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Volume 332
MAY 18, 1995
Number 20
Copyright, 1995, by the Massachusetts Medical Society
EFFECT OF HYDROXYUREA ON THE FREQUENCY OF PAINFUL CRISES IN SICKLE CELL
ANEMIA
S
AMUEL
C
HARACHE
, M.D., M
ICHAEL
L. T
ERRIN
, M.D., R
ICHARD
D. M
OORE
, M.D., G
EORGE
J. D
OVER
, M.D.,
F
RANCA
B. B
ARTON
, M.S., S
USAN
V. E
CKERT
, R
OBERT
P. M
C
M
AHON
, P
H
.D., D
UANE
R. B
ONDS
, M.D.,
AND THE
I
NVESTIGATORS OF THE
M
ULTICENTER
S
TUDY OF
H
YDROXYUREA IN
S
ICKLE
C
ELL
A
NEMIA
*
Abstract Background. 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. By inhibiting sickling, increased
levels of fetal hemoglobin might decrease the frequency
of painful crises.
Methods. In a double-blind, randomized clinical trial,
we tested the efficacy of hydroxyurea in reducing the fre-
quency of painful crises in adults with a history of three or
more such crises per year. The trial was stopped after a
mean follow-up of 21 months.
Results. 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). 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. Fewer patients assigned to hydroxyurea had
chest syndrome (25 vs. 51, P 0.001), and fewer under-
went transfusions (48 vs. 73, P 0.001). At the end of
the study, the doses of hydroxyurea ranged from 0 to 35
mg per kilogram of body weight per day. Treatment with
hydroxyurea did not cause any important adverse ef-
fects.
Conclusions. Hydroxyurea therapy can ameliorate the
clinical course of sickle cell anemia in some adults with
three or more painful crises per year. Maximal tolerated
doses of hydroxyurea may not be necessary to achieve a
therapeutic effect. The beneficial effects of hydroxyurea
do not become manifest for several months, and its use
must be carefully monitored. The long-term safety of hy-
droxyurea in patients with sickle cell anemia is uncertain.
(N Engl J Med 1995;332:1317-22.)
From the Johns Hopkins University School of Medicine, Baltimore (S.C.,
R.D.M., G.J.D., S.V.E.); the Maryland Medical Research Institute, Baltimore
(M.L.T., F.B.B., R.P.M.); and the National Heart, Lung, and Blood Institute, Be-
thesda, Md. (D.R.B.). Address reprint requests to Dr. Charache at B121 Meyer
Bldg., Johns Hopkins Hospital, 600 N. Wolfe St., Baltimore, MD 21287-7061.
Supported by cooperative agreements between the National Heart, Lung, and
Blood Institute and Johns Hopkins University (UO1-HL45692) and the Maryland
Medical Research Institute (UO1-HL45696), by General Clinical Research Cen-
ter grants (RR 00046, RR 00065, and RR 00083), and by a grant from Bristol-
Myers Squibb, Princeton, N.J.
*The institutions and investigators participating in the Multicenter Study of
Hydroxyurea in Sickle Cell Anemia are listed in the Appendix.
S
ICKLING of red cells in patients with sickle cell
anemia is caused by the polymerization of mole-
cules of deoxygenated hemoglobin S (a
2
b
2
S
) into rigid,
rod-like polymers. Fetal hemoglobin (a
2
g
2
), which lacks
b-globin chains, inhibits sickling in vitro by interfering
with the polymerization of hemoglobin S. Clinical ob-
servations have suggested that increased fetal hemoglo-
bin concentrations may have beneficial effects in sickle
cell anemia.
1
Considerable interest was aroused by the
discovery that the administration of 5-azacytidine to
adult baboons stimulated the production of fetal hemo-
globin.
2
Other cytotoxic agents had a similar effect,
3-5
but among them, hydroxyurea appeared to be most
suited for clinical trials
6
because of its ease of adminis-
tration and relative safety.
An open-label study of hydroxyurea in 32 patients
with sickle cell anemia showed that fetal-hemoglobin
synthesis increased in most patients treated with doses
of hydroxyurea that produced limited myelotoxicity.
7
Fetal-hemoglobin responses were dose related, and in
some patients the levels were as high as 15 to 20 per-
cent. Laboratory studies suggested that fetal-hemoglo-
bin levels of at least 15 to 20 percent might be required
for a clinical benefit,
8
but in a study of untreated pa-
tients, it appeared that any increase above 4 percent
might be beneficial.
