Adverse Social Determinants Independently Predict Outcomes After Allogeneic HSCT.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative therapy for many patients with high-risk myeloid neoplasms, yet relapse and transplant-related toxicity continue to limit durable benefit. Venetoclax (VEN), a selective BCL-2 inhibitor, provides a biologically compelling strategy for conditioning augmentation through chemotherapy sensitization and potential lowering of host immune resistance to engraftment. We performed a hybrid scoping review and evidence-mapping analysis to summarize published clinical experience and the active investigational landscape of VEN-containing conditioning or sequential regimens prior to allo-HSCT. Eighteen studies (20 reports) met the inclusion criteria, including nine published cohorts comprising 238 patients and 11 ongoing clinical trials. Reported platforms were heterogeneous, spanning reduced-intensity, myeloablative, and sequential approaches. Engraftment and graft-versus-host disease outcomes were generally comparable to expected benchmarks, although available data remain preliminary and non-randomized, underscoring that the primary aim of this scoping review is to map existing evidence and ongoing trials rather than to inform clinical practice or guideline recommendations.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for hematological malignancies. However, it is often complicated by chronic graft-versus-host disease (cGVHD), a leading cause of late non-relapse morbidity and mortality. Early identification of patients at risk is therefore critical, yet reliable biomarkers are still lacking. In this study, we evaluated serum endothelial mediator profiles collected 1 year after allo-HSCT and their association with subsequent cGVHD development. Serum samples taken 1 year post-transplant from 82 transplanted patients, of whom 61% developed cGVHD, were analyzed for 19 mediators using Luminex and ELISA assays. Associations between mediator levels and cGVHD were assessed using statistical analysis, logistic regression, and hierarchical clustering. Six mediators, endocan, EMMPRIN, VCAM-1, MMP-1, MMP-8, and MMP-9; differed significantly between patients with and without cGVHD (P < 0.05). Endocan and VCAM-1 remained independently associated with cGVHD in multivariable regression adjusted for age, body mass index (BMI), and prior acute GVHD (aGVHD). Cluster analysis based on these mediators identified distinct patient subgroups. Clusters with generally lower mediator levels had fewer cases of cGVHD, whereas a central cluster with elevated levels showed a higher disease prevalence. Integration of clinical variables confirmed known risk factors, including older age, higher BMI, and previous aGVHD. The identified mediators are biologically linked to endothelial activation and extracellular matrix remodeling. This study is the first to demonstrate that a distinct endothelial- and matrix-remodeling-related serum mediator signature measured 1 year after allo-HSCT is associated with cGVHD. The identified patient clusters provide insight into disease biology and highlight potential biological markers of the disease. These findings support further prospective studies combining longitudinal mediator profiling with clinical data and advanced modeling to improve risk stratification and identify therapeutic targets for the prevention and treatment of cGVHD.

Prospective evaluation of patient reported outcome measures (PROMs) and correlation with clinical parameters of chronic ocular graft-versus-host disease (GVHD).

Chimeric antigen receptor (CAR) T cell therapy is now widely used for the treatment of various haematological malignancies, with emerging applications in solid tumours and autoimmune diseases. Alongside its demonstrated clinical activity, this therapeutic modality has a toxicity profile that differs from those associated with traditional cytotoxic therapies, other immunotherapies, and even other cell therapy approaches such as allogeneic haematopoietic stem cell transplantation. One increasingly recognized yet poorly understood complication is the development of post-CAR T cell therapy lymphoproliferative and lymphomatous disorders, which have a clinical and biological spectrum that remains incompletely characterized. These rare events include both CAR-transgene-positive and transgene-negative lymphomas with variable and sometimes overlapping clinical features. Causal attribution is difficult, given that these proliferations often emerge in the context of clonal haematopoiesis, inflammatory or infectious triggers, immune suppression and/or viral reactivation. In this Review, we synthesize the growing body of evidence on post-CAR T cell therapy lymphoproliferative disorders, drawing on the limited but increasing number of well-characterized cases. We outline the spectrum of lymphoproliferations described so far, highlight recurrent pathological and molecular features, and discuss factors that might promote clonal expansion or transformation, including pre-existing clonal haematopoiesis, dysregulated signalling pathways, inflammatory stimuli and, rarely, CAR-transgene vector integration. A clearer framework for these disorders might improve early recognition, guide diagnostic evaluation, support treatment decision-making, facilitate classification and consensus-building efforts, and inform future mechanistic studies and pharmacovigilance efforts.

