bims-conane 2025-04-20 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2025–04–20
eleven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Genetic landscape and hematological profiling of thalassemia in patients from the Malwa region, Central India.
Patterns of hemolysis, erythropoiesis, and iron distribution define unique disease trajectories in three mouse models of genetic anemia.
Assessment of ferritin and hepcidin levels in splenectomised and non-splenectomised β-thalassemia major patients and exploring a potential correlation with von Willebrand factor and ADAMTS-13.
The evolving landscape of hereditary stomatocytosis.
COVID- 19 in patients affected by red blood cell disorders, results from the European registry ERN-EuroBloodNet.
Case report: neonatal cyanosis secondary to congenital methemoglobinemia, a cause to consider in newborn cyanosis.
A genome-wide screen identifies genes required for erythroid differentiation.
Evaluated NSUN3 in reticulocytes from HbH-CS disease that reflects cellular stress in erythroblasts.
Clinically approved small-molecule drugs for anemia therapy.
RNA Editors Sculpt the Transcriptome During Terminal Erythropoiesis.
Outcome of Haematopoietic Stem Cell Transplant in Beta-Thalassaemia Major: Single Centre Experience from a Low- and Middle-Income Country.

Mol Genet Genomics. 2025 Apr 12. 300(1): 42

Genetic landscape and hematological profiling of thalassemia in patients from the Malwa region, Central India.

Susmit Kosta, Shweta Bhandari, Roshni Sahu, Pallavi Joshi, Vinod Bhandari.

  Thalassemia is a significant health issue in the Malwa region of Central India, contributing to a substantial burden of inherited hemoglobin disorders. Understanding the genetic mutations and their clinical impact is crucial for effective management. To analyze the genetic mutations in thalassemia patients from the Malwa region and correlate them with hematological parameters and clinical severity. Ninety-two patients with clinically diagnosed thalassemia underwent hemoglobin electrophoresis and whole exome sequencing (WES) for genetic analysis. Blood tests, including complete blood count (CBC) and iron studies, were conducted. Statistical analyses were applied to identify genotype-phenotype correlations. WES identified mutations in 91 patients, with Codon 26 (G→A) and IVS-I-5 (G→C) being the most common mutations, affecting 32.6% and 23.9% of the cohort, respectively. Novel mutations were detected in 9 patients (9.7%). Frameshift mutations, particularly at codons 41/42, were associated with more severe anemia (mean hemoglobin 6.9 g/dL) and higher transfusion dependency (85%). Patients with high serum ferritin levels (mean 280 ± 90 ng/mL) exhibited significant iron overload, correlating with increased splenomegaly (p < 0.01). A strong genotype-phenotype correlation was established, with statistical significance observed between mutation types and clinical outcomes (p < 0.01). Our study highlights the genetic and clinical heterogeneity of β-thalassemia in the Malwa region, emphasizing the need for population-based screening and region-specific genetic counselling strategies. The identification of novel mutations, there in-silico pathogenicity predictions, and comparisons with mutation databases further strengthen the claim of novelty and clinical relevance. WES remains a critical tool for improving early diagnosis, risk assessment, and personalized treatment approaches for thalassemia patients.

Keywords:  Genetic mutations; Genotype-phenotype correlation; Hemoglobin electrophoresis; Malwa region; Thalassemia; Whole exome sequencing

DOI:  https://doi.org/10.1007/s00438-025-02245-7
Exp Hematol. 2025 Apr 15. pii: S0301-472X(25)00078-5. [Epub ahead of print] 104787

Patterns of hemolysis, erythropoiesis, and iron distribution define unique disease trajectories in three mouse models of genetic anemia.

Irina L Dubach, Raphael M Buzzi, Dominik J Schaer, Florence Vallelian.

