Evaluating efficacy and safety of hydroxyurea and thalidomide for beta-thalassemia: A systematic review andmeta-analysis.

Abstract INTRODUCTION Therapeutic interventions such as hydroxyurea and thalidomide have individually demonstrated a reduction in transfusion requirements in beta-thalassemia; however, the combined effects of these agents remain inadequately studied. This meta-analysis aims to determine the efficacy and safety of the combined use of hydroxyurea and thalidomide in transfusion-dependent beta-thalassemia patients. METHODS Using PRISMA guidelines a comprehensive search was conducted across PubMed, Scopus, Cochrane Library, and ClinicalTrials.gov from inception till May 30, 2025. Four studies evaluating the safety and efficacy of thalidomide plus hydroxyurea in beta-thalassemia patients were included. Data was analyzed using OpenMetaAnalyst software. Pooled estimates were reported as mean ± standard deviation (SD) and 95 % confidence intervals (CI), using a random-effects model. Heterogeneity was assessed using I2 statistics. Subgroup analyses were conducted based on follow-up duration (≤ 6 months vs. > 6 months). Quality assessment was performed using the Newcastle-Ottawa Scale. Some characteristics were described systematically. RESULTS A total of 372 patients (60% male; age range: 2-50 years) from 4 observational studies were included in this analysis. The median baseline hemoglobin was 7.3 g/dL (range, 6.4-9), ferritin was 2436 ng/ml (range, 1482-2974), and the median serum bilirubin was 1.865 mg/dl (range, 1.8-1.9). The treatment regimen consisted of hydroxyurea, thalidomide and aspirin. The pooled rates for overall response (OR) and complete response (CR) were 72% (95% CI 0.679-0.776, I2= 16.39%, p = 0.310) and 61.6% (95% CI 0.521-0.707, I2 = 71.57%, p = 0.014), respectively. The pooled rates for increase in hemoglobin and reduction in serum ferritin were -87% (95% CI -1.526 to -0.219, I2 = 94.12%, p < 0.0.001) and 58% (95% CI 0.229-0.931, I2 = 80.65%, p = 0.001). Subgroup analysis reported an ORR of 72.1% (95% CI: 58.4 to 85.9%, I2 = 66.36 %, p = 0.085) for ≤ 6 months and 71.0% (95% CI: 65.9 to77.0%, I2 = 0%, p = 0.074) for > 6months, respectively. CR was 57.3% (95%CI: 38.2 - 76.3%, I2 = 79.85% , p= 0.026) and 64.6% (95% CI: 49.7 - 79.6%, I2 = 82.26% , p= 0.018) in the respective subgroups. Ferritin levels showed non-significant change at < 6 months (0.560 ng/dl; 95% CI: -0.197 to 1.316 ng/dl, I2 = 88.4%, p= 0.003), but a significant reduction at > 6 months (0.639 ng/dl; 95% CI: 0.294 to 0.984, I2 = 61.29%, p= 0.108). Hemoglobin increased by 1.385 g/dl (95% CI: 0.947 to 1.823, I2 = 63.24%, p= 0.099) and 0.37 g/dl (95% CI: 0.170 to 0.570, I2 = 0%, p= 0.346), respectively. Billirubin levels demonstrated no significant change (-0.03 mg/dl 95% CI: -0.200 to 0.140, I2 = 90.62%, p= 0.001). Adverse effects were reported in 29.9% (95% CI: 5.7 to 54%, I2 = 0%, p= 0.001) of patients. CONCLUSION The combination therapy of hydroxyurea and thalidomide has shown safety and efficacy in the treatment of beta-thalassemia. The results have shown improved haemoglobin levels and reduced ferritin levels, while bilirubin levels showed no significant change. However, given lack of high quality data, further randomised controlled trials are required to validate these results and assess long-term outcomes.