β-Thalassaemia is caused by reduced or absent production of β-haemoglobin1-4. Previously, we performed laboratory-scale electroporation of CD34+ haematopoietic stem and progenitor cells from patients with β-thalassaemia using a transformer base editor5,6. The aim was to target the binding motif of the transcription repressor BCL11A in the HBG1 and HBG2 promoters7 to reactivate fetal haemoglobin (HbF) production. Here we present results of a phase 1 clinical trial (ClinicalTrials.gov identifier: NCT06024876) of five patients who received autologous CD34+ cells modified using a transformer base editor at clinical scale (CS-101). With a median follow-up of 23.0 months after CS-101 infusion, the median times to neutrophil and platelet engraftment were 16 days and 25 days, respectively. Moreover, all patients had stopped red blood cell transfusions, with a median time to the last transfusion of 18 days after CS-101 infusion. The mean total haemoglobin and HbF concentrations were 12.4 ± 1.0 and 11.5 ± 0.9 g dl-1, respectively, at month 3 after infusion. These levels remained at similar or higher levels throughout the follow-up period, which indicated rapid haematopoietic reconstitution. The adverse events of CS-101 were generally consistent with those of busulfan myeloablative conditioning and autologous haematopoietic stem and progenitor cell transplantation. No deaths or cancer occurrences were reported. In summary, CS-101 can lead to rapid and sustained increases in both total haemoglobin and HbF levels, which resulted in early and enduring transfusion independence.

BACKGROUND:This cross-sectional study assessed health-related quality of life (HRQOL) outcomes and the factors affecting HRQOL in Chinese patients with β-thalassemia major (β-TM) receiving transfusion and iron chelation therapy. RESEARCH DESIGN AND METHODS:The Pediatric Quality of Life Inventory (PedsQL)4.0 Generic Core Scales were administered to 198 patients and 431 heathy controls aged 4-18 years old. The relationship of sociodemographic and clinical factors with HRQOLscores were analyzed using association and linear regression analyses. RESULTS:Compared with healthy peers, patients exhibited significantly lower PedsQL scores across all domains (p < 0.001). Patients with Body Mass Index (BMI) below the 50th percentile (the median BMI for Chinese children and adolescents) exhibited poorer HRQOL scores than those with BMI ator above this threshold in physical functioning (p = 0.034). Iron chelation therapy and pre-transfusion hemoglobin levels exceeding 7.5 g/dL emerged as significant positive predictors of total summary score, while the presence of two comorbidities was identified as significant negative predictors (p = 0.037, p < 0.001 and p = 0.001, respectively). CONCLUSIONS:Standardized treatment involving blood transfusion and iron chelation therapy in β-TM patients requires further enhancement. Additionally, improving nutritional status and preventing and treating comorbidities may benefit patients' HRQOL.

Chronic anemia and systemic iron overload in thalassemia major (TM) patients may result in neurological deficits, although researchers have not completely elucidated their specific impacts on the brain. This study employed a multimodal research methodology to investigate the characteristics and intrinsic connections of cerebral iron deposition, cerebral dysfunction, and cognitive impairment in TM patients, providing theoretical support for brain monitoring and neuroprotective interventions in this condition. We prospectively enrolled 88 patients with TM, including 46 transfusion-dependent thalassemia (TDT) and 42 non-transfusion-dependent thalassemia (NTDT) patients, alongside 79 healthy controls (HCs), between September 2022 and September 2025. All participants underwent quantitative susceptibility mapping (QSM), resting-state functional MRI (rs-fMRI), and assessments using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA). Serum biomarkers including S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE) were quantified. A parallel murine model of iron overload was created for validation purposes. QSM revealed localised iron deposition in the red nucleus, substantia nigra, subthalamic nucleus, and globus pallidus of patients with TM (F = 3.294–13.305, P = 0.001–0.040). The susceptibility values in these basal ganglia regions demonstrated a negative link with cognitive scores (r = − 0.27 to − 0.43, P < 0.05), suggesting that localised iron buildup correlates with cognitive decline.Rs-fMRI revealed significant irregularities in spontaneous brain activity across the frontal lobe-limbic system-cerebellar network, which correlated with deficits in attention, memory, and language functions as assessed by the cognitive evaluation scale. A murine iron overload model further demonstrated that cerebral iron deposition originates in the choroid plexus.Serum S100B and NSE concentrations increased progressively from HCs to NTDT and TDT groups (P < 0.05), reflecting gradual loss of astrocytic and neuronal integrity driven by worsening systemic iron overload. TM patients, especially those with TDT, exhibit measurable cognitive impairment and cerebral functional remodeling, which are tightly associated with regional brain iron deposition. This study’s findings establish a theoretical foundation for the early detection of thalassemia-associated neurological problems and the formulation of focused therapeutic strategies.