Hemolytic anemias involve premature red blood cell (RBC) destruction and present complex phenotypes, including disturbances in iron metabolism, extramedullary erythropoiesis, and systemic organ involvement. To guide the selection of appropriate murine models for studying pathophysiology and pharmacological treatments of human hemolytic disorders, we systematically characterized three genetic mouse models commonly used to investigate such conditions: sickle cell disease (SCD), beta-thalassemia (THAL), and hereditary spherocytosis (SPH). We sought to clarify how these models differ in the severity and nature of hemolysis, the balance between erythropoietic responses and iron regulation, and the long-term patterns of iron distribution. Our findings reveal that SPH mice exhibit severe intravascular hemolysis and suppressed hepcidin levels, leading to unopposed intestinal iron absorption and extensive tissue iron loading, especially in the liver. In contrast, SCD and THAL mice display predominantly extravascular hemolysis, moderate anemia, relatively stable hepcidin levels, and balanced erythropoiesis with partially regulated iron overload. Single-cell RNA sequencing of spleens highlighted distinct erythropoietic progenitor distributions, while iron isotope tracing experiments confirmed divergent RBC turnover kinetics and tissue distribution. This study defines distinct disease trajectories for common hemolytic disease models by providing a unique comparative framework. Our work will support more informed model selection and refined experimental design to investigate hemolytic anemia pathobiology and therapeutics. TEASER ABSTRACT: We compared three genetic mouse models - sickle cell disease, beta-thalassemia, and hereditary spherocytosis - to reveal distinct disease mechanisms in hemolytic anemia. Our findings show that hereditary spherocytosis induces severe intravascular hemolysis and iron overload, while sickle cell and beta-thalassemia models exhibit extravascular hemolysis with more regulated iron distribution. This study offers critical insights into model selection for hemolytic anemia research and provides a framework for studying pathophysiology and treatments.

DOI: https://doi.org/10.1016/j.exphem.2025.104787
Ann Hematol. 2025 Apr 15.

Assessment of ferritin and hepcidin levels in splenectomised and non-splenectomised β-thalassemia major patients and exploring a potential correlation with von Willebrand factor and ADAMTS-13.

Anwar Al-Awadhi, Materah Salem Alwehaidah, Kefayah Al-Sabaan, Nouf Al-Ajmi.

  Iron overload is a major complication in β-thalassemia major (β-TM) patients, resulting from ineffective erythropoiesis, increased gastrointestinal iron absorption and multiple blood transfusions. Excess iron accumulates in various organs, leading to organ dysfunction, and increased risk of thrombotic events. In this study we aim to determine levels of ferritin and its regulation hormone hepcidin in multi-transfused splenectomised and non-splenectomised β-thalassemia major patients and assess a possible correlation with the coagulation protein von Willebrand factor (vWF) and its cleaving protease ADAMTS-13. The study was conducted on 80 β-thalassemia major patients and 80 age- and sex-matched healthy controls. Plasma levels of vWF, ADAMTS-13, and hepcidin were assessed using the ELISA method. All patients presented with significantly higher levels of ferritin compared to normal controls (p < 0.001), while hepcidin levels were barely higher in patients (p = 0.05). Ferritin had a positive correlation with vWF antigen levels (r = 0.222, p = 0.05), ADAMTS-13 antigen levels (r = 0.334, p = 0.002) and ADAMTS-13 activity levels (r = 0.353, p = 0.001) in patients. Splenectomised patients had significantly higher levels of white blood cell counts, platelet counts and vWF antigen levels compared to non-splenectomised patients (p < 0.05), but ferritin and hepcidin levels were comparable between the two groups (p > 0.05). Hepcidin was not found to be correlated with any of the measured parameters in patients (p > 0.05). Iron overload is well manifested in our study group despite continuous chelation therapy. Unlike hepcidin, ferritin appeared to be associated with increased secretion of vWF and ADAMTS-13 in patients, while splenectomy had no effect on ferritin or hepcidin levels. These findings highlight the importance of proper iron monitoring in β-TM and recognition of thrombotic risks in managing this anemia.

Keywords:  Hepcidin; Hypercoagulability; Iron overload; Splenectomy; Thalassemia

DOI:  https://doi.org/10.1007/s00277-025-06360-8
Blood. 2025 Apr 15. pii: blood.2024024294. [Epub ahead of print]

The evolving landscape of hereditary stomatocytosis.

Immacolata Andolfo, Achille Iolascon, Roberta Russo.

