Efficacy of luspatercept in reducing transfusion burden and its impact on liver iron concentration in beta-thalassemia major: A systematic review and meta-analysis

Abstract Introduction Beta thalassemia is an inherited blood disorder caused by mutations in the genes encoding beta globin. In transfusion-dependent patients, transfusions can lead to iron overload, associated with organ damage and increased mortality. Luspatercept has emerged as a promising therapeutic agent to reduce the need for transfusions and to improve iron management in these patients. Objective Evaluate the efficacy of luspatercept versus placebo in reducing transfusion burden and liver iron concentration (LIC) in patients with transfusion-dependent beta-thalassemia. Methods A systematic search was performed in Pubmed, Embase and Cochrane for studies comparing luspatercept versus placebo in patients with transfusion-dependent beta-thalassemia. The main outcomes of interest were reduction of transfusion burden by ≥33% and ≥50% and LIC. Statistical analysis was performed using Review Manager. The I2 test was used to assess heterogeneity, and risk of bias was assessed using ROBINS-I. Results We included 368 patients from two clinical trials. The use of luspatercept was associated with a higher proportion of patients achieving both ≥33% (RR = 2.22; 95%CI 1.70-2.89; p = 0.00001) and ≥50% (RR= 6.22; 95%CI 3.28-11.80; p = 0.00001) reduction in transfusion burden compared to the placebo group. Regarding LIC, no statistically significant difference was observed when comparing both groups (mean difference: 1.33 mg/g; 95% CI -0.79 to 3.45; p = 0.22) Conclusion Luspatercept demonstrated significant efficacy in reducing transfusion requirement in patients with transfusion-dependent beta-thalassemia. Although no clear effect on LIC was demonstrated, the results support its use as a promising alternative. Nevertheless, these findings should be interpreted with caution, as one of the studies did not include a placebo group, which limits the robustness of the comparison. Further confirmation by additional randomized clinical trials is needed to validate these results and to determine in more detail their role in clinical practice.