-alcoholic steatohepatitis. The patient weighed 36.7 kg with a BMI of 14.3 kg/m2. On physical exam, the patient had complete loss of subcutaneous fat mass in the chest, abdomen, upper and lower extremities, and palmar-plantar region; there was minimal appreciable subcutaneous fat in the face and supraclavicular region. Abdominal exam revealed visceral fat and hepatomegaly with percussion of the liver 5 cm below the costal margin. The quantitative adiponectin level was low at 3.1 ug/mL (2.0-19.3 ug/mL), and the diagnosis of acquired generalized lipodystrophy (AGL) was made. Laboratory work-up was notable for SGOT 50 U/L (15-46 U/L), SGPT 88 U/L (7-56 U/L), glucose of 435 mg/dL (80-128 mg/dL), hemoglobin A1c 14.4% (<=6.4%), C-peptide 9.7 ng/mL (0.8-3.5 ng/mL), fasting triglyceride 4268 mg/dL (<=150 mg/dL), total cholesterol 297 mg/dL (<=200 mg/dL), HDL 34 mg/dL (>=39 mg/dL), and LDL 32 mg/dL (<=100 mg/dL). Abdominal ultrasound with elastography showed hepatomegaly, fatty liver, mild-moderate fibrosis. The patient was treated with statin, fish oil, gemfibrozil, Humulin R U-500 insulin, insulin pump, pioglitazone, and multiple oral hypoglycemic agents, and her metabolic complications were refractory to these standard therapies. She was started on treatment with metreleptin by subcutaneous injection for treatment of AGL. The dose was titrated upwards as tolerated, and the patient had improvement in her metabolic parameters while on treatment, including improved insulin sensitivity and lipoprotein profile. Metreleptin was discontinued after two years due to significant pain at the injection site. She was referred to plastic surgery to assess for auto-transplantation of adipose tissue, which was not an option due to complete loss of subcutaneous adipose tissue. Conclusion: Childhood cancer survivors with a history of TBI and HSCT can develop acquired lipodystrophy with associated metabolic complications later in life. This case demonstrates the role of metreleptin in improving insulin sensitivity and lipoprotein profiles in a patient with AGL. Presentation: Monday, July 14, 2025
cell therapies
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.
2026-07-28 | Distinct murine chronic graft-versus-host disease models enable the delineation of the diverging and converging contributors to fibrotic scleroderma 2250854
Abstract Introduction Chronic graft-versus-host disease (cGVHD) is a debilitating complication of allogenic hematopoietic stem cell transplantation (alloHSTC) characterized by immune dysregulation, autoimmunity, and fibrosis. Particularly devastating is scleroderma (Scl), a systemic sclerotic disease that targets the skin causing stiffness and delayed wound healing. Despite FDA approved therapies, complete responses in Scl-cGVHD are rare, highlighting an unmet need for more targeted therapies. Methods To delineate the inflammatory and profibrotic mechanisms underlying Scl disease, we used two distinct murine alloHSCT model in which hosts were lethally irradiated and given bone marrow (BM) ± T cells to induce cGVHD. We compared multiple minor antigen mismatch, B10.D2 into Balb/c to a semi-allogeneic, parent-into-F1 C57BL/6 (B6) into (B6D2) F1 models. Results Mice developed scleroderma signs at different rates facilitating the study of overlapping and diverging fibrosis mechanisms. Mice in the B10.D2into Balb/c model had visible skin lesions by d19 with immune cell infiltration seen as early as d3. In contrast, mice in the parent-into-F1 model had comparatively delayed Scl onset with visible lesions appearing ∼d35. In the B10.D2 into Balb/c model, a 20-fold increase in the frequency of IFNg producing CD4 conventional T cells (Tcon) as compared to BM controls was apparent by d21 (p = 0.0119) with very little IL-17 production (< 0.04% IL-17+ of Foxp3-CD4+ Tcon). Conversely, mice in the parent-into-F1 Scl-GVHD model had a strong signature of IL-17 production, with 60% of CD4 Tcon producing IL-17 at d21 (p = 0.0395). To begin to uncover Scl mechanisms, Scl and BM control skin biopsies (d3, 6, 9, 13 and 21; n = 3 mice/group/time) in the B10.D2into BALB/c model are being analyzed by Nanostring GeoMx along with multiplex immunofluorescence of skin from both models and will be presented. Conclusion Together, our data highlight the need for comprehensive studies of cGVHD/Scl models to develop improved translational therapeutics. Funding Source National Institutes of Health (grants P01 HL158505, P01 AI056299, and R37AI34495) Topic Categories Transplantation Immunology (TRAN)
2026-07-14 | CAR19 Tregs treat murine chronic Graft-Versus-Host Disease through immune suppression in absence of measurable B-cell cytolysis.
Chronic Graft-Versus-Host disease (cGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic transplantation. CGVHD pathophysiology involves cooperation between Tfollicular helper cells (TFH) and germinal center B-cells (GCB), allo- and auto-antibody depositions in cGVHD tissues, and fibrosis. We evaluated human CD19-directed chimeric antigen receptor (CAR19) T-cell therapy in a clinically relevant murine cGVHD model with bronchiolitis obliterans syndrome (BOS). Although CD8 CAR19 T-cells effectively reduced peripheral B-cell and GCB frequencies, pulmonary function was unimproved. In contrast, a single CAR19 CD4 regulatory T-cells (Treg) infusion mitigated ongoing pulmonary disease and modulated germinal centers (GC) associated with reduced TFH frequencies compared to control Tregs but without measurable B-cell depletion. Compared to EGFR Treg infusion, mice receiving CAR19 Tregs exhibited enhanced suppression of B-cell activation, preserved splenic architecture, and provided greater opportunities for interaction with CD19+ B-cells at the B-cell follicle boundary zones. Taken together with the absence of detectable B-cell cytolysis, these findings are most consistent with GC suppression rather than B-cell depletion as the dominant mechanism. Overall, our findings suggest that CAR19 Tregs represent a promising and safe cGVHD/BOS therapeutic strategy, offering immunosuppressive benefits and improved disease outcomes that may be more limited with CD8 CAR19 T-cell treatment.
2026-07-06 | System-level Redesign of an Allogeneic Hematopoietic Cell Transplantation Program Associated With High One-year Survival and Reduced Cost.
Practice variation in allogeneic hematopoietic cell transplantation may contribute to preventable toxicity, nonrelapse mortality, and excess cost. We evaluated outcomes occurring with the implementation of a program-wide standardization initiative in a medium-sized program. We conducted a single-center retrospective cohort study of consecutive patients undergoing first allogeneic hematopoietic cell transplantation in 2024 during implementation of a system-level redesign. The intervention emphasized high-reliability operations through concise standard operating procedures, formal quality management, standardized recipient and donor selection, a limited conditioning regimen formulary, fluid-sparing conditioning and graft infusion practices, post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis, and an early-discharge outpatient care model. The primary endpoint was 1-year overall survival. Secondary endpoints included graft-versus-host disease-free, relapse-free survival, nonrelapse mortality, acute and chronic graft-versus-host disease, length of stay, and pharmaceutical cost. Ninety-four patients underwent a first allogeneic hematopoietic cell transplantation in 2024. One-year overall survival was 92.6%, graft-versus-host disease-free, relapse-free survival was 56%, and nonrelapse mortality was 1%. The cumulative incidence of grade II to IV acute graft-versus-host disease was 32%, with grade III to IV acute graft-versus-host disease in 5%, and chronic graft-versus-host disease requiring systemic therapy in 18% at 1 year. Median hospital length of stay was 19 days overall and 14 days among adults. Average pharmaceutical cost per patient decreased from $88,810 across the preceding 3 fiscal years to $39,019 under the redesigned care model. In this single-center cohort, implementation of a standardized, high-reliability allogeneic hematopoietic cell transplantation care model was associated with excellent 1-year survival, low nonrelapse mortality, and lower pharmaceutical cost. These findings support the potential value of disciplined operational standardization as a complement to contemporary transplant platforms.
2026-06-12 | Chronic graft-versus-host disease.
Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic haematopoietic cell transplantation. cGVHD has a heterogeneous biology and morbid manifestations, affecting 30-70% of recipients and substantially impairing quality of life and is the leading cause of non-relapse mortality in allo-HCT recipients. This immune-mediated condition arises from complex immune dysregulation involving B cell and T cell activation, regulatory T cell dysfunction, and fibrosis driven by macrophages and fibroblasts. Glucocorticoids remain the first-line treatment; however, ~50% of patients develop steroid-refractory or steroid-dependent cGVHD, necessitating prolonged immunosuppression causing considerable toxicity. Four second-line treatments have been approved by the FDA - ibrutinib, ruxolitinib, belumosudil and axatilimab - targeting B cell signalling, JAK-STAT, ROCK2 and CSF1R pathways, respectively, and emerging therapies such as rovadicitinib show promise. However, substantial challenges persist in cGVHD treatment, including the heterogeneous biology and morbid manifestations (that is, lung and skin sclerosis), drug resistance and suboptimal supportive care. Biomarkers for early diagnosis and personalized treatment remain under investigation. Multidisciplinary care, infection control and psychosocial support are critical to improving quality of life in patients with cGVHD. Future research should prioritize mechanistic insights, antifibrotic therapies and integrating organ-specific interventions to enhance outcomes in patients with cGVHD.
other
2025-12-16 | Real-World Effectiveness of Recombinant Zoster Vaccine in Allogeneic Hematopoietic Cell Transplant Recipients.
Herpes zoster (HZ) is a frequent and clinically significant complication following allogeneic hematopoietic cell transplantation (allo-HCT), arising from delayed immune reconstitution and impaired varicella-zoster virus-specific immunity. Although acyclovir prophylaxis reduces early risk, prolonged use is often limited by toxicity and poor adherence. The recombinant zoster vaccine (RZV), a non-live adjuvanted subunit vaccine, has demonstrated high efficacy in immunocompetent adults and in several immunocompromised populations; however, real-world data in allo-HCT recipients remain scarce. To evaluate the real-world effectiveness of RZV in preventing HZ among allo-HCT recipients and to assess vaccine performance across clinical subgroups and in relation to antiviral prophylaxis. We conducted a retrospective cohort study of 506 allo-HCT recipients at a tertiary transplantation center, including 152 patients who completed the two-dose RZV series and 354 historical unvaccinated controls. The primary outcome was HZ incidence within 2 years after transplantation. Time-dependent Cox regression models were applied to estimate adjusted hazard ratios (aHRs), with RZV and acyclovir modelled as time-varying covariates. Competing risk and 9-month landmark analyses were performed to validate robustness. The 2-year cumulative HZ incidence was 19.7% in unvaccinated versus 5.9% in vaccinated patients (Gray's P < .001). RZV significantly reduced HZ risk (aHR 0.287, 95% confidence interval [CI] 0.131 to 0.627), corresponding to 71.3% effectiveness, consistent across subgroup analyses. Continued acyclovir prophylaxis was independently protective (aHR 0.323, 95% CI, 0.147 to 0.711). Importantly, no HZ events occurred in RZV recipients who discontinued acyclovir prematurely. Thirteen of 76 HZ cases (17.1%) met the criteria for complicated disease, strongly associated with chronic graft-versus-host disease and HLA mismatch; however, no significant effect of RZV was observed. RZV demonstrated substantial effectiveness in reducing HZ risk among allo-HCT recipients in real-world clinical practice. These findings provide compelling evidence for incorporating RZV into after transplantation preventive care as a valuable complement to, or alternative to, traditional antiviral prophylaxis strategies.
2024-02-14 | Differential expression of miRNA-769-5p and Smad2 in patients with or without oral cGVHD
Background.Oral chronic graft-versus-host disease (cGVHD) impacts quality of life of patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT).However, its precise pathogenesis remains unknown, with potential associations with differential microRNA (miRNA) expression and the TGF-β/Smad signaling pathway.Objectives.This study aims to explore miRNA expression profiles in the peripheral blood of oral cGVHD patients, focusing on miRNA-769-5p and its relationship with Smad2. Materials and methods.Peripheral venous blood samples were collected for RNA extraction from 8 patients with oral cGVHD, 8 patients without cGVHD and 8 participants from the healthy control group.The miRNA library was constructed using the Illumina Hiseq 2500 platform.We focused on identifying miRNAs associated with the TGF-β/Smad signaling pathway and subsequently conducted validation experiments.The oral cGVHD and without cGVHD groups were each expanded to include 15 individuals.Peripheral blood samples were subjected to polymerase chain reaction (PCR) analysis to assess miRNA levels and to evaluate Smad2 mRNA levels in peripheral blood mononuclear cells (PBMC).Additionally, enzyme-linked immunosorbent assay (ELISA) was conducted to determine the Smad2 protein levels in peripheral blood.Results.The most significantly differentially expressed miRNAs among the 3 groups were miRNA-505-5p and miRNA-769-5p.Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated an enrichment of the target genes of miRNA-769-5p in the TGF-β signaling pathway.It was observed that miRNA-769-5p expression was higher in patients without oral cGVHD in comparison to those with oral cGVHD.Receiver operating characteristic (ROC) analysis demonstrated that miRNA-769-5p holds diagnostic value for oral cGVHD.As a target of miRNA-769-5p, Smad2 mRNA exhibited a negative correlation with it.Moreover, both Smad2 mRNA and protein levels were higher in patients with oral cGVHD as opposed to those without cGVHD.Conclusions.Differential expression of miRNAs, particularly the downregulation of miRNA-769-5p, may influence the development of oral cGVHD by diminishing its inhibitory effect on the TGF-β/Smad signaling pathway through its interaction with Smad2.
2022-05-20 | MicroRNA-31 regulates T-cell metabolism via HIF1α and promotes chronic GVHD pathogenesis in mice.
Chronic graft-versus-host disease (cGVHD) remains a major obstacle impeding successful allogeneic hematopoietic cell transplantation (HCT). MicroRNAs (miRs) play key roles in immune regulation during acute GVHD development. Preclinical studies to identify miRs that affect cGVHD pathogenesis are required to develop these as potential lifesaving interventions. Using oligonucleotide array, we identified miR-31, which was significantly elevated in allogeneic T cells after HCT in mice. Using genetic and pharmacologic approaches, we demonstrated a key role for miR-31 in mediating donor T-cell pathogenicity in cGVHD. Recipients of miR-31-deficient T cells displayed improved cutaneous and pulmonary cGVHD. Deficiency of miR-31 reduced T-cell expansion and T helper 17 (Th17) cell differentiation but increased generation and function of regulatory T cells (Tregs). MiR-31 facilitated neuropilin-1 downregulation, Foxp3 loss, and interferon-γ production in alloantigen-induced Tregs. Mechanistically, miR-31 was required for hypoxia-inducible factor 1α (HIF1α) upregulation in allogeneic T cells. Therefore, miR-31-deficient CD4 T cells displayed impaired activation, survival, Th17 cell differentiation, and glycolytic metabolism under hypoxia. Upregulation of factor-inhibiting HIF1, a direct target of miR-31, in miR-31-deficient T cells was essential for attenuating T-cell pathogenicity. However, miR-31-deficient CD8 T cells maintained intact glucose metabolism, cytolytic activity, and graft-versus-leukemia response. Importantly, systemic administration of a specific inhibitor of miR-31 effectively reduced donor T-cell expansion, improved Treg generation, and attenuated cGVHD. Taken together, miR-31 is a key driver for T-cell pathogenicity in cGVHD but not for antileukemia activity. MiR-31 is essential in driving cGVHD pathogenesis and represents a novel potential therapeutic target for controlling cGVHD.
2019-05-14 | MicroRNA-17-92 is required for T-cell and B-cell pathogenicity in chronic graft-versus-host disease in mice.
