Search Results (435)

Background/Objectives: Allogeneic hematopoietic stem cell transplantation is associated with increased cardiovascular risk driven by endothelial dysfunction, chronic inflammation, and treatment-related metabolic disturbances, including dyslipidemia. In the contemporary era of post-transplant cyclophosphamide-based prophylaxis, the prognostic significance of dyslipidemia—particularly as assessed by non-HDL cholesterol—remains unclear. In this study, we aimed to compare the engraftment days, graft-versus-host disease (GVHD) development, relapse, overall survival rates, and cardiovascular mortality in patients using myeloablative/reduced intensity conditioning regimens with post-transplant cyclophosphamide (PTCy) 50 mg/kg/day for 2 days in patients with acute leukemias. Methods: A total of 95 adult patients with acute leukemias were included in their first remission who underwent matched sibling donor transplantation with PTCy (50 mg/kg on days +3 and +4). Patients were stratified according to pre-transplant non-HDL-C levels (<160 mg/dL vs. ≥160 mg/dL). Matched related donors were selected for the patients. All patients received either myeloablative or reduced-intensity conditioning based on EBMT criteria, with fludarabine-based combinations including busulfan, treosulfan, or TBI, along with ATLG administered at a total dose of 15 mg/kg. Peripheral blood stem cells were used for all transplants, and GVHD prophylaxis consisted of cyclosporine. Results: Platelet (median 13 vs. 14 days) and neutrophil (median 14 vs. 15 days) engraftment times and veno-occlusive disease (VOD) rates were comparable across groups (all p > 0.05); cumulative incidences of grade II–IV aGVHD at +100 days, grade III–IV aGVHD at +100 days, and moderate-severe cGVHD at 1 year, relapse-free survival, and non-relapse mortality at 1 year were comparable in two cohorts (all p > 0.05). GVHD-free/relapse-free survival (GRFS) at 1 year was also comparable across groups (p = 0.15). Median GRFS was 150 (95% CI: 120–330) days and 270 (95% CI: 154-not reached) days, respectively [HR was 0.68 (0.40–1.15), p = 0.15; GRFS at 1 year was 66.6% vs. 52.0%, respectively]. The groups were also comparable in terms of overall survival (OS). Follow-up ranged from 0.5 to 108 months, and median follow-up was 60 months in two cohorts. Median OS was not reached in non-HDL-C < 160 (95% CI: 70 months–not reached) and 67 months in non-HDL-C ≥ 160 groups (95% CI: 13 months–not reached) (Log rank = 0.21). No cardiovascular death events occurred during the follow-up period. Conclusions: In this homogeneous matched sibling donor transplant cohort with extended follow-up and uniform administration of post-transplant cyclophosphamide, cyclosporine-based GVHD prophylaxis, and anti-thymocyte lymphoglobulin (ATLG), pre-existing dyslipidemia was not associated with an adverse impact on GRFS, NRM, PFS, CMV reactivation, OS or long-term cardiovascular mortality. Full article

Vitamin D is a pleiotropic secosteroid with endocrine and intracrine actions that influence key phases of allogeneic hematopoietic stem cell transplantation. Epithelial barriers, antigen-presenting cells and effector lymphocytes express the vitamin D receptor and enzymes required for local activation, allowing circulating 25-hydroxyvitamin D to be converted into its active form and modulate immune interactions. During the peri-transplant period, sunlight deprivation, reduced intake, mucosal injury, cholestasis and corticosteroid exposure markedly reduce vitamin D levels at a time when antigen presentation and immune reconstitution occur. This review integrates mechanistic immunology with clinical observations and interventional data to outline strategies that prevent severe deficiency. It summarizes epidemiology before and after transplantation, associations with acute and chronic graft-versus-host disease, relapse, engraftment, infections, bone health and survival, and evaluates dosing approaches including pre-conditioning loading and reassessment at day thirty with escalation if needed. Absorption-savvy formulations such as oral thin-film and intramuscular cholecalciferol are considered when gastrointestinal function is compromised. Given the high prevalence of deficiency, biological plausibility, safety and low cost, a structured approach that includes screening, repletion and monitoring to achieve concentrations of at least thirty nanograms per milliliter by day thirty represents a pragmatic and low-risk component of supportive care pending definitive evidence. Full article

