Impact of ABO compatibility on outcomes after allogeneic hematopoietic cell transplantation (HCT): increased risk of acute GVHD with ABO bidirectional mismatch, independent of traditional and emerging GVHD prophylaxis strategies.

Cell death pathways in graft-versus-host disease.

Anti-thymocyte globulin (ATG Thymoglobulin®) and anti-T-lymphocyte globulin (ATLG Grafalon®) are commonly used in hematopoietic stem cell transplantation (HSCT) for in vivo T-cell depletion, aiming to reduce graft failure and graft-versus-host disease (GvHD). Despite their widespread use, the precise mechanisms by which ATG/ATLG affect immune recovery post-transplantation remain partially understood. In this study, in 289 pediatric HSCT patients treated with ATG (n=213) or ATLG (n=76), the relationship between longitudinal serum levels of the active T-lymphocyte-binding component of ATG/ATLG and immune reconstitution was evaluated. High levels of active ATG/ATLG did not prevent the recovery of neutrophils or NK-cells; however, T-cell recovery was delayed until active ATG/ATLG concentrations fell below 1AU/mL. This is in apparent contradiction with the fact that ATG/ATLG are known not only to contain antibodies against antigens present on T-cells but also to antigens present on other immune and non-immune cells, including B-, NK-cells, granulocytes, monocytes and hematopoietic stem and progenitor cells (HSPC). To address this, we assessed the binding capacities of ATG and ATLG to immune cell subsets and HSPC both in vitro directly from the vial and in vivo from patients serum samples taken at multiple time points pre- and post-HSCT. Shortly after infusion, we observed a rapid reduction of ATG and ATLG binding to all cell types except for T-cells. This real-life specificity of ATG and ATLG explains their selective impact on T-cell reconstitution. These findings enhance our understanding of the mechanisms of action of ATG and ATLG and may contribute to optimization of these therapies.

Corneal staining: Beyond the grade.

Teenage and young adult (TYA) patients undergoing allogeneic stem cell transplant have distinct psychosocial needs, yet they are poorly represented in research and their outcomes are not well understood. This study uses prospectively collected data from the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT) registry to explore UK transplant practice and outcomes for TYA patients (aged 16-24) in this healthcare setting, alongside children (aged 1-15) and adults (aged 25-39), transplanted for acute leukaemia (including lymphoblastic, acute lymphoblastic leukaemia [ALL], and myeloid, acute myeloid leukaemia [AML]). Nine hundred and forty TYA patients, transplanted between 1999 and 2018, are included, representing 87% of all UK activity during the study period. On adjusted analyses, overall survival after transplant for ALL worsened from children, through TYA, to adults; survival for patients with AML was similar across age groups. Non-relapse mortality was not significantly worse in TYA patients compared with children (p = 0.117 in ALL, p = 0.379 in AML). The risk of chronic graft-versus-host disease (GvHD) was strongly correlated with age, with rates in the TYA group much closer to those seen in adults. While a graft-versus-leukaemia effect may be suppressing relapse, the high rate of GvHD represents an unmet need in this group, who are at a crucial juncture in their personal, educational and social development.

Tacrolimus (TAC) is recognized as a promising therapy for Dry Eye Disease (DED). Recent experimental studies indicate that TAC formulations, such as nanoemulsions and liposomes, notably improve tear production, stabilize the tear film, and reduce corneal damage in animal models. TAC achieves these effects by inhibiting T-cell activation and suppressing the production of inflammatory cytokines, primarily through the NF-κB signaling pathway. Clinical trials report that topical TAC, especially at 0.03% concentration, significantly alleviates both symptoms and signs in patients with Sjögren's syndrome and ocular graft-versushost disease. Critical clinical improvements include higher Schirmer test values, prolonged tear film break-up time, and decreased ocular surface staining. Comparative analyses suggest that TAC is at least as effective as cyclosporine and offers a favorable safety profile. Combining TAC with agents such as sodium hyaluronate may further enhance therapeutic outcomes. Despite the need for further studies to optimize dose and longterm safety, current evidence supports the use of TAC as an effective solution for individuals with refractory or severe DED, providing a vital option where conventional treatments may fail.

Current role of ATG in GVHD prevention: optimizing post-transplantation outcomes through combination with PTCY.

Narrative Review of Preparative Regimens Predictive of Mixed Chimerism After HLA-Mismatched Hematopoietic Stem Cell Transplantation: A Starting Point for Combined Solid Organ and Stem Cell Transplantation.