β-Hemoglobinopathies are monogenic disorders. We previously applied a transformer base editor (tBE) to reactivate fetal hemoglobin (HbF) expression, and five Chinese transfusion-dependent β-thalassemia (TDT) patients achieved transfusion independence. However, the applicability of tBE to sickle cell disease (SCD) and genetically different TDT populations remained unknown. Here, we show a four-patient descriptive report from three trials, including one African SCD patient and three TDT patients carrying mutations common in South and Southeast Asia. All patients achieve hematopoietic recovery, and red blood cell transfusions are discontinued in all cases. After more than 12 months of follow-up, all patients show durable editing, sustained high-level pan-cellular HbF expression, and transfusion independence. No vaso-occlusive episodes occur in the SCD patient. No off-target mutations, malignancies, or deaths are observed. These initial results support the feasibility of applying tBE to treat SCD and the reported TDT genotypes, warranting broader evaluation across diverse populations. ClinicalTrials.gov identifiers are as follows: NCT06328764, NCT06065189, and NCT06565026.

BackgroundThalassemia is a common disease worldwide. Oxidative stress contributes to ineffective erythropoiesis and hemolysis in β-thalassemia major (β-TM). Increasing cellular adenosine triphosphate (ATP) production by activating the activity of the pyruvate kinase (PK) may counteract oxidative stress. SNH-119014 is a novel allosteric PK activator targeting the same protein as mitapivat (AG-348), a first-in-class agent known to ameliorate anemia in thalassemia. This study aim to evluate the effects of SNH-119014 in erythroid cells from β-TM patients.MethodsPK activity was measured in recombinant human PKLR isoforms incubated with a range of concentrations of SNH-119014. Peripheral blood samples were obtained from 30 β-TM patients and 30 healthy controls (HCs), and the isolated red blood cells (RBCs) were assessed for ATP content and analyzed by metabolomics. Bone marrow samples were collected from 14 β-TM patients and four healthy volunteers, and CD34+ hematopoietic stem and progenitor cells (HSPCs) were isolated. HSPCs were differentiated into erythroid precursors. Erythroid precursors were treated with 5 μM SNH-119014, 5 µM AG-348, or vehicle, followed by assessment of ATP content, reactive oxygen species (ROS) levels, the reduced/oxidized glutathione ratio, and metabolomic profiling.ResultsSNH-119014 activated PK with an AC50 of 28.90 nM and was characterized by a higher maximal efficacy (Emax = 949.9%) compared to AG-348 (AC50 = 13.71 nM; Emax = 749.4%). Consistently, in RBCs from β-TM patients, SNH-119014 increased ATP by a mean of 129% compared to 131% for AG-348 (p = 0.0928). Based on metabolomics, KEGG pathway analysis revealed that glycolysis/gluconeogenesis and the pentose phosphate pathway were among the top ten most significantly enriched pathways for both SNH-119014 and AG-348. Considering ineffective erythropoiesis is a important factor contributor to thalassemia pathology, we further investigated the effects of SNH-119014 in erythroid precursors. SNH-119014 increased ATP levels, reduced ROS, and improved the GSH/GSSG ratio in erythroid precursors.ConclusionIn conclusion, SNH-119014 activates PK, thereby increasing ATP production and alleviating oxidative stress in erythroid cells from β-TM patients. SNH-119014 exhibits a promising pharmacological profile, supporting its further development as a potential therapy for thalassemia.

Allogeneic stem cell transplantation (allo-HSCT) has recently been approved as standard therapy for transfusion-dependent thalassemia (TDT) but remains limited to the use of HLA-matched sibling donors (MSDs), due to a lack of large-scale prospective studies evaluating the use of grafts from alternative donors. Here, we report the results of a non-randomised, interventional, phase 4 clinical trial evaluating allo-HSCT from alternative donors for the treatment of TDT. A total of 823 patients with TDT were transplanted with grafts from MSDs (n = 331) or alternative donors, including matched unrelated donors (MUDs; n = 352) and haploidentical related donors (Haplos; n = 140). Conditioning was with busulfan, cyclophosphamide, fludarabine and anti-thymocyte globulin. Graft-versus-host disease (GvHD) prophylaxis was cyclosporine, methotrexate (MTX) and mycophenolate mofetil (MMF) for recipients of MSDs and tacrolimus, MTX, MMF for others. The primary endpoints were 2-year overall survival (OS) and event-free survival (EFS). Two-year OS for MSDs, MUDs, Haplos was 97.2% (95% CI, 95.4-99.0), 93.1% (90.5-95.9) and 95.4% (91.9-99.1); EFS was 97.2% (95.4-99.0), 92.9% (90.1-95.7) and 94.7% (90.9-98.6); GvHD-free, relapse-free survival (GRFS) was 91.4% (88.4-94.6), 77.0% (72.6-82.7) and 75.6% (68.5-83.4) respectively. Two-year OS and EFS for MUDs were lower than those for MSDs (both P < 0.05) and were not significantly different with those for Haplos (both P > 0.05). Transplant-related mortality was 4.4% (3.0-5.9) and graft failure rate was 0.5%. The incidence of grades 2-4 acute GvHD and moderate-severe chronic GvHD from alternative donors were higher than those from MSDs (28.9% [24.7-33.2] vs 7.5% [4.9-10.7], P < 0.001; 12.3% [9.2-15.7] vs 5.0% [2.9-7.9], P < 0.01). In summary, these findings may help expand the donor pool for patients with TDT lacking MSDs (ClinicalTrials.gov: NCT04009525).

Abstract Hematopoietic stem cell transplantation (HSCT) is the only definitive cure for transfusion-dependent α-thalassemia, though comprehensive studies on its effectiveness are limited. In this retrospective study, we analyzed the clinical characteristics of 21 pediatric patients with transfusion-dependent α-thalassemia who underwent HSCT, all of whom received a standardized conditioning regimen consisting of busulfan, cyclophosphamide, fludarabine, and anti-thymocyte globulin. After a median follow-up of 25 months (range: 7–92 months), the two-year overall survival (OS) and event-free survival (EFS) rates were both 90.2% (95% CI: 66.2–97.4%), and the two-year graft-versus-host disease-free, relapse-free survival (GRFS) rate was 82.3% (95% CI: 52.6–94.3%). The transplant-related mortality rate at two years was 5.0% (95% CI: 0.7–30.0%), with no cases of graft failure observed. Among the 19 surviving patients, hemoglobin levels significantly increased compared to pre-transplant levels (p < 0.05), and all became transfusion-independent. Hematopoietic stem cell transplantation is a curative treatment for α-thalassemia. For patients with transfusion-dependent α-thalassemia, HSCT should be performed as early as possible at an experienced transplant center when a suitable donor is available.