Hereditary stomatocytosis represents a heterogeneous group of inherited erythrocyte membrane defects characterized by hemolytic anemia of variable degree, with alterations in cellular salt and water, ranging from dehydration to overhydration, and the presence of stomatocytes on peripheral blood smear. This condition encompasses various subtypes, each with distinct clinical and genetic features. The pathophysiology underlying these conditions involves altered red blood cell membrane properties, leading to impaired deformability, alterations in cation permeability and volume, causing increased susceptibility to hemolysis. Advancements in genetic testing have enabled the identification of some causative genes in the last years, such as PIEZO1, KCNN4, and ABCB6. These genetic discoveries have facilitated a deeper understanding of the molecular mechanisms underlying the pathogenesis and have paved the way for improved diagnostic accuracy and genetic counseling. This review provides an overview of the clinical presentation, pathophysiology, molecular genetics, diagnosis, and management strategies of hereditary stomatocytosis, highlighting recent advancements in the field of dehydrated hereditary stomatocytosis, or hereditary xerocytosis, and hepatic iron overload. This latter is directly associated with the physiological role of PIEZO1, the causative gene of DHS, at hepatic and macrophagic levels. Particularly, gain-of-function mutations in PIEZO1 account for a pleiotropic syndrome characterized by different phenotypes depending on the expression of PIEZO1 at multiple cells and tissues.

DOI: https://doi.org/10.1182/blood.2024024294
Orphanet J Rare Dis. 2025 Apr 16. 20(1): 183

COVID- 19 in patients affected by red blood cell disorders, results from the European registry ERN-EuroBloodNet.

Pablo Velasco Puyo, Soteroula Christou, Saveria Campisi, Maria A Rodríguez-Sánchez, Sara Reidel, Santiago Perez-Hoyo, Miriam Mota, Irene Savvidou, Anna Rekleiti, Alessandra Salvo, Vincenzo Voi, Giovanni Battista Ferrero, Giorgia Mandrile, Carmen Maria Gaglioti, Elena Cela, Beatriz Ponce-Salas, Eduardo J Bardón-Cancho, Pagona Flevari, Ersi Voskaridou-Dimoula, Erfan Nur, Bart J Biemond, Polynexi Delaporta, David Beneitez-Pastor, Anna Collado Gimbert, Anna Spasiano, Tatiana Besse-Hammer, Ioannis G Lafiatis, Laurence Dedeken, Simona Raso, Anna Ruiz-Llobet, Sabrina Bagnato, Veerle Labarque, Andreas Glenthøj, Giovan Battista Ruffo, Maria Elena Guerzoni, Kaoutar Hafraoui, Laura Pistoia, Rosamaria Rosso, Laura Tagliaferri, Paula Gonzalez-Urdiales, Fleur Samantha Benghiat, Mariane de Montalembert, Maria Jose Teles, Anna Vanderfaeillie, Elisa Bertoni, Daniela Cuzzubbo, Teresa Ferreira, Christopher J Saunders, Eftichia Stiakaki, Ann L Van de Velde, Michael D Diamantidis, Jean-Louis H Kerkhoffs, Marisa I Oliveira, Alessandra Quota, Roberta Russo, An Van Damme, María Argüello Marina, Mikael Lorite Reggiori, Anita W Rijneveld, Alexis Rodríguez Gallego, Raffaella Colombatti, Achille Iolascon, Ali Taher, Béatrice Gulbis, Noémi B A Roy, María Del Mar Mañú-Pereira.

   BACKGROUND: Despite several publications covering patients from multiple centers, no international registry covered all patients with red blood cell diseases (RBCD) affected by COVID- 19. The ERN-EuroBloodNet's registry provided real-time registration of SARS-CoV- 2 patients with RBCD, promoting timely disease-specific knowledge sharing during the pandemic's early stages.
PROCEDURES: The study evaluated patient distribution, the infection across different RBCDs, and severity risk factors across similar healthcare systems, using data collected from the ERN-EuroBloodNet's REDCap platform.
RESULTS: From April 2020 to April 2023, 681 infections were recorded among 663 patients, of which 373 had transfusion-dependent thalassemia or non-transfusion-dependent thalassemia (TDT/NTDT), and 269 had sickle cell disease (SCD). SCD patients had a higher incidence of COVID- 19 than those with TDT/NTDT (10.5 vs. 4.8 COVID/100 patients). Notably, 92% of the cases were mild, with neither age nor the specific RBCD affecting severity. The number of comorbidities, notably obesity and hypertension, that patients had prior to infection was associated with more severe COVID- 19. During the infection, the presence of vaso-occlusive crises, acute chest syndrome, kidney failure, and ground-glass opacities on chest tomography scans were associated with a more severe clinical picture. The vaccination rate (32%) mirrored that of the general population and showed a protective effect against severe COVID- 19. The observed mortality rate was 0.7%, aligning with Europe's general population.
CONCLUSION: SARS-CoV- 2 infection in SCD and TDT/NTDT patients is mild and without higher mortality than the general population. The ERN-Eurobloodnet's registry collaborative structure exemplifies the power of international cooperation in tackling rare diseases, especially during health emergencies.