Background: B-cell malignancies have been effectively treated using chimeric antigen receptor-T (CAR-T) treatment employing traditional αβT cells. However, because of several obstacles, application in acute myeloid leukemia (AML) is still restricted. A safer “off-the-shelf” alternative can be supplied by CAR-γδT cells, which have major histocompatibility complex (MHC)-independent tumor identification capabilities and a decreased risk of graft versus host disease (GvHD). This study aimed to develop FLT3-targeted CAR-γδT cells that co-express cytokines (IL-2 or IL-7) to increase their anti-AML persistence and therapeutic efficacy. Methods: FLT3-CAR-γδT cells, FLT3-IL2-CAR-γδT cells, and FLT3-IL7-CAR-γδT cells were constructed. Their antitumor potency was comprehensively assessed through cytotoxicity assays, cytokine release, and persistence evaluation in vitro (using AML cell lines and primary AML cells) and in vivo (via mouse model). Results: Superior cytotoxicity against AML cell lines (OCI-AML3, MOLM-13, THP-1, and MV4-11) was demonstrated by FLT3-IL2-CAR-γδT cells, which also released higher levels of granzyme B, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). FLT3-IL2-CAR-γδT cells exhibited cytotoxicity in some primary AML cells in vitro. During the antigen-repeated stimulation assay, FLT3-IL2-CAR-γδT cells preserved the stem cell-like memory T (T_SCM) cell subsets, sustained cytokine release, and maintained excellent viability. FLT3-IL2-CAR-γδT cells considerably slowed the development of AML in vivo and extended the existence (>68 days) of mice. Conclusions: FLT3-IL2-CAR-γδT cells exhibit potent and durable anti-AML activity, providing a novel strategy for clinical AML immunotherapy. Full article

Adoptive immunotherapy using ex-vivo-amplified autologous αβ T cells has achieved notable success in the treatment of diverse cancer types. Pre-eminent among these developments has been the advent of chimeric antigen receptor (CAR) T cell therapy, which has revolutionised the treatment of selected haematological malignancies. However, autologous CAR T cell immunotherapy is poorly scalable and has demonstrated limited efficacy against solid tumours. Accordingly, there has been significant interest in alternative strategies that may bridge these gaps. The use of γδ T cells is an attractive alternative since they possess intrinsic anti-tumour activity and do not elicit graft versus host disease (GvHD) when employed as an allogeneic drug product. In this review, we evaluate the potential use of γδ T cells for cancer immunotherapy and how manufacturing and genetic engineering refinements can be used to potentiate this activity. We also summarise current clinical experience with CAR γδ T cell therapies and discuss the implications of these findings for the next generation of cellular immunotherapies. Full article

Introduction & Objective: Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), with limited treatment options for steroid-resistant cases. Ruxolitinib, a JAK1/2 inhibitor, has shown promise in treating steroid-resistant acute (aGVHD), chronic (cGVHD), and overlap GVHD (oGVHD), but real-world data remain limited. This study evaluated the real-world efficacy and safety of ruxolitinib in allo-HSCT patients with steroid-resistant GVHD. Materials & Methods: This retrospective, multicenter study included adult patients treated with ruxolitinib for Grade II or higher aGVHD or moderate-to-severe cGVHD at nine centers in Turkey (2017–2024). Clinical characteristics, treatment responses, and adverse events were recorded. Primary outcomes were overall response rate (ORR) and overall survival (OS). Results: Among 80 patients (mean age: 39.3 ± 13.3 years; 60 males), 39 had aGVHD, 68 cGVHD, and 15 oGVHD. The ORR was 72 of 80 patients (90.0%) (complete response: 37 of 80 [46.3%], partial response: 35 of 80 [43.8%]). The 1-year and 2-year OS rates were 91.3% and 82.5%. Severe cGVHD (p < 0.001) and lack of response to ruxolitinib (p = 0.018) were associated with reduced OS. Adverse events included infections in 40 of 80 patients (50.0%), cytopenias in 23 of 80 (28.7%), and cytomegalovirus reactivation in 20 of 80 (25.0%). Conclusion: In this retrospective multicenter cohort, ruxolitinib was associated with high response rates in steroid-refractory GVHD, while disease severity remained a key determinant of survival, and findings should be interpreted as exploratory. Full article

