Diagnosis and Treatment of Alpha Thalassemia Major.

Alpha thalassemia major (ATM) is the most severe form of α-thalassemia, with thousands of cases annually throughout the world. It was historically incompatible with life, with almost all affected individuals dying at or before birth. Recent advances utilizing early, serial intrauterine transfusions have resulted in improved outcomes, including improved neurocognitive functioning and less congenital anomalies. At-risk families should be identified pre-conceptually for counseling and options such as preimplantation genetic testing. ATM, when diagnosed prenatally, requires counseling about termination options and transfusion therapy. Postnatally, aggressive transfusion, in contrast to standard thalassemia transfusion protocols, suppresses ineffective erythropoiesis and hemoglobin Barts formation. These advances have changed the course of ATM and postnatally. Preliminary results suggest iron chelation may be safely administered after one year of age with monitoring, including quantitative liver iron measurements. Patients with ATM can now survive on chronic transfusion therapy and potentially be cured by hematopoietic cell transplantation (HCT). New therapies continue to emerge, including stem cell transplantation using maternal stem cells and Phase 1 gene therapy trials evaluating reactivation of the embryonic α-globin (zeta) gene and encoding the α-globin gene. Globally, an international working group has been formed to address ATM, which should lead to advances worldwide.