Chronic graft-versus-host disease (cGVHD) is characterized as autoimmune-like fibrosis and antibody production mediated by pathogenic T cells and B cells. MicroRNA-17-92 (miR-17-92) influences the survival, differentiation, and function of lymphocytes in cancer, infections, and autoimmunity. To determine whether miR-17-92 regulates T- and B-cell responses in cGVHD, we generated mice conditionally deficient for miR-17-92 in T cells, B cells, or both. Using murine models of allogeneic bone marrow transplantation, we demonstrate that expression of miR-17-92 in donor T and B cells is essential for the induction of both scleroderma and bronchiolitis obliterans in cGVHD. Mechanistically, miR-17-92 expressed in T cells not only enhances the differentiation of pathogenic T helper 1 (Th1) and Th17 cells, but also promotes the generation of follicular Th cells, germinal center (GC) B cells, and plasma cells. In B cells, miR-17-92 expression is required for autoantibody production and immunoglobulin G deposition in the skin. Furthermore, we evaluated a translational approach using antagomirs specific for either miR-17 or miR-19, key members in miR-17-92 cluster. In a lupus-like cGVHD model, systemic administration of anti-miR-17, but not anti-miR-19, alleviates clinical manifestations and proteinuria incidence in recipients through inhibiting donor lymphocyte expansion, B-cell activation, and GC responses. Blockade of miR-17 also ameliorates skin damage by reducing Th17 differentiation in a scleroderma-cGVHD model. Taken together, our work reveals that miR-17-92 is required for T-cell and B-cell differentiation and function, and thus for the development of cGVHD. Furthermore, pharmacological inhibition of miR-17 represents a potential therapeutic strategy for the prevention of cGVHD.
2019-05-14 | Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease.
Chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) is characterized by multiorgan fibrosis and profoundly affects the quality of life of transplant survivors. Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, plays a critical role in collagen synthesis in myofibroblasts. We explored the role of HSP47 in the fibrotic process of cutaneous chronic GVHD in mice. Immunohistochemical analysis showed massive fibrosis with elevated amounts of collagen deposits and accumulation of F4/80+ macrophages, as well as myofibroblasts expressing HSP47 and retinol-binding protein 1 in the skin after allogeneic SCT. Repeated injection of anti-colony-stimulating factor (CSF-1) receptor-blocking antibodies significantly reduced HSP47+ myofibroblasts in the skin, indicating a macrophage-dependent accumulation of myofibroblasts. Vitamin A-coupled liposomes carrying HSP47 small interfering RNA (siRNA) (VA-lip HSP47) delivered HSP47 siRNA to cells expressing vitamin A receptors and knocked down their HSP47 in vitro. Intravenously injected VA-lip HSP47 were specifically distributed to skin fibrotic lesions and did not affect collagen synthesis in healthy skin. VA-lip HSP47 knocked down HSP47 expression in myofibroblasts and significantly reduced collagen deposition without inducing systemic immunosuppression. It also abrogated fibrosis in the salivary glands. These results highlight a cascade of fibrosis in chronic GVHD; macrophage production of transforming growth factor β mediates fibroblast differentiation to HSP47+ myofibroblasts that produce collagen. VA-lip HSP47 represent a novel strategy to modulate fibrosis in chronic GVHD by targeting HSP47+ myofibroblasts without inducing immunosuppression.
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2026-08-14 | Ruxolitinib-Associated Improvement in Post-transplant Air-Leak Syndrome Complicating Steroid-Dependent Organizing Pneumonia: A Case Report.
Air-leak syndrome (ALS), including pneumothorax, pneumomediastinum, and subcutaneous emphysema, is a rare but life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). However, no standard treatment has yet been established. Here, we report the case of a 60-year-old man with acute myeloid leukemia who underwent allogeneic HSCT. He developed chronic graft-versus-host disease (GVHD) and cryptogenic organizing pneumonia (COP) on day 126 after transplantation. Although initial corticosteroid therapy improved the COP, the relapse occurred during tapering, and repeated steroid treatment failed to achieve sustained disease control. The patient subsequently developed pneumomediastinum, consistent with ALS. Ruxolitinib treatment was initiated on day 265 for steroid-dependent chronic GVHD and organizing pneumonia. Following treatment, oxygenation improved, pneumomediastinum improved, and corticosteroids were successfully tapered and discontinued without COP recurrence. Serum Krebs von den Lungen-6 (KL-6) levels decreased in parallel with clinical and radiological improvement. The introduction of ruxolitinib is associated with improvements in ALS and enabled the discontinuation of steroids. Adverse events included cytopenia and mild liver dysfunction, consistent with known safety profiles. The patient died of acute respiratory failure after transfusion, which was not considered a direct complication of the ruxolitinib treatment. This case suggests that ruxolitinib may facilitate corticosteroid tapering and radiographic improvement of organizing pneumonia-associated ALS after allogeneic transplantation.
2026-08-10 | Reduced Cumulative Post-Transplant Cyclophosphamide Exposure Is Associated with Increased Acute and Chronic Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation.
Post-transplant cyclophosphamide (PTCy) is conventionally administered at a cumulative dose of 100 mg/kg for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation (allo-HCT). In clinical practice, cumulative PTCy exposure may be reduced because of institutional protocols, physician-directed dose modifications, or body weight-adjusted dosing strategies. However, the clinical consequences of receiving cumulative PTCy doses below the standard 100 mg/kg remain poorly defined. We retrospectively evaluated 251 consecutive allo-HCT recipients transplanted between 2015 and 2025. Among them, 180 patients receiving PTCy-based GVHD prophylaxis were stratified according to cumulative PTCy exposure (<100 vs. ≥100 mg/kg), irrespective of the reason for dose reduction. Acute GVHD, chronic GVHD, relapse, non-relapse mortality (NRM), and overall survival (OS) were analyzed using logistic regression, Cox proportional hazards models, and competing-risk methods. Among the 180 PTCy recipients, 71 received <100 mg/kg and 109 received ≥100 mg/kg; the median cumulative dose in the reduced-exposure group was approximately 80 mg/kg. Reduced cumulative PTCy exposure (<100 mg/kg) was associated with a significantly increased incidence of acute GVHD compared with standard exposure (57.7% vs. 37.0%; OR 2.31, 95% CI 1.21-4.49; p=0.009). Patients receiving <100 mg/kg also experienced a higher burden of clinically significant GVHD, including grade II-IV acute GVHD (25.4% vs. 12.8%; OR 2.30, 95% CI 1.07-5.08; p=0.035), moderate-to-severe chronic GVHD (21.1% vs. 7.3%; OR 3.48, 95% CI 1.29-10.12; p=0.010), and greater use of second-line GVHD-directed therapy with ruxolitinib and/or extracorporeal photopheresis (34.4% vs. 19.8%; OR 2.12, 95% CI 1.05-4.31; p=0.036). In multivariable analyses, reduced cumulative PTCy exposure remained independently associated with acute GVHD (OR 2.29, 95% CI 1.18-4.53; p=0.016) and moderate-to-severe chronic GVHD (OR 4.07, 95% CI 1.52-11.63; p=0.005). Competing-risk analysis confirmed a higher cumulative incidence of acute GVHD (SHR 1.83, 95% CI 1.18-2.83; p=0.007). No significant differences were observed in relapse, non-relapse mortality, or overall survival. In this cohort, cumulative PTCy exposure below 100 mg/kg was associated with increased acute GVHD, a greater burden of clinically significant chronic GVHD, and increased use of second-line GVHD-directed therapies, without significant differences in relapse, non-relapse mortality, or overall survival. These findings suggest that effective GVHD prophylaxis with PTCy may depend on achieving adequate cumulative drug exposure and support prospective studies to define the optimal cumulative PTCy dose for GVHD prophylaxis.
2026-08-09 | Loss of MGAT3 Amplifies TGF-β Signaling to Promote Bronchiolitis Obliterans Progression.
