The evolving role of DNA demethylating agents in the treatment of sickle cell disease and thalassemia.

NHANCED concentrations of fetal hemoglobin (HbF) can inhibit sickle hemoglobin polymerization and red cell sickling, resulting in an improved outcome for patients with sickle cell disease. Hydroxyurea, a ribonucleotide reductase inhibitor and the current standard of care, prevents DNA synthesis and has been shown to increase levels of HbF in patients with sickle cell disease. Early studies also investigated the use of DNA methylation inhibitors as a means of HbF induction; however, due to the potential risk of carcinogenicity, these studies were halted. Recently, there has been renewed interest in the use of inhibitors of DNA methylation in the treatment of hemoglobinopathies. This renewed interest results from appreciating: (1) that these agents, when used at appropriate doses, are likely not carcinogenic, but rather act as a tumor suppressor; and (2) the importanceofDNAmethylationinepigeneticregulationduring development and differentiation. This supplement to Seminars in Hematology summarizes the presentations and deliberations of the Sickle Cell Advisory Board Meeting held in Scottsdale, AZ on January 24, 2004. It has been suggested that methylation of CpG dinucleotide sequences found in the 5= -globin promoter region may be a major factor in the silencing of HbF during development. 1 In this supplement, Dr Lavelle describes the molecular mechanisms of HbF reactivation. Treatment with DNA methyltransferase inhibitors results in hypomethylation of these regions and accompanying reactivation of HbF. Studies to define the exact role of DNA methylation in -globin gene silencing are ongoing. Dr Saunthararajah and colleagues discuss current clinical data in patients with sickle cell disease. Hydroxyurea, the current standard of care for patients with sickle cell disease, has been shown to reduce the frequency of hospitalization and blood transfusions, as well as incidence of pain in patients with sickle cell disease. 2 Recent studies have shown that fetal HbF and F cells in patients with sickle cell anemia treated with decitabine increase to 20% and 80%, respectively, and there is a significant decrease in several surrogate clinical endpoints. When treated with hydroxyurea, HbF increased to only 8% in this group of patients, suggesting that decitabine is an alternative medication. 3 The treatment of-thalassemia is discussed by Drs Lal and Vichinsky. Unlike sickle cell disease, thalassemia requires a somewhatgreaterlevelofHbFreactivation,makingclinically meaningful responses rare. 4 Thus, the use of novel agents in this setting could represent a significant development. Early studies using 5-azacytidine, the ribose derivative, for the treatment of thalassemia demonstrated that intravenous administration consistently increased hemoglobin level greater than 3 g/dL, and individuals were maintained transfusionfree for over 2 years. 5 However, this therapy was associated with myelosuppression and potential carcinogenicity. Decitabine, a less toxic analogue of 5-azacytidine, holds considerable promise in the treatment of this disease. In order to confirm the efficacy and safety of decitabine in thetreatmentofhemoglobinopathies,phaseII/IIIstudieswill need to be performed. Following the presentations at this meeting, it was recommended that a phase II/III study be performed in sickle cell anemia with crisis frequency as the primary endpoint. It was also recommended that a phase I/II study of decitabine in the treatment of thalassemia be initiated with increase in hemoglobin as an endpoint. Dr DeBaun discusses some of the issues that will need to be taken into account in designing these recommended studies.