Gastrointestinal acute graft-versus-host disease (GI aGvHD) remains a leading cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Current diagnostic methods rely on invasive procedures with limited sensitivity. While circulating biomarkers have been proposed, little is known about the local transcriptomic landscape within inflamed GI tissue. We performed integrated profiling of mRNA and microRNA expression in colonoscopically resected GI biopsies from n = 8 HSCT patients, including n = 3 with histologically confirmed GI aGvHD and n = 5 without. Using NanoString nCounter technology, we quantified 770 immune-related mRNAs and 799 mature human microRNAs. Differential expression analysis, pathway enrichment, cell type deconvolution, and machine learning–based biomarker prioritisation were conducted to define disease-specific molecular signatures. GI aGvHD was marked by upregulation of inflammatory genes (e.g., IL1B, IL17RA, HLA-DRA) and immune-regulatory microRNAs (e.g., miR-155-3p, miR-223-3p), alongside downregulation of epithelial and anti-inflammatory markers (ST6GAL1, THBS1, miR-1915-3p, miR-145-5p). Enrichment analyses revealed activation of IL2/STAT5, JAK/STAT3, TCR signalling, and antigen presentation pathways. Machine learning identified LCN2, CXCL13, and miR-1269b as top-ranked biomarker candidates. Cell deconvolution showed increased M0 macrophage and decreased dendritic cell signatures in aGvHD tissue. This is the first study to integrate mRNA and microRNA profiling in GI tissue using NanoString technology to characterise the immune and epithelial transcriptomic landscape of aGvHD. Our findings reveal dysregulated immune pathways, altered myeloid cell populations, and novel biomarker candidates, offering tissue-specific insights into disease pathogenesis and potential diagnostic targets. Larger validation studies and functional assays are warranted to confirm clinical utility. Full article

Ocular graft-versus-host disease (oGVHD) remains one of the most challenging complications of allogeneic hematopoietic stem cell transplantation (HSCT), often leading to severe ocular surface morbidity and irreversible vision loss if not properly managed. Diagnostic uncertainty persists due to variability in clinical presentation and a lack of universally accepted criteria, but the greatest clinical burden lies in establishing effective, durable treatment protocols. Current strategies range from lubricants and topical immunomodulators to advanced surgical interventions; however, outcomes remain inconsistent due to delayed recognition and heterogeneous practices across institutions. At institutions like MD Anderson Cancer Center (MDACC), a structured treatment strategy has been developed that emphasizes early recognition and targeted therapy based on the specific ocular tissues affected. This approach integrates patient-reported outcomes with objective ocular findings and applies stepwise therapeutic escalation aligned with tissue-specific pathology. This review offers a brief overview of the clinical burden and pathophysiology of oGVHD, outlines the key diagnostic challenges, and a more detailed discussion on therapeutic strategies with particular emphasis on the targeted tissue-based approaches. Full article