Bronchiolitis obliterans syndrome (BOS), a severe complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT), presents as chronic graft-versus-host disease characterized by inflammation and fibrosis of the small airway epithelium. This progressive fibrosis obstructs bronchiolar airways, leading to respiratory distress in patients. Due to the lack of effective treatments, a deeper understanding of the underlying mechanisms is crucial. This study explored the molecular mechanisms underlying the abnormal glycosylation regulation in BOS, aiming to provide new insights for early diagnosis and treatment of this disease. Bronchoalveolar lavage fluid (BALF) was collected from patients with and without BOS following allo-HSCT. N-glycans from the BALF were enriched using a solid-phase extraction method. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/TOF-MS) was used to detect N-glycosylation characteristics in the BALF of BOS patients. This phenomenon was validated using a graft-versus-host disease (GVHD) mouse model. The impact of MGAT3 knockdown on the biological functions of airway epithelial cells (BEAS-2B) was then examined using lentivirus transfection. The molecular mechanism by which the loss of MGAT3 enhances TGF-β signaling was explored using western blotting, enzyme-linked immunosorbent assay (ELISA), and immunofluorescence (IF). Our study investigated N-glycosylation changes in BALF of BOS patients and identified a strong correlation between the loss of bisecting-GlcNAc N-glycans and BOS progression. We found a novel mechanism where MGAT3, the enzyme synthesizing bisecting-GlcNAc structures, critically regulates TGF-β signaling. MGAT3 and bisecting-GlcNAc deficiency significantly enhance TGF-β signaling by increasing TGF-β storage through upregu-lation of latent TGF-β binding protein 1 (LTBP1) and by increasing the availability of TGF-β receptors. Our discovery highlights the crucial role of aberrant glycosylation in BOS progression and holds significant promise for developing novel biomarkers for early diagnosis, identifying new therapeutic targets, and ultimately improving the quality of life for BOS patients.
2026-08-06 | Novel highly selective ROCK2 inhibitor (TDI01) for the treatment of chronic graft-versus-host disease: a multicenter, open-label phase Ib/II study.
Chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic hematopoietic stem cell transplantation for long-term survival. Emerging evidence highlights Rho-associated coiled-coil kinase 2 (ROCK2) as a promising therapeutic target for cGVHD, which can modulate immune responses and profibrotic reactions. TDI01, a potent and highly selective ROCK2 inhibitor, represents a potential breakthrough in cGVHD treatment. This was the dose-finding, phase Ib portion of a multicenter, open-label phase Ib/II study (NCT06169722) designed to evaluate the safety and preliminary efficacy of TDI01 in patients with moderate-to-severe cGVHD after failure of 1 to 5 prior therapies. Sixty patients were enrolled in two once-daily dosing cohorts: 200 mg (n = 30) and 400 mg (n = 30). The primary endpoints were the 24-week best overall response rate (BORR) and safety. As of January 17, 2025, 57 patients were evaluated for efficacy. The 24-week BORRs were 67.9% (200 mg cohort) and 86.2% (400 mg cohort), with an overall BORR of 77.2%. The median times to response were 44.5 days (200 mg cohort) and 30.0 days (400 mg cohort). Neither the median duration of response nor the median failure-free survival (FFS) was achieved. The probability of FFS at 24 weeks was 83.9%. The most common adverse events ( ≥ 20% of patients) were transient bilirubin elevation (total bilirubin elevation 81.7%, unconjugated 56.7%, conjugated 45.0%) and headache (23.3%), without significant increases in liver enzymes. Thus, TDI01, particularly at the 400 mg QD dose, demonstrated promising efficacy and safety in moderate-to-severe cGVHD, which will be confirmed in a forthcoming phase III randomized controlled trial.
2026-08-06 | Long-term follow-up of ruxolitinib pre-approval use in acute and chronic graft-versus-host disease.
Steroid-refractory (SR) acute and chronic graft-versus-host disease (aGVHD/cGVHD) are frequent and serious complications after allogeneic hematopoietic stem cell transplantation. Ruxolitinib (RUX) is approved for the treatment of both conditions. Real world evidence may provide valuable complementary information beyond prospective trials because of significant divergences in study populations, endpoints, treatment strategies, and observation time. We report long-term outcomes of 118 patients with acute (n = 61), classic chronic (n = 43) and overlap chronic GVHD (n = 14) who received RUX within a named-patient-program in the pre-approval era as second-line treatment or beyond. In 22 patients, GVHD occurred after donor lymphocyte infusion (DLI). The cohort included heavily pretreated patients, with 26.2% of aGVHD in 3rd -line or beyond, and 29.8% of cGVHD in 4th -line or beyond. Only 22 patients (18.6%) met all in-/exclusion criteria of the respective pivotal phase III studies. The most frequent incompatibilities were unmet SR criteria, excessive pretreatment, previous DLI, overlap chronic GVHD, and medical/hematological criteria. Overall response rate to RUX was 68.9% in aGVHD, and 66.7% in cGVHD. In all three GVHD types, > 50% of patients were able to discontinue systemic steroids. With a survivors' median follow up of 60.3 months (range, 25.5-99.3) from RUX initiation, 4-year survival probability was 57.4% in aGVHD, 81.1% in classic cGVHD, and 78.6% in overlap cGVHD. Our findings reveal favorable survival probabilities associated with a long-term steroid-sparing/replacing potential of RUX in treatment-refractory aGVHD and cGVHD, including overlap syndrome and DLI-associated GVHD.
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2026-08-11 | Comorbid conditions after allogeneic haematopoietic stem cell transplantation in young adults in Germany-A prospective, multicentre trial.
Young adults (YA) are particularly affected by comorbid conditions following allogeneic haematopoietic stem cell transplantation (alloHSCT), as they have to live with them for many years. This is the first multicentre prospective study investigating sequelae after alloHSCT in YA in Germany. In total, 107 patients who survived relapse-free until day 100 after alloHSCT were enrolled. Median patient age was 29.3 years. Chronic graft-versus-host disease (cGvHD) occurred in 40.2%. Comorbidities were captured at days 100, 180, 365 and 910 by applying the post-transplant multimorbidity index (PTMI). Considering all time points, 12.5%-23.5% of patients had no comorbidity, while 39.2%-49.5% had 1-3, 26.3%-33.0% had 4-6 and 5.7%-8.4% had >6 PTMI-defined comorbidities respectively. The most prevalent PTMI-based comorbidities were iron overload, hypogonadism, arterial hypertension, infections, hepatic dysfunction and osteopenia/osteoporosis. However, the spectrum of PTMI-recorded comorbidities and those concurrently self-reported by patients differed substantially. Factors linked to a higher PTMI were total body irradiation and active cGvHD. Investigating single PTMI-defined comorbidities, we found significant associations of osteopenia/osteoporosis with cGvHD, ongoing immunosuppression and hypogonadism, which was more common among female survivors. These results provide a detailed analysis of the occurrence of a vast spectrum of PTMI-defined comorbidities in YA after alloHSCT.
2026-07-23 | Chronic GVHD Consortium CATCH Study: Incidence, initial presentation and risk factors for chronic GVHD development.
The incidence of chronic graft-versus-host disease (GVHD) is declining but up to 30% of survivors are still diagnosed with chronic GVHD. We conducted a prospective, multi-center, observational study to understand the incidence and earliest presenting signs and symptoms of chronic graft vs. host disease (GVHD) in the current era to inform trials testing early therapy. Patients were enrolled and assessed prior to allogeneic transplantation (HCT), and approximately every 2 months through the first year post-HCT, and at time of chronic GVHD diagnosis. Clinician assessments, patient-reported measures (Lee Symptom Score (LSS), PROMIS), and biologic samples were collected at each time point. A total of 208 subjects were enrolled across 7 HCT centers. The cumulative incidence of any chronic GVHD was 54% by 24 months post-HCT, while chronic GVHD requiring systemic immune suppressive therapy (IST) was 38%. At onset, organ involvement included skin (32%), eye (41%), mouth (42%), liver (17%), GI (9%), lung (11%), and joint/fascia (5%) with overall severity of mild (or less) in 55%, moderate in 37%, or severe in 8%. Management practices were heterogeneous. Subsequent chronic GVHD requiring IST was significantly associated with baseline donor/recipient CMV positivity and non-PTCY-based acute GVHD prophylaxis, as well as serial changes in skin/mouth/joint (PROM) organ scores and LSS summary score. These data provide current estimates of chronic GVHD incidence and presenting features, new data on risk predictors, and a data resource for future overall and organ-specific biomarker studies.
2026-07-22 | Chronic graft-versus-host disease: Update on pathobiology, biomarkers, and evolving treatment algorithms.
Chronic graft-versus-host disease (cGVHD) remains the leading cause of late non-relapse mortality and long-term disability after allogeneic hematopoietic cell transplantation (allo-HCT), affecting 30-70% of long-term survivors. Despite its substantial morbidity and the toxicities associated with prolonged corticosteroid use, therapeutic advances have accelerated considerably. This review synthesizes current mechanistic insights and clinical evidence within the framework of the well-established three-phase pathogenesis model of cGVHD. Phase 1 (early inflammation) involves tissue injury and innate immune activation; Phase 2 (months 2-12) is characterized by impaired central and peripheral tolerance with aberrant B- and T-cell responses; Phase 3 (>1 year) features macrophage-driven fibrosis and end-organ damage. Recognizing that these phases are conceptual and frequently overlap in clinical practice, we explore the alignment of contemporary biomarkers with each phase-ST2/CXCL9 (Phase 1), BAFF/autoantibodies (Phase 2), and MMP3/TGF-β (Phase 3)-and discuss how FDA-approved agents (ibrutinib, ruxolitinib, belumosudil, axatilimab) may target phase-specific pathways. A conceptual, risk-stratified treatment algorithm is proposed to link pathobiology to clinical decision-making, with the important caveat that biomarker-guided selection remains investigational and currently complements, rather than replaces, comprehensive clinical assessment. Notably, the adoption of prophylaxis and upfront strategies to prevent cGVHD has substantially reduced cGVHD incidence in modern cohorts.
2026-07-07 | Short-course blinatumomab as a bridge-to-transplantation improves the survival of Ph-negative MRD-positive B-ALL.
Post-transplant relapse remains the chief therapeutic challenge in Ph-negative B cell acute lymphoblastic leukemia (Ph- B-ALL). This retrospective study evaluated whether short-course blinatumomab for measurable resident disease (MRD) eradication could improve transplant outcomes. We compared 23 patients receiving pre-transplant short-course blinatumomab (2-week) for MRD eradication with 46 chemotherapy-only controls. All achieved MRD-negative before allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Only two patients developed grade 2 cytokine release syndrome with blinatumomab. The neutrophil and platelet engraftment times were similar between the two groups. The blinatumomab cohort had a significantly lower 18-month cumulative incidence (CI) of relapse (p = 0.05) and chronic graft-versus-host disease (GVHD) (14.8% vs. 41.8%; p = 0.05), with comparable non-relapse mortality (NRM) (p = 0.98) and 180-day grade II-IV acute GVHD rates (p = 0.93). Consequently, this cohort showed superior 18-month relapse-free survival (RFS) (90.9% vs. 65.2%; HR 0.30, 95% CI 0.09-1.04; p = 0.04), improved 18-month overall survival (OS) (95.7% vs. 81.9%; HR 0.20, 95% CI 0.03-1.71), and a trend toward better GVHD-free and relapse-free survival (GRFS) (74.71% vs. 63.71%; HR 0.64, 95% CI 0.23-1.78). Multivariate analysis confirmed blinatumomab as an independent favorable factor for RFS. In conclusion, short-course blinatumomab as a bridge-to-transplantation could reduce the risk of relapse and improve survival for Ph- B-ALL patients undergoing allo-PBSCT.
2026-07-06 | Targeting CD162 for Life-Threatening Cutaneous Chronic Graft-Versus-Host Disease: A Case Report.
Steroid-refractory chronic cutaneous graft-versus-host disease (GVHD) causes substantial morbidity, prolonged hospitalization, and non-relapse mortality after allogeneic hematopoietic cell transplantation. We report a young adult with multisystem chronic GVHD and recurrent life-threatening inflammatory skin flares refractory to multiple standard therapies, with cumulative inpatient care exceeding 1 year. Under an institutional review board-approved compassionate-use protocol, he received a non-cytotoxic monoclonal antibody targeting CD162 (P-selectin glycoprotein ligand-1). Treatment was associated with durable resolution of active cutaneous GVHD, corticosteroid reduction, improved mobility, and meaningful recovery in daily function and quality of life. The author has confirmed clinical trial registration is not needed for this submission.
proteins
2026-06-05 | Growth hormone therapy after hematopoietic cell transplantation in childhood: a nationwide survey and longitudinal cohort study.
Growth impairment is a major late effect in survivors of childhood hematopoietic cell transplantation (HCT); however, the long-term effectiveness and response patterns of growth hormone (GH) therapy after HCT remain unclear. Thus, this study aimed to evaluate the effectiveness of GH therapy and clinical factors associated with GH response in patients who underwent HCT during childhood and were diagnosed with short stature and to further examine long-term response patterns among those receiving GH therapy. We conducted a nationwide, multicenter retrospective cohort study of childhood HCT survivors with post-transplant short stature. Height outcomes were evaluated using final adult height standard deviation scores (SDS) and changes in SDS (ΔSDS). Factors associated with height outcomes and GH responsiveness were analyzed using multivariable regression models, and longitudinal growth trajectories after GH initiation were assessed at 1 year, 5 years, and final height. Among 171 patients with available final height data, 58 received GH therapy. GH-treated patients showed significantly greater improvement in final height SDS and ΔSDS than untreated patients, although growth responses were heterogeneous. Total body irradiation (TBI), HCT before 5 years of age, and chronic graft-versus-host disease were independently associated with poorer height outcomes. Factors associated with GH responsiveness differed by transplant type: absence of TBI and female sex were favorable in allogeneic HCT. Regarding complications, GH therapy was not associated with an increased risk of slipped capital femoral epiphysis, secondary malignancies, or relapse of the primary disease. GH therapy improves height outcomes after childhood HCT, but responses vary and are strongly influenced by transplant-related toxicity and long-term complications. To improve height outcomes, optimizing GH therapy and developing strategies for patients expected to respond poorly remain important challenges.
2026-03-28 | Alpha 1 Antitrypsin Suppresses Autoantibody Production and Cellular Autoimmunity in Chronic Graft-Versus-Host Disease (cGVHD) in a Lupus Mouse Model.
Systemic lupus erythematosus (SLE) is a severe autoimmune disease that is challenging to treat due to poor understanding of its pathogenesis and etiology. Clearly understanding and dissecting the therapeutic effects of potential treatment in animal models are important. It has been shown that human alpha-1 antitrypsin (hAAT) holds therapeutic potential for the treatment of autoimmune diseases including lupus. However, the mechanism underlying its protective effect requires further investigation. In the present study, we used a chronic graft-versus-host disease-induced lupus mouse model to test the effect of hAAT on lupus development. We performed adoptive transfer of MHC I-aβ mismatched bm12 splenocytes into hAAT transgenic mice and showed that hAAT significantly blocked the production of anti-dsDNA IgG autoantibodies. Mechanistically, hAAT inhibited T cell activation and proliferation, including that of effector memory T (Tem) and T follicular helper (Tfh) cells. In addition, hAAT suppressed germinal center formation and functions. These results advanced the current understanding of hAAT functions and provide a new insight for the treatment of SLE.
2026-01-01 | Increasing safety of pediatric hematopoietic stem cell transplantation by targeted approaches to chronic graft-versus-host disease
Hematopoietic stem cell transplant (HSCT) is a critical medical procedure used to treat various blood and bone marrow diseases. However, it is often associated with severe complications, including chronic graft-versus-host disease (cGVHD), a systemic condition that occurs when donor immune cells attack the recipient's tissues, leading to significant morbidity, with an incidence of 42% within three years and a non-relapse mortality rate of 30%. To date, most studies on cGvHD biomarkers have focused on adults, and the scientific mechanisms underlying the onset of cGvHD in the pediatric population remain poorly understood. Building on previous work that identified sCD13, an aminopeptidase, and the key intermediate metabolite in the TCA cycle, α-KG, as potential biomarkers, this thesis investigated their roles in cGvHD. Using two independent pediatric cohorts, I validated the elevation of α-KG at cGvHD onset. In vitro, recombinant sCD13 suppressed CD4⁺ and CD8⁺ T cell proliferation in a dose-dependent manner with minimal effects on cell survival, indicating an immunomodulatory role. Although no truncation of CXCL9, CXCL10, or CXCL11 was observed, sCD13 levels correlated with increased CD26, suggesting possible cooperative regulation of chemokines. Complementary experiments showed that α-KG enhanced NK cell cytotoxicity against K562 targets, slightly increased perforin expression, and exhibited trends towards improved metabolic fitness, while not significantly altering T cell proliferation. Together, these findings validate α-KG as a reproducible biomarker in children, establish sCD13 as an immune regulator of T cell responses, and reveal α-KG as a modulator of NK cell function. By uncovering mechanisms of biomarker activity, this work advances understanding of cGvHD pathogenesis and supports biomarker-driven strategies to improve diagnosis and treatment in pediatric HSCT.
