Search Results (549)

Background: Acute graft-versus-host disease (aGVHD) is a leading cause of morbidity and mortality following pediatric hematopoietic stem cell transplantation (HSCT). Approximately half of children achieve complete response (CR) to corticosteroids, whereas steroid-refractory (SR) disease carries a 1–2-year mortality of 41–44%. Mortality risk is 2.6-fold higher in children >13.9 years, and respiratory failure accounts for 26% of deaths. Existing second-line agents—ruxolitinib, tocilizumab, or extracorporeal photopheresis—have delayed onset or high toxicity. Begelomab (BEGESAND^®), a monoclonal antibody targeting CD26/dipeptidyl peptidase-4 (DPP4), inhibits CD26-mediated T-cell activation and has demonstrated 75% response in adults with minimal toxicity. However, pediatric data are lacking. Methods: We retrospectively reviewed five consecutive pediatric patients (ages 3–20 years) treated with Begelomab (BEGESAND^®) for SR (n = 4) or steroid-dependent (SD; n = 1) aGVHD between 2017–2021 under emergency IND authorization. Begelomab (BEGESAND^®) was administered intravenously at 2.7 mg/m²/day on days 1–5, 10, 14, 17, 21, 24, and 28. GVHD was graded by MAGIC criteria; flow cytometry and immunohistochemistry (IHC) assessed CD26 expression and immune effects. Results: All patients had grade IV disease after ≥2 prior agents. Two with pre-existing sepsis died early, before treatment response could be assessed. Of three evaluable patients, two (67%) achieved CR within 21 days and one achieved durable control by 6 months. All three remain alive; no Begelomab (BEGESAND^®)-related toxicity, cytopenia, or new infections occurred. Flow cytometry showed preserved T-cell subsets, and IHC demonstrated CD26 localization at sites of epithelial injury. Conclusions: Begelomab (BEGESAND^®) showed promising timely and durable responses with excellent safety in pediatric SR/SD-aGVHD, supporting further evaluation in multicenter pediatric trials. Full article

Background: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only curative therapy for myelofibrosis (MF), but its use is limited by substantial transplant related morbidity and mortality, particularly in older or comorbid patients. Treosulfan has emerged as a less toxic alternative to busulfan, with potential advantages in myeloablative and reduced intensity conditioning. Methods: We conducted a comprehensive, multi-database literature search (PubMed, Scopus/EMBASE, Cochrane Library, Web of Science, and grey literature) for studies published between 2000 and 2025 evaluating treosulfan-based conditioning in MF patients undergoing allo-HCT. Data on patient characteristics, conditioning regimens, engraftment, graft-versus-host disease (GVHD), and survival outcomes were synthesized. Results: Eight studies including more than 800 patients were analyzed. Treosulfan was most commonly combined with fludarabine, with or without additional agents. Engraftment rates were consistently high at 94 to 100%, with low non-relapse mortality (NRM) and favorable progression-free survival (PFS). An EBMT registry study demonstrated superior survival and significantly lower NRM compared with busulfan based regimens. Benefits were observed across older patients, alternative donors, and second transplants. Higher treosulfan doses were associated with increased toxicity in some cohorts. Conclusions: Treosulfan based conditioning offers an effective and better tolerated option for MF transplantation. Prospective trials are needed to refine dosing and patient selection. Full article

The role of zonulin as a biomarker of intestinal permeability in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) setting remains poorly understood. In this study, we aimed to evaluate serum zonulin dynamics, identify its predictors, and assess its prognostic significance in patients undergoing allo-HSCT. This multicenter, prospective cohort study was conducted across four Brazilian hospitals. Eligible participants were patients aged ≥12 years who provided at least one blood sample during the allo-HSCT course. A control group of 15 healthy adult individuals was also included. Serum zonulin levels were quantified using enzyme-linked immunosorbent assay multiple times over the allo-HSCT course. Outcomes included acute graft-versus-host disease, overall survival, and bloodstream infections. A total of 477 blood samples were collected from 140 patients. Compared with the control group, zonulin levels were persistently elevated at all evaluated time points throughout the allo-HSCT course. However, no significant differences were observed among the different time points assessed during transplantation. No clinical or transplantation-related characteristics were identified as significant predictors of elevated zonulin levels. Finally, zonulin did not demonstrate prognostic value for allo-HSCT-related outcomes. Future studies should investigate whether other intestinal permeability biomarkers have prognostic relevance in the allo-HSCT setting. Full article

