Hydroxyurea and HbF in Sickle Cell Disease

Abstracts & Commentary

Sources: Steinberg MH, et al. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia. Risks and benefits up to 9 years of treatment. JAMA. 2003;289:1645-1651; Weiner DL, Brugnara C. Editorial: Hydroxyurea and sickle cell disease. A chance for every patient. JAMA. 2003;289:1692-1694.

In patients with sickle cell anemia (SCA), increasing the levels of fetal hemoglobin (HbF) decreases sickle cell hemoglobin polymerization and erythrocyte sickling. In SCA, HbF levels are inversely related to mortality.1 The discovery that hydroxyurea, a myelosuppressive agent, increased levels of HbF in SCA patients led to the Multicenter Study of Hydroxyurea (MSH) in sickle cell anemia.2 In MSH, 299 adults with SCA randomly were assigned to receive hydroxyurea (n = 152) or placebo (n = 147) and were followed up for a mean of 21 months. In the hydroxyurea group, morbidity was reduced by nearly half, but there was no difference in mortality or the incidence of stroke.

In the present study, Steinberg and colleagues report follow-up information on 233 of 299 patients from the MSH for up to 9 years. Upon completion of the original MSH trial, patients receiving or not receiving hydroxyurea were no longer randomized: Patients could start, stop, or continue taking hydroxyurea. Therefore, all but 47 of 233 patients were taking hydroxyurea for at least some part of the follow-up period.

Mortality rates were analyzed in 3-month intervals based on hydroxyurea use and cumulatively over 9 years.

Mortality was reduced 40% for patients taking hydroxyurea. Cumulative mortality at 9 years was 28% when HbF levels were lower than 0.5 g/dL compared with 15% when HbF levels were 0.5 g/dL or higher (P = .03). Mortality was greatest in patients with hemoglobin concentrations lower than 9g/dL and reticulocyte counts less than 250,000/mm3. Mortality was not associated with neutrophil count. There was no difference in the occurrence of strokes between the 2 groups: There were 8 strokes in the original hydroxyurea group and 6 in the original placebo group. Eleven of the stroke patients had more than 1 year of exposure to hydroxyurea, 2 had less than 1 year of exposure, and 1 patient had unknown exposure prior to the event.

Three patients developed cancer, one each of cervical, breast, and uterine cancer; all had taken hydroxyurea for some period of time.


The results of this follow-up study suggest that adults with moderate-to-severe SCA who take hydroxyurea have reduced mortality compared with patients not taking this drug. The precise mechanism for the increase in levels of HbF induced by hydroxyurea in SCA is not known. In their editorial, Weiner and Brugnara point out that hydroxyurea increases levels of nitric oxide (NO) both in vitro and in vivo. An absolute or functional deficiency of NO, defective NO-dependent mechanisms, or both may underlie some of the physiologic disturbances of sickle cell disease since NO is a central regulator of vascular tone, cytokines, platelet aggregation, thrombosis, endothelial red cell, and leukocyte adhesion, among other mechanisms.

The demonstration that hydroxyurea benefits adult SCA patients means that pediatricians and neurologists need to carry out similar treatment trials in children with SCA who have had or are at risk for stroke. More studies are needed to determine how and when to substitute hydroxyurea for chronic transfusion therapy, which at present is the best means of reducing cerebrovascular events in children with SCA.3,4 There is no reason to doubt that the use of hydroxyurea should and will be expanded in SCA patients of all ages. — John J. Caronna

Dr. Caronna is Vice-Chairman, Department of Neurology, Cornell University Medical Center; Professor of Clinical Neurology, New York Hospital.


1. Platt OS, et al. N Engl J Med. 1994;330:1639-1644.

2. Charache S, et al. N Engl J Med. 1995;332:1317-1322.

3. Adams RJ, et al. N Engl J Med. 1998;339:5-11.

4. Ware RE, et al. Blood. 1999;94:3022-3026.