Fetal globin stimulant therapies in the beta-hemoglobinopathies: principles and current potential.

For the majority of children with beta- hemoglobinopathies and -thalassemias who do not have a transplant donor, survival is shortened and morbidity is high. Hydroxyurea, EPO preparations, sodium phenylbutyrate, arginine butyrate, and 5-azacytidine/decitabine have shown efficacy in approximately 40% to 70% of sickle cell and beta-thalassemia patients. Many responses, although significant, were not completely ameliorating of symptoms or pathology, and trials of new agents with dual actions, or drug combinations, are needed. Ideally, limiting chemotherapeutic exposure is desirable for long-term treatment of children, and an oral therapeutic at tolerable doses is necessary for practical use. A new oral therapeutic candidate that induces fetal hemoglobin production and also stimulates erythropoiesis is entering clinical evaluation. Use of agents that should have additive or synergistic effects in combination, such as EPO and hydroxyurea or a short-chain fatty acid derivative (SCFAD), offer better therapeutic potential than hydroxyurea alone. Childhood is an optimal time to introduce such therapies, particularly the non-mutagenic SCFADs, while the erythroid marrow reserve is preserved and before organ damage has become widespread. A challenge for successful application of these therapies is to define patient subsets that are most likely to respond to a particular agent, or which require combination therapies, and to develop optimal dose regimens in thalassemias with rapid erythroid apoptosis. Development of this therapeutic avenue will require close collaboration among treating and academic physicians, families and patients, funding agencies, and researchers.