Fanconi anemia (FA) is a rare inherited disorder associated with impaired DNA repair, characterized by congenital anomalies, bone marrow failure, and a significantly increased risk of developing malignancies, particularly squamous cell carcinoma (SCC) of the head and neck. Treatment options for advanced SCC in FA are limited due to hypersensitivity to DNA-damaging agents. This article presents a unique case of SCC that developed in a 17-year-old patient with FA caused by a homozygous mutation in the FANCA gene. At the age of 10, he received a bone marrow transplant from a compatible related donor. Conditioning therapy included busulfan, thymoglobulin, and fludarabine, while graft-versus-host disease (GvHD) prophylaxis was administered with rituximab, methotrexate, and cyclosporine A. Nevertheless, he developed chronic cutaneous GVHD, which was treated for four years with ruxolitinib and tacrolimus, achieving only partial control. During this period, locally advanced cutaneous SCC (T3N0M0, stage III) manifested on the face. Surgery, radiation therapy, and immunotherapy with pembrolizumab led only to an initial partial response. This first pediatric case of immunotherapy for SCC in FA highlights the challenges of treating this rare patient group. Nevertheless, combining radiation therapy with immunotherapy may represent a possible option for disease control. Full article

Mesenchymal stem/stromal cells (MSCs) are multipotent progenitor cells with potent immunomodulatory properties, making them attractive candidates for treating inflammatory and autoimmune diseases. A key mediator of MSC-induced immunosuppression is programmed death-ligand 1 (PD-L1), a checkpoint molecule that interacts with PD-1 on immune cells to regulate immune responses and promote tolerance. This review synthesizes current evidence on the role of PD-L1 expression in MSCs, emphasizing its effects on both the innate and adaptive immune systems, its therapeutic potential, and its utility as a biomarker for MSC potency and clinical efficacy. We examine how PD-L1 modulates T cell activation, dendritic cell maturation, macrophage polarization, and cytokine profiles, including its role in exosomal contexts. Additionally, we highlight its synergistic interactions with other immune checkpoints and discuss its dual function as both a therapeutic effector and a dynamic biomarker. Finally, we explore its relevance in clinical contexts such as autoimmune diseases, graft-versus-host disease, sepsis, and transplantation and conclude with a discussion of challenges and future directions in harnessing PD-L1 for MSC-based therapies. Full article

Background: Cyclosporine A (CsA) is a cornerstone in graft-versus-host disease (GVHD) prophylaxis in allogeneic hematopoietic cell transplantation (allo-HCT), and a higher starting dose of 5 vs. 3 mg/kg reduces the risk of acute GVHD. Since hypertension is a relevant side effect of CsA, data on whether a higher CsA starting dose affects the incidence of hypertension are warranted. Methods: In this monocentric cohort study, 367 patients with no preexisting hypertension and treated with a CsA-containing GVHD prophylaxis were included: 230 (63%) with a CsA starting dose of 3 mg/kg and 137 (37%) with 5 mg/kg. The primary outcome was the incidence of early new-onset hypertension during the engraftment period. Potential risk factors for early new-onset hypertension were assessed using uni- and multivariable Cox regression models. Results: Overall, the cumulative incidence of early new-onset hypertension was 67% (246/367), but the incidence rate for early new-onset hypertension in the higher CsA group was lower (CsA 5 vs. 3 mg/kg: 57 vs. 67 per 1,000 patient-days; p = 0.414). In the multivariable analysis, risk factors for early new-onset hypertension were advanced patient age, obesity and prior autologous HCT, while a higher CsA starting dose was not associated with increased early new-onset hypertension (adjusted hazard ratio, 0.90; 95% CI, 0.67–1.21). Conclusions: A higher CSA starting dose of 5 vs. 3 mg/kg did not increase the risk of hypertension. Since previous analyses demonstrated a reduction in GVHD with a higher CsA starting dose of 5 mg/kg, current findings further support the safety of a higher CsA starting dose. Full article

Background: Acute Graft versus Host Disease (aGvHD) is a serious complication of allogeneic stem cell transplantation (Allo-SCT) associated with substantial morbidity and mortality. Enteral nutrition (EN) has been associated with improved transplant outcomes, yet standardized early EN practices remain inconsistently adopted across centers. Methods: This retrospective cohort study evaluated the adoption and clinical outcomes of a standardized Day +1 EN protocol in patients undergoing Allo-SCT. The protocol included feeding tube (FT) placement on Day +1 with EN initiated at 25 mL/h. Demographic and clinical data were extracted from electronic health records for patients treated after protocol adoption (post-protocol) and retrospective controls from one year prior (pre-protocol group). Outcomes included successful Day +1 EN initiation, gastrointestinal (GI) complications, FT removal reason, and occurrence and severity of lower GI and overall aGvHD by Day +100 (Modified Glucksberg Criteria). Group comparisons used Welch’s t-test and Fisher’s Exact test (p < 0.05). Results: The final cohort included 108 patients (67 pre-protocol and 41 post-protocol). Successful Day +1 EN initiation occurred in 95.1% (n = 39) of patients post-protocol versus 4.5% (n = 3) pre-protocol (p < 0.001). GI complications and FT removal reason did not differ significantly between groups, and no FTs were removed due to adverse events. The occurrence of lower GI aGvHD was significantly lower post-protocol (12.2% vs. 28.4%, p = 0.05). Conclusions: Adoption of a standardized Day +1 EN protocol in Allo-SCT patients was successfully implemented and well-tolerated without adverse FT-related events. The significant difference in lower GI GvHD occurrence in the post-protocol group warrants confirmation of Day+1 EN in patients receiving an Allo-SCT in a future randomized trial. Full article

Background: Hematologic malignancies (HMs), including leukemia and lymphoma, are systemic diseases that may cause a wide range of ocular manifestations. Methods: We searched PubMed/MEDLINE (2015-2026) and identified articles with an emphasis on clinically relevant studies and recent developments. Results: Clinically, ocular involvement presents with diverse manifestations, including retinal hemorrhage, vitreoretinal lymphoma, choroidal infiltration, orbital masses, treatment-related ocular toxicities, graft-versus-host disease, and secondary infectious complications. These findings may mimic other ocular diseases and consequently lead to delayed diagnosis. In some cases, ocular manifestations may represent the initial presentation of hematologic malignancies or indicate disease recurrence. Diagnostic evaluation relies on comprehensive ophthalmic examination, imaging, and laboratory analysis. Management strategies include systemic treatment of the underlying malignancy, local ocular therapy, and targeted treatment of infectious or treatment-related complications. Conclusions: Ocular manifestations of hematologic malignancies have significant diagnostic and prognostic implications. Early recognition, multidisciplinary collaboration, and comprehensive ophthalmic assessment are essential for timely diagnosis and optimal management. Improved awareness of disease-related, treatment-related, and infection-related ocular manifestations may facilitate earlier intervention and contribute to better visual and systemic outcomes. Full article

Background: Graft-versus-host disease (GVHD) is a common severe complication of allogeneic hematopoietic stem cell transplant. The current treatments are limited by steroid toxicity, broad immunosuppression, and the potential suppression of the graft-versus-tumor (GVT) effect. Developing less toxic therapies is an unmet need. We previously showed that systemically infused negatively charged immune-modifying microparticles (IMPs) composed of carboxylated poly-lactic-co-glycolic acid are taken up by inflammatory monocytes via the MARCO receptor, reducing symptoms and improving survival in inflammatory conditions. We hypothesized that IMPs could reduce acute GVHD manifestations. Methods: Acute GVHD was induced in an MHC-mismatched murine transplant model with radiation conditioning. IMPs were infused for five days; outcomes were compared to saline controls. We assessed organ histopathology, immune cell populations in the spleen and intestine, serum cytokine levels, and the GVT effect. Results: IMP-treated mice showed significant improvements in terms of clinical GVHD scores, histopathology, and survival. They had increased regulatory T-cells in the spleen and intestine and decreased colonic inflammatory monocytes and cytokines such as IL-6 and IFN-γ. IMPs were ineffective in MARCO knockout mice, confirming receptor dependence. Importantly, GVT activity was preserved, as evidenced by improved survival in mice with A20 lymphoma treated with IMPs. Conclusions: Systemic IMPs reduce clinical GVHD signs and improve survival, likely by decreasing inflammatory monocytes via MARCO and expanded regulatory T-cells numbers, while maintaining GVT activity. These findings support further investigation of IMPs as a targeted GVHD therapy. Full article