Introduction:GATA binding protein 2 (GATA2) deficiency is an autosomal dominant disorder characterized by immunodeficiency, progressive cytopenias, and an increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Novel variants continue to broaden the clinical and genetic spectrum of this condition.Case Presentation:An 11-year-old girl presented with recalcitrant cutaneous warts, recurrent infections, and multilineage cytopenias. Her father had longstanding leukopenia and MDS that progressed to AML. Laboratory evaluation revealed monocytopenia, B- and Natural killer-cell lymphopenia, and dysplastic bone marrow findings. Genetic analysis identified a previously unreported heterozygous splice-site variant in GATA2 (c.1017 + 1 G > A), confirmed in stored DNA from her deceased father. Despite supportive care and allogeneic hematopoietic stem cell transplantation from a matched unrelated donor, she developed severe graft-versus-host disease and died from transplant-related complications.Conclusion:This report identifies a previously unreported GATA2 splice-site variant with clinical and familial evidence supporting pathogenicity, contributing to the expanding mutational spectrum and enhancing understanding of genotype-phenotype correlations in GATA2 deficiency.

Extracorporeal photopheresis preserves fertility in a GVHD mouse model by remodeling the testicular immune microenvironment.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for paroxysmal nocturnal hemoglobinuria (PNH). Post-transplant cyclophosphamide (PTCy) has improved HSCT safety in other diseases, but its use in PNH is poorly characterized. In this retrospective study, we analyzed outcomes of 19 patients with large PNH clones (≥ 50%) undergoing HSCT (2016-2025). Seven patients received a PTCy-based platform (fludarabine-busulfan-cyclophosphamide conditioning with PTCy-based graft-versus-host disease [GvHD] prophylaxis), whereas 12 received conventional prophylaxis. Patients' median age was 32 years; 68% had PNH with bone marrow failure. After a median follow-up of 1349 days, overall and event-free survival rates were 100% and 94.4%, respectively. All patients engrafted rapidly with full donor chimerism. No cases of chronic or grades II-IV acute GvHD occurred in the PTCy group (0/7); however, chronic GvHD and grades II-IV acute GvHD occurred in 15.8% and 10.5% of patients in the conventional group, respectively. No transplant-related mortality or thrombotic events occurred. This study, representing the largest reported experience with PTCy-based HSCT for PNH, suggests that this platform is feasible and associated with excellent survival and a promising GvHD profile. These preliminary findings support further investigation of PTCy in transplant strategies for PNH.

Survival benefit of allogeneic HSCT in CMML patients during the molecular stratification era.

Immunocompromised children with hematologic malignancies or undergoing allogeneic haematopoietic stem cell transplantation (HSCT) are at high risk for invasive fungal diseases (IFDs). Reported incidence varies considerably due to heterogeneous diagnostic criteria, antifungal strategies and environmental conditions. Environmental preventive measures, although highly relevant, remain underrecognised determinants of IFD incidence. This retrospective, single-centre trial included paediatric cancer or transplant patients at high risk for IFD treated before (Cohort 1) and after (Cohort 2) relocation of a paediatric cancer centre from a 1990s building to a state-of-the-art facility with improved environmental protection standards (observation periods: 56 and 12 months, respectively). Antifungal prophylaxis continuously followed local standards. IFD was diagnosed according to 2019 EORTC/MSGERC criteria. Primary endpoint was IFD incidence; secondary endpoints included prophylaxis use, IFD management and mortality. This study included 186 patients (Cohort 1: n = 140; Cohort 2: n = 46). Baseline characteristics were comparable between both cohorts. Adherence to prophylaxis standards exceeded 98%, with liposomal amphotericin B being the most common agent. In Cohort 1, 25 possible, probable, or proven IFD occurred, mainly pulmonary aspergillosis, whereas no cases were observed following implementation of environmental measures in Cohort 2 (17.9% vs. 0%, p = 0.002). Most IFD cases occurred in HSCT recipients. IFD was associated with increased mortality (p < 0.0001). In this contemporary paediatric cancer and transplant setting, environmental protective measures were associated with a marked reduction in IFD incidence, complementing consistent pharmacologic prophylaxis. These findings underscore environmental protection as essential for IFD prevention in high-risk paediatric populations.