Background: In transfusion-dependent thalassaemia (TDT), transplantation success is determined not only by engraftment but by freedom from graft-versus-host disease (GVHD). The increasing use of unrelated and haploidentical donors has expanded access to cure but has also increased the risk of acute GVHD, for which optimal prophylaxis in non-malignant transplantation remains uncertain. We evaluated whether scheduled administration of an anti-CD25 monoclonal antibody could reduce acute GVHD after alternative-donor haematopoietic stem cell transplantation. Methods: We performed a retrospective cohort study of children with TDT undergoing alternative-donor transplantation at the First Affiliated Hospital of Guangxi Medical University (Jan 1, 2020–Dec 31, 2024). All patients received tacrolimus, methotrexate, and mycophenolate mofetil prophylaxis, with or without a humanised anti-CD25 monoclonal antibody given at 1 mg/kg on days +7, +14, +28, and +42. The primary endpoint was grade III–IV acute GVHD by day 100. Secondary endpoints included GVHD-free survival and post-transplant complications. Findings: Among 229 recipients (114 anti-CD25; 115 controls; median follow-up 41 months), severe acute GVHD by day 100 occurred in 7·0% of patients receiving anti-CD25 prophylaxis compared with 21·7% of controls, and grade II–IV acute GVHD in 22·8% versus 39·1%. Two-year GVHD-free survival was higher with anti-CD25 prophylaxis (84·2% vs 70·4%). No graft failure occurred, and bacterial or fungal infections were not increased. Viral DNAemia was less frequent in the anti-CD25 cohort. Interpretation: In children with TDT undergoing alternative-donor transplantation, scheduled anti-CD25 prophylaxis was associated with reduced severe acute GVHD and improved GVHD-free survival without excess toxicity. These findings support early GVHD prevention as a key strategy in non-malignant transplantation and warrant prospective evaluation.

Background:Anti-thymocyte globulin (ATG) is used as prophylaxis for graft-versus-host disease (GvHD) and graft failure (GF) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with transfusion-dependent thalassemia (TDT). However, the optimal dose of ATG remains unknown. Objectives:To compare the 3-year overall survival (OS) of 8 mg/kg and 10 mg/kg ATG in allo-HSCT for patients with TDT. Methods:We compared two different doses of ATG for patients with TDT undergoing allo-HSCT from HLA-matched sibling donors (MSDs). Between 2015 and 2023, 147 patients were randomized to the 8 mg/kg ATG group and 148 patients to the 10 mg/kg ATG group. Primary endpoints were 3-year OS and thalassemia-free survival (TFS). Survival analysis for OS and TFS was performed using the Kaplan-Meier method. Results:The 8 and 10 mg/kg ATG groups had similar 3-year OS and TFS (both 98.6% (95% confidence interval [CI]: 96.8-100) vs 95.3% (95% CI: 91.9-98.7), p = 0.066). There were no significant differences in graft-versus-host disease and GF between groups. In the subgroup with co-transplantation of cord blood (CB) and bone marrow (BM) as stem cell sources, the 8 mg/kg ATG group had higher 3-year OS and TFS than the 10 mg/kg ATG group (both 100% (95% CI: not applicable) vs 86.5% (95% CI: 75.5-98.2), p = 0.012). Conclusion:This study provides evidence that an 8 mg/kg ATG is an effective treatment for TDT transplanted from MSDs. A notable finding was the superior survival associated with the 8 mg/kg ATG in the CB and BM co-transplantation. These results provide critical evidence for guiding ATG dosing strategies in allo-HSCT for TDT, particularly in the context of stem cell source selection. Design:Open-label, randomized clinical trial. Trial registration:ChiCTR-IPR-15005779 (Chinese Clinical Trial Registry; https://www.chictr.org.cn/showproj.html?proj=10208; date of registration: December 29, 2014).