To improve the tolerability of posttransplant maintenance and outcomes despite poor-risk disease genetics, we conducted a phase 1 study of venetoclax (Ven) with FluBu2 (fludarabine/busulfan) reduced-intensity chemotherapy transplantation using tacrolimus/methotrexate graft-versus-host disease (GVHD) prophylaxis, followed by all-oral Ven/decitabine-cedazuridine (Ven/Dec-c) maintenance in patients with poor-risk MDS/AML (myelodysplastic syndrome/acute myeloid leukemia; N = 30). Overall, 58% had previous Ven exposure and 63% had TP53 mutation; 15/19 had TP53 multihit state. At a median of +55 days, prophylactic maintenance therapy with Ven (400 mg on days 1-14) and Dec-c (35 mg decitabine and 100 mg cedazuridine tablet on days 1, 3, and 5, or days 1, 2, and 3) was initiated for 8 cycles of 42 days each in 26 of 30 patients (87%; of the remaining patients, 3 relapsed early and 1 withdrew). On maintenance, grade 3/4 neutropenia (96%) occurred although infections were rare (n = 2). No dose-limiting toxicities occurred. The 6-month acute GVHD grade 2 to 4 rate was 13%. The 1-year moderate/severe chronic GVHD rate was 31%. At a median follow-up of 25.1 months (range, 15-33), median overall survival (OS) and progression-free survival (PFS) were not reached. On maintenance, 2-year OS was 77%, PFS was 62%, nonrelapse mortality was 0%, and cumulative incidence of relapse was 38%. Exploratory studies identified 96% of patients had pretransplant next-generation sequencing molecular residual disease (MRD) positivity, favorable survival in those with non-TP53 MRD positivity, and delayed conversion on maintenance in 11 of 18 (61%) with TP53-MRD positivity. Patient-reported outcomes assessed in the first 6 months of maintenance were stable except for emotional function, which significantly improved. This trial was registered at www.ClinicalTrials.gov as NCT03613532.

Disease progression, graft-versus-host disease (GVHD), and non-relapse mortality (NRM) are the main causes of failure after allogeneic hematopoietic cell transplantation (SCT) for myeloid neoplasms. T-cell epitope-based models classify HLA-DPB1 mismatches by permissiveness and have been associated with differential risks of GVHD, relapse, and NRM. However, most studies were conducted before the routine use of post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis for unrelated donor (UD) SCT. We retrospectively analyzed 541 adults undergoing 8/8 UD SCT with PTCy prophylaxis, categorized as DP-matched (DP-M, n = 176), permissive mismatch (DP-P, n = 219), non-permissive graft-versus-host (DP-NP-GVH, n = 82), or host-versus-graft (DP-NP-HVG, n = 64). Outcomes were compared across groups with stratification by disease risk and remission/MRD status. Two-year relapse incidence was lower with DP-P versus DP-M (18% vs 28%; HR 0.6, 95% CI 0.4-0.9, p = 0.03), most pronounced in high-risk AML/MDS, where relapse rates approached those of lower-risk disease. This effect persisted after adjustment for remission and MRD status. GVHD incidence was unaffected by DPB1 status. OS and PFS did not differ significantly; age and comorbidity were dominant predictors of NRM. In UD SCT with PTCy, DPB1-permissive mismatching reduces relapse in high-risk AML/MDS without increasing GVHD or NRM, supporting DP-P mismatching as an actionable donor-selection criterion.

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.

This narrative review synthesizes contemporary evidence regarding critical care complications following hematopoietic stem cell transplantation (HSCT) and evaluates management strategies for improving outcomes in this complex population. We conducted a comprehensive literature search of MEDLINE/PubMed databases from January 2014 to December 2024, focusing on critical care complications, prognostic factors, and therapeutic interventions in HSCT recipients. Intensive care unit (ICU) admission affects 8.8%-40% of HSCT recipients, with contemporary 30-day survival reaching 57.7% in specialized centers. Respiratory failure predominates as the primary indication for ICU support. The Lung Injury Prevention Score for Bone Marrow Transplant demonstrates strong predictive accuracy for acute respiratory distress syndrome development. Novel therapeutic approaches show promise, including inhaled tranexamic acid protocols for diffuse alveolar hemorrhage showing promising hemostasis rates in cohort studies, though randomized controlled trial data are lacking. JAK inhibitors achieve improved response rates compared to best available therapy for steroid-refractory graft-versus-host disease (GVHD). The Mount Sinai Acute GVHD International Consortium algorithm provides validated biomarker-based prognostication. Post-transplant cyclophosphamide reduces acute GVHD incidence, while complement inhibition improves outcomes in transplant-associated thrombotic. Early recognition using validated scoring systems and integration of standard ICU protocols with specialized HSCT expertise are essential for optimizing outcomes. Despite advances, significant knowledge gaps remain regarding optimal management strategies for many complications, with most evidence derived from retrospective cohort studies.

