During the dose titration, blood counts consistent with a finding of marrow depression were observed at least once in 35 percent of the patients who received placebo. (Results)

Treatment was temporarily stopped in almost all patients in the hydroxyurea group because of marrow depression; blood counts usually recovered within two weeks. (Results)

Treatment was interrupted in four patients in the placebo group because of increased bilirubinemia (bilirubin, > 10 mg per deciliter [103 umol per liter]). (Results)

Hair loss, rash, fever, and gastrointestinal disturbance were as common in patients receiving placebo as in those taking hydroxyurea. (Results)

In six patients (one in the hydroxyurea group) parvovirus b19 infection developed during treatment. (Results)

The aplastic crises caused by the virus were not prolonged, and all the patients recovered uneventfully. (Results)

We did not address the reversibility of chronic organ damage; it is unknown whether the inhibition of sickling could affect such preexisting lesions. (Discussion)

Hematopoietic depression did occur during therapy, as anticipated, but it was short lived. (Discussion)

Adverse reactions were equally common in both treatment groups. (Discussion)

There is concern that long-term hydroxyurea therapy may be carcinogenic or leukemogenic, because some other antineoplastic agents have such effects. (Discussion)

By inhibiting sickling, increased levels of fetal hemoglobin might decrease the frequency of painful crises. (Abstract)

In a double-blind, randomized clinical trial, we tested the efficacy of hydroxyurea in reducing the frequency of painful crises in adults with a history of three or more such crises per year. (Abstract)

Among 148 men and 151 women studied at 21 clinics, the 152 patients assigned to hydroxyurea treatment had lower annual rates of crises than the 147 patients given placebo (median, 2.5 vs. 4.5 crises per year, P < 0.001). (Abstract)

Treatment with hydroxyurea did not cause any important adverse effects. (Abstract)

Hydroxyurea therapy can ameliorate the clinical course of sickle cell anemia in some adults with three or more painful crises per year. (Abstract)

No deaths were related to treatment with hydroxyurea (Table 3). (Results)

No neoplastic disorders developed during the study. (Results)

In no case was morbidity associated with a high hemoglobin concentration or platelet count. (Results)

In this controlled trial of the efficacy of hydroxyurea in patients with sickle cell anemia, treatment with hydroxyurea caused a 44 percent reduction in the median annual rate of painful crises. (Discussion)

Reductions in the frequency of chest syndrome and the number of transfusions strengthen the conclusion that hydroxyurea is a useful agent in sickle cell anemia. (Discussion)

The mechanism by which hydroxyurea reduced the frequency of vaso-occlusive crises is unclear. (Discussion)

Since the results in the hydroxyurea and placebo groups began to diverge at about eight weeks (Fig. 1), it is possible that the increase in fetal hemoglobin is only one way in which hydroxyurea can affect sickle cell anemia. (Discussion)

Other explanations of the antisickling effect of hydroxyurea are increased water content of red cells, with secondarily increased deformability, and decreased adhesion of red cells to endothelium. (Discussion)

Used carefully, with frequent monitoring, hydroxyurea  therapy was safe. (Discussion)

Hydroxyurea is the first clinically acceptable drug shown to prevent painful crises in adults with sickle cell anemia; it has no role in the treatment of crises in progress. (Discussion)

In a previous open-label study of hydroxyurea therapy, the synthesis of fetal hemoglobin increased in most patients with sickle cell anemia, with only mild myelotoxicity. (Abstract)

The trial was stopped after a mean follow-up of 21 months. (Abstract)

The median times to the first crisis (3.0 vs. 1.5 months, P=0.01) and the second crisis (8.8 vs. 4.6 months, P=0.001) were longer with hydroxyurea treatment. (Abstract)

Fewer patients assigned to hydroxyurea had chest syndrome (25 vs. 51, P=0.001), and fewer underwent transfusions (48 vs. 73, P=0.001). (Abstract)

At the end of the study, the doses of hydroxyurea ranged from 0 to 35 mg per kilogram of body weight per day. (Abstract)

Maximal tolerated doses of hydroxyurea may not be necessary to achieve a therapeutic effect. (Abstract)