Hematopoietic stem cell transplant (HSCT) is a curative therapy for acute lymphoblastic leukemia (ALL), but its success is limited by chronic graft-versus-host disease (cGvHD) and disease relapse. A central challenge is uncoupling the graft-versus-leukemia (GvL) effect from cGvHD. Early changes in the bone marrow microenvironment following HSCT may offer a predictive window into these divergent outcomes. We conducted a retrospective, single-center, exploratory study on 14 pediatric ALL HSCT patients. Applying single-cell antibody-sequencing (AbSeq) on archived bone marrow aspirates collected 60–100 days post-HSCT, we evaluated immune patterns associated with the development of cGvHD or ALL relapse after day 114. cGvHD after day 114 was associated with upregulation of the endoplasmic reticulum (ER) stress transcription factor XBP1 in transitional B cell and IgM memory B cell populations, a mincle^highPD1⁻ neutrophil population, and exhausted LAG3⁺ effector memory T cells (T_EM). ALL relapse after day 114 was associated with higher CD22, CD24, and ARG1 expression in M(IL-4)-like macrophages and exhausted TIGIT⁺ T_EM. Results from this exploratory study suggest that marrow immune signatures of B cell ER stress preceding later development of cGvHD and macrophage-mediated immune evasion preceding relapse may potentially be early biomarkers for separating GvL from cGvHD in ALL HSCT. Validation with larger cohorts is warranted. Full article

Allogeneic hematopoietic stem cell transplantation (HSCT) is a medical procedure to treat hematologic malignancies and restore bone marrow function. However, this approach may lead to graft-versus-host disease (GvHD), a major cause of mortality and morbidity after allogeneic HSCT. Some studies have suggested the involvement of gut microbiota in the development and prognosis of GvHD. In this context, the main objective of this study was to compare the fecal microbiome composition and short-chain profile of pediatric patients who underwent successful HSCT, developed GvHD or died. The bacterial composition was analyzed using 16S rRNA gene sequencing, while short-chain fatty acids (SCFAs) were quantified by gas chromatography. Fecal samples at engraftment were mainly characterized by a loss of bacterial diversity, a depletion of sequences belonging to the genus Blautia and significantly lower concentrations of fecal butyrate and acetate compared with those obtained before HSCT and 100 days after HSCT. Our findings confirm that children experiencing GvHD after HSCT have distinct gut microbiota and SCFA profiles, which might contribute to developing new microbiota-targeted strategies for GvHD prevention during HSCT procedures. Full article

Hematopoietic stem cell transplant (HSCT) recipients are at high risk for opportunistic infections due to profound immunosuppression and graft-versus-host disease (GvHD). Molds and nontuberculous mycobacteria (NTM) pose diagnostic and therapeutic challenges, especially when infections overlap. A 42-year-old woman with prior allogeneic HSCT for acute myeloid leukemia (AML) developed pulmonary infections with Microascus spp. and Mycobacterium chimaera, later complicated by Aspergillus calidoustus and RSV infection. Initial therapy included voriconazole, amphotericin B, and a macrolide-based multidrug regimen for NTM. Modifications were required for drug resistance and hepatotoxicity. Despite partial response, recurrent fungal infection necessitated prolonged antifungal therapy, including adjunctive inhaled amphotericin B and terbinafine. Ultimately, progressive bronchiolitis obliterans prompted bilateral lung transplantation. Explant pathology revealed necrotizing granulomas positive for NTM and Microascus spp. Post-transplant prophylaxis with voriconazole, rifabutin, azithromycin, and inhaled amikacin prevented recurrence, and the patient remained clinically stable at 6-month follow-up. This case illustrates the complexity of managing overlapping mold and NTM infections in HSCT recipients, highlighting the need for individualized, multidisciplinary care. Therapeutic drug monitoring, careful adjustment for drug–drug interactions, and the use of adjunctive inhaled antifungals were critical to achieving a favorable outcome. Full article

