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
2,416 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:
2,416 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
2026-09-25 | A randomized phase 2 placebo-controlled trial of clobetasol solution for oral chronic graft-versus-host disease therapy.
Chronic graft-versus-host disease (cGVHD) affects multiple organ systems and frequently the mouth. There is an unmet need for more effective topical therapy to adequately control cGVHD in the oral cavity. Clobetasol is a super-potent synthetic glucocorticoid formulated here as an oral solution in an aqueous base (clobetasol solution) to enhance mucosal coverage and steroid delivery. We conducted a randomized, double-blind, placebo-controlled phase 2 clinical trial to evaluate the safety and efficacy of clobetasol 0.05% solution at 28 days of clobetasol treatment (primary endpoint). Of the 35 of 40 randomized subjects who reached the day 28, 19% achieved a complete response (CR), 72% a partial response (PR), and 9% had stable disease (SD), resulting in an overall response rate (ORR) of 91%. During the 14-day placebo-controlled phase, greater improvement was measured in clinical disease and oral pain for clobetasol versus placebo. Although clobetasol solution was well-tolerated, day 28 cosyntropin testing demonstrated significant suppression of peak serum cortisol, indicating new adrenal insufficiency in 14 patients who were not already receiving supraphysiologic glucocorticoids. Paired oral mucosal biopsies from baseline and day 28 show reduction in the frequency of all T cells, including effector and proliferating T cells and a reduction in non-T cells with cytoplasmic IL-17, accompanied by reduced salivary IL-6 and CXCL10. These controlled study data demonstrate that 0.05% clobetasol oral rinse is clinically effective and induces measurable tissue-level immunologic changes in the treatment of oral GVHD, including among patients who failed clobetasol ointment. This trial was registered at www.clinicialtrials.gov as #NCT01557517.
2026-09-24 | Cell Therapy Transplant Canada (CTTC) Consensus-Based Review for the Use of Supportive Care and Topical Therapies for Chronic Graft-Versus-Host Disease.
This is a consensus-based Canadian review with the primary purpose of expanding knowledge regarding supportive and topical therapies for chronic graft vs. host disease (cGvHD). There is often a lack of confidence in treating certain organ specific manifestations, and access to specialists with organ specific expertise varies across the country. This paper covers information gained from a literature review and Canadian transplanter expertise and will serve as a guide for hematopoietic cell transplant healthcare providers to topical cGvHD therapies accessible in Canada. We will review common symptoms and signs focused specifically on skin, mouth, eye and genital tract cGvHD and on lifestyle modifications and topical treatments as an adjunct to our recent publication on systemic treatment for cGvHD.
2026-09-16 | Topical ruxolitinib for chronic cutaneous graft-versus-host disease: a single-centre, randomised, double-blind, intra-patient-controlled phase 2 trial.
Oral ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, is approved for both acute and chronic graft-versus-host disease (cGVHD), whereas the topical formulation is approved for atopic dermatitis and vitiligo. Topical corticosteroids remain the mainstay for cutaneous cGVHD but their use is limited by adverse effects. We aimed to evaluate the clinical activity and safety of ruxolitinib 1·5% cream for epidermal or superficially sclerotic cutaneous cGVHD. In this single-centre, randomised, double-blind, intra-patient-controlled phase 2 trial at Memorial Sloan Kettering Cancer Center (NY, USA), patients aged 12 years or older with history of allogenic haematopoietic stem cell transplantation, with clinically confirmed, histologically confirmed, or both, cutaneous cGVHD involving at least 2% body surface area were randomly assigned to the body side receiving topical ruxolitinib 1·5% cream twice daily for 28 days; placebo vehicle was applied to contralateral lesional skin as a control. The primary endpoint was the absolute day-28 between-side difference in affected lesional body surface area (BSA), recorded as percentage of total BSA on each assigned side and analysed in evaluable patients; baseline between-side BSA differences were controlled for with adjusted mixed-effects regression. Only patients who completed the day 28 visit were included in the primary endpoint analysis; all patients who received any study treatment were included in the safety analysis. The trial is closed to enrolment and registered with ClinicalTrials.gov, NCT03954236. The trial is complete. Between June 28, 2019, and Sept 8, 2022, 24 patients were randomly assigned, with a median follow-up of 128 days (IQR 90-280). Median age was 47·5 years (IQR 32·5-67·5); 13 (54%) were female and 11 (46%) were male. At day 28, 23 patients were evaluable (one patient did not start treatment after screening visit due to intensive care unit admission). Mean affected lesional body surface area changed from 14·3% (SD 7·9) at baseline to 6·2% (6·7) with ruxolitinib and from 14·5% (8·0) to 10·4% (9·1) with placebo vehicle (difference -4·2 percentage points, 95% CI -6·8 to -1·5; p=0·0030); after adjustment for baseline between-side body surface are difference, the difference was -4·0 percentage points (-5·5 to -2·4; p<0·0010). Grade 3-5 treatment emergent adverse events were CNS leukaemia, sinusitis, and lung infection (one [4%] each); no treatment-related deaths occurred. Topical ruxolitinib showed significant clinical activity and favourable harms profile in active cutaneous cGVHD. Ruxolitinib cream could represent a steroid-sparing, skin-directed alternative or second-line therapy, expanding treatment options for patients with cutaneous cGVHD. Incyte.
2026-09-09 | Safety and Efficacy of Belumosudil for Steroid-Resistant Chronic-Graft-Versus-Host Disease: A Systematic Review.
Chronic graft-versus-host disease (cGVHD) remains a significant challenge after allogeneic hematopoietic cell transplantation. Although corticosteroids are commonly used as the first-line treatment, a substantial number of patients either do not respond adequately or suffer from considerable side effects; there is a need for more effective and better-tolerated alternatives. Belumosudil, a selective ROCK2 inhibitor, has shown encouraging potential in this context; however, detailed and comprehensive data regarding its effectiveness and safety are still limited. This systematic review evaluates the clinical efficacy, safety, and corticosteroid-sparing effects of belumosudil in cGVHD patients who have failed prior therapies. Following PRISMA 2020 guidelines, we systematically searched in PubMed, Embase, Scopus, Web of Science, and the Cochrane Library to identify studies evaluating the use of belumosudil in cGVHD. Six studies, including clinical trials and observational studies, encompassing a combined cohort of 315 patients, were included. Outcomes measured were overall response rate (ORR), complete and partial responses (CR/PR), duration of response (DOR), failure-free survival (FFS), overall survival (OS), incidence of adverse events (AEs), and steroid reduction. Belumosudil had an ORR of 46.7-85.7%, with partial responses predominant (PR: 70-85.7%). The median time to response was 4.1-5 weeks, with 6-month FFS ranging from 73 to 76%. Reduction in Corticosteroid dose was seen in 28.9-67% of patients, with discontinuation in up to 26%. Organ-specific responses were observed in the joints/fascia (25-80%), mouth (19-66.7%), and skin (14-40%). Adverse events were mostly mild to moderate, with 17.8-27% discontinuation rates. Belumosudil is an effective and well-tolerated treatment for refractory cGVHD, with fast responses, sustained disease control, and significant steroid-sparing effects. Its novel mechanism involving the inhibition of inflammation and fibrosis offers an important therapeutic alternative, although additional research and further comparative and long-term studies are required. The online version contains supplementary material available at https://doi.org/10.1007/s12288-025-02298-z.