The beneficial effects of hydroxyurea do not become manifest for several months, and its use must be carefully monitored. (Abstract)

The long-term safety of hydroxyurea in patients with sickle cell anemia is uncertain. (Abstract)

There were no significant differences between the two groups of patients with respect to sex, age, race, or ethnic group, number of a-globin genes, or b-globin haplotype, and blood counts in the two groups were similar before treatment was begun (Table 1). (Results)

After treatment had begun, one patient in the hydroxyurea group was discovered to have sickle-cell-b-thalassemia (a small amount of hemoglobin A was present). (Results)

As of June  30, 1994, 279 of the 299 patients who were enrolled (93 percent) were being seen regularly for follow-up visits at the clinics and 5034 medical contacts (occurring during two years of follow-up) had been classified. (Results)

The ranks of the crisis rates differed in the two treatment groups (Table 2), with median rates of 2.5 crises per year in the hydroxyurea group and 4.5 crises per year in the placebo group - a 44 percent difference (P<0.001). (Results)

When only crises severe enough to cause hospitalization were considered, the median annual rates were 1.0 and 2.4,  respectively (P<0.001). (Results)

The incidence of death, stroke, and hepatic sequestration did not differ significantly in the two groups. (Results)

By contrast, the two groups did differ with respect to the number of patients in whom chest syndrome developed (25 in the hydroxyurea  group vs. 51 in the placebo group, P<0.001), the number of patients who received transfusions (48 vs. 73, P=0.001), and the number of units of blood transfused (336 vs. 586, P=0.004 by Van der Waerden's test). (Results)

The median time to the first vaso-occlusive crisis was longer in patients treated with hydroxyurea than in those given placebo (3.0 vs. 1.5 months, P=0.01), as was the time to the second crisis (8.8 vs. 4.6 months, P<0.001) (Fig. 1). (Results)

There was no evidence to suggest that the effect of hydroxyurea changed during two years of treatment (P=0.77 for the analysis of the time to the first crisis and P=0.86 for the analysis of the time to the second crisis). (Results)

After the study ended (January 1995), examination of the doses of hydroxyurea revealed that after six months of treatment, only 33 percent of the patients in the hydroxyurea group were receiving the maximal tolerated dose or had been receiving a higher dose that was subsequently reduced. (Results)

By the time the study ended, 51 percent of the patients treated with hydroxyurea were receiving the maximal tolerated doses, and doses for the remainder of patients were nearly maximal. (Results)

The daily doses of hydroxyurea ranged from 0 mg per kilogram in the 2 percent of patients who could not tolerate hydroxyurea to 35 mg per kilogram - the maximal prescribed dose - in 21 percent of patients. (Results)

Capsule counts suggested that about 75 percent of the patients took more than 80 percent of their capsules. (Results)

Hemoglobin levels, mean corpuscular volumes, fetal hemoglobin levels, and proportions of F cells were higher in the hydroxyurea group than in the placebo group at the time the study ended, and white-cell, platelet, reticulocyte, and dense-cell counts were lower. (Results)

Differences between the groups in the mean corpuscular volume and proportion of F cells appeared within 8 weeks of the initiation of the study, reached a peak at about 40 weeks, and then declined (Fig. 2). (Results)

Treatment was permanently stopped for medical reasons in 14 patients in the hydroxyurea group (2 because of myelotoxicity at a dose of 2.5 mg per kilogram per day) and 6 patients in the placebo group. (Results)

In 12 patients who did not receive transfusions (11 in the hydroxyurea group), hemoglobin levels repeatedly exceeded 12.8 g per deciliter, a potentially adverse effect because of increased blood viscosity (if fetal hemoglobin levels in red cells were not high enough to inhibit sickling in vivo). (Results)

Four patients assigned to hydroxyurea and five patients assigned to placebo had platelet counts of more than 800,000 per cubic millimeter. (Results)

Pregnancies occurred in 10 patients or their partners (Table 3). (Results)

These patients were informed of their treatment assignments and counseled. (Results)