Immune-mediated side effects of cancer immunotherapies.

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.

To evaluate the safety, pharmacokinetics, and preliminary clinical activity of UTAA06, an "off-the-shelf" allogeneic B7-H3-targeted chimeric antigen receptor (CAR)-Vδ1T cell therapy, in patients with pretreated, advanced B7-H3-positive solid tumors. In this first-in-human, phase I, dose-escalation study (NCT06372236), ten patients with advanced solid tumors (including gastric, colorectal, hepatocellular, ovarian, and neuroendocrine cancers) were enrolled. Following lymphodepletion chemotherapy (cyclophosphamide and fludarabine), patients received UTAA06 infusion across three dose levels (5×10⁸, 8×10⁸, or 1×10⁹ cells). The primary endpoint was safety. Secondary endpoints included pharmacokinetics and anti-tumor efficacy. UTAA06 demonstrated a manageable safety profile; no graft-versus-host disease (GvHD) was observed, and cytokine release syndrome (CRS) was limited to two transient Grade 1 events. A single dose-limiting toxicity (Grade 3 pneumonitis) was reported in one patient at the 5×10⁸ cells dose level. While UTAA06 demonstrated signals of biological activity, including transient reductions in serum tumor markers in 50% of patients, no objective response by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria was observed. Further analysis identified that the limited CAR-T cell persistence was likely driven by subclinical host-versus-graft rejection (HvGR). This study provides clinical proof-of-concept for allogeneic B7-H3-targeted CAR-Vδ1T cells as a safe platform with low risk of GvHD and demonstrable biological activity in solid tumors. However, clinical efficacy was constrained by limited cellular persistence caused by host immune rejection. Future strategies are required to enhance the durability and therapeutic potential of this allogeneic approach.

Renal dysfunction after allogeneic hematopoietic stem cell transplantation (allo-HSCT) often results from common causes like drug toxicity, infection, or transplant-associated thrombotic microangiopathy (TA-TMA). However, renal graft-versus-host disease (GVHD) may be ignored. We discuss a 49-year-old man who experienced worsening kidney function despite being in hematologic remission and having negative results for infections and autoimmune diseases. A renal biopsy showed chronic tubulointerstitial injury consistent with renal GVHD, along with existing TMA. Treatment with eculizumab did not lead to improvement, likely indicating significant chronic damage. This case highlights the need to maintain clinical suspicion and to perform timely renal biopsies in cases of unexplained kidney dysfunction after transplant.

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.

Graft versus host disease treatment and prevention in older adults: A single-database review.

Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic cell transplantation (HCT), and glucocorticoids remain the standard first-line treatment. However, glucocorticoid responses vary widely and are influenced by genetic polymorphisms in glucocorticoid signaling pathways. Their impact after cord blood transplantation (CBT) is unclear. We retrospectively analyzed adult patients who underwent single-unit CBT at our institution between 2005 and 2023 with available donor or recipient DNA. Genotyping of NR3C1 (rs33388) and GLCCI1 (rs37972, rs37973) was performed using TaqMan® assays. In univariate analyses, donor GLCCI1 rs37973 AG/AA genotypes were associated with a higher incidence of grades II to IV acute GVHD but a lower incidence of chronic GVHD compared with GG donors. Multivariate analysis confirmed that GLCCI1 rs37973 AG/AA donors had a significantly reduced risk of chronic GVHD (hazard ratio 0.57, 95% confidence interval 0.35-0.93, P = 0.025). Among 30 patients who developed grades III to IV acute GVHD treated with glucocorticoids, recipient NR3C1 rs33388 TT genotype was associated with significantly lower overall survival compared with AT/AA (24.4% vs. 63.5% at 5years, P = 0.044). These findings suggest that donor GLCCI1 rs37973 and recipient NR3C1 rs33388 polymorphisms may influence GVHD risk and survival after CBT.

Incidence and Outcomes of Adenovirus Infections after Allogeneic Hematopoietic Cell Transplant with Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis.