The role of fetal hemoglobin-enhancing agents in thalassemia.

Augmentation of fetal hemoglobin (HbF) synthesis can reduce the severity of beta-thalassemia by improving the imbalance between alpha- and non-alpha-globin chains. However, previous clinical trials of pharmacologic induction of HbF in thalassemia produced inconsistent results. Striking responses in HbF and total hemoglobin synthesis were occasionally observed, but in most patients, the increase in gamma-globin synthesis was inadequate to influence the clinical course of thalassemia. A small number of patients treated with azacytidine demonstrated a consistent response, but the development of this drug was abandoned due to concerns over toxicity. Decitabine, an analog of azacytidine, is a more potent inhibitor of DNA methyltransferase, and may be less toxic in clinical use. Trials in sickle cell anemia have confirmed that decitabine is effective in patients refractory to hydroxyurea. The clinical trials of decitabine in thalassemia must carefully evaluate the dose and route of administration, and address concerns about long-term side effects.