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Hydroxyurea for sickle cell disease: Has the time finally come?
At its annual meeting in May 2008, the American Society of Pediatric Hematology/Oncology presented a special symposium entitled “Therapy for Children with Sickle Cell Anemia: Yes, No, or Maybe?” After the presentation of four hypothetical cases of children with sickle cell anemia, audience members used hand-held devices to vote their preference for therapy for each case. The options were: (1) observation alone, (2) chronic transfusion therapy, (3) hydroxyurea therapy, or (4) stem cell transplantation. Following an initial vote, a panel of distinguished speakers presented deliberately polarizing arguments for each therapy; then the vote was repeated. The impassioned arguments for each option and erudite discussion by expert panelists swayed the voters not a whit; the distributions were nearly the same before and after their presentations.
Not surprisingly, the “winner” of the debate was hydroxyurea. Averaging across the four cases, hydroxyurea was preferred at the end of the presentations by most voters (52%), compared with transplantation (30%), transfusions (11%), or observation alone (7%). Almost everyone (78%) favored hydroxyurea for the case designed to highlight this option, a hypothetical 4-year-old girl with a history of dactylitis, splenic sequestration, seven prolonged hospitalizations for severe pain episodes during the past two years, and a baseline hemoglobin level of 7.5 g/dL.
The irony here is that many adult and pediatric sickle cell programs, including those of many participants, currently treat only a fraction of eligible patients with hydroxyurea. Although systematic data have not been collected, researchers from a recent study conducted at one hospital in Maryland found that 70% of adult patients with sickle cell anemia who were appropriate candidates for hydroxyurea were not taking the drug, and data from a survey in Florida and North Carolina showed that only half of the reporting hematologist/oncologists prescribed hydroxyurea to more than 10% of their adult patients with sickle cell anemia.
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Hydroxyurea has been studied in sickle cell anemia for 25 years, and the accumulating evidence clearly documents short-term laboratory improvement and clinical benefit without known serious long-term risks.
Reversible myelosuppression is the most common short-term toxicity, and long-term reproductive issues include the potential risks for fetal abnormalities and effects on spermatogenesis. However, carcinogenesis remains the risk of greatest concern of both patients and physicians. Data from a large prospective observational study in patients with polycythemia vera, a disorder with inherent risk for leukemia, showed no increased risk attributable to hydroxyurea. Although a small risk could not be ruled out, it would likely be even lower in the setting of a primary non-malignant hematological disorder such as sickle cell disease.
If hydroxyurea is the standard of care for most patients with sickle cell anemia, why is it not standard practice? Why is the drug offered so sparingly? What are the barriers to providing hydroxyurea to patients? To help address these important questions, the NIH recently published a consensus development conference statement, “Hydroxyurea Treatment for Sickle Cell Disease,” which carefully outlines the problems and thoughtfully discusses five pertinent questions:
1) What is the efficacy (results from clinical studies) of hydroxyurea treatment for patients who have sickle cell disease in three groups: infants, preadolescents, and adolescents/adults?
2) What is the effectiveness (in everyday practice) of hydroxyurea treatment for patients who have sickle cell disease?
3) What are the short- and long-term harms of hydroxyurea treatment?
4) What are the barriers to hydroxyurea treatment for patients who have sickle cell disease, and what are the potential solutions?
5) What are the future research needs?
This article should be considered must-read material for all people, at any level, who have interactions with people affected by sickle cell disease.
Underserved patients
Sickle cell disease is a national and global health care problem. In the United States, the disease affects about 100,000 people, most of whom are members of minority populations who suffer from poverty, inadequate insurance, suboptimal access to specialty health care, and limited numbers of trained health care providers. Worldwide, sickle cell disease affects millions of individuals, many of whom live in underdeveloped regions with inadequate health care programs. The plight of this underserved patient population is increasingly apparent and efforts to meet their medical needs are desperately needed.
In this context, hydroxyurea offers an inexpensive and effective therapeutic option that can help ameliorate clinical severity by improving hematological parameters, decreasing the number of acute vaso-occlusive episodes, reducing hemolysis and possibly offering protection against chronic organ damage. Hydroxyurea is not a cure for sickle cell disease and may eventually be superseded by better therapies. For now, it offers the best form of therapy for most patients but remains sorely underused. Beliefs and attitudes of government agencies, the medical community, treating physicians, disease advocate groups, the lay community and patients and families must be examined carefully to determine why patients are not receiving this potentially helpful drug. The questions are difficult and the answers are complex, but patients with sickle cell disease should not suffer for lack of this proven therapy.
Russell E. Ware, MD, PhD, is the Lemuel Diggs Endowed Chair of Sickle Cell Disease and Chair of the Department of Hematology, St. Jude Children’s Research Hospital, Memphis, Tenn.
Peter E. Newburger, MD, is Ali and John Pierce Professor of Pediatric Hematology/Oncology and Vice-Chair of the Department of Pediatrics at the University of Massachusetts Medical School, Worcester, Mass., and is a member of the HemOnc Today Editorial Board.
For more information:
- Brawley OW, Cornelius LJ, Edwards LR, et al. National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Intern Med. 2008;148:932-938.
- Finazzi G, Caruso V, Marchioli R, et al. Acute leukemia in polycythemia vera: an analysis of 1,638 patients enrolled in a prospective observational study. Blood. 2005;105:2664-2670.
- Lanzkron S, Strouse JJ, Wilson R, et al. Systematic review: Hydroxyurea for the treatment of adults with sickle cell disease. Ann Intern Med. 2008;148:939-955.
- Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008;358:1362-1369.