Effects of @entity11508 on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in XXXX with @entity3458 .

@entity1 @entity137 @entity1862 @entity3458 @entity10355 @entity5538 @entity15838 @entity432 @entity2395 @entity11508
Fetal hemoglobin (HbF) decreases polymerization of sickle hemoglobin (HbS) and improves outcomes in @entity3458 ( @entity15838 ). Therefore, a therapeutic goal in @entity15838 is pharmacologic reactivation of HbF. Silencing of the @entity10355 (HbF) gene is associated with DNA methylation. The @entity5538 analog @entity11508 ( @entity11508 ) hypomethylates DNA by inhibiting DNA methyltransferase. We examined if subcutaneous @entity11508 could increase HbF levels and improve @entity15838 pathophysiology without @entity137 . Eight symptomatic @entity15838 @entity1 resistant or intolerant of standard treatment with @entity1862 received @entity11508 0.2 mg/kg subcutaneously 1 to 3 times per week in 2 cycles of 6-week duration. Treatment decreased neutrophils and increased mean HbF (6.5% to 20.4%, P <.0001) and mean total hemoglobin (76 to 96 g/L [7.6 to 9.6 g/dL], P <.001). Features of @entity432 pathophysiology such as red cell adhesion, endothelial damage, and coagulation pathway activity significantly improved. @entity10355 gene promoter methylation decreased, and platelets and the proportion of megakaryocytes and erythroid cells in the marrow increased without a decrease in marrow cellularity, consistent with a DNA hypomethylating, noncytotoxic mechanism of action. Weekly subcutaneous @entity11508 produces cumulative increases in HbF and total hemoglobin through a noncytotoxic mechanism of action. Chronic dosing and sustained increases in hemoglobin F and total hemoglobin levels may be possible. Further studies in @entity15838 and @entity2395 are indicated.