We report the results of an open-label, single-centre phase 4 clinical trial evaluating haploidentical haematopoietic stem cell transplantation (Haplo-HSCT) in patients with transfusion-dependent thalassaemia (TDT). A total of 134 patients with TDT were enrolled; the median age was 8.7 years (interquartile range [IQR], 6.0-11.7 years; range, 3-20 years). All patients received a uniform conditioning regimen consisting of busulfan, cyclophosphamide, fludarabine and anti-thymocyte globulin (ATG). Graft-versus-host disease (GVHD) prophylaxis included methotrexate (MTX), mycophenolate mofetil (MMF) and tacrolimus. The primary end-point was 2-year overall survival (OS). Median follow-up is 23.4 months (IQR: 11.5-38.7; range: 6.1-81.5). The 2-year OS, event-free survival (EFS) and graft-versus-host disease-free, relapse-free survival (GRFS) rates were 93.4%, 92.6% and 77.5% respectively. The cumulative incidence rates of aGVHD, grade 2-4 aGVHD and grade 3-4 aGVHD were 47.8%, 30.9% and 12.5% respectively. Donor-specific antibodies (DSAs) and male-recipient/female-donor pairing were associated with inferior OS (p = 0.021; p = 0.010) and EFS (p = 0.040; p = 0.020). Hepatomegaly (≥5 cm) was associated with inferior OS (p = 0.037). Collectively, these findings support Haplo-HSCT as a key curative option for TDT patients in the absence of fully matched donors.

Background: Hemorrhagic cystitis (HC) is a frequent and debilitating complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with thalassemia major (TM), with limited tools available for early identification. This study aimed to identify clinical risk factors for HC and construct a predictive model using both conventional and machine learning (ML) approaches. Methods: We retrospectively analyzed TM patients who underwent allo-HSCT at the First Affiliated Hospital of Guangxi Medical University from Oct 2020 to Apr 2023. Risk factors were screened using least absolute shrinkage and selection operator (LASSO) regression and univariate area under the curve (AUC) analysis, with variables intersected via Venn diagram. Logistic regression was used to construct a clinical nomogram incorporating the selected predictors. Model performance was evaluated through discrimination (AUC, C-index), calibration, and decision curve analysis in both training and testing cohorts. Additional machine learning models—including random forest, decision tree, support vector machine (SVM), neural network, XGBoost, and LightGBM—were developed to validate the nomogram's predictive value. Results: A total of 222 patients (mean age 8.5 years, range 2–19; 60.4% male) were included, with 72 (32.4%) developing HC at a median onset of 27 days post-transplant. Five predictors were identified: age, serum ferritin, acute graft-versus-host disease (aGVHD), sepsis, and tacrolimus exposure. The nomogram yielded an AUC of 0.690 (95% CI: 0.595–0.785) in the training set, with a C-index of 0.690 and internal validation C-index of 0.647. Calibration curves showed good agreement between predicted and observed risks, and decision curve analysis demonstrated favorable clinical utility. In the testing set, AUC was 0.672 (95% CI: 0.531–0.812) with a consistent C-index. Among all ML models tested, logistic regression remained the most robust, with superior interpretability and performance. Conclusion: This study identified key clinical risk factors for HC after allo-HSCT in TM patients and developed a machine learning–enhanced prediction tool. The nomogram model demonstrated stable performance and clinical utility, offering a potential strategy for early identification and intervention in high-risk patients.

Introduction Pulmonary complications frequently occur as comorbidities in individuals with transfusion-dependent thalassaemia (TDT). Despite their clinical significance, the existing literature lacks a systematic review and meta-analysis examining the prevalence and risk factors for pulmonary dysfunction in this patient cohort. Therefore, we propose to conduct a systematic review and meta-analysis to report the prevalence and associated risk factors of pulmonary dysfunction in TDT patients.Methods and analysis This systematic review and meta-analysis will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. We will search PubMed, EMBASE, the Cochrane Library, Scopus and Web of Science to identify English-language literature from the inception of each database up to 31 May 2024. We will include studies that involve TDT patients and report on the method of pulmonary function assessment, the proportion of pulmonary dysfunction and the analysis of risk factors for pulmonary dysfunction. The study designs included will be cohort, case-control and cross-sectional studies. Exclusions will apply to studies on non-TDT or patients with other diseases, reviews, case reports and animal experiments, as well as duplicated published studies, studies without full-text availability or studies from which raw data cannot be extracted. The screening process, including title, abstract and full texts, will be conducted independently by two reviewers. Data extraction will be performed following standardised protocols. The quality of the included studies will be assessed using the Newcastle-Ottawa Scale and the Agency for Healthcare Research and Quality criteria. The meta-analysis will be conducted using Stata 14.0 and Review Manager (RevMan) 5.4 software, incorporating subgroup analyses, heterogeneity assessments and publication bias evaluations to ensure the robustness and reliability of the findings.Ethics and dissemination As the data for this systematic review and meta-analysis are sourced exclusively from previously published literature, there is no requirement for ethical approval. The dissemination of the results will occur through publication in a peer-reviewed scholarly journal and presentations at relevant scientific conferences.PROSPERO registration number CRD42024504353.

