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Background β-thalassemia major (BTM) constitutes one of the most prevalent monogenic disorders worldwide, with approximately 65% of thalassemia patients exhibiting transfusion dependence. This burden disproportionately affects resource-limited regions. Current therapeutic strategies include hematopoietic stem cell transplantation (HSCT), iron chelation, emerging gene therapies, and agents promoting erythroid maturation. 1–5 Pharmacological induction of fetal hemoglobin (HbF)—exemplified by hydroxyurea (HU)—represents a cornerstone intervention, demonstrating efficacy in reducing transfusion requirements. However, significant interpatient heterogeneity exists: while a subset achieves robust hematological response, others exhibit partial or non-response to HU. This therapeutic limitation underscores the critical need for novel agents targeting HU-refractory BTM populations to improve clinical outcomes.Methods The study was a single-center prospective study and was conducted at Children’s Hospital Karachi (CHK) which is a tertiary care hospital providing specialized care to haematology-oncology pediatric patients located in the centre of the city. In this study, 31 patients age > 2 years who were known cases of BTM were recruited. Firstly, the baseline investigations like Urea, creatinine, electrolytes, bilirubin, ALP (alkaline phosphatase), ALT (alanine transaminase), AST (aspartate aminotransferase), and gamma-glutmayl transferase were taken of these patients and treated as control. The aforementioned investigations like Urea, creatinine, electrolytes, bilirubin, ALP (alkaline phosphatase), ALT (alanine transaminase), AST (aspartate aminotransferase), and gamma-glutmayl transferase were taken after 3 or 6 months of follow-up and were compared with baseline investigations and then classified grade 3 and 4 toxicities as per CTCAE guidelines.Results In this study 31 patients were recruited of which 10 (32.3%) were female and 21 (67.7%) were male. The study reported 28 patients (90.3%) without comorbidities. Among the few with co-existing conditions, autoimmune hemolytic anemia, hypoparathyroidism, and post-splenectomy complications were noted, each affecting 1 patient (3.2%). The clinical response to treatment was overwhelmingly positive, with 26 patients (83.9%) categorized as good responders. However, 2 patients (6.5%) showed no response, and an additional 2 patients (6.5%) were classified as partial responders, reflecting a varied spectrum of therapeutic outcomes.Conclusions In conclusion, this study provides strong evidence that the treatment is both effective and well-tolerated. The majority of patients demonstrated a positive clinical response, with significant improvements in hemoglobin and stable kidney function and immune markers. While rare side effects were reported, these were minimal and did not significantly affect the overall safety profile.Acknowledgements Saint judes hospital for organising workshop for synopsis writing and review.References Cappellini MD, Porter JB, Viprakasit V, Taher AT. A paradigm shift on betathalassaemia treatment: how will we manage this old disease with new therapies? Blood Rev. 2018;32:300–311.Weatherall D. J. in Williams Hematology (eds Kaushansky, K., et al.) (McGraw-Hill Education, 2016).Shah FT, Sayani F, Trompeter S, Drasar E, Piga A. Challenges of blood transfusions in β-thalassemia. Blood Rev. 2019;37:100588.Thompson AA, et al. Gene therapy in patients with transfusion-dependent β-thalassemia. N. Engl. J. Med. 2018;378:1479–1493.Cappellini MD, et al. A phase 3 trial of luspatercept in patients with transfusiondependent β- thalassemia. N. Engl. J. Med. 2020;382:1219–1231.Ethics Approval The Institutional review board of University of Karachi and The Children hospital has approved the study prior collecting the data.Consent Consent has also been taken.