Investigators from the Medical College of Georgia, Augusta, performed a retrospective analysis of 226 patients with sickle cell disease (SCD) aged 16 to 68 years of age who were treated with hydroxyurea (HU) over a 15-year period. The investigators compared the characteristics of the 38 patients who died during this period with those of surviving patients. Of these 38 patients, 26 were on HU therapy at the time of death, and 12 were not compliant with therapy. Four patients died of causes unrelated to SCD. Of the 34 patients who died of sickle cell–related causes, 12 died of acute chest syndrome (ACS), 5 of multiorgan failure, 4 of stroke, 2 of end-stage renal disease, and 1 each of cardiac arrest, sepsis, cardiac arrhythmia, and pulmonary embolism. In 7 patients, the precise cause of death could not be determined. Deceased and surviving patients did not differ significantly with regard to average HU dose, duration of HU therapy, baseline hemoglobin F (Hb F), or maximum Hb F response. Men and women had equivalent survival rates.
The deceased group of patients was older (30.6 vs 26.4 years) and more anemic (Hb 7.7 vs 8.4 g/dL) at the time of HU initiation than the group of patients who survived. Patients with BAN (Bantu [Central African Republic]) and CAM (Cameroon) gene cluster haplotypes of the βs genotype were over-represented in the group of patients who died. These observations are consistent with previous reports that BAN haplotype,1,2 which is also associated with poorer response to HU, increases the risk for irreversible complications and worsens the prognosis in patients with SCD.
The investigators concluded that sickle cell patients who die while on HU therapy may represent a subgroup of older patients with more severe disease and organ damage. This subgroup may require the institution of HU therapy at an earlier age (prior to organ damage) or administration of higher HU doses or combination therapies, particularly with erythropoietin, in order for HU to effectively lower mortality. Other approaches may be needed for patients whose βs genotype renders them less responsive to HU.
Dr. Villella has disclosed no financial relationships relevant to this commentary.
The major effect of HU is to increase Hb F levels in red blood cells, which leads to amelioration of the vaso-occlusive complications of SCD. The Multi-center Study of Hydroxyurea in Sickle Cell Anemia (MSH) was a landmark randomized, double-blinded, placebo-controlled clinical trial that demonstrated a 44% reduction in the annual number of pain episodes and a 51% reduction in episodes of ACS.3 Based on these results, HU has become the standard of care for SCD patients with severe disease as defined by 3 or more pain crises annually, but it is not effective in all patients with SCD. The current study identifies a subgroup of older and more anemic patients who may not benefit...