Background: The Endothelial Activation and Stress Index (EASIX) is a biomarker initially developed to predict survival in patients with acute graft-versus-host disease after allogeneic haemato-poietic stem cell transplantation and is regarded as a surrogate of endothelial dysfunction. This study aimed to evaluate whether EASIX reflects early hemodynamic instability and vasopressor requirement in critically ill patients. Methods: We retrospectively analysed 447 patients admitted to the intensive care unit (ICU) at the University Clinical Centre in Gdańsk. Illness severity scores—including the Simplified Acute Physiology Score II (SAPS II), Acute Physiology and Chronic Health Evaluation II (APACHE II), and Sequential Organ Failure Assessment (SOFA)—and laboratory parameters, were collected at admission. EASIX, simplified EASIX (sEASIX), and modified EASIX (mEASIX) were calculated using established formulas. Vasopressor requirements, ex-pressed as norepinephrine equivalents (NEE), were recorded during the first 72 h. Statistical analyses included Spearman’s correlation, logistic regression, and receiver operating characteristic curve analysis. Results: In univariate analysis, EASIX was associated with ICU mortality (OR 1.333; 95% CI 1.135–1.576), but this association was not significant after adjustment. EASIX positively correlated with vasopressor requirements, severity scores (SOFA, SAPS II, APACHE II), and inflammatory and metabolic markers (PCT, CRP, lactate). It correlated with norepinephrine-equivalent doses within the first 48 h and moderately discriminated high-dose vaso-pressor use (>0.1 µg/kg/min). A weak negative correlation with ICU length of stay was observed. No association with age was found. Conclusions: EASIX is an age-independent marker associated with disease severity and early vaso-pressor burden in ICU patients. Rather than providing a direct measurement of endothelial function, it reflects a global signal of systemic stress and microvascular derangement and should be interpreted accordingly. Full article

