Multicenter Study of Hydroxyurea in Patients With Sickle Cell Anemia (MSH)

BACKGROUND:

In spite of the fact that advances have been made in the management or prevention of some of the complications of sickle cell disease, the management of the most common complication--the painful crisis--is still unsatisfactory, and appropriate methods for its prevention are unknown. The morbidity associated with a painful crisis is much more than the suffering from pain alone. The interference with a normal lifestyle, the resulting obstacles to obtaining an education and holding a job, the risk of narcotics addiction, the cost of multiple hospitalizations, and the financial impact on the family and the individual must all be considered.

Evidence from the Cooperative Study of Sickle Cell Disease (CSSCD) study showed that there is an association between multiple pain events and early death in young adults. If this association is true, then MSH has the potential to not only reduce morbidity but mortality as well. The CSSCD study has shown that over 50 percent of patients with sickle cell disease have at least one crisis per year, and a considerable number have more. These episodes are believed to occur as a result of hemoglobin S within the red cells leading to rigid, non-deformable cells which can no longer traverse the microvasculature and as a result produce obstruction with consequent pain, ischemia, and tissue necrosis.

Previous approaches to the therapy of this group of disorders have included: attempts to modify the hemoglobin molecule so as to prevent polymerization; the use of vasoreactive drugs; and increasing red cell volume. All of these attempts have been abandoned either because of their inefficacy, toxicity, or impracticality. Chronic exchange transfusion programs have been of limited usefulness because of high rates of isoimmunization, iron overload, and risk of transmission of hepatitis and retroviral disease.

The rationale for the present study draws its substance from the observation that patients with higher levels of fetal hemoglobin (Hb F) (particularly the Saudi Arabian group), and infants who also have high Hb F levels have fewer crises. Several myelosuppressive drugs, such as 5-azacytidine and hydroxyurea, have been shown to increase Hb F production. The work with 5-azacytidine has had to be abandoned because of the known risk of malignancy.