β-thalassemia is a common inherited hemoglobin disorder caused by reduced or absent β-globin production, leading to ineffective erythropoiesis, chronic anemia, and, in severe cases, lifelong transfusion dependence. Although allogeneic hematopoietic stem cell transplantation can be curative, its use is limited by donor availability and transplant-related complications. In recent years, gene therapy has emerged as a promising alternative and has rapidly changed the treatment landscape for β-thalassemia. In this review, we summarize both established and emerging gene-based strategies, including lentiviral gene addition to restore HBB expression and gene editing approaches aimed at reactivating fetal hemoglobin. We discuss key targets such as the erythroid-specific BCL11A enhancer, repressor-binding sites in the HBG promoters, and other regulatory elements involved in globin switching. We also highlight the growing potential of newer technologies such as base editing and prime editing, which may offer greater precision and reduce the risks associated with double-strand DNA breaks. Finally, we address the major challenges that still need to be resolved, including safety, durability, technical complexity, and access to treatment. Overall, gene therapy is moving β-thalassemia closer to a broadly applicable curative approach.

The optimal strategy to prevent and treat invasive fungal infections (IFIs) in children receiving allogeneic haematopoietic stem cell transplantation (HSCT) is not well established. A paediatric bone marrow transplant (BMT) working group set up UK national guidelines for the management of IFI and conducted a prospective study to assess the impact of these on incidence and outcomes. From March 2017 to December 2021, 358 children who received HSCT were prospectively included. Most children (82%) received either itraconazole (41%) or liposomal amphotericin B (41%) prophylaxis with a median duration of 170 days (interquartile range [IQR] 101-279). Cumulative incidence of possible/probable/proven IFI at 1 year was 17.6%, with no significant differences in children receiving itraconazole or liposomal amphotericin B (15.7% vs. 15.9%, 0.997). In multivariate analysis models (Fine-Gray hazard ratio) underlying malignant disease and low azoles therapeutic drug monitoring levels were independently associated with development of IFI. Children with probable/proven IFI had a higher 1-year transplant-related mortality (22% vs. 5.7%, Gray's test, p < 0.001). By adopting standardized anti-fungal prophylaxis, the incidence of proven/probable IFI in a large cohort of transplanted children was 5% and these showed significant decreased survival, warranting tailored prophylactic strategies in high-risk patients.

Aplastic anemia is a rare hematologic disorder characterized by bone marrow hypoplasia and peripheral pancytopenia. While most pediatric cases are acquired, inherited bone marrow failure syndromes (IBMFS) are important differential diagnoses. ERCC6L2-associated IBMFS is a newly recognized and rare condition with significant implications for diagnosis and long-term care in hematology. A case report of a 3-year-old Ethiopian girl presenting with dry cough, low-grade fever, poor appetite, and spontaneous gum bleeding. Examination revealed microcephaly, café-au-lait spots, and dysmorphic facial features. Laboratory evaluation revealed pancytopenia. Bone marrow biopsy revealed hypocellularity without blasts. Whole-exome sequencing revealed compound heterozygous variants in the ERCC6L2 gene, confirming a diagnosis of ERCC6L2-related IBMFS. The patient is currently scheduled for allogeneic hematopoietic stem cell transplantation. This case report highlights the importance of considering rare genetic causes, such as ERCC6L2 mutations, in pediatric aplastic anemia patients with dysmorphic features. Early diagnosis through genetic testing allows for definitive management and surveillance of hematologic malignancies.