Background and Methods: Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is a severe complication of allogeneic stem cell transplant (allo-SCT). Given the increased use of allo-SCT and variability of SOS/VOD incidence in published reports, cases of allo-SCT from two major transplant centers in Ontario, Canada (2019–2021), were reviewed to identify risk factors prognostic for SOS/VOD onset and to assess outcomes. Results: This study included 536 allo-SCT cases, with a mean age of 53.4 years [min–max: 17–76], including 322 male recipients and 214 female recipients. There were 17 SOS/VOD cases diagnosed during the first 100 days, representing 3% of allo-SCT cases, with a median age of 48 years [18–72] and equally distributed between genders. All cases were classical SOS/VOD, with onset prior to day 21 [1–20]. These cases were graded as one mild, six moderate, six severe, and four very severe cases. The mild case of SOS/VOD recovered after treatment with diuretics. In respect to the 16 cases graded as ≥moderate SOS/VOD, the average inpatient stay was 56 days [24–178], and eight patients were in the ICU for an average of 6 days [0–42], with a median of zero days. Five of the sixteen ≥moderate SOS/VOD patients died within 100 days [9–59]—four from SOS/VOD. After day +100, five remained alive, and six died between days 125 and 419. Treatments for ≥moderate SOS/VOD included diuretics [n = 15], steroids [n = 3], and defibrotide [n = 9]. The nine patients treated with defibrotide were graded as moderate [n = 2], severe [n = 4], and very severe [n = 3]. Three of the nine patients treated with defibrotide died before day 100, and the other six survived beyond day 100. None of the six surviving patients died from SOS/VOD. Univariable regression analysis identified a higher baseline absolute neutrophil count (ANC) of 4.2 × 10⁹/L compared to 2.6 × 10⁹/L [p = 0.035] and lower baseline platelet count of 104 × 10⁹/L compared to 140 × 10⁹/L [p = 0.034] in SOS/VOD and non-SOS/VOD cases, respectively, as independent risks for ≥moderate SOS/VOD. Treatment with inotuzumab ozogamicin was also identified as a risk factor for ≥moderate SOS/VOD (p = 0.016). The absence of late-onset SOS/VOD in the cohort of 536 patients prompted a retrospective analysis of the data to identify potentially missed cases. Seven cases were identified as meeting the diagnostic criteria for SOS/VOD: four classical and three late-onset. One case would have been graded as severe, and the remaining six would have been graded as very severe. Six patients were reported to have died between days 11 and 107, with four deaths before day 100. The clinical diagnoses of patients meeting diagnostic criteria for SOS/VOD included infection (n = 3), graft-versus-host disease (GVHD) (n = 3), and pulmonary hemorrhage (n = 1). The inclusion of potentially missed cases in the analysis again suggested a lower baseline platelet count (p = 0.002) and prior treatment with inotuzumab ozogamicin (p = 0.003) as potential risk factors for SOS/VOD. The baseline ANC was lower in this combined cohort but did not reach statistical significance (p = 0.089) as it did in the confirmed SOS/VOD cohort (p = 0.035). Additional clinical features that were identified as statistically significant for the onset of SOS/VOD (potential and confirmed cases) included a lower Karnofsky Performance Status (p = 0.01), the presence of pulmonary hypertension (p = 0.012), lower baseline hemoglobin (p = 0.017), and higher baseline serum ferritin (p = 0.01). Conclusions: The incidence of classical SOS/VOD in this cohort was consistent with recent published reports and carried a high fatality rate. A higher ANC, lower platelet count at the start of the preparative regimen, and prior treatment with inotuzumab ozogamicin were identified as potential risk factors for diagnosed SOS/VOD. Hospital and intensive care unit stays were longer in SOS/VOD patients. There were no cases of late-onset VOD diagnosed within the first 100 days of allo-SCT transplant, which is inconsistent with recently reported incidence rates. Potentially missed cases of SOS/VOD were identified, suggesting that this disease may be under-diagnosed and underscoring the need for ongoing education and resources to allow for early intervention. Full article

Graft-versus-host disease (GVHD) remains the most severe complications following allogeneic hematopoietic cell transplantation (allo-HCT). Mesenchymal stromal cells (MSCs) have shown therapeutic potential in GVHD due to their immunomodulatory properties. However, their clinical application is constrained by safety concerns, including ectopic engraftment, microvascular obstruction, rejected by host, and potential tumor-supportive effects. Increasing evidence suggests that MSC-derived exosomes (MSC-Exos), as cell-free mediators, retain many of the beneficial effects of MSCs while exhibiting improved safety and stability profiles. MSC-Exos carry diverse bioactive cargo, including nucleic acids, lipids, and proteins, and can modulate immune responses, promote tissue repair, and restore barrier integrity. In this review, we place particular emphasis on both immunoregulation and tissue barrier protection as dual mechanisms underlying MSC-Exos efficacy in GVHD. We further discuss emerging preclinical and clinical evidence, as well as key challenges in translation. Full article