2025-12-13 | Recombinant human soluble thrombomodulin prevents murine sclerodermatous chronic graft-versus-host disease.
Chronic graft-versus-host disease (cGVHD) develops with complex interactions between immune cells and cytokines, leading to irreversible fibrosis. Severe cGVHD impairs quality of life and is associated with nonrelapse mortality; however, effective treatments are limited. Recombinant human soluble thrombomodulin (rTM), a novel anticoagulant consisting of the extracellular domains of thrombomodulin, has shown efficacy in patients with transplantation-associated coagulation disorders and, recently, anti-inflammatory properties in animal studies. Here, we investigated the effects of rTM on cGVHD using a sclerodermatous cGVHD (Scl-cGVHD) mouse model. Prophylactic rTM administration suppressed the development of Scl-cGVHD skin lesions both clinically and histopathologically, prolonging event-free and overall survival. The rTM significantly reduced the infiltration of inflammatory cells, including activated T cells and transforming growth factor β1 (TGFβ1)-producing macrophages into the skin, while inflammation in the draining lymph nodes during priming phase and in spleen during chronic phase was unaffected. TGFβ1 expression in keratinocytes also decreased with rTM. Domain analysis suggested that these effects were mainly attributed to the N-terminal lectin-like domain (domain 1) of rTM, whose functions, including inhibition of inflammatory cell activation and recruitment related to interactions with endothelial cells, has recently been recognized in a limited number of preclinical studies. In conclusion, rTM prevented Scl-cGVHD development, likely by inhibiting the recruitment of inflammatory cells to the skin and subsequent TGFβ1 production by keratinocytes. The rTM may represent a novel prophylactic agent for cGVHD.
2025-10-01 | MON-682 Acquired Generalized Lipodystrophy Treated With Metreleptin in a Patient With Total Body Irradiation and Chronic Graft-Versus-Host Disease
Abstract Disclosure: T. Moazezi: None. B. Salehian: None. Background: Acquired lipodystrophy, both partial and generalized, is a rare disease that can be seen in patients with a history of total-body irradiation (TBI) and hematopoietic stem cell transplantation (HSCT). The widespread metabolic complications that arise from this disorder warrant attention and treatment. Clinical Case: A 25-year-old female with a history of Non-Hodgkin Lymphoma status post TBI and HSCT in 2000 and 2004 complicated by chronic graft-versus-host disease (GVHD) presented with multiple endocrinopathies to the endocrinology clinic. She presented with type 2 diabetes mellitus with severe insulin resistance, severe hypertriglyceridemia, and non-alcoholic steatohepatitis. The patient weighed 36.7 kg with a BMI of 14.3 kg/m2. On physical exam, the patient had complete loss of subcutaneous fat mass in the chest, abdomen, upper and lower extremities, and palmar-plantar region; there was minimal appreciable subcutaneous fat in the face and supraclavicular region. Abdominal exam revealed visceral fat and hepatomegaly with percussion of the liver 5 cm below the costal margin. The quantitative adiponectin level was low at 3.1 ug/mL (2.0-19.3 ug/mL), and the diagnosis of acquired generalized lipodystrophy (AGL) was made. Laboratory work-up was notable for SGOT 50 U/L (15-46 U/L), SGPT 88 U/L (7-56 U/L), glucose of 435 mg/dL (80-128 mg/dL), hemoglobin A1c 14.4% (<=6.4%), C-peptide 9.7 ng/mL (0.8-3.5 ng/mL), fasting triglyceride 4268 mg/dL (<=150 mg/dL), total cholesterol 297 mg/dL (<=200 mg/dL), HDL 34 mg/dL (>=39 mg/dL), and LDL 32 mg/dL (<=100 mg/dL). Abdominal ultrasound with elastography showed hepatomegaly, fatty liver, mild-moderate fibrosis. The patient was treated with statin, fish oil, gemfibrozil, Humulin R U-500 insulin, insulin pump, pioglitazone, and multiple oral hypoglycemic agents, and her metabolic complications were refractory to these standard therapies. She was started on treatment with metreleptin by subcutaneous injection for treatment of AGL. The dose was titrated upwards as tolerated, and the patient had improvement in her metabolic parameters while on treatment, including improved insulin sensitivity and lipoprotein profile. Metreleptin was discontinued after two years due to significant pain at the injection site. She was referred to plastic surgery to assess for auto-transplantation of adipose tissue, which was not an option due to complete loss of subcutaneous adipose tissue. Conclusion: Childhood cancer survivors with a history of TBI and HSCT can develop acquired lipodystrophy with associated metabolic complications later in life. This case demonstrates the role of metreleptin in improving insulin sensitivity and lipoprotein profiles in a patient with AGL. Presentation: Monday, July 14, 2025
cell therapies
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.
2026-07-28 | Distinct murine chronic graft-versus-host disease models enable the delineation of the diverging and converging contributors to fibrotic scleroderma 2250854
Abstract Introduction Chronic graft-versus-host disease (cGVHD) is a debilitating complication of allogenic hematopoietic stem cell transplantation (alloHSTC) characterized by immune dysregulation, autoimmunity, and fibrosis. Particularly devastating is scleroderma (Scl), a systemic sclerotic disease that targets the skin causing stiffness and delayed wound healing. Despite FDA approved therapies, complete responses in Scl-cGVHD are rare, highlighting an unmet need for more targeted therapies. Methods To delineate the inflammatory and profibrotic mechanisms underlying Scl disease, we used two distinct murine alloHSCT model in which hosts were lethally irradiated and given bone marrow (BM) ± T cells to induce cGVHD. We compared multiple minor antigen mismatch, B10.D2 into Balb/c to a semi-allogeneic, parent-into-F1 C57BL/6 (B6) into (B6D2) F1 models. Results Mice developed scleroderma signs at different rates facilitating the study of overlapping and diverging fibrosis mechanisms. Mice in the B10.D2into Balb/c model had visible skin lesions by d19 with immune cell infiltration seen as early as d3. In contrast, mice in the parent-into-F1 model had comparatively delayed Scl onset with visible lesions appearing ∼d35. In the B10.D2 into Balb/c model, a 20-fold increase in the frequency of IFNg producing CD4 conventional T cells (Tcon) as compared to BM controls was apparent by d21 (p = 0.0119) with very little IL-17 production (< 0.04% IL-17+ of Foxp3-CD4+ Tcon). Conversely, mice in the parent-into-F1 Scl-GVHD model had a strong signature of IL-17 production, with 60% of CD4 Tcon producing IL-17 at d21 (p = 0.0395). To begin to uncover Scl mechanisms, Scl and BM control skin biopsies (d3, 6, 9, 13 and 21; n = 3 mice/group/time) in the B10.D2into BALB/c model are being analyzed by Nanostring GeoMx along with multiplex immunofluorescence of skin from both models and will be presented. Conclusion Together, our data highlight the need for comprehensive studies of cGVHD/Scl models to develop improved translational therapeutics. Funding Source National Institutes of Health (grants P01 HL158505, P01 AI056299, and R37AI34495) Topic Categories Transplantation Immunology (TRAN)
2026-07-14 | CAR19 Tregs treat murine chronic Graft-Versus-Host Disease through immune suppression in absence of measurable B-cell cytolysis.