Keywords:  COVID- 19; Europe; Red blood cell disorders; Sickle cell disease; Thalassemia

DOI:  https://doi.org/10.1186/s13023-025-03683-7
Transl Pediatr. 2025 Mar 31. 14(3): 500-506

Case report: neonatal cyanosis secondary to congenital methemoglobinemia, a cause to consider in newborn cyanosis.

Anabel Carmona-Nunez, Rosa Adan Pedroso, Javier Arzuaga Mendez, Piedad Alba Pavón, María Cruz López Herrera, Andrea Miguélez Velasco, Sara Ansó Olivan, Itziar Astigarraga Aguirre.

   Background: Congenital methemoglobinemia (metHb), a rare cause of neonatal cyanosis, results from the oxidation of ferrous to ferric iron in hemoglobin (Hb). The aim of this case report is to highlight the need to broaden the differential diagnosis of neonatal cyanosis and emphasizes the role of capillary blood gas analysis and genetic testing to exclude hereditary hematological causes. We report a previously unreported genetic mutation associated with congenital metHb.
Case Description: We report the case of a term male neonate with cyanosis unresponsive to oxygen administration. Complementary studies were normal, including echocardiography, cerebral ultrasound, blood tests, blood culture, cytomegalovirus testing, glucose-6-phosphate dehydrogenase (G6PD) assessment, and Hb electrophoresis, with the exception of a mild left anterior pneumothorax. There was a discrepancy between arterial oxygen pressure (PaO2) and oxygen saturation by pulse oximetry. Ultimately, co-oximetry revealed a metHb level of 20%, confirming the diagnosis of metHb. Next generation sequencing (NGS) identified a compound heterozygous missense mutation in the cytochrome B5 reductase (CYB5R3) gene: c673C>T (p.Arg225Cys) and c977A>G (p.His326Arg), both considered pathogenic/probably pathogenic. While the first mutation is documented, the second is not previously reported as a cause of congenital metHb. This compound heterozygous genotype in the CYB5R3 gene may explain the phenotype observed in this patient with congenital metHb. Erythrocyte enzyme testing confirmed reduced CYB5R3 activity. Family genetic studies confirmed the patient's compound heterozygosity, with one mutation inherited from each parent and genetic counseling was offered. The patient has progressed favorably, achieving appropriate psychomotor development without neurological disorders. There has been a decrease in perioral cyanosis, with metHb levels dropping to 3%. Oxygen saturation reached normal levels (96%) by 2 years of age.
Conclusions: MetHb is a rare cause of cyanosis in children. The acquired form is the most common, due to exposure to oxidizing substances that increase metHb production. Congenital forms, however, are more frequent in neonates, and their evolution depends on specific mutations. Genetic testing is crucial for family counseling. Clinicians should suspect metHb in cases of cyanosis and hypoxia without respiratory distress, especially when there is no improvement with oxygen therapy and normal PaO2, after excluding other more common causes such as respiratory, infectious and cardiological conditions.

Keywords:  Case report; congenital hereditary methemoglobinemia (congenital hereditary metHb); cyanosis; cytochrome B5 reductase (CYB5R3); neonatal

DOI:  https://doi.org/10.21037/tp-2024-553
Nat Commun. 2025 Apr 12. 16(1): 3488

A genome-wide screen identifies genes required for erythroid differentiation.

Greggory Myers, Ann Friedman, Lei Yu, Narges Pourmandi, Claire Kerpet, Masaki A Ito, Rilie Saba, Vi Tang, Ayse Bilge Ozel, Ingrid L Bergin, Craig N Johnson, Chia-Jui Ku, Yu Wang, Ginette Balbin-Cuesta, Kim-Chew Lim, Zesen Lin, Claire Drysdale, Beth McGee, Ryo Kurita, Yukio Nakamura, Xiaofang Liu, David Siemieniak, Sharon A Singh, Costas A Lyssiotis, Ivan Maillard, Lois S Weisman, James Douglas Engel, Rami Khoriaty.