2026-09-08 | Ruxolitinib-associated pulmonary alveolar proteinosis successfully managed by switching to belumosudil in chronic graft-versus-host disease.
Secondary pulmonary alveolar proteinosis (PAP) is a rare but serious complication that can occur during immunosuppressive therapy for chronic graft-versus-host disease (GVHD). It is characterized by the intra-alveolar accumulation of surfactant due to drug-induced alveolar macrophage dysfunction. Managing PAP while maintaining control of active chronic GVHD represents a significant clinical challenge, particularly with regard to the optimal strategy for transitioning between immunosuppressive agents. A 25-year-old male with severe chronic GVHD developed a dry cough and bilateral ground-glass opacities (GGOs) after 2.8 years of ruxolitinib treatment. A lung biopsy confirmed secondary PAP. Ruxolitinib was tapered and replaced with belumosudil. Following the switch, the GGOs resolved rapidly within one month, and chronic GVHD remained stable, eventually allowing for successful corticosteroid tapering. Unlike ruxolitinib, belumosudil is thought to preserve the signaling pathways essential for alveolar macrophage activation. Transitioning to belumosudil may therefore represent a promising therapeutic strategy for managing secondary PAP in patients with chronic GVHD who require ongoing immunosuppressive therapy.
antibodies
2026-09-24 | Prognostic factors of acute and chronic graft-versus-host disease in pediatric patients undergoing bone marrow haploidentical transplant with post-transplantation cyclophosphamide.
Haploidentical hematopoietic stem cell transplantation has become an important therapeutic option for pediatric patients lacking an HLA-identical donor. This study aimed to identify clinical and transplant-related predictors of graft-versus-host disease in Tunisian children undergoing haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide. A retrospective study, conducted at the National Blood Transfusion Center, in collaboration with the National Bone Marrow Transplantation Center, included 47 pediatric patients transplanted between January 2019 and December 2023. Associations with acute and chronic graft-versus-host disease were assessed using contingency tables with odds ratios and 95% confidence intervals, followed by multivariate logistic regression for relevant variables. Forty-eight transplant procedures were analyzed. In the univariate analysis, most parameters, including graft cellular content, conditioning regimen, donor age, underlying disease, donor-specific antibodies and ABO incompatibility, were not associated with graft-versus-host disease. In contrast, donor-recipient sex mismatch significantly increased the risk of acute graft-versus-host disease (OR = 10.0; 95% CI: 2.26-44.20; p = 0.0024) and was confirmed as an independent predictor on multivariate analysis (OR = 17.7; 95% CI: 0.13-297.9; p = 0.0068). No variable emerged as a significant determinant of chronic graft-versus-host disease. In this cohort, donor-recipient sex mismatch was the main risk factor for acute graft-versus-host disease, while no clear predictor was identified for chronic disease. Larger prospective studies are needed to validate these findings and to refine predictive models, with the ultimate aim of optimizing haploidentical hematopoietic stem cell transplantation protocols and improving outcomes.
2026-09-07 | [Impact of recipient age on outcomes of allogeneic hematopoietic stem cell transplantation: an analysis from the Chinese Bone Marrow Transplant Registry Group (CBMTRG)].
Objective: To investigate whether recipient age independently affects outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT), including the predominant patterns of treatment failure, after adjustment for confounding factors. Methods: This retrospective, multicenter cohort study included 1 619 patients who underwent a single allo-HSCT at five transplant centers from January 1 2018, to December 31 2023. Patients were categorized into younger (≤35 years) or older recipient groups (≥50 years). After propensity score matching to balance 11 covariates, the analysis included 694 patients (347 in each group). Overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse (CIR), and cumulative incidence of acute and chronic graft-versus-host disease (aGVHD and cGVHD) were compared between the groups. Results: The median follow-up was 33.4 months (95% CI: 31.2 - 36.1 months). The 3-year OS rate was significantly lower in older than in younger recipients (75.5% ± 2.5% vs 83.1% ± 2.2%, HR=1.59, P=0.007). The 3-year NRM was higher in older recipients [13.3% ± 1.9% vs 8.5% ± 1.6%, univariable subdistribution HR (SHR) =1.61, P=0.044]. This association did not reach conventional statistical significance after multivariable adjustment (adjusted SHR=1.59, 95% CI: 0.99 - 2.54, P=0.053) ; however, the stable effect estimate indicated clinical relevance. No statistically significant between-group differences were observed in CIR or in the cumulative incidences of grade Ⅱ-Ⅳ aGVHD and cGVHD. Infection was the leading cause of NRM in both groups, whereas the proportions of deaths attributable to organ dysfunction and bleeding were higher among older recipients. Conclusion: After propensity score matching, older recipient age remained independently associated with poorer OS. This unfavorable outcome was primarily characterized by an increased risk of NRM, rather than that of relapse.
2026-08-22 | A randomized pilot trial comparing anti-thymocyte globulin with anti-thymocyte globulin plus post transplant cyclophosphamide for prophylaxis against acute and chronic graft versus host disease in matched donor hematopoietic cell transplants - a study from the Cell Therapy Transplant Canada/ Australasian Leukemia Lymphoma Group Consortium.
In a randomized pilot trial we compared ATG (standard Arm A, 4.5 mg/kg) with ATG plus PTCy (experimental Arm BE, ATG 4.5 mg/kg, PTCy 100 mg/kg). The primary safety endpoint was overall survival at 100 days. We analyzed 79 patients with AML (n = 55) or MDS (n = 24). Median age (range) was 59 (19 to 74), 47 (59.5%) were male. Conditioning was either myeloablative (n = 49) or reduced intensity (n = 30). Donors were 8/8 HLA-matched. Overall survival at 100 days was 95.0% (37 of 39 patients) vs 94.9% (38 of 40 patients) in arm A vs arm BE (p > 0.9). In arms A versus BE, serious adverse events (SAEs) occurred in 26 (65.0%) and 25 (64.1%) patients, graft failure occurred in 3 and 1 patients (p > 0.9), median (range) days to neutrophil engraftment were 19 (10-45) versus 22 (15-56) days p = 0.007), cytomegalovirus and Epstein-Barr virus reactivations occurred in 11 and 7 patients (p = 0.45) and in 6 and 5 patients (p = 0.29). Overall survival at 12 months was 72.5% versus 75.8% (p = 0.79), cumulative incidence at 6 months of relapse was 15.0% versus 15.7% (p = 0.88) and of non-relapse mortality (NRM) 7.5% versus 8.0 (p = 0.45). The combination of ATG and PTCy can safely be used in phase III trials.Registration: clinicaltrials.gov (NCT04202835), November 29, 2019.
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.
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
2026-09-18 | HLA-DPB1 TCE mismatch vector differentially affects HCT outcomes in 10/10 and ≤9/10 HLA matched patients in the UK.