Chronic Graft-Versus-Host disease (cGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic transplantation. CGVHD pathophysiology involves cooperation between Tfollicular helper cells (TFH) and germinal center B-cells (GCB), allo- and auto-antibody depositions in cGVHD tissues, and fibrosis. We evaluated human CD19-directed chimeric antigen receptor (CAR19) T-cell therapy in a clinically relevant murine cGVHD model with bronchiolitis obliterans syndrome (BOS). Although CD8 CAR19 T-cells effectively reduced peripheral B-cell and GCB frequencies, pulmonary function was unimproved. In contrast, a single CAR19 CD4 regulatory T-cells (Treg) infusion mitigated ongoing pulmonary disease and modulated germinal centers (GC) associated with reduced TFH frequencies compared to control Tregs but without measurable B-cell depletion. Compared to EGFR Treg infusion, mice receiving CAR19 Tregs exhibited enhanced suppression of B-cell activation, preserved splenic architecture, and provided greater opportunities for interaction with CD19+ B-cells at the B-cell follicle boundary zones. Taken together with the absence of detectable B-cell cytolysis, these findings are most consistent with GC suppression rather than B-cell depletion as the dominant mechanism. Overall, our findings suggest that CAR19 Tregs represent a promising and safe cGVHD/BOS therapeutic strategy, offering immunosuppressive benefits and improved disease outcomes that may be more limited with CD8 CAR19 T-cell treatment.
2026-07-06 | System-level Redesign of an Allogeneic Hematopoietic Cell Transplantation Program Associated With High One-year Survival and Reduced Cost.
Practice variation in allogeneic hematopoietic cell transplantation may contribute to preventable toxicity, nonrelapse mortality, and excess cost. We evaluated outcomes occurring with the implementation of a program-wide standardization initiative in a medium-sized program. We conducted a single-center retrospective cohort study of consecutive patients undergoing first allogeneic hematopoietic cell transplantation in 2024 during implementation of a system-level redesign. The intervention emphasized high-reliability operations through concise standard operating procedures, formal quality management, standardized recipient and donor selection, a limited conditioning regimen formulary, fluid-sparing conditioning and graft infusion practices, post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis, and an early-discharge outpatient care model. The primary endpoint was 1-year overall survival. Secondary endpoints included graft-versus-host disease-free, relapse-free survival, nonrelapse mortality, acute and chronic graft-versus-host disease, length of stay, and pharmaceutical cost. Ninety-four patients underwent a first allogeneic hematopoietic cell transplantation in 2024. One-year overall survival was 92.6%, graft-versus-host disease-free, relapse-free survival was 56%, and nonrelapse mortality was 1%. The cumulative incidence of grade II to IV acute graft-versus-host disease was 32%, with grade III to IV acute graft-versus-host disease in 5%, and chronic graft-versus-host disease requiring systemic therapy in 18% at 1 year. Median hospital length of stay was 19 days overall and 14 days among adults. Average pharmaceutical cost per patient decreased from $88,810 across the preceding 3 fiscal years to $39,019 under the redesigned care model. In this single-center cohort, implementation of a standardized, high-reliability allogeneic hematopoietic cell transplantation care model was associated with excellent 1-year survival, low nonrelapse mortality, and lower pharmaceutical cost. These findings support the potential value of disciplined operational standardization as a complement to contemporary transplant platforms.
2026-06-12 | Chronic graft-versus-host disease.
Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic haematopoietic cell transplantation. cGVHD has a heterogeneous biology and morbid manifestations, affecting 30-70% of recipients and substantially impairing quality of life and is the leading cause of non-relapse mortality in allo-HCT recipients. This immune-mediated condition arises from complex immune dysregulation involving B cell and T cell activation, regulatory T cell dysfunction, and fibrosis driven by macrophages and fibroblasts. Glucocorticoids remain the first-line treatment; however, ~50% of patients develop steroid-refractory or steroid-dependent cGVHD, necessitating prolonged immunosuppression causing considerable toxicity. Four second-line treatments have been approved by the FDA - ibrutinib, ruxolitinib, belumosudil and axatilimab - targeting B cell signalling, JAK-STAT, ROCK2 and CSF1R pathways, respectively, and emerging therapies such as rovadicitinib show promise. However, substantial challenges persist in cGVHD treatment, including the heterogeneous biology and morbid manifestations (that is, lung and skin sclerosis), drug resistance and suboptimal supportive care. Biomarkers for early diagnosis and personalized treatment remain under investigation. Multidisciplinary care, infection control and psychosocial support are critical to improving quality of life in patients with cGVHD. Future research should prioritize mechanistic insights, antifibrotic therapies and integrating organ-specific interventions to enhance outcomes in patients with cGVHD.
other
2025-12-16 | Real-World Effectiveness of Recombinant Zoster Vaccine in Allogeneic Hematopoietic Cell Transplant Recipients.
Herpes zoster (HZ) is a frequent and clinically significant complication following allogeneic hematopoietic cell transplantation (allo-HCT), arising from delayed immune reconstitution and impaired varicella-zoster virus-specific immunity. Although acyclovir prophylaxis reduces early risk, prolonged use is often limited by toxicity and poor adherence. The recombinant zoster vaccine (RZV), a non-live adjuvanted subunit vaccine, has demonstrated high efficacy in immunocompetent adults and in several immunocompromised populations; however, real-world data in allo-HCT recipients remain scarce. To evaluate the real-world effectiveness of RZV in preventing HZ among allo-HCT recipients and to assess vaccine performance across clinical subgroups and in relation to antiviral prophylaxis. We conducted a retrospective cohort study of 506 allo-HCT recipients at a tertiary transplantation center, including 152 patients who completed the two-dose RZV series and 354 historical unvaccinated controls. The primary outcome was HZ incidence within 2 years after transplantation. Time-dependent Cox regression models were applied to estimate adjusted hazard ratios (aHRs), with RZV and acyclovir modelled as time-varying covariates. Competing risk and 9-month landmark analyses were performed to validate robustness. The 2-year cumulative HZ incidence was 19.7% in unvaccinated versus 5.9% in vaccinated patients (Gray's P < .001). RZV significantly reduced HZ risk (aHR 0.287, 95% confidence interval [CI] 0.131 to 0.627), corresponding to 71.3% effectiveness, consistent across subgroup analyses. Continued acyclovir prophylaxis was independently protective (aHR 0.323, 95% CI, 0.147 to 0.711). Importantly, no HZ events occurred in RZV recipients who discontinued acyclovir prematurely. Thirteen of 76 HZ cases (17.1%) met the criteria for complicated disease, strongly associated with chronic graft-versus-host disease and HLA mismatch; however, no significant effect of RZV was observed. RZV demonstrated substantial effectiveness in reducing HZ risk among allo-HCT recipients in real-world clinical practice. These findings provide compelling evidence for incorporating RZV into after transplantation preventive care as a valuable complement to, or alternative to, traditional antiviral prophylaxis strategies.
2024-02-14 | Differential expression of miRNA-769-5p and Smad2 in patients with or without oral cGVHD
Background.Oral chronic graft-versus-host disease (cGVHD) impacts quality of life of patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT).However, its precise pathogenesis remains unknown, with potential associations with differential microRNA (miRNA) expression and the TGF-β/Smad signaling pathway.Objectives.This study aims to explore miRNA expression profiles in the peripheral blood of oral cGVHD patients, focusing on miRNA-769-5p and its relationship with Smad2. Materials and methods.Peripheral venous blood samples were collected for RNA extraction from 8 patients with oral cGVHD, 8 patients without cGVHD and 8 participants from the healthy control group.The miRNA library was constructed using the Illumina Hiseq 2500 platform.We focused on identifying miRNAs associated with the TGF-β/Smad signaling pathway and subsequently conducted validation experiments.The oral cGVHD and without cGVHD groups were each expanded to include 15 individuals.Peripheral blood samples were subjected to polymerase chain reaction (PCR) analysis to assess miRNA levels and to evaluate Smad2 mRNA levels in peripheral blood mononuclear cells (PBMC).Additionally, enzyme-linked immunosorbent assay (ELISA) was conducted to determine the Smad2 protein levels in peripheral blood.Results.The most significantly differentially expressed miRNAs among the 3 groups were miRNA-505-5p and miRNA-769-5p.Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated an enrichment of the target genes of miRNA-769-5p in the TGF-β signaling pathway.It was observed that miRNA-769-5p expression was higher in patients without oral cGVHD in comparison to those with oral cGVHD.Receiver operating characteristic (ROC) analysis demonstrated that miRNA-769-5p holds diagnostic value for oral cGVHD.As a target of miRNA-769-5p, Smad2 mRNA exhibited a negative correlation with it.Moreover, both Smad2 mRNA and protein levels were higher in patients with oral cGVHD as opposed to those without cGVHD.Conclusions.Differential expression of miRNAs, particularly the downregulation of miRNA-769-5p, may influence the development of oral cGVHD by diminishing its inhibitory effect on the TGF-β/Smad signaling pathway through its interaction with Smad2.