Post-transplant cyclophosphamide (PTCy) is increasingly used for graft-versus-host disease (GVHD) prophylaxis, but long-term outcomes remain incompletely defined. We analyzed 874 relapse-free survivors at 2 years from 2,046 patients who underwent allogeneic hematopoietic stem-cell transplantation (HSCT) for hematologic malignancies between 2010 and 2022. GVHD prophylaxis included PTCy plus rabbit antithymocyte globulin (ATG) and a calcineurin inhibitor (CnI; Group I, n = 429) or alternative regimens (Group II, n = 445). With an overall follow-up of 5,275 person-years after HSCT, overall survival (OS) 3 years after the landmark was 88.7% (95% CI, 86 to 91). Patients receiving ATG-PTCy-CnI had improved outcomes compared with those receiving alternative regimens, with OS of 93.2% versus 85.0% (P < .001), and lower nonrelapse mortality (NRM; 3.4% v 10.8%; P < .001). On multivariable analysis, ATG-PTCy-CnI was independently associated with improved OS (hazard ratio [HR], 0.41; 95% CI, 0.21 to 0.79; P = .007) and lower NRM (HR, 0.34; 95% CI, 0.17 to 0.74; P = .006). Chronic GVHD remained the leading cause of late mortality; deaths from GVHD, infections, treatment-related toxicity, and second primary malignancies were all reduced with ATG-PTCy-CnI. The cumulative incidence of relapse was similar between groups. Standardized mortality ratios were 1.32 for ATG-PTCy-CnI and 2.06 for other regimens, corresponding to a 1.6-fold higher excess mortality with alternative prophylaxis (P = .036). Among patients alive and relapse-free at least 2 years after HSCT, long-term outcomes were excellent. The use of ATG-PTCy-CnI prophylaxis was associated with further improvements in survival through reductions in GVHD-related mortality and late complications.

Transplantation-related complications remain a major clinical challenge in patients with acute leukemia, and evidence regarding high-dose oral magnesium supplementation in this setting is limited. This study investigated the effects of oral magnesium citrate on inflammatory responses and clinical outcomes, including graft-versus-host disease (GVHD), following allogeneic hematopoietic stem cell transplantation (allo-HSCT). This randomized, double-blind, placebo-controlled clinical trial was conducted at Taleghani Hospital, Tehran, Iran, and included 45 patients aged 18-60 years undergoing bone marrow transplantation. Participants, all of whom received a standard neutropenic diet, were randomly assigned to receive a neutropenic diet with magnesium supplementation (n = 23) or placebo (n = 22). The intervention group received 420mg/day of magnesium citrate or placebo for three weeks, with follow-up at day 100. Assessments included 24-hour dietary recalls, questionnaires, clinical evaluations, and laboratory measurements of inflammatory markers, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). The incidence of GVHD increased non-significantly in both groups during the 3-week intervention period but declined during follow-up, with a significantly greater reduction observed in the magnesium group by day 100. Fever incidence decreased in both groups at week 3, with a significantly larger reduction in the magnesium group 56.5% compared with placebo, 22.7%. ESR increased in both groups during the intervention period, with a greater rise observed in the placebo group, which was significant only in the crude model; however, by day 100, ESR had significantly decreased by 15% in the magnesium group and significantly increased by 13% in the placebo group across all models. TNF-α and IL-6 levels decreased in the magnesium group but increased in the placebo group at week 3, although these changes were not statistically significant over time in all models. Magnesium supplementation in allo-HSCT patients receiving a neutropenic diet may have a potential benefit, being associated with reductions in some clinical and inflammatory outcomes, including a lower incidence of GVHD and fever and reduced ESR. However, these findings were not consistent across all inflammatory markers and require confirmation in larger studies with longer intervention durations.Trial registration Iranian Registry of Clinical Trials. IRCT20240812062726N1. URL of trial registry record https//irct.behdasht.gov.ir/trial/78,589, Registration date 17 September 2024.

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative option for secondary acute myeloid leukemia (sAML). Post-transplant cyclophosphamide has improved graft-versus-host disease (GVHD) prophylaxis, enabling the broader use of alternative donors. For patients lacking a human leukocyte antigen (HLA)-matched donor, haploidentical donor (Haplo) or 9/10 HLA mismatched unrelated donor (MMUD) HSCTs are widely used, yet their relative effectiveness in sAML is uncertain. We retrospectively compared outcomes after Haplo versus MMUD HSCT in adults with sAML in first complete remission transplanted between 2010 and 2022. Among 711 patients, 602 received Haplo and 109 MMUD grafts. Patient and transplant characteristics differed between cohorts, including donor age, conditioning intensity, graft source, and transplant year. Neutrophil recovery was faster after MMUD transplantation, while platelet recovery was comparable. Rates of acute and chronic GVHD, relapse incidence, non-relapse mortality, overall survival, leukemia-free survival, and GVHD-free/relapse-free survival were similar. Reduced intensity conditioning lowered acute GVHD risk, while peripheral blood grafts increased chronic GVHD. Lower Karnofsky score, older age and adverse-risk cytogenetics were adverse prognostic factors. Haplo and MMUD transplantation demonstrated comparable efficacy and safety with post-transplant cyclophosphamide, supporting both approaches as viable alternatives in the absence of an HLA-matched donor.