Understanding permissive and beneficial HLA mismatches is a primary area of hematopoietic cell transplant (HCT) research. HLA-DPB1 is well studied in this context, due to its separation from HLA-A∼DQB1 by a recombination hot-spot. The primary study aim was to retrospectively assess the clinical impact of using the latest iteration of the HLA-DPB1 T cell epitope model (TCEv3) for selecting HLA-DPB1 mismatched donors in a UK cohort. The results were also compared to the previous, TCEv2 model. We used the TCEv3 model to assign core and non-core permissive mismatches, to a cohort of 1743 UK volunteer unrelated donor HCTs for malignant diseases between 1996 and 2020. We considered HLA-DPB1 mismatch vector (graft versus host (GvH), host versus graft (HvG), and bi-directional (Bi-D)) across TCE groups, and existing HLA-A∼DQB1 mismatching. In 10/10 HLA matched patients, Bi-D HLA-DPB1 non-core permissive/non-permissive mismatches were associated with significantly worse 5-year overall survival, transplant related mortality, progression-free survival, chronic graft versus host disease (GvHD) and GvHD-free, relapse-free survival (GRFS) compared to HLA-DPB1 matched/permissively mismatched patients. In ≤9/10 HLA matched patients, both Bi-D and HLA-DPB1 matched/permissive mismatches were associated with similarly poor survival, while HvG HLA-DPB1 mismatches reduced mortality and improved GRFS. Overall risk of grades 2-4 acute GvHD (aGvHD) increased with the presence of GvH HLA-DPB1 mismatches and HLA-A∼DQB1 mismatching. Assessing mismatch vector revealed that some canonical non-permissive HLA-DPB1 mismatches are equivalent to an HLA-DPB1 match/permissive mismatch and can be beneficial. Similarly, some canonical permissive mismatches and, surprisingly, HLA-DPB1 matching in an already mismatched setting were detrimental. Bi-D HLA-DPB1 mismatched patients consistently had the poorest outcomes. This UK first, multicenter study shifts our understanding of HLA-DPB1 permissibility in UK HCT, with potential to improve patient survival and quality of life post-HCT through alternative donor selection.
2026-09-17 | Orca-T: First Approval.
Allogeneic regulatory T cell immunotherapy with haematopoietic stem and progenitor cells (HSPC) and T cells-vldq, hereafter referred to as Orca-T (TREGZI™), has been developed by Orca Bio under license from Stanford University for the prevention of chronic graft-versus-host disease (cGVHD). On 30 June 2026, Orca-T received its first approval in the USA for use in matched donor haematopoietic stem cell transplantation (HSCT) with myeloablative preparative regimen, for haematopoietic and immunologic reconstitution and to improve cGVHD-free survival, in the treatment of adults with haematological malignancies. This article summarizes the milestones in the development of Orca-T leading to this first approval for the prevention of cGVHD.
2026-09-07 | Cord Blood-Derived Platelet Gel in Wound Healing: From Biological Rationale to Clinical Application.
Chronic and complex wounds are a major burden worldwide, and a considerable number remain unresponsive to traditional therapy. Cord blood-derived platelet gel (CBPG) is a novel allogeneic wound therapy providing a fibrin-based scaffold enriched with neonatal platelet-derived growth factors, including high concentrations of VEGF, HGF and FGF, directly into the wound bed, without the need for blood collection from the patient. This narrative review provides an overview of the biological features of CBPG, discusses clinical evidence across different wound indications, and assesses ethical, regulatory, and translational issues important to its development. CBPG has been studied in clinical trials in recessive dystrophic epidermolysis bullosa, cutaneous and oral chronic graft versus host disease after allogeneic haematopoietic stem cell transplantation, partial thickness burns, neonatal pressure injuries and diabetic foot ulcers. Across these conditions, CBPG has shown a consistent safety profile and promising signals of benefit, but evidence is restricted by small sample sizes, diverse methods and short follow-up. CBPG offers a biologically rational alternative to complex wound management in fragile patient populations. To move toward validated clinical application, manufacturing standardisation, regulatory classification, multicentre randomised trials with embedded health-economic endpoints, and transparent governance of cord blood allocation are needed.
2026-08-26 | Incidence and risk factors of Epstein-Barr virus infection and post-transplant lymphoproliferative disorder in paediatric haploidentical allogeneic hematopoietic stem cell transplantation.
Epstein-Barr virus (EBV) reactivation after haploidentical stem cell transplant (haplo-HSCT) is a serious complication, which sometimes progresses to post-transplant lymphoproliferative disorder (PTLD). We retrospectively analyzed 448 pediatric patients ( ≤ 18 years) undergoing anti-thymocyte globulin (ATG)-based haplo-HSCT with letermovir prophylaxis at Peking University People's Hospital (Oct 2022-Oct 2025), using a 1:3 propensity score-matched design. EBV viremia and PTLD incidences were 12.4% and 4.9%. Multivariate analysis showed prior Chimeric Antigen Receptor (CAR) T-cell therapy (Hazard ratio (HR) = 2.040, 95% CI 1.061-3.920; p = 0.033) and Cytomegalovirus (CMV) viremia preceding EBV viremia (HR = 6.075, 95% CI 3.377-10.928; p < 0.001) were risk factors for EBV viremia. The PTLD risk was higher with a total body irradiation (TBI)-based conditioning regimen (HR = 1.917, 95% CI 0.980-3.750; p = 0.050). Overall survival did not differ between groups (EBV + : 92.9% vs. EBV-: 96.4%; p = 0.10), but event-free survival was inferior in EBV-infected patients (86.6% vs. 94.6%; p = 0.004). Chronic graft-versus-host disease (17.0% vs. 6.5%; p < 0.001) and transplant-related mortality (7.1% vs. 2.1%; p = 0.005) were significantly higher in the EBV viremia cohort. EBV reactivation and PTLD pose serious challenges, and risk factors include TBI conditioning, prior CAR-T therapy, and CMV viremia preceding EBV viremia. Preemptive cytotoxic T lymphocyte therapy may benefit high-risk patients.
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.
other
2026-04-03 | Abstract 7791: PAI-1 inhibition attenuates the inflammatory response in a murine model of sclerodermatous chronic graft-versus-host disease
Abstract Hematopoietic stem cell transplantation (HSCT) is a critical tool for managing malignant and defective disorders of hematopoiesis but is limited by graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) remains a leading cause of non-relapse morbidity and mortality following allogeneic HSCT. Due to its high immunoreactivity, the skin is most commonly affected in cGVHD, where it undergoes aberrant tissue repair and progressive fibrosis. Therapeutic options for sclerodermatous cGVHD are limited and disease progression drives long-term morbidity and functional impairment. Plasminogen Activator Inhibitor-1 (PAI-1) is a mediator of tissue remodeling and fibrosis, regulating extracellular matrix deposition and the migration of fibrogenic cell populations. In this study, we hypothesized that pharmacologic inhibition of PAI-1 may improve clinical and histopathological outcomes in a murine model of sclerodermatous cGVHD by reducing pro-fibrotic signaling. C57BL/6 mice were conditioned with total body irradiation followed by intravenous infusion of bone marrow cells and splenocytes of either syngeneic (C57BL/6) or allogeneic (LP/J) donors. Mice received oral PAI-1 inhibitor PAI-039 (10 mg/kg) or vehicle every other day from day +14 until day +56. Clinical signs of GVHD and survival were monitored throughout this duration. At day +56, tissues and serum were collected for downstream molecular analyses. PAI-039 treatment improved survival and clinical GVHD scores. Serum levels of pro-inflammatory cytokines IFN-γ (P=0.006) and TNF-α (P=0.002) were significantly reduced in PAI-039 treated mice compared to controls, alongside decreased expression of IFN-γ (P=0.04) in skin isolates. These findings indicate that PAI-1 inhibition may provide therapeutic benefit in the treatment of sclerodermatous cGVHD by disrupting pathogenic fibrotic signaling, warranting further investigation. Citation Format: Sahra Gabure, Yogamaya Divakar Prabhu, Vasantharaja Raguraman, Shanid Mohiyuddin, Yan Ji, William Fay, Senthilnathan Palaniyandi, Gerhard Hildebrandt. PAI-1 inhibition attenuates the inflammatory response in a murine model of sclerodermatous chronic graft-versus-host disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7791.