2022-05-20 | MicroRNA-31 regulates T-cell metabolism via HIF1α and promotes chronic GVHD pathogenesis in mice.
Chronic graft-versus-host disease (cGVHD) remains a major obstacle impeding successful allogeneic hematopoietic cell transplantation (HCT). MicroRNAs (miRs) play key roles in immune regulation during acute GVHD development. Preclinical studies to identify miRs that affect cGVHD pathogenesis are required to develop these as potential lifesaving interventions. Using oligonucleotide array, we identified miR-31, which was significantly elevated in allogeneic T cells after HCT in mice. Using genetic and pharmacologic approaches, we demonstrated a key role for miR-31 in mediating donor T-cell pathogenicity in cGVHD. Recipients of miR-31-deficient T cells displayed improved cutaneous and pulmonary cGVHD. Deficiency of miR-31 reduced T-cell expansion and T helper 17 (Th17) cell differentiation but increased generation and function of regulatory T cells (Tregs). MiR-31 facilitated neuropilin-1 downregulation, Foxp3 loss, and interferon-γ production in alloantigen-induced Tregs. Mechanistically, miR-31 was required for hypoxia-inducible factor 1α (HIF1α) upregulation in allogeneic T cells. Therefore, miR-31-deficient CD4 T cells displayed impaired activation, survival, Th17 cell differentiation, and glycolytic metabolism under hypoxia. Upregulation of factor-inhibiting HIF1, a direct target of miR-31, in miR-31-deficient T cells was essential for attenuating T-cell pathogenicity. However, miR-31-deficient CD8 T cells maintained intact glucose metabolism, cytolytic activity, and graft-versus-leukemia response. Importantly, systemic administration of a specific inhibitor of miR-31 effectively reduced donor T-cell expansion, improved Treg generation, and attenuated cGVHD. Taken together, miR-31 is a key driver for T-cell pathogenicity in cGVHD but not for antileukemia activity. MiR-31 is essential in driving cGVHD pathogenesis and represents a novel potential therapeutic target for controlling cGVHD.
2019-05-14 | MicroRNA-17-92 is required for T-cell and B-cell pathogenicity in chronic graft-versus-host disease in mice.
Chronic graft-versus-host disease (cGVHD) is characterized as autoimmune-like fibrosis and antibody production mediated by pathogenic T cells and B cells. MicroRNA-17-92 (miR-17-92) influences the survival, differentiation, and function of lymphocytes in cancer, infections, and autoimmunity. To determine whether miR-17-92 regulates T- and B-cell responses in cGVHD, we generated mice conditionally deficient for miR-17-92 in T cells, B cells, or both. Using murine models of allogeneic bone marrow transplantation, we demonstrate that expression of miR-17-92 in donor T and B cells is essential for the induction of both scleroderma and bronchiolitis obliterans in cGVHD. Mechanistically, miR-17-92 expressed in T cells not only enhances the differentiation of pathogenic T helper 1 (Th1) and Th17 cells, but also promotes the generation of follicular Th cells, germinal center (GC) B cells, and plasma cells. In B cells, miR-17-92 expression is required for autoantibody production and immunoglobulin G deposition in the skin. Furthermore, we evaluated a translational approach using antagomirs specific for either miR-17 or miR-19, key members in miR-17-92 cluster. In a lupus-like cGVHD model, systemic administration of anti-miR-17, but not anti-miR-19, alleviates clinical manifestations and proteinuria incidence in recipients through inhibiting donor lymphocyte expansion, B-cell activation, and GC responses. Blockade of miR-17 also ameliorates skin damage by reducing Th17 differentiation in a scleroderma-cGVHD model. Taken together, our work reveals that miR-17-92 is required for T-cell and B-cell differentiation and function, and thus for the development of cGVHD. Furthermore, pharmacological inhibition of miR-17 represents a potential therapeutic strategy for the prevention of cGVHD.
2019-05-14 | Vitamin A-coupled liposomes containing siRNA against HSP47 ameliorate skin fibrosis in chronic graft-versus-host disease.
Chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (SCT) is characterized by multiorgan fibrosis and profoundly affects the quality of life of transplant survivors. Heat shock protein 47 (HSP47), a collagen-specific molecular chaperone, plays a critical role in collagen synthesis in myofibroblasts. We explored the role of HSP47 in the fibrotic process of cutaneous chronic GVHD in mice. Immunohistochemical analysis showed massive fibrosis with elevated amounts of collagen deposits and accumulation of F4/80+ macrophages, as well as myofibroblasts expressing HSP47 and retinol-binding protein 1 in the skin after allogeneic SCT. Repeated injection of anti-colony-stimulating factor (CSF-1) receptor-blocking antibodies significantly reduced HSP47+ myofibroblasts in the skin, indicating a macrophage-dependent accumulation of myofibroblasts. Vitamin A-coupled liposomes carrying HSP47 small interfering RNA (siRNA) (VA-lip HSP47) delivered HSP47 siRNA to cells expressing vitamin A receptors and knocked down their HSP47 in vitro. Intravenously injected VA-lip HSP47 were specifically distributed to skin fibrotic lesions and did not affect collagen synthesis in healthy skin. VA-lip HSP47 knocked down HSP47 expression in myofibroblasts and significantly reduced collagen deposition without inducing systemic immunosuppression. It also abrogated fibrosis in the salivary glands. These results highlight a cascade of fibrosis in chronic GVHD; macrophage production of transforming growth factor β mediates fibroblast differentiation to HSP47+ myofibroblasts that produce collagen. VA-lip HSP47 represent a novel strategy to modulate fibrosis in chronic GVHD by targeting HSP47+ myofibroblasts without inducing immunosuppression.
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Drug Discovery Landscape
16 orphan drug designations for Chronic graft versus host disease, including 2 approved therapies.
16 orphan drug designations for Chronic graft versus host disease, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
sterile processed derived multiple allogeneic proteins paracrine signaling | cell therapies | FDA | 2026-05-20 | — | Regenerative Ocular Immunobiologics LLC |
rituximab | antibodies | FDA | 2026-05-12 | — | ODDIFACT SAS |
Pegtarazimod | peptides | EMA | 2025-08-22 | — | Clinipace GmbH |
axatilimab-csfr [Niktimvo] | antibodies | FDA | 2021-03-29 | 2024-08-14 | Incyte Corporation |
entospletinib | small molecules | FDA | 2017-08-10 | — | Kronos Bio, Inc. |
Ibrutinib [Imbruvica] | small molecules | EMA | 2016-11-18 | — | Janssen Cilag International |
Avdoralimab | antibodies | EMA | 2016-08-29 | — | [INACTIVE] Alexion Europe |
ibrutinib [Imbruvica] | small molecules | FDA | 2016-06-23 | 2017-08-02 | Pharmacyclics, LLC |
Rimiducid [AP1903] | small molecules | EMA | 2016-05-30 | — | Bellicum Pharma GmbH |
Mocravimod [KRP203] | small molecules | EMA | 2015-12-14 | — | Novartis Europharm Limited |
Efprezimod alfa | proteins | EMA | 2015-11-11 | — | Merck Sharp & Dohme B.V. |
Allogeneic peripheral blood mononuclear cells induced to an early apoptotic state [ApoCell] | cell therapies | EMA | 2015-01-15 | — | [INACTIVE] Richardson Associates Regulatory Affairs Limited |
Donor lymphocyte preparation depleted of functional alloreactive T-cells [Luxceptar] | cell therapies | EMA | 2008-09-05 | — | [INACTIVE] Kiadis Pharma Netherlands B.V. |
autologous lymphocytes depleted ex vivo of immunoreactive T cells using 4,5 | cell therapies | FDA | 2008-04-03 | — | Kiadis Pharma Netherlands B.V. |
Gavilimomab | antibodies | EMA | 2002-11-14 | — | [INACTIVE] SangStat UK Limited |
Thalidomide [Thalidomide Laphal 50 mg Hard capsules] | small molecules | EMA | 2001-07-09 | — | [INACTIVE] Pharmion France |
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