Background: Chimerism analysis is a key tool for monitoring donor-cell engraftment and the risk of relapse and graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT). The advantage of lineage-specific chimerism assessment, and its dynamics in patients receiving post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis, remains unclear. Objective: This review summarizes the current state of the art on chimerism analysis in patients with myeloid neoplasms undergoing allo-HCT with PTCy, with emphasis on lineage-specific testing and modern methodologies. Methods: A structured literature review was conducted to assess chimerism dynamics in whole blood (WB), bone marrow, and peripheral blood (PB) subpopulations, including T-cells, CD34⁺, myeloid, B, and NK (natural killer) cells, and their association with clinical outcomes following PTCy. Results: Lineage-specific PB chimerism, particularly in T-cells, myeloid lineage and CD34⁺ cells, is more sensitive than WB chimerism for predicting relapse. Declining donor myeloid chimerism or persistent myeloid mixed donor chimerism (MDC) may precede hematologic relapse and provide an early signal of graft instability or ineffective graft-versus-leukemia activity. T-cell MDC has been associated with an increased risk of relapse and a lower risk of GVHD, although persistent T-cell MDC in some patients may instead indicate immune tolerance. Declining CD34⁺ donor chimerism correlates with a higher risk of relapse and inferior survival outcomes and may therefore complement measurable residual disease testing. Data regarding B-cell and NK-cell chimerism remain inconsistent, likely influenced by delayed immune reconstitution. Compared to anti-thymocyte globulin, PTCy may promote higher donor T-cell chimerism, though findings across studies are variable. Next-generation sequencing (NGS) enables more sensitive detection of microchimerism and relapse prediction. Conclusions: Chimerism analysis, particularly when lineage-specific and NGS-based, offers valuable prognostic insight in allo-HCT with PTCy. Further prospective studies are needed to standardize testing and guide personalized post-HCT strategies. Full article

Background: Graft-versus-host disease is the most common complication after allogeneic hematopoietic stem cell transplantation. While ocular graft-versus-host disease typically manifests as dry eye syndrome and anterior segment involvement, posterior segment complications are rare. Previously reported posterior segment complications in graft-versus-host disease have been limited to acute presentations with significant functional visual impairment. Methods: A 41-year-old man developed progressive retinal nerve fiber layer and ganglion cell layer loss four years after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia. The patient had established chronic graft-versus-host disease with cutaneous involvement and ocular surface disease. Results: Despite preserved visual acuity and visual fields, and only subtle functional involvement on visual evoked potentials, optical coherence tomography revealed significant reduction in retinal nerve fiber layer thickness and ganglion cell layer. Magnetic resonance imaging showed no optic nerve or brain abnormalities. Conclusions: This case describes an uncommon presentation of chronic, subclinical posterior segment involvement in chronic GVHD and suggests that optical coherence tomography may detect progressive structural retinal changes in the absence of clinically evident visual impairment, supporting its potential role in longitudinal monitoring. Full article

Graft-versus-host disease (GVHD) is one of the principal complications seen in the recipients of allogenic hematopoietic stem cell transplantation (allo-HSCT), and persists as a leading cause of post-transplant morbidity and mortality. Increasing evidence highlights the crucial influence of the gut microbiome (GM) on transplant outcomes. Microbial dysbiosis, characterized by reduced bacterial diversity and pathogenic overgrowth, is strongly associated with higher rates of complications and mortality. Patients with lower microbial diversity exhibit poorer overall survival (OS) and an increased incidence of acute GVHD (aGVHD). Conversely, restoration of beneficial commensal communities has been shown to enhance immune homeostasis, mitigate GVHD severity, and decrease infection risk. Emerging therapeutic strategies now focus on modulating the intestinal microbiome through dietary interventions, probiotics, prebiotics, and fecal microbiota transplantation (FMT). It has been demonstrated that bacterial metabolites, such as short-chain fatty acids (SCFAs) from the diet, especially a diet rich in fibers, reduce the occurrence/severity of GVHD by inducing regulatory T cells (Tregs), which release anti-inflammatory cytokines and regulate the host immune system. Hence, the implementation of dietary fibers (DFs) could increase beneficial commensals, Treg induction, and improve outcomes such as GVHD and OS in recipients of allo-HCT. Hereupon, this review addresses how a fiber-rich diet modulates GM composition, reinforces epithelial barrier integrity, and improves the efficacy of Treg-based immunotherapy by stabilizing their regulatory phenotype and increasing their functional persistence, ultimately leading to a reduction in GI complications associated with GVHD. Unlike prior reviews that primarily cover the microbiome–GVHD axis or Treg therapies in isolation, this review emphasizes fermentable dietary fibers as a mechanistically grounded, clinically actionable strategy to support Treg stability and persistence via microbiota-derived metabolites. We integrate mechanistic evidence with emerging clinical feasibility data and ongoing trials of prebiotic supplementation in allogeneic HSCT. Full article