Contemporary Management of Thalassemia: A Perspective on Current Standards and the Emergence of FDA‐Approved Oral Therapy

Abstract

ABSTRACT Background and Aims Thalassemia is an inherited hemoglobin disorder characterized by ineffective erythropoiesis, chronic anemia, and progressive multisystem complications that require lifelong management. Current treatment relies on regular red blood cell transfusions, iron chelation therapy, and supportive multidisciplinary care, while hematopoietic stem cell transplantation offers a curative option for selected patients. Although gene‐based therapies and novel pharmacological agents have expanded therapeutic options, their widespread implementation is limited by cost, accessibility, and long‐term safety considerations. This article summarizes contemporary management strategies for α and β thalassemia, with particular emphasis on the recent emergence of the FDA‐approved oral pyruvate kinase activator, mitapivat. Methods A structured literature review was conducted using PubMed and PubMed Central. Searches included the terms “thalassemia,” “mitapivat,” “pyruvate kinase activator,” “gene therapy,” “hydroxyurea,” and “luspatercept.” Priority was given to recent systematic reviews, clinical practice guidelines, pivotal phase II and III clinical trials, regulatory publications, and peer‐reviewed studies relevant to current therapeutic practice. Results Conventional therapies remain essential but are associated with significant limitations, including transfusion dependence, iron overload, and treatment‐related complications. Curative strategies such as hematopoietic stem cell transplantation and gene therapy are effective in selected patients but remain constrained by donor availability, toxicity, cost, and limited accessibility. Emerging pharmacological therapies target ineffective erythropoiesis and iron dysregulation. Phase III ENERGIZE and ENERGIZE‐T trials demonstrated that mitapivat significantly improved hemoglobin response in non‐transfusion‐dependent disease and reduced transfusion burden in transfusion‐dependent disease, with an acceptable safety profile, leading to FDA approval as the first oral therapy for adults with α or β thalassemia. Conclusion Mitapivat represents a significant advance in thalassemia management by targeting erythrocyte metabolism and providing the first FDA‐approved oral treatment for anemia in adults with α or β thalassemia. Multi‐year follow‐up and real‐world studies are needed to further define its durability, safety, and role within evolving treatment strategies.