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. Full article

Background: Donor lymphocyte infusion (DLI) is commonly used to prevent or treat leukemic relapse following allogeneic hematopoietic cell transplantation; however, efficacy is limited by immune exhaustion, checkpoint-mediated inhibition, and the risk of graft-versus-host disease (GvHD). Gamma delta (γδ) T-cells represent a promising “off-the-shelf” adoptive cell therapy (ACT) with favorable safety and MHC-independent cytotoxicity, yet their function is similarly constrained by the leukemic tumor microenvironment (TME). Acute exercise mobilizes cytotoxic lymphocyte subsets, and is an emerging strategy to enhance cellular immunotherapies, including DLI and expanded γδ T-cells. This study examined how exercise-mobilized lymphocytes and exercise-expanded γδ T-cells interact with TIGIT blockade to improve anti-leukemic activity. Methods: Healthy participants completed an acute cycling bout, after which peripheral blood mononuclear cells (PBMCs) and ex vivo expanded γδ T-cells were phenotyped and cytotoxicity was determined against leukemia cells with TIGIT checkpoint inhibition. The therapeutic relevance of combining TIGIT blockade with rest- or exercise-expanded γδ T-cells was further evaluated in NSG-IL15 mice challenged with K562-luc leukemia. Results: Acute exercise increased circulating CD8⁺ and γδ T-cells with higher TIGIT and PD-1 expression. Exercise-expanded γδ T-cells maintained increased PD-1 and TIGIT expression and exhibited increased co-expression of DNAM-1 and TIGIT. Exercise mobilized PBMCs and exercise-expanded γδ T-cells demonstrated enhanced cytotoxicity, further amplified by TIGIT blockade. In vivo, TIGIT-treated exercise-expanded γδ T-cells modestly improved tumor suppression and prolonged tumor-free survival compared to untreated controls. Conclusions: Exercise primes DLI and γδ T-cell products for enhanced responsiveness to TIGIT checkpoint inhibition. Targeting TIGIT likely augments DNAM-1 dependent cytotoxicity and improves anti-leukemic activity, supporting the integration of exercise-enhanced DLI and γδ T-cell therapies with immune checkpoint blockade as a safe strategy to improve relapse control in leukemia. Full article

Introduction: Intensive chemotherapy protocols and hematopoietic stem cell transplantation (HSCT) in children with cancer frequently lead to severe complications, such as mucositis and immune dysfunction. A growing body of evidence indicates that these complications are closely associated with the patient’s nutritional status and the composition of the gut microbiome, which becomes profoundly destabilized as a result of cytotoxic therapy and antibiotic use. Background: The aim of this review is to critically evaluate the current state of knowledge on the interplay between gut dysbiosis, metabolomic profiles—with particular emphasis on short-chain fatty acids (SCFAs)—and treatment-related toxicity in pediatric patients, as well as to delineate pathways toward personalized nutritional therapy. Methods: A narrative review was conducted, including clinical and preclinical studies published between January 2015 and October 2025. PubMed/MEDLINE, Embase, Cochrane Library, and other databases were searched, focusing on changes in microbiome composition, correlations between gut-derived metabolites and the severity of complications (sepsis, graft-versus-host disease [GvHD], mucositis), and the effects of targeted nutritional interventions (probiotics, prebiotics, postbiotics, and fecal microbiota transplantation [FMT]) on microbiome modulation during anticancer therapy. Results: The analysis demonstrates that pediatric oncologic treatment leads to a marked reduction in microbial diversity, including the loss of protective Clostridiales taxa (e.g., Faecalibacterium), accompanied by an overgrowth of Proteobacteria pathobionts. Metabolomic profiling indicates that low SCFA levels (e.g., butyrate < 20–50 µmol/g) are a strong predictor of severe mucositis, prolonged neutropenia, and an increased risk of sepsis. Interventions aimed at restoring eubiosis and enhancing SCFA production show potential in strengthening the intestinal barrier, modulating immune responses, and enabling maintenance of the planned relative dose intensity (RDI) of chemotherapy by reducing treatment-related toxicity. Conclusions: Gut microbiome profiling and fecal metabolomics represent promising prognostic tools in pediatric oncology. There is an urgent need for further research employing “omics”-based approaches to develop precise, individually tailored nutritional protocols. Such strategies, including postbiotics and FMT, may minimize treatment-related adverse effects and improve long-term clinical outcomes in pediatric patients. Full article