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.
2025-09-11 | Approved and emerging therapies for glucocorticoid-refractory chronic graft-versus-host disease.
Glucocorticoid-refractory chronic graft-versus-host disease (glucocorticoid-refractory cGVHD) remains a major barrier to long-term survival and quality of life following allogeneic hematopoietic stem cell transplantation (allo-HSCT), affecting 30-70% to half of patients with chronic GVHD who fail corticosteroid therapy. In recent years, the Food and Drug Administration (FDA) has approved four agents - ibrutinib, ruxolitinib, belumosudil, and axatilimab - each targeting distinct immune and fibrotic pathways. This review systematically evaluates their mechanisms of action, efficacy across organ systems, and safety profiles while highlighting persistent limitations. We further summarize emerging therapies in clinical and preclinical development, including kinase inhibitors, monoclonal antibodies, cellular approaches, and tissue-specific interventions. A dual-axis framework - distinguishing inflammatory versus fibrotic phenotypes and organ-specific manifestations - is proposed to support biomarker-guided, individualized treatment. In addition, combination regimens and AI-assisted strategies offer new opportunities to optimize outcomes and reduce treatment burden. Despite these advances, challenges remain, including irreversible fibrosis, disease heterogeneity, lack of standardized diagnostic criteria, and balanced GVHD and graft versus tumor effect. Greater incorporation of patient-reported outcomes and long-term functional assessments into clinical trials and practice is urgently needed. Collectively, this review offers a roadmap for optimizing glucocorticoid-refractory cGVHD management, and evolving strategies hold promise for transforming glucocorticoid-refractory cGVHD from a life-limiting condition into a manageable chronic disease.
2025-04-04 | High Melphalan Exposure Increases the Risk of Graft-Versus-Host Disease in Pediatric Patients Undergoing Alpha-Beta T-Cell Depleted Haploidentical Transplantation
BACKGROUND: Melphalan is often used as the backbone agent for conditioning prior to A/B-T-cell depleted (A/B-TCD) hematopoietic cell transplant (HCT) due to lower rates of organ toxicity compared to busulfan or total-body irradiation, albeit with significant mucosal injury. Traditional dosing based on body-surface-area (BSA) may result in non-optimal melphalan exposure among certain patient subsets. OBJECTIVES: As mucosal injury is linked to initiation of alloreactivity, we hypothesized that high exposure of melphalan predicted via a pharmacokinetic (PK) model would be associated with an increased risk of acute graft-versus-host disease (aGVHD). STUDY DESIGN: using actual body weight; others received a dose adjusted for obesity or age <2 years. We analyzed outcomes based on whether melphalan exposure was above or below the median exposure for the group. RESULTS: The 100-day cumulative incidences of engraftment syndrome (ES), grade II-IV aGVHD, and grade III-IV aGVHD were 34.2%, 24.8%, and 17.1%, respectively. The 3-year cumulative incidence of chronic GVHD (cGVHD), non-relapse mortality (NRM), and relapse were 17.5%, 8.7%, 21.8%, respectively. The 3-year cumulative incidence of disease-free survival (DFS) and severe GVHD-relapse-free survival (GRFS) were 71.4% and 55.6%, respectively. ES was significantly associated with the subsequent development of aGVHD, both grade II-IV (41.4% vs. 17.3% in those with and without ES, P = .01) and grade III-IV (34.5% vs. 8.5% in those with and without ES; P = .003). Chronic GVHD occurred at significantly higher rates in patients with prior Grade II-IV (66.7% vs. 0% for Grade 0-I; P < .001) and Grade III-IV aGVHD (75% vs. 4.3% for Grade 0-II; P < .001). Compared to non-obese patients, the PK model predicted lower melphalan exposure (P = .02) in obese patients where adjusted ideal body weight was utilized, suggesting overcorrection of the dose. There was no impact of melphalan exposure on immunologic rejection. The median melphalan exposure was 6.81 mg*hr/L (range, 4.4-8.8). Compared to a melphalan exposure ≤6.8 mg*hr/L, a melphalan exposure >6.8 mg*hr/L was associated with a higher incidence of ES (48.8% vs. 19.1%; P = .005), grade II-IV aGVHD (39.3% vs. 10.1%; P = .002), and grade III-IV aGVHD (31.5% vs. 2.5%; P < .001). The 3-year incidence of cGVHD was 27.2% in those with high predicted melphalan exposure compared to 7.4% for low exposure (P = .03); with no difference in 3-year NRM incidence (9.2% vs. 7.7%; P = .82) or 3-year relapse incidence (16.8% vs. 27.6%; P = .31) for high compared to low exposure. However, GRFS was significantly worse in patients with high exposure (46.4%) vs. low exposure (64.6%; P = .02). CONCLUSIONS: High melphalan exposure predicted by a validated population PK model is associated with an increased likelihood of developing ES and subsequently acute and chronic GVHD. Given that a substantial number of patients already require adjustment of standard BSA-based dosing for young age or obesity, a prospective trial of model-based dosing to individualize melphalan exposure is warranted to confirm these results.
2025-03-14 | Dupilumab for Atopic Dermatitis-like Chronic Graft-versus-Host Disease in Three Pediatric Hematopoietic Cell Transplant Recipients.
Atopic dermatitis (AD)-like graft-versus-host disease (GVHD) is a chronic form of skin GVHD with features that include erythema, xerosis, scaling, and pruritus. Patients often require treatment with systemic immunosuppression and aggressive topical therapies for relief. Long-term effects of chronic immunosuppression are undesirable and alternative therapies are needed. A retrospective review of 3 patients receiving dupilumab (DUP) for AD-like cGVHD was conducted. Data collected included demographics, transplant history, and GVHD management and outcomes. Information relating to DUP included dose, route, frequency, and safety based on dermatologic reactions, ocular toxicities, and infections. Patients had differing underlying conditions, transplant types, cell sources, and GVHD prophylactic therapies. Three patients received tacrolimus and topical corticosteroids for GVHD treatment, and 1 also received sirolimus and ruxolitinib. After the initial DUP dose, all patients experienced improvement in their GVHD. To date, all patients have complete remission of their skin cGVHD and have weaned off other therapies. No patients experienced dermatologic or ocular toxicities, and no infections were reported. DUP was efficacious and safe for treating AD-like cGVHD in our 3 pediatric patients. Further investigations are warranted to determine the appropriate placement in therapy.
small molecules
2026-09-25 | A randomized phase 2 placebo-controlled trial of clobetasol solution for oral chronic graft-versus-host disease therapy.