The complete array of genes required for terminal erythroid differentiation remains unknown. To address this knowledge gap, we perform a genome-scale CRISPR knock-out screen in the human erythroid progenitor cell line HUDEP-2 and validate candidate regulators of erythroid differentiation in a custom secondary screen. Comparison of sgRNA abundance in the CRISPR library, proerythroblasts, and orthochromatic erythroblasts, resulted in the identification of genes that are essential for proerythroblast survival and genes that are required for terminal erythroid differentiation. Among the top genes identified are known regulators of erythropoiesis, underscoring the validity of this screen. Notably, using a Log2 fold change of <-1 and false discovery rate of <0.01, the screen identified 277 genes that are required for terminal erythroid differentiation, including multiple genes not previously nominated through GWAS. NHLRC2, which was previously implicated in hemolytic anemia, was a highly ranked gene. We suggest that anemia due to NHLRC2 mutation results at least in part from a defect in erythroid differentiation. Another highly ranked gene in the screen is VAC14, which we validated for its requirement in erythropoiesis in vitro and in vivo. Thus, data from this CRISPR screen may help classify the underlying mechanisms that contribute to erythroid disorders.

DOI: https://doi.org/10.1038/s41467-025-58739-w
Ann Hematol. 2025 Apr 17.

Evaluated NSUN3 in reticulocytes from HbH-CS disease that reflects cellular stress in erythroblasts.

Haodong Liu, Chunting Peng, Qisheng Su, Shijie Liang, Yuling Qiu, Wuning Mo, Zheng Yang.

  Hemoglobin H Disease-Constant Spring (HbH-CS) represents a severe variant of α-thalassemia characterized by a fundamental pathological mechanism involving inadequate synthesis of α-globin chains. This deficiency results in the formation of unstable Hemoglobin H (HbH) due to the aggregation of free β-globin chains, which subsequently induces an imbalance in oxidative stress within erythrocytes. This imbalance leads to an abnormal accumulation of reactive oxygen species (ROS), which in turn promotes lipid peroxidation, culminating in the production of malondialdehyde (MDA) and a significant depletion of glutathione (GSH). Concurrently, Nrf2 is translocated to the nucleus, where it activates the antioxidant response element (ARE) to mitigate cellular stress. Here, we report that NSUN3 (which, together with ALKBH1, maintains mitochondrial function through m5C→f5C modification) is abnormally overexpressed in reticulocytes from patients with HbH-CS, and an in vitro cellular model of NSUN3 overexpression/silencing was constructed using K562 cells, which have the potential for erythroid lineage differentiation and retain an intact cluster of bead protein genes. Functional assays indicated that the overexpression of NSUN3 significantly intensified the accumulation of intracellular ROS and MDA, led to a reduction in GSH levels, and diminished the overall cellular antioxidant capacity (T-AOC). This may be due to ROS accumulation resulting from inhibition of mitochondrial respiratory chain complex I, II, and IV synthesis through aberrant m5C→f5C modification. In addition, NSUN3 overexpression further exacerbates oxidative stress by inhibiting the phosphorylation of Nrf2 hindering its translocation into the nucleus and weakening the cellular antioxidant system. Moreover, we also observed that NSUN3 overexpression exacerbated intracellular DNA damage and inhibited cellular value-added activity, and silencing NSUN3 showed the opposite result. Our research offers initial insights into the molecular mechanisms through which NSUN3 modulates oxidative stress in erythrocytes via its role in epigenetic modifications. These findings contribute to a deeper understanding of the clinical management of patients with Hb H-CS.

Keywords:  Hemoglobin H-constant spring disease; NRF2; NSUN3; Oxidative stress

DOI:  https://doi.org/10.1007/s00277-025-06359-1
Eur J Med Chem. 2025 Apr 14. pii: S0223-5234(25)00388-5. [Epub ahead of print]291 117623

Clinically approved small-molecule drugs for anemia therapy.

Yang Wang, Wancheng Zhao, Shenshen Yao, Sha Ni, Chong Feng, Dan Wang.

  Anemia, a common blood disorder characterized by reduced red blood cell or hemoglobin levels, affects a significant portion of the global population. Traditional treatments, including dietary supplements and blood transfusions, often fail to address the underlying causes of anemia, particularly in chronic or genetic forms. This review highlights representative small-molecule drugs approved for anemia treatment, focusing on their synthetic routes and clinical applications. The synthetic routes of these drugs, often involving advanced organic chemistry techniques are crucial for optimizing production efficiency and scalability. Clinically, these small-molecule drugs have shown broad-spectrum therapeutic potential, with applications extending to various forms of anemia. This review underscores the importance of understanding the synthetic pathways of these drugs, which not only facilitates industrial-scale production but also paves the way for the development of next-generation therapies. Future research is expected to further optimize these small-molecule drugs, potentially leading to more effective and accessible treatments for anemia.