Introduction: Chronic lymphocytic leukemia (CLL) is a common adult leukemia often treated with fludarabine, cyclophosphamide, and rituximab (FCR). While effective, FCR can lead to therapy-related myeloid neoplasms (t-MN), including aggressive therapy-related acute myeloid leukemia (t-AML). Stem cell transplantation offers the best chance for long-term remission in these cases. Here, we report a rare case of t-AML with plasmacytoid dendritic cells (pDC-AML) developing after FCR treatment for CLL that was successfully treated with haplotransplantation. Case Presentation: A 57-year-old woman with CLL-B was treated with six cycles of FCR, achieving a complete response. Six years later, at age 63, she developed t-AML with a rare morphophenotypic subtype: acute myelomonocytic leukemia with plasmacytoid dendritic cells (pDC-AML) and monosomy 8. Diagnostic challenges included distinguishing this subtype from blastic plasmacytoid dendritic cell neoplasm (BPDCN). She was treated with high-dose cytarabine followed by haploidentical stem cell transplantation from her son. Haploidentical transplantation was prioritized due to the urgent clinical need in a patient with high-risk acute leukemia (therapy-related leukemia secondary to prior chemoimmunotherapy and failure to achieve complete remission following the standard 3 + 7 induction protocol). In this critical setting, the patient’s son was immediately available as an HLA-haploidentical donor. Prior to the performance of the haploidentical stem cell transplant from her son, no HLA-matched unrelated donor (MUD) could be identified. Another viable alternative would have been the utilization of umbilical cord blood-derived stem cells harvested from the patient’s twin granddaughters. She was closely monitored post-transplant for potential complications, including graft-versus-host disease (GVHD), post-transplant lymphoproliferative disorder, and thyroid dysfunction, all of which were ruled out during follow-up. The patient remains in complete remission 15 years after her initial CLL diagnosis and 8 years after the t-AML diagnosis and haplotransplantation. Notably, no residual CLL clone was detected at the time of t-AML development, and a benign polyclonal lymphocytosis observed between 2018 and 2020 spontaneously resolved without intervention. Conclusions: This case illustrates the potential for long-term survival in high-risk patients with therapy-related AML developed after cytotoxic treatment for lymphoid malignancies. Haplotransplantation from a semi-identical Human Leukocyte Antigen (HLA) donor proved to be a viable and effective treatment option despite the patient’s age and dual hematologic malignancies. Full article

Autologous serum (AS) tears are an effective therapeutic option for advanced DED, mimicking the biochemical composition of natural tears. However, the absence of universally accepted guidelines has resulted in variability in AS tear concentration, diluents, processing of collected blood, and storage conditions, raising questions regarding the optimal parameters for AS tear use. This perspective provides a framework to inform clinical implementation and to guide future research on AS tear therapy optimization. PubMed, Scopus, and the Cochrane Library were searched for English-language articles from January 2022 through September 2025 using the terms “autologous serum,” “dry eye disease,” “dry eye syndrome,” “dry eye,” and “DED.” Evidence suggests that AS tears diluted to 20% are widely used for moderate DED, whereas higher concentrations may provide faster, more pronounced and more durable improvements, particularly in severe cases. Levofloxacin-containing eye drops, artificial tears without emphasis on a specific component, sodium hyaluronate (SH)-containing eye drops, cyclosporine A (CsA)-containing ultra-nano emulsions, and methylcellulose have been investigated as alternatives to conventional diluents. Standardization of clotting, centrifugation and storage parameters is expected to enhance efficacy of AS tears and ensure stability of growth factors. Combination with estrogen replacement therapy in perimenopausal women or with topical insulin eye drops, as well as perioperative prophylactic use in patients with graft-versus-host disease (GVHD)-associated dry eye undergoing cataract surgery, represent emerging applications of AS tears that demonstrate potential to improve therapeutic outcomes. Overall, this perspective highlights the need for consensus protocols, supports severity-based concentration tailoring, and notes that diluents and processing methods require further refinement. Full article