Increasing fetal hemoglobin production in sickle cell disease: results of clinical trials.

Five years experience using 5AZA and HU in a limited number of patients with SS disease, have resulted in the following conclusions. First, these drugs can rapidly induce increases in HbF production. Rapid increases in HbF production are not associated with reductions in overall reticulocyte levels, or reductions in late erythroid precursors, such as CFU-E. Indeed, where higher doses of these drugs are used or where the patient is unable to clear the drug rapidly, cytotoxicity is associated with reduced HbF production. These drugs not only increase the number of cells containing HbF, but also increase the MCV and the MCH of both F cells and non-F cells. Uncontrolled clinical trials suggest that the clinical severity of the disease measured by reduction in anemia and fewer vasoocclusive SS crises, may result from use of these drugs. The mechanisms by which these drugs result in increased F-cell production and increased MCH of F cells and non-F cells, may be due to their ability to reversibly block cells during their cell-cycle. This reversible blockade does not inhibit either on-going protein production or the establishment of origins of replications of DNA. Even though the mechanisms whereby the increased HbF production is not known, early clinical results seem to justify the initiation of controlled clinical trials of HU in severely affected SS patients.