Keywords:  Anemia; Clinical applications; Small-molecule drugs; Synthesis

DOI:  https://doi.org/10.1016/j.ejmech.2025.117623
bioRxiv. 2025 Apr 05. pii: 2025.04.03.647020. [Epub ahead of print]

RNA Editors Sculpt the Transcriptome During Terminal Erythropoiesis.

Areum Han, Alena Yermalovich, Mohamad Ali T Najia, Daniel S Pearson, Yuko Fujiwara, Michael Bolgov, Caroline Kubaczka, Trista E North, Vanessa Lundin, Stuart Orkin, George Q Daley.

Selective RNA degradation during terminal erythropoiesis results in a globin-rich transcriptome in mature erythrocytes, but the specific RNA decay pathways remain unknown. We found that deficiency of the terminal uridylyl transferase enzyme Zcchc6 and the 3'-5' exoribonuclease Dis3l2 in mouse models led to fetal and perinatal reticulocytosis, an accumulation of RNA-rich precursors of terminal erythroid cells, suggesting their crucial roles in terminal red cell differentiation. Notably, knockout embryos exhibited persistent high-level expression of Hbb-bh1 globin, the ortholog of human fetal γ- globin. Perturbation of the Zcchc6-Dis3l2 pathway in mice engineered to express the human β-globin locus likewise increased γ -globin levels in fetal erythroid cells, suggesting that globin switching entails post-transcriptional mechanisms of mRNA destabilization in addition to transcriptional down-regulation. We cultured human hematopoietic stem and progenitor cells (HSPCs), performed CRISPR/Cas9-mediated knockout of ZCCHC6 and DIS3L2, and observed accumulation of RNA and elevated γ-globin levels in terminal erythroid cells. Our findings reveal a conserved role for the ZCCHC6/DIS3L2 RNA editors in terminal erythropoiesis and demonstrate a post-transcriptional mechanism for γ- globin gene switching, advancing research into in vitro erythrocyte generation and γ- globin stabilization to ameliorate hemoglobinopathies.

DOI: https://doi.org/10.1101/2025.04.03.647020
J Coll Physicians Surg Pak. 2025 Apr;35(4): 513-518

Outcome of Haematopoietic Stem Cell Transplant in Beta-Thalassaemia Major: Single Centre Experience from a Low- and Middle-Income Country.

Hashim Khan, Tariq Ghafoor, Nighat Shahbaz, Tariq Azam Khattak, Uzma Rahim, Munazza Nabi Awan.

OBJECTIVE: To determine the outcome of haematopoietic stem transplant (HSCT) in beta-thalassaemia major (BTM) patients.
STUDY DESIGN: Descriptive Study. Place and Duration of the Study: Department of Clinical Haematology, Armed Forces Bone Marrow Transplant Centre (AFBMTC), Rawalpindi, Pakistan, from April 2018 to December 2023.
METHODOLOGY: All cases of BTM undergoing HLA-matched allogeneic HSCT after myeloablative conditioning were included. Cases undergoing second HSCT and HSCT with treosulfan-based conditioning were excluded. Age, gender, complications, mortality, and associated factors were evaluated.
RESULTS: This study analysed the data of 118 cases of BTM including 71 (60.2%) males undergoing HSCT after myeloablative conditioning during the study period. The mean age at the time of HSCT was 85.7 ± 33.6 months. Eighty-one (68.6%) cases were in Pesaro Class III. Neutropenic fever was the most common complication documented in 117 (99.2%) cases. Mortality at day-100 was 14 (11.9%). Overall treatment-related mortality (TRM) was 23 (19.4%). In univariate analysis, factors having a statistically significant association with TRM were graft failure (p = 0.001), Pesaro class (p = 0.03), severity of acute graft versus host disease (aGVHD) (p = 0.02), and veno-occlusive disease (VOD) (p = 0.02). The median follow-up time was 26.87 ± 16.60 months with overall survival (OS) and disease free survival (DFS) rates of 80.5% and 78.0%, respectively.
CONCLUSION: The OS of around 80% is promising which can be further improved with better transfusion services, regular iron chelation, and HSCT at a younger age.
KEY WORDS: Haematopoietic stem cell transplant, Beta-thalassaemia major, Pakistan.

DOI: https://doi.org/10.29271/jcpsp.2025.04.513