BACKGROUND:Graft-versus-host disease (GvHD) remains a major barrier to long-term survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although calcineurin inhibitors (CNIs) are the cornerstone of GvHD prophylaxis, some patients cannot tolerate them, creating a critical need for alternative strategies. OBJECTIVE:To evaluate the efficacy and safety of sirolimus plus low-exposure CNIs as an alternative GvHD prophylaxis in CNI-intolerant recipients undergoing allo-HSCT. METHODS:We retrospectively analyzed 16 allo-HSCT recipients who received alternative GvHD prophylaxis due to CNI intolerance, evaluating GvHD incidence, survival and relapse outcomes, infectious complications, and immune reconstitution. RESULTS:The median time to regimen initiation was 27.5 days (range, -2 to 114 days), and the median treatment duration was 53 days (range, 14-319 days). Only one patient (6.3%) experienced grade 2 acute GvHD, and none developed grade 3-4 acute GvHD. No cases of chronic GvHD were observed in the 15 evaluable patients. Over a median follow-up of 271 days (range, 58-505 days), one non-relapse mortality and three relapses (18.7%) occurred, with no relapse-related deaths. The alternative regimen was well-tolerated with manageable infections and, importantly, did not impair early T, B, or NK cell reconstitution. CONCLUSION:For allo-HSCT recipients with CNI intolerance, this study provides the first evaluation of sirolimus combined with low-exposure CNIs as a GvHD prophylaxis. Our findings suggest this regimen is a promising and feasible alternative, although validation in larger, prospective studies is warranted.

Ex vivo autologous haematopoietic stem cell (HSC) gene therapy provides a promising treatment option for haematological disorders. However, current methods involve complex processes and chemotherapeutic conditioning, leading to limited accessibility for treatment and major side effects. Here we develop antibody-free targeted lipid nanoparticles (LNPs) for mRNA delivery to HSCs in vivo, enabling efficient base editing of the γ-globin gene (HBG1/2) promoter target in human HSCs to reactivate fetal haemoglobin in derived erythroid cells. Delivery of ABE8e/sgRNA mRNA with optimized LNPs achieves efficient in vivo base editing of HBG1/2 in transfusion-dependent β-thalassaemia (TDT) patient-derived HSCs engrafted in immunodeficient NCG-X mice, showing restored globin chain balance in erythroid cells. Our research indicates that using LNPs for genome editor delivery achieves efficient editing of endogenous genes of human HSCs. This non-viral delivery system eliminates the need for collecting or mobilizing HSCs, providing a potent and one-time treatment potential for blood disorders such as sickle cell disease and TDT. A lipid nanoparticle is used to deliver a base editor in vivo to haematopoietic stem cells in mice.