Chronic graft-versus-host disease (cGVHD) affects multiple organ systems and frequently the mouth. There is an unmet need for more effective topical therapy to adequately control cGVHD in the oral cavity. Clobetasol is a super-potent synthetic glucocorticoid formulated here as an oral solution in an aqueous base (clobetasol solution) to enhance mucosal coverage and steroid delivery. We conducted a randomized, double-blind, placebo-controlled phase 2 clinical trial to evaluate the safety and efficacy of clobetasol 0.05% solution at 28 days of clobetasol treatment (primary endpoint). Of the 35 of 40 randomized subjects who reached the day 28, 19% achieved a complete response (CR), 72% a partial response (PR), and 9% had stable disease (SD), resulting in an overall response rate (ORR) of 91%. During the 14-day placebo-controlled phase, greater improvement was measured in clinical disease and oral pain for clobetasol versus placebo. Although clobetasol solution was well-tolerated, day 28 cosyntropin testing demonstrated significant suppression of peak serum cortisol, indicating new adrenal insufficiency in 14 patients who were not already receiving supraphysiologic glucocorticoids. Paired oral mucosal biopsies from baseline and day 28 show reduction in the frequency of all T cells, including effector and proliferating T cells and a reduction in non-T cells with cytoplasmic IL-17, accompanied by reduced salivary IL-6 and CXCL10. These controlled study data demonstrate that 0.05% clobetasol oral rinse is clinically effective and induces measurable tissue-level immunologic changes in the treatment of oral GVHD, including among patients who failed clobetasol ointment. This trial was registered at www.clinicialtrials.gov as #NCT01557517.
2026-09-24 | Cell Therapy Transplant Canada (CTTC) Consensus-Based Review for the Use of Supportive Care and Topical Therapies for Chronic Graft-Versus-Host Disease.
This is a consensus-based Canadian review with the primary purpose of expanding knowledge regarding supportive and topical therapies for chronic graft vs. host disease (cGvHD). There is often a lack of confidence in treating certain organ specific manifestations, and access to specialists with organ specific expertise varies across the country. This paper covers information gained from a literature review and Canadian transplanter expertise and will serve as a guide for hematopoietic cell transplant healthcare providers to topical cGvHD therapies accessible in Canada. We will review common symptoms and signs focused specifically on skin, mouth, eye and genital tract cGvHD and on lifestyle modifications and topical treatments as an adjunct to our recent publication on systemic treatment for cGvHD.
2026-09-16 | Topical ruxolitinib for chronic cutaneous graft-versus-host disease: a single-centre, randomised, double-blind, intra-patient-controlled phase 2 trial.
Oral ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, is approved for both acute and chronic graft-versus-host disease (cGVHD), whereas the topical formulation is approved for atopic dermatitis and vitiligo. Topical corticosteroids remain the mainstay for cutaneous cGVHD but their use is limited by adverse effects. We aimed to evaluate the clinical activity and safety of ruxolitinib 1·5% cream for epidermal or superficially sclerotic cutaneous cGVHD. In this single-centre, randomised, double-blind, intra-patient-controlled phase 2 trial at Memorial Sloan Kettering Cancer Center (NY, USA), patients aged 12 years or older with history of allogenic haematopoietic stem cell transplantation, with clinically confirmed, histologically confirmed, or both, cutaneous cGVHD involving at least 2% body surface area were randomly assigned to the body side receiving topical ruxolitinib 1·5% cream twice daily for 28 days; placebo vehicle was applied to contralateral lesional skin as a control. The primary endpoint was the absolute day-28 between-side difference in affected lesional body surface area (BSA), recorded as percentage of total BSA on each assigned side and analysed in evaluable patients; baseline between-side BSA differences were controlled for with adjusted mixed-effects regression. Only patients who completed the day 28 visit were included in the primary endpoint analysis; all patients who received any study treatment were included in the safety analysis. The trial is closed to enrolment and registered with ClinicalTrials.gov, NCT03954236. The trial is complete. Between June 28, 2019, and Sept 8, 2022, 24 patients were randomly assigned, with a median follow-up of 128 days (IQR 90-280). Median age was 47·5 years (IQR 32·5-67·5); 13 (54%) were female and 11 (46%) were male. At day 28, 23 patients were evaluable (one patient did not start treatment after screening visit due to intensive care unit admission). Mean affected lesional body surface area changed from 14·3% (SD 7·9) at baseline to 6·2% (6·7) with ruxolitinib and from 14·5% (8·0) to 10·4% (9·1) with placebo vehicle (difference -4·2 percentage points, 95% CI -6·8 to -1·5; p=0·0030); after adjustment for baseline between-side body surface are difference, the difference was -4·0 percentage points (-5·5 to -2·4; p<0·0010). Grade 3-5 treatment emergent adverse events were CNS leukaemia, sinusitis, and lung infection (one [4%] each); no treatment-related deaths occurred. Topical ruxolitinib showed significant clinical activity and favourable harms profile in active cutaneous cGVHD. Ruxolitinib cream could represent a steroid-sparing, skin-directed alternative or second-line therapy, expanding treatment options for patients with cutaneous cGVHD. Incyte.
2026-09-09 | Safety and Efficacy of Belumosudil for Steroid-Resistant Chronic-Graft-Versus-Host Disease: A Systematic Review.
Chronic graft-versus-host disease (cGVHD) remains a significant challenge after allogeneic hematopoietic cell transplantation. Although corticosteroids are commonly used as the first-line treatment, a substantial number of patients either do not respond adequately or suffer from considerable side effects; there is a need for more effective and better-tolerated alternatives. Belumosudil, a selective ROCK2 inhibitor, has shown encouraging potential in this context; however, detailed and comprehensive data regarding its effectiveness and safety are still limited. This systematic review evaluates the clinical efficacy, safety, and corticosteroid-sparing effects of belumosudil in cGVHD patients who have failed prior therapies. Following PRISMA 2020 guidelines, we systematically searched in PubMed, Embase, Scopus, Web of Science, and the Cochrane Library to identify studies evaluating the use of belumosudil in cGVHD. Six studies, including clinical trials and observational studies, encompassing a combined cohort of 315 patients, were included. Outcomes measured were overall response rate (ORR), complete and partial responses (CR/PR), duration of response (DOR), failure-free survival (FFS), overall survival (OS), incidence of adverse events (AEs), and steroid reduction. Belumosudil had an ORR of 46.7-85.7%, with partial responses predominant (PR: 70-85.7%). The median time to response was 4.1-5 weeks, with 6-month FFS ranging from 73 to 76%. Reduction in Corticosteroid dose was seen in 28.9-67% of patients, with discontinuation in up to 26%. Organ-specific responses were observed in the joints/fascia (25-80%), mouth (19-66.7%), and skin (14-40%). Adverse events were mostly mild to moderate, with 17.8-27% discontinuation rates. Belumosudil is an effective and well-tolerated treatment for refractory cGVHD, with fast responses, sustained disease control, and significant steroid-sparing effects. Its novel mechanism involving the inhibition of inflammation and fibrosis offers an important therapeutic alternative, although additional research and further comparative and long-term studies are required. The online version contains supplementary material available at https://doi.org/10.1007/s12288-025-02298-z.
2026-09-08 | Ruxolitinib-associated pulmonary alveolar proteinosis successfully managed by switching to belumosudil in chronic graft-versus-host disease.
Secondary pulmonary alveolar proteinosis (PAP) is a rare but serious complication that can occur during immunosuppressive therapy for chronic graft-versus-host disease (GVHD). It is characterized by the intra-alveolar accumulation of surfactant due to drug-induced alveolar macrophage dysfunction. Managing PAP while maintaining control of active chronic GVHD represents a significant clinical challenge, particularly with regard to the optimal strategy for transitioning between immunosuppressive agents. A 25-year-old male with severe chronic GVHD developed a dry cough and bilateral ground-glass opacities (GGOs) after 2.8 years of ruxolitinib treatment. A lung biopsy confirmed secondary PAP. Ruxolitinib was tapered and replaced with belumosudil. Following the switch, the GGOs resolved rapidly within one month, and chronic GVHD remained stable, eventually allowing for successful corticosteroid tapering. Unlike ruxolitinib, belumosudil is thought to preserve the signaling pathways essential for alveolar macrophage activation. Transitioning to belumosudil may therefore represent a promising therapeutic strategy for managing secondary PAP in patients with chronic GVHD who require ongoing immunosuppressive therapy.
antibodies
2026-09-24 | Prognostic factors of acute and chronic graft-versus-host disease in pediatric patients undergoing bone marrow haploidentical transplant with post-transplantation cyclophosphamide.