Evidences supporting the use of myeloablative-dose Treosulfan combined with Fludarabine remain largely retrospective, with outdated prospective studies available. In this phase II multicenter prospective trial, we evaluated the safety and efficacy of FT14 conditioning regimen in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation in first complete remission.(EudraCT Number:2021-006515-28; Clinical trial number NCT07232953). The study was designed to provide a non-inferior alternative to standard busulfan-containing regimens, which would enable effective transplantation while minimizing toxicity. The primary objective was 1-year Leukemia-free survival (LFS). In total, 82 patients were enrolled in the study with a median follow up of 19.7 months; donor used were matched sibling in 22, matched unrelated 52 and mismatched unrelated in 8 cases, respectively. LFS at 180-day and 365-day were 87.8% and 81.7%, respectively. Cumulative incidence of relapse at 1 year after allo-HSCT was 14.9% with mean time to relapse of 5.6 months. Also, FT14 regimen provided an excellent safety with nearly absent NRM, no cases of septic death, and no cases of primary graft failure. Our study supports the use of FT14 as effective myeloablative conditioning regimen for AML patients aged 40-65 y in first complete remission, especially in patients for whom busulfan based conditioning regimens poses excessive toxic risks.

Single-Cell Analysis of Adaptive NK and CMV-Specific T Cell Dynamics after Allogeneic HSCT.

Meibomian gland dysfunction (MGD) can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). MGD is characterized by reduced lipid secretion by the meibomian glands, causing tear-film instability. Because chemotherapy and radiation can induce oxidative stress, we hypothesize that these exposures will increase the hazard of MGD after allo-HSCT. This retrospective cohort study analyzed 139 allo-HSCT recipients at the University of Maryland Medical Center who completed post-transplant eye examinations from 2013 to 2025. Descriptive analysis summarized demographic characteristics in our sample. Unadjusted and adjusted Cox proportional hazard models were used to evaluate the independent effects of conditioning regimens on MGD. Unadjusted Cox proportional hazards models showed that fludarabine was associated with a higher MGD hazard compared with nonfludarabine based regimens (HR = 3.671, 95% CI, 1.338-10.070; P = 0.012). After adjusting for age at transplant, sex, race, transplant type, cancer type, and presence of pretransplant ocular conditions, fludarabine-based conditioning remained associated with a higher hazard of MGD (HR = 5.242, 95% CI, 1.725-15.928; P = 0.003). These findings suggest that fludarabine-based conditioning increases the hazard of developing MGD post-transplant. Alternatives to fludarabine in conditioning regimens are warranted to reduce the likelihood of MGD. Allo-HSCT patients who receive fludarabine may also benefit from education, monitoring, and interventions aimed at mitigating MGD severity.

Gastrointestinal graft-versus-host disease (GI-GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT), often requiring invasive endoscopy for diagnosis. Fecal calprotectin (FC) offers a non-invasive marker of intestinal inflammation, but its utility in GI-GVHD needs clarification. In this prospective observational study of 165 adult allo-HSCT recipients, FC was measured on days +7, +14, and +21 post-transplant, at GI-GVHD onset, and 7 days post-treatment, alongside clinical, endoscopic, and histological data. GI-GVHD developed in 52.7% of patients, with histological confirmation in 90.3% of cases. FC lacked predictive value on day +7 (AUC = 0.50) but showed moderate-to-high accuracy on days +14 (AUC = 0.69) and +21 (AUC = 0.77), with an optimal day +21 cutoff of 52.5 µg/g (sensitivity 75%, specificity 87%). At diagnosis, median FC was 120 µg/g, correlating with endoscopic severity (r = 0.31; p = 0.02) but not clinical or histological grades. FC declined significantly post-treatment (120 to 51.5 µg/g; p = 0.04), though concurrent infections elevated levels without compromising discriminative ability. FC serves as a dynamic biomarker for predicting, diagnosing, and monitoring GI-GVHD, but requires integrated clinical interpretation due to limited specificity amid other inflammations.