Their study treatments were stopped, but they continued to be seen for follow-up. (Results)

All live-born babies appeared to be normal. (Results)

This result is both clinically meaningful and statistically significant. (Discussion)

This study was designed to measure clinical responses among patients treated with maximal tolerated doses of hydroxyurea. (Discussion)

A difference in the frequency of painful crises between the hydroxyurea and placebo groups began to emerge within about two months of the initiation of treatment and was clearly evident at four months (Fig. 1). (Discussion)

Since only a minority of patients (33 percent) were receiving maximal tolerated doses of hydroxyurea by six months, it might be concluded that such doses are unnecessary for all patients. (Discussion)

Our understanding of the effect of hydroxyurea is too limited to permit such a conclusion, but evaluation of alternative dosage regimens is clearly needed. (Discussion)

The proportion of F cells rose between 8 and 24 weeks (Fig. 2), and changes in the mean corpuscular volume also occurred at this time. (Discussion)

The increase in mean corpuscular volume during hydroxyurea treatment is primarily due to an increase in the hemoglobin content of the cells, but it may also reflect altered properties of red cell membranes. (Discussion)

In no instance could the death of a study patient be related to treatment with hydroxyurea. (Discussion)

Patients known to have antibodies to HIV were excluded from the study, but there is no evidence that hydroxyurea is harmful to such persons. (Discussion)

A recent report suggests that hydroxyurea can inhibit the replication of HIV in vitro, but the clinical implications of those findings are unknown. (Discussion)

The safety of hydroxyurea therapy in pregnancy is unclear. (Discussion)

In animals, very large doses (>=250 mg per kilogram) are teratogenic, 25,26 possibly as a result of interference with uterine blood flow. (Discussion)

The cytologic appearance of mouse sperm is altered by doses exceeding 25 mg per kilogram, but no abnormalities have been described in the offspring of male mice treated with hydroxyurea. (Discussion)

Normal pregnancies have been reported in five women who took hydroxyurea for chronic myelocytic leukemia, and there have been no reports of teratogenesis or mutagenesis in humans. (Discussion)

The children born to our patients have shown no evidence of birth defects or developmental abnormalities to date. (Discussion)

Hydroxyurea blocks the synthesis of DNA by inhibiting ribonucleotide reductase. (Discussion)

Its cytostatic effects thus differ from those of radiation, alkylating agents, and other anticancer drugs. (Discussion)

The incidence of leukemia in patients treated with hydroxyurea for polycythemia vera has been reported by the Polycythemia Vera Study Group. (Discussion)

They compared 51 hydroxyurea-treated patients who had received no prior therapy with 134 previously untreated patients who were treated by phlebotomy alone. (Discussion)

In the most recent report, the incidence of acute leukemia after a median follow-up of 8.6 years was 5.9 percent in the hydroxyurea  group, as compared with 1.5 percent in the phlebotomy group (P=0.18 by the log-rank test). (Discussion)

Reports of leukemia in smaller groups of hydroxyurea-treated patients with polycythemia vera continue to arouse concern about the leukemogenic effect of the drug. (Discussion)

However, the relevance of these reports to sickle cell anemia is unclear because of the inherent tendency of myeloproliferative diseases to evolve into acute leukemia. (Discussion)

Perhaps more relevant to our study is the report on a group of 64 patients with erythrocytosis due to inoperable cyanotic congenital heart disease who were treated with hydroxyurea at doses comparable to those we used (9 to 21 mg per kilogram per day) for 2 to 15 years (mean, 5.65). (Discussion)

Cancer or leukemia did not develop in any of the patients during the period of observation. (Discussion)

The uncertain safety of long-term hydroxyurea therapy with respect to leukemogenesis must be carefully balanced against its anticipated benefit. (Discussion)

It is not approved by the Food and Drug Administration for the prevention of crises, and short-term and long-term use of this drug is potentially dangerous. (Discussion)

Our data support the use of hydroxyurea  therapy for the prevention of painful crises in adult patients who are able to follow directions about dosages and monitoring and can appreciate the still unclear long-term risks of such treatment. (Discussion)