Haploidentical hematopoietic stem cell transplantation has become an important therapeutic option for pediatric patients lacking an HLA-identical donor. This study aimed to identify clinical and transplant-related predictors of graft-versus-host disease in Tunisian children undergoing haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide. A retrospective study, conducted at the National Blood Transfusion Center, in collaboration with the National Bone Marrow Transplantation Center, included 47 pediatric patients transplanted between January 2019 and December 2023. Associations with acute and chronic graft-versus-host disease were assessed using contingency tables with odds ratios and 95% confidence intervals, followed by multivariate logistic regression for relevant variables. Forty-eight transplant procedures were analyzed. In the univariate analysis, most parameters, including graft cellular content, conditioning regimen, donor age, underlying disease, donor-specific antibodies and ABO incompatibility, were not associated with graft-versus-host disease. In contrast, donor-recipient sex mismatch significantly increased the risk of acute graft-versus-host disease (OR = 10.0; 95% CI: 2.26-44.20; p = 0.0024) and was confirmed as an independent predictor on multivariate analysis (OR = 17.7; 95% CI: 0.13-297.9; p = 0.0068). No variable emerged as a significant determinant of chronic graft-versus-host disease. In this cohort, donor-recipient sex mismatch was the main risk factor for acute graft-versus-host disease, while no clear predictor was identified for chronic disease. Larger prospective studies are needed to validate these findings and to refine predictive models, with the ultimate aim of optimizing haploidentical hematopoietic stem cell transplantation protocols and improving outcomes.
2026-09-07 | [Impact of recipient age on outcomes of allogeneic hematopoietic stem cell transplantation: an analysis from the Chinese Bone Marrow Transplant Registry Group (CBMTRG)].
Objective: To investigate whether recipient age independently affects outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT), including the predominant patterns of treatment failure, after adjustment for confounding factors. Methods: This retrospective, multicenter cohort study included 1 619 patients who underwent a single allo-HSCT at five transplant centers from January 1 2018, to December 31 2023. Patients were categorized into younger (≤35 years) or older recipient groups (≥50 years). After propensity score matching to balance 11 covariates, the analysis included 694 patients (347 in each group). Overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse (CIR), and cumulative incidence of acute and chronic graft-versus-host disease (aGVHD and cGVHD) were compared between the groups. Results: The median follow-up was 33.4 months (95% CI: 31.2 - 36.1 months). The 3-year OS rate was significantly lower in older than in younger recipients (75.5% ± 2.5% vs 83.1% ± 2.2%, HR=1.59, P=0.007). The 3-year NRM was higher in older recipients [13.3% ± 1.9% vs 8.5% ± 1.6%, univariable subdistribution HR (SHR) =1.61, P=0.044]. This association did not reach conventional statistical significance after multivariable adjustment (adjusted SHR=1.59, 95% CI: 0.99 - 2.54, P=0.053) ; however, the stable effect estimate indicated clinical relevance. No statistically significant between-group differences were observed in CIR or in the cumulative incidences of grade Ⅱ-Ⅳ aGVHD and cGVHD. Infection was the leading cause of NRM in both groups, whereas the proportions of deaths attributable to organ dysfunction and bleeding were higher among older recipients. Conclusion: After propensity score matching, older recipient age remained independently associated with poorer OS. This unfavorable outcome was primarily characterized by an increased risk of NRM, rather than that of relapse.
2026-08-22 | A randomized pilot trial comparing anti-thymocyte globulin with anti-thymocyte globulin plus post transplant cyclophosphamide for prophylaxis against acute and chronic graft versus host disease in matched donor hematopoietic cell transplants - a study from the Cell Therapy Transplant Canada/ Australasian Leukemia Lymphoma Group Consortium.
In a randomized pilot trial we compared ATG (standard Arm A, 4.5 mg/kg) with ATG plus PTCy (experimental Arm BE, ATG 4.5 mg/kg, PTCy 100 mg/kg). The primary safety endpoint was overall survival at 100 days. We analyzed 79 patients with AML (n = 55) or MDS (n = 24). Median age (range) was 59 (19 to 74), 47 (59.5%) were male. Conditioning was either myeloablative (n = 49) or reduced intensity (n = 30). Donors were 8/8 HLA-matched. Overall survival at 100 days was 95.0% (37 of 39 patients) vs 94.9% (38 of 40 patients) in arm A vs arm BE (p > 0.9). In arms A versus BE, serious adverse events (SAEs) occurred in 26 (65.0%) and 25 (64.1%) patients, graft failure occurred in 3 and 1 patients (p > 0.9), median (range) days to neutrophil engraftment were 19 (10-45) versus 22 (15-56) days p = 0.007), cytomegalovirus and Epstein-Barr virus reactivations occurred in 11 and 7 patients (p = 0.45) and in 6 and 5 patients (p = 0.29). Overall survival at 12 months was 72.5% versus 75.8% (p = 0.79), cumulative incidence at 6 months of relapse was 15.0% versus 15.7% (p = 0.88) and of non-relapse mortality (NRM) 7.5% versus 8.0 (p = 0.45). The combination of ATG and PTCy can safely be used in phase III trials.Registration: clinicaltrials.gov (NCT04202835), November 29, 2019.
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.
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
2026-09-18 | HLA-DPB1 TCE mismatch vector differentially affects HCT outcomes in 10/10 and ≤9/10 HLA matched patients in the UK.
Understanding permissive and beneficial HLA mismatches is a primary area of hematopoietic cell transplant (HCT) research. HLA-DPB1 is well studied in this context, due to its separation from HLA-A∼DQB1 by a recombination hot-spot. The primary study aim was to retrospectively assess the clinical impact of using the latest iteration of the HLA-DPB1 T cell epitope model (TCEv3) for selecting HLA-DPB1 mismatched donors in a UK cohort. The results were also compared to the previous, TCEv2 model. We used the TCEv3 model to assign core and non-core permissive mismatches, to a cohort of 1743 UK volunteer unrelated donor HCTs for malignant diseases between 1996 and 2020. We considered HLA-DPB1 mismatch vector (graft versus host (GvH), host versus graft (HvG), and bi-directional (Bi-D)) across TCE groups, and existing HLA-A∼DQB1 mismatching. In 10/10 HLA matched patients, Bi-D HLA-DPB1 non-core permissive/non-permissive mismatches were associated with significantly worse 5-year overall survival, transplant related mortality, progression-free survival, chronic graft versus host disease (GvHD) and GvHD-free, relapse-free survival (GRFS) compared to HLA-DPB1 matched/permissively mismatched patients. In ≤9/10 HLA matched patients, both Bi-D and HLA-DPB1 matched/permissive mismatches were associated with similarly poor survival, while HvG HLA-DPB1 mismatches reduced mortality and improved GRFS. Overall risk of grades 2-4 acute GvHD (aGvHD) increased with the presence of GvH HLA-DPB1 mismatches and HLA-A∼DQB1 mismatching. Assessing mismatch vector revealed that some canonical non-permissive HLA-DPB1 mismatches are equivalent to an HLA-DPB1 match/permissive mismatch and can be beneficial. Similarly, some canonical permissive mismatches and, surprisingly, HLA-DPB1 matching in an already mismatched setting were detrimental. Bi-D HLA-DPB1 mismatched patients consistently had the poorest outcomes. This UK first, multicenter study shifts our understanding of HLA-DPB1 permissibility in UK HCT, with potential to improve patient survival and quality of life post-HCT through alternative donor selection.
