Correspondence

Hydroxyurea in Sickle Cell Disease

N Engl J Med 1996; 334:333-334February 1, 1996

Article

To the Editor:

We wish to comment further on the possible risks of hydroxyurea therapy in sickle cell disease, a subject of considerable attention since the results of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia were reported by Charache et al. (May 18 issue).1

We agree that the caution advised by Ho and Murgo2 and Silver3 in their letters (Oct. 12 issue) is necessary. Unfortunately, the single sentence from our editorial4 quoted by Ho and Murgo distorts the thrust of our paragraph on the long-term safety of hydroxyurea. Continued monitoring of patients with sickle cell disease and others receiving hydroxyurea for secondary cancers and other unanticipated side effects of this drug is essential.

Equally important are the implications of data from the multicenter study on hemoglobin F levels in patients treated with hydroxyurea, presented on December 4, 1995, at the meeting of the American Society of Hematology in Seattle. Steinberg et al.5 noted that between 25 percent and 50 percent of the treated patients had no change in hemoglobin F levels during two years of therapy, confirming earlier observations in a study in which compliance was ensured.6 Data from the multicenter study showing a strong correlation between the clinical response and the hemoglobin F level were also briefly reported.

These results, in our opinion, suggest that hemoglobin F levels should be monitored closely in patients being treated with hydroxyurea. If a marked increase in the level of hemoglobin F (an absolute increase of at least several percentage points) fails to occur after three to six months, consideration should be given to discontinuing the drug. It is possible that mechanisms other than the inhibition of hemoglobin-S polymerization by hemoglobin F could make treatment with hydroxyurea beneficial. Until there is better evidence for these postulated effects, however, they should not influence routine decisions about therapy.

In addition, the fact that a considerable fraction of patients do not have a response to hydroxyurea reinforces our plea for “continued study of other dosage regimens, other drugs, and combinations of agents”4 to effect greater responses in hemoglobin F levels and possibly greater clinical benefits. A recent report to the director of the National Institutes of Health is quite cautious about the clinical prospects for gene therapy in the foreseeable future.7 It is also essential that the results of current therapies, based on modulating endogenous gene expression, not be overinterpreted, which might result in a de-emphasis on the necessary basic and clinical research.

Alan N. Schechter, M.D.
Griffin P. Rodgers, M.D.
National Institutes of Health, Bethesda, MD 20892

7 References

1. 1

   Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995;332:1317-1322
   Full Text | Web of Science | Medline

2. 2

   Ho PTC, Murgo AJ. Hydroxyurea and sickle cell crisis. N Engl J Med 1995;333:1008-1008
   Full Text | Web of Science | Medline

3. 3

   Silver RT. Hydroxyurea and sickle cell crisis. N Engl J Med 1995;333:1008-1009
   Full Text | Web of Science | Medline

4. 4

   Schechter AN, Rodgers GP. Sickle cell anemia -- basic research reaches the clinic. N Engl J Med 1995;332:1372-1374
   Full Text | Web of Science | Medline

5. 5

   Steinberg MH, Lu ZM, Barton F, et al. Fetal hemoglobin (Hb F) in sickle cell anemia (Hb SS): determinants of response to hydroxyurea (HU). Blood 1995;86:Suppl:418a-418a abstract.
   

6. 6

   Rodgers GP, Dover GJ, Noguchi CT, Schechter AN, Nienhuis AW. Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea. N Engl J Med 1990;322:1037-1045
   Full Text | Web of Science | Medline

7. 7

   Orkin SH, Motulsky AG. Report and recommendations of the panel to assess the NIH investment in research on gene therapy, Bethesda, Md.: National Institutes of Health, December 7, 1995 (http://www.NIH.gov/news/panelrep.html).
   

To the Editor:

Charache et al. report a 44 percent reduction in the median annual rate of painful crises in adults with sickle cell disease treated with oral hydroxyurea. However, the long-term risks of such treatment remain unclear. Although melanonychia (hyperpigmentation of the nails) has been reported in patients receiving hydroxyurea for chronic myelogenous leukemia,1,2 this finding has not been reported in patients with sickle cell disease. Hydroxyurea-induced horizontal hyperpigmentation of the nails has been described,2-4 but there are only a few cases with the hydroxyurea-induced longitudinal form of hyperpigmentation.1,3

We treated six adults with sickle cell disease (four women and two men; age range, 18 to 45 years) with hydroxyurea (1 to 1.5 g daily). Five of the six patients had hemoglobin SS disease; one patient had hemoglobin S–β⁰-thalassemia. Before therapy, each patient had reported at least three severe painful events per year requiring parenteral analgesics.