Introduction: Graft-versus-host disease (GvHD) remains a major obstacle to long-term survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Calcineurin inhibitors (CNIs) are the standard for GvHD prophylaxis, but intolerance due to comorbidities necessitates alternative approaches. Methods: This retrospective study included 16 patients with hematologic disorders who were intolerant to standard-dose CNIs and received sirolimus plus low-exposure CNIs between Dec 2023 and Feb 2025. We assessed GvHD incidence, infection rates, survival outcomes, relapse, and immune reconstitution. Results: The cohort (10 males, 6 females) had a median age of 22.5 years (range 5–60). The regimen was initiated a median of 27.5 days post-transplant (range –2 to 114) and continued for a median of 53 days. Five patients (31.2%) received sirolimus and low-dose CNI alone, 10 (62.5%) received additional mycophenolate mofetil (MMF), and 1 patient received MMF plus anti-CD25 antibody. Only one patient (6.3%) developed grade II aGvHD; no grade III–IV aGvHD or chronic GvHD was observed. After a median follow-up of 271 days (range 58–505), there was one non-relapse death and three relapses (18.7%) without relapse-related mortality. The regimen was well-tolerated, with CMV and EBV viremia observed in 2 (12.5%) and 1 (6.3%) patient(s), respectively. Immune reconstitution analyses revealed preserved T, B, and NK cell recovery during early post-transplant period. Conclution: This study presents the first clinical evidence supporting sirolimus plus low-exposure CNIs as a feasible and safe GvHD prophylaxis in CNI-intolerant allo-HSCT recipients. The regimen showed promising efficacy with low toxicity and preserved immune reconstitution. Larger prospective studies are warranted to validate these findings.

Introduction：Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment for transfusion-dependent alpha-thalassemia (TDT-α), yet data on clinical indications and long-term outcomes in pediatric patients remain limited. This study aimed to describe the clinical features and transplant outcomes of TDT-α children receiving HSCT. Methods：We retrospectively analyzed pediatric TDT-α patients who underwent HSCT between 2016 and 2025 at the First Affiliated Hospital of Guangxi Medical University. All patients received a standardized myeloablative conditioning regimen (GX-07-TM: busulfan, cyclophosphamide, fludarabine, ATG). GVHD prophylaxis was stratified by donor type. Key outcomes included 2-year overall survival (OS), thalassemia-free survival (TFS), and graft-versus-host disease and relapse-free survival (GRFS). Results：A total of 21 children (median age 8 years; 57.1% female) were included. Most patients (95.2%) had hemoglobin H (HbH) disease, with 81.0% carrying non-deletional α-thalassemia mutations. Common pretransplant complications included splenomegaly (90.5%), extramedullary hematopoiesis (90.5%), and growth delays (71.4%). The median age at first transfusion was 8 months. Alternative donors were used in 57.1% of cases. After a median follow-up of 25 months, the 2-year OS and TFS were both 90.2% (95% CI: 66.2–97.4%), and the GRFS was 82.3% (95% CI: 52.6–94.3%). The transplant-related mortality was 5.0%; no graft failures were observed. Conclusion: This study characterizes the clinical features and transplant outcomes of TDT-α pediatric patients undergoing HSCT. The presence of early severe manifestations —such as non-deletional genotypes, transfusion dependency, growth restriction, and extramedullary hematopoiesis— may support early HSCT consideration. HSCT provides excellent long-term outcomes and should be considered a frontline curative option in this population.

Background:Patients with transfusion-dependent beta-thalassemia (TDT) frequently experience osteoporosis, and low bone mass (LBM) is particularly common. However, there is no accurate predictive model for LBM risk in the pediatric and adolescent TDT cohort. This study aimed to create a predictive model to assess LBM risk in this specific population. Methods:Retrospective demographic and laboratory data of pediatric TDT patients were analyzed. The dataset was divided into training and test sets at an 8:2 ratio. Independent predictors of LBM were identified through logistic regression analysis and subsequently incorporated into six machine learning models to develop risk prediction models. Cross-validation was employed to evaluate the models' generalizability, while the test set was used to assess the effectiveness of the final optimal model. The predictive performance of the models was evaluated using receiver operating characteristic curves, calibration curves, and decision curve analysis. Results:A total of 389 TDT patients were analyzed, and age, insulin-like growth factor 1 (IGF-1) below -2 standard deviation (-2SD), and hypogonadism were identified as predictors of LBM. The Gaussian Naive Bayes (NB) model was optimal, showing areas under the curve (AUCs) of 0.732, 0.734, and 0.730 in training, validation, and test sets, respectively. An online tool was developed to calculate the precise probability of LBM in this population. Conclusions:We develop and validate a risk prediction model for LBM in pediatric and adolescent TDT patients, which facilitates the efficient identification of high-risk individuals in clinical practice and enables early intervention to prevent disease progression.