2026-09-17 | Orca-T: First Approval.
Allogeneic regulatory T cell immunotherapy with haematopoietic stem and progenitor cells (HSPC) and T cells-vldq, hereafter referred to as Orca-T (TREGZI™), has been developed by Orca Bio under license from Stanford University for the prevention of chronic graft-versus-host disease (cGVHD). On 30 June 2026, Orca-T received its first approval in the USA for use in matched donor haematopoietic stem cell transplantation (HSCT) with myeloablative preparative regimen, for haematopoietic and immunologic reconstitution and to improve cGVHD-free survival, in the treatment of adults with haematological malignancies. This article summarizes the milestones in the development of Orca-T leading to this first approval for the prevention of cGVHD.
2026-09-07 | Cord Blood-Derived Platelet Gel in Wound Healing: From Biological Rationale to Clinical Application.
Chronic and complex wounds are a major burden worldwide, and a considerable number remain unresponsive to traditional therapy. Cord blood-derived platelet gel (CBPG) is a novel allogeneic wound therapy providing a fibrin-based scaffold enriched with neonatal platelet-derived growth factors, including high concentrations of VEGF, HGF and FGF, directly into the wound bed, without the need for blood collection from the patient. This narrative review provides an overview of the biological features of CBPG, discusses clinical evidence across different wound indications, and assesses ethical, regulatory, and translational issues important to its development. CBPG has been studied in clinical trials in recessive dystrophic epidermolysis bullosa, cutaneous and oral chronic graft versus host disease after allogeneic haematopoietic stem cell transplantation, partial thickness burns, neonatal pressure injuries and diabetic foot ulcers. Across these conditions, CBPG has shown a consistent safety profile and promising signals of benefit, but evidence is restricted by small sample sizes, diverse methods and short follow-up. CBPG offers a biologically rational alternative to complex wound management in fragile patient populations. To move toward validated clinical application, manufacturing standardisation, regulatory classification, multicentre randomised trials with embedded health-economic endpoints, and transparent governance of cord blood allocation are needed.
2026-08-26 | Incidence and risk factors of Epstein-Barr virus infection and post-transplant lymphoproliferative disorder in paediatric haploidentical allogeneic hematopoietic stem cell transplantation.
Epstein-Barr virus (EBV) reactivation after haploidentical stem cell transplant (haplo-HSCT) is a serious complication, which sometimes progresses to post-transplant lymphoproliferative disorder (PTLD). We retrospectively analyzed 448 pediatric patients ( ≤ 18 years) undergoing anti-thymocyte globulin (ATG)-based haplo-HSCT with letermovir prophylaxis at Peking University People's Hospital (Oct 2022-Oct 2025), using a 1:3 propensity score-matched design. EBV viremia and PTLD incidences were 12.4% and 4.9%. Multivariate analysis showed prior Chimeric Antigen Receptor (CAR) T-cell therapy (Hazard ratio (HR) = 2.040, 95% CI 1.061-3.920; p = 0.033) and Cytomegalovirus (CMV) viremia preceding EBV viremia (HR = 6.075, 95% CI 3.377-10.928; p < 0.001) were risk factors for EBV viremia. The PTLD risk was higher with a total body irradiation (TBI)-based conditioning regimen (HR = 1.917, 95% CI 0.980-3.750; p = 0.050). Overall survival did not differ between groups (EBV + : 92.9% vs. EBV-: 96.4%; p = 0.10), but event-free survival was inferior in EBV-infected patients (86.6% vs. 94.6%; p = 0.004). Chronic graft-versus-host disease (17.0% vs. 6.5%; p < 0.001) and transplant-related mortality (7.1% vs. 2.1%; p = 0.005) were significantly higher in the EBV viremia cohort. EBV reactivation and PTLD pose serious challenges, and risk factors include TBI conditioning, prior CAR-T therapy, and CMV viremia preceding EBV viremia. Preemptive cytotoxic T lymphocyte therapy may benefit high-risk patients.
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.
other
2026-04-03 | Abstract 7791: PAI-1 inhibition attenuates the inflammatory response in a murine model of sclerodermatous chronic graft-versus-host disease
Abstract Hematopoietic stem cell transplantation (HSCT) is a critical tool for managing malignant and defective disorders of hematopoiesis but is limited by graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) remains a leading cause of non-relapse morbidity and mortality following allogeneic HSCT. Due to its high immunoreactivity, the skin is most commonly affected in cGVHD, where it undergoes aberrant tissue repair and progressive fibrosis. Therapeutic options for sclerodermatous cGVHD are limited and disease progression drives long-term morbidity and functional impairment. Plasminogen Activator Inhibitor-1 (PAI-1) is a mediator of tissue remodeling and fibrosis, regulating extracellular matrix deposition and the migration of fibrogenic cell populations. In this study, we hypothesized that pharmacologic inhibition of PAI-1 may improve clinical and histopathological outcomes in a murine model of sclerodermatous cGVHD by reducing pro-fibrotic signaling. C57BL/6 mice were conditioned with total body irradiation followed by intravenous infusion of bone marrow cells and splenocytes of either syngeneic (C57BL/6) or allogeneic (LP/J) donors. Mice received oral PAI-1 inhibitor PAI-039 (10 mg/kg) or vehicle every other day from day +14 until day +56. Clinical signs of GVHD and survival were monitored throughout this duration. At day +56, tissues and serum were collected for downstream molecular analyses. PAI-039 treatment improved survival and clinical GVHD scores. Serum levels of pro-inflammatory cytokines IFN-γ (P=0.006) and TNF-α (P=0.002) were significantly reduced in PAI-039 treated mice compared to controls, alongside decreased expression of IFN-γ (P=0.04) in skin isolates. These findings indicate that PAI-1 inhibition may provide therapeutic benefit in the treatment of sclerodermatous cGVHD by disrupting pathogenic fibrotic signaling, warranting further investigation. Citation Format: Sahra Gabure, Yogamaya Divakar Prabhu, Vasantharaja Raguraman, Shanid Mohiyuddin, Yan Ji, William Fay, Senthilnathan Palaniyandi, Gerhard Hildebrandt. PAI-1 inhibition attenuates the inflammatory response in a murine model of sclerodermatous chronic graft-versus-host disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7791.
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.
2025-09-11 | Approved and emerging therapies for glucocorticoid-refractory chronic graft-versus-host disease.