After six months of treatment with hydroxyurea, five of the six patients reported a decrease in the number of painful events. Melanonychia developed in two of the four women after six weeks of therapy. The 20 nailbeds of each affected woman showed heterogeneous patterns of nonpainful longitudinal bands to the tips of the nails, as well as diffuse horizontal bands of hyperpigmentation (Figure 1Figure 1Fingernails of a 31-Year-Old Black Woman with Hemoglobinopathy SS and Hydroxyurea-Induced Melanonychia Characterized by Longitudinal (Large Arrow) and Diffuse Horizontal (Small Arrow) Bands.). The longitudinal bands ranged from 0.5 to 4 mm in width, whereas the horizontal bands appeared diffuse and were difficult to measure. The nails did not appear to be thickened or atrophic, and the adjacent skin was normal.

One of the two affected women had a small area of hyperpigmentation on the left lateral aspect of the tongue, as well as on her palms and soles, suggesting a systemic effect. The face, gums, and buccal mucosa have not been involved to date. In the other woman, only the nails were involved. The two affected patients considered discontinuing hydroxyurea because of this undesirable cosmetic effect. However, both patients decided to continue taking the drug because of the reduction in painful events.

We do not know of predisposing factors for melanonychia and whether this cosmetic feature will have a negative effect on compliance with treatment. It may be reversible, as has been demonstrated in one patient with chronic myelogenous leukemia.4

Pat Adams-Graves, M.D.
Cathy Heltsley, M.D.
Steven Deitcher, M.D.
University of Tennessee, Memphis, TN 38163

4 References

1. 1

   Baran R, Kechijian P. Longitudinal melanonychia (melanonychia striata): diagnosis and management. J Am Acad Dermatol 1989;21:1165-1175
   CrossRef | Web of Science | Medline

2. 2

   Kennedy BJ, Smith LR, Goltz RW. Skin changes secondary to hydroxyurea therapy. Arch Dermatol 1975;111:183-187
   CrossRef | Web of Science | Medline

3. 3

   Vomvouras S, Pakula AS, Shaw JM. Multiple pigmented nail bands during hydroxyurea therapy: an uncommon finding. J Am Acad Dermatol 1991;24:1016-1017
   CrossRef | Web of Science | Medline

4. 4

   Majumdar G, Heard SE, Slater NG. Reversible hyperpigmentation associated with high dose hydroxyurea. BMJ 1990;300:1468-1468
   CrossRef | Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   Nicolas Leveziel, Sylvie Bastuji-Garin, Franck Lalloum, Giuseppe Querques, Pascale Benlian, Michel Binaghi, Gabriel Coscas, Gisèle Soubrane, Dora Bachir, Frédéric Galactéros, Eric H. Souied. (2011) Clinical and Laboratory Factors Associated With the Severity of Proliferative Sickle Cell Retinopathy in Patients With Sickle Cell Hemoglobin C (SC) and Homozygous Sickle Cell (SS) Disease. Medicine 90:6, 372-378
   CrossRef

2. 2

   Debabrata Chatterjee, Kalyan Asis Nayak, Erika Ember, Rudi van Eldik. (2010) [RuIII(edta)(H2O)]− mediated oxidation of hydroxyurea with H2O2. Kinetic and mechanistic investigation. Dalton Transactions 39:7, 1695
   CrossRef

3. 3

   Katarzyna Albrecht-Stanisławska, Michał Matysiak. (2009) Co nowego w rozpoznawaniu i leczeniu talasemii. Pediatria Polska 84:3, 207-216
   CrossRef

4. 4

   MARTIN H. STEINBERG, GRIFFIN P. RODGERS. (2001) Pharmacologic Modulation of Fetal Hemoglobin. Medicine 80:5, 328-344
   CrossRef

5. 5

   Yutaka Niihara, Charles R. Zerez, Dean S. Akiyama, Kouichi R. Tanaka. (1998) Oral L-glutamine therapy for sickle cell anemia: I. subjective clinical improvement and favorable change in red cell NAD redox potential. American Journal of Hematology 58:2, 117-121
   CrossRef

6. 6

   S Liebschutz, I Quéré, E Lukasik, O Dereure, J Rondes, C Janbon. (1998) Un ulcère malléolaire hyperalgique: guérison à l'arrêt de l'hydroxyurée. La Revue de Médecine Interne 19:5, 360-361
   CrossRef