Glucocorticoid-refractory chronic graft-versus-host disease (glucocorticoid-refractory cGVHD) remains a major barrier to long-term survival and quality of life following allogeneic hematopoietic stem cell transplantation (allo-HSCT), affecting 30-70% to half of patients with chronic GVHD who fail corticosteroid therapy. In recent years, the Food and Drug Administration (FDA) has approved four agents - ibrutinib, ruxolitinib, belumosudil, and axatilimab - each targeting distinct immune and fibrotic pathways. This review systematically evaluates their mechanisms of action, efficacy across organ systems, and safety profiles while highlighting persistent limitations. We further summarize emerging therapies in clinical and preclinical development, including kinase inhibitors, monoclonal antibodies, cellular approaches, and tissue-specific interventions. A dual-axis framework - distinguishing inflammatory versus fibrotic phenotypes and organ-specific manifestations - is proposed to support biomarker-guided, individualized treatment. In addition, combination regimens and AI-assisted strategies offer new opportunities to optimize outcomes and reduce treatment burden. Despite these advances, challenges remain, including irreversible fibrosis, disease heterogeneity, lack of standardized diagnostic criteria, and balanced GVHD and graft versus tumor effect. Greater incorporation of patient-reported outcomes and long-term functional assessments into clinical trials and practice is urgently needed. Collectively, this review offers a roadmap for optimizing glucocorticoid-refractory cGVHD management, and evolving strategies hold promise for transforming glucocorticoid-refractory cGVHD from a life-limiting condition into a manageable chronic disease.
2025-04-04 | High Melphalan Exposure Increases the Risk of Graft-Versus-Host Disease in Pediatric Patients Undergoing Alpha-Beta T-Cell Depleted Haploidentical Transplantation
BACKGROUND: Melphalan is often used as the backbone agent for conditioning prior to A/B-T-cell depleted (A/B-TCD) hematopoietic cell transplant (HCT) due to lower rates of organ toxicity compared to busulfan or total-body irradiation, albeit with significant mucosal injury. Traditional dosing based on body-surface-area (BSA) may result in non-optimal melphalan exposure among certain patient subsets. OBJECTIVES: As mucosal injury is linked to initiation of alloreactivity, we hypothesized that high exposure of melphalan predicted via a pharmacokinetic (PK) model would be associated with an increased risk of acute graft-versus-host disease (aGVHD). STUDY DESIGN: using actual body weight; others received a dose adjusted for obesity or age <2 years. We analyzed outcomes based on whether melphalan exposure was above or below the median exposure for the group. RESULTS: The 100-day cumulative incidences of engraftment syndrome (ES), grade II-IV aGVHD, and grade III-IV aGVHD were 34.2%, 24.8%, and 17.1%, respectively. The 3-year cumulative incidence of chronic GVHD (cGVHD), non-relapse mortality (NRM), and relapse were 17.5%, 8.7%, 21.8%, respectively. The 3-year cumulative incidence of disease-free survival (DFS) and severe GVHD-relapse-free survival (GRFS) were 71.4% and 55.6%, respectively. ES was significantly associated with the subsequent development of aGVHD, both grade II-IV (41.4% vs. 17.3% in those with and without ES, P = .01) and grade III-IV (34.5% vs. 8.5% in those with and without ES; P = .003). Chronic GVHD occurred at significantly higher rates in patients with prior Grade II-IV (66.7% vs. 0% for Grade 0-I; P < .001) and Grade III-IV aGVHD (75% vs. 4.3% for Grade 0-II; P < .001). Compared to non-obese patients, the PK model predicted lower melphalan exposure (P = .02) in obese patients where adjusted ideal body weight was utilized, suggesting overcorrection of the dose. There was no impact of melphalan exposure on immunologic rejection. The median melphalan exposure was 6.81 mg*hr/L (range, 4.4-8.8). Compared to a melphalan exposure ≤6.8 mg*hr/L, a melphalan exposure >6.8 mg*hr/L was associated with a higher incidence of ES (48.8% vs. 19.1%; P = .005), grade II-IV aGVHD (39.3% vs. 10.1%; P = .002), and grade III-IV aGVHD (31.5% vs. 2.5%; P < .001). The 3-year incidence of cGVHD was 27.2% in those with high predicted melphalan exposure compared to 7.4% for low exposure (P = .03); with no difference in 3-year NRM incidence (9.2% vs. 7.7%; P = .82) or 3-year relapse incidence (16.8% vs. 27.6%; P = .31) for high compared to low exposure. However, GRFS was significantly worse in patients with high exposure (46.4%) vs. low exposure (64.6%; P = .02). CONCLUSIONS: High melphalan exposure predicted by a validated population PK model is associated with an increased likelihood of developing ES and subsequently acute and chronic GVHD. Given that a substantial number of patients already require adjustment of standard BSA-based dosing for young age or obesity, a prospective trial of model-based dosing to individualize melphalan exposure is warranted to confirm these results.
2025-03-14 | Dupilumab for Atopic Dermatitis-like Chronic Graft-versus-Host Disease in Three Pediatric Hematopoietic Cell Transplant Recipients.
Atopic dermatitis (AD)-like graft-versus-host disease (GVHD) is a chronic form of skin GVHD with features that include erythema, xerosis, scaling, and pruritus. Patients often require treatment with systemic immunosuppression and aggressive topical therapies for relief. Long-term effects of chronic immunosuppression are undesirable and alternative therapies are needed. A retrospective review of 3 patients receiving dupilumab (DUP) for AD-like cGVHD was conducted. Data collected included demographics, transplant history, and GVHD management and outcomes. Information relating to DUP included dose, route, frequency, and safety based on dermatologic reactions, ocular toxicities, and infections. Patients had differing underlying conditions, transplant types, cell sources, and GVHD prophylactic therapies. Three patients received tacrolimus and topical corticosteroids for GVHD treatment, and 1 also received sirolimus and ruxolitinib. After the initial DUP dose, all patients experienced improvement in their GVHD. To date, all patients have complete remission of their skin cGVHD and have weaned off other therapies. No patients experienced dermatologic or ocular toxicities, and no infections were reported. DUP was efficacious and safe for treating AD-like cGVHD in our 3 pediatric patients. Further investigations are warranted to determine the appropriate placement in therapy.
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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 | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
sterile processed derived multiple allogeneic proteins paracrine signaling | cell therapies | FDA | Regenerative Ocular Immunobiologics LLC | |
rituximab | antibodies | FDA | ODDIFACT SAS | |
Pegtarazimod | peptides | EMA | Clinipace GmbH | |
axatilimab-csfr [Niktimvo] | antibodies | FDA | Approved | Incyte Corporation |
entospletinib | small molecules | FDA | Kronos Bio, Inc. | |
Ibrutinib [Imbruvica] | small molecules | EMA | Janssen Cilag International | |
Avdoralimab | antibodies | EMA | [INACTIVE] Alexion Europe | |
ibrutinib [Imbruvica] | small molecules | FDA | Approved | Pharmacyclics, LLC |
Rimiducid [AP1903] | small molecules | EMA | Bellicum Pharma GmbH | |
Mocravimod [KRP203] | small molecules | EMA | Novartis Europharm Limited | |
Efprezimod alfa | proteins | EMA | Merck Sharp & Dohme B.V. | |
Allogeneic peripheral blood mononuclear cells induced to an early apoptotic state [ApoCell] | cell therapies | EMA | [INACTIVE] Richardson Associates Regulatory Affairs Limited | |
Donor lymphocyte preparation depleted of functional alloreactive T-cells [Luxceptar] | cell therapies | EMA | [INACTIVE] Kiadis Pharma Netherlands B.V. | |
autologous lymphocytes depleted ex vivo of immunoreactive T cells using 4,5 | cell therapies | FDA | Kiadis Pharma Netherlands B.V. | |
Gavilimomab | antibodies | EMA | [INACTIVE] SangStat UK Limited | |
Thalidomide [Thalidomide Laphal 50 mg Hard capsules] | small molecules | EMA | [INACTIVE] Pharmion France |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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