9
We conducted a randomized, double-blind, place-
bo-controlled clinical trial to test the hypothesis that
hydroxyurea could substantially reduce the frequency
of painful crises (often called vaso-occlusive crises) in
adults with sickle cell anemia. Because of the benefi-
cial effects observed, the trial was stopped before the
planned 24 months of treatment were completed for
all patients.
M
ETHODS
The design of the study and the methods used are described else-
where.
10
Patients were enrolled from 21 sites in the United States and
Canada (see the Appendix). The study was approved by the institu-
tional review boards of the Johns Hopkins Medical Institutions and
the Maryland Medical Research Institute and at each of the clinical
sites. All patients gave written consent for participation.
The original plan was to follow all patients until a uniform closing
date, two years after the last patient was enrolled; however, because
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1318
THE NEW ENGLAND JOURNAL OF MEDICINE
May 18, 1995
the study ended early, only 134 of the 299 patients enrolled had fin-
ished two years of follow-up.
Eligibility Criteria
To be eligible, the patients had to be at least 18 years old and had
to have sickle cell anemia; patients known to have sickle cell–b -thal-
assemia and sickle cell–b°-thalassemia were excluded, but those with
sickle cell–a-thalassemia were not. If patients had received transfu-
sions, hemolysates of their red cells could not contain more than 15
percent hemoglobin A at the time treatment was initiated. The pa-
tients had to have reported at least three crises to the study physician
in the year before entry into the study; for purposes of eligibility, doc-
umentation of crises was not necessary. There was no upper limit on
the number of crises per year.
Other reasons for exclusion from the study included pregnancy;
known narcotic addiction or regular consumption of more than 30
oxycodone capsules (or the equivalent) every two weeks; participa-
tion in a long-term program of transfusion; concurrent treatment
with another potential antisickling agent; pretreatment blood counts
that could not be distinguished from levels considered to indicate
marrow depression; a history of stroke during the preceding six years;
prior hydroxyurea therapy; and the presence of antibody to the hu-
man immunodeficiency virus (HIV).
Titration of Treatment Dose and Laboratory Analyses
After an initial four-week run-in period, during which only folic
acid tablets were dispensed, the patients were randomly assigned to
a treatment group. Hydroxyurea (provided in powder form by Bris-
tol-Myers Squibb) and placebo (Starch 1500) were encapsulated by
Johns Hopkins Manufacturing Pharmacy into 200-mg and 500-mg
capsules and dispensed to the clinics by the treatment distribution
center. Patients assigned to hydroxyurea received an initial dose of 15
mg per kilogram of body weight per day, and the dose was increased
by 5 mg per kilogram per day every 12 weeks, unless marrow depres-
sion (indicated by a neutrophil count below 2000 per cubic millimeter,
a reticulocyte or platelet count below 80,000 per cubic millimeter, or
a hemoglobin level below 4.5 g per deciliter) was present. If marrow
depression occurred, treatment was stopped until blood counts recov-
ered; it was then resumed at a dose that was 2.5 mg per kilogram
lower than the dose associated with marrow depression, starting a
new 12-week cycle. The dose of placebo was adjusted by the data co-
ordinating center in a similar manner in order to maintain blinding.
All patients were given 1 mg of folic acid per day. At each follow-up
visit, the capsules were counted and patients were asked whether they
had had any adverse effects.
The patients were seen every two weeks, and blood samples were
shipped to Baltimore and analyzed at Johns Hopkins Hospital. Fetal
hemoglobin and red cells containing fetal hemoglobin (F cells) were
assayed,
7
dense cells were counted,
11
and a-globin and b-globin DNA
were analyzed (at the Veterans Affairs Medical Center, Jackson,
Miss.) according to previously described methods.
12
Primary Outcome
A painful crisis was defined as a visit to a medical facility that last-
ed more than four hours for acute sickling-related pain (hereinafter
referred to as a medical contact), which was treated with a parenter-
ally administered narcotic (except for a few facilities in which only
orally administered narcotics were used); the definition is similar to
that used in a previous study.
9
The measurement of the length of the
visit included all time spent after registration at the medical facility,
including the time spent waiting to be seen by a physician. The oc-
currence of chest syndrome (chest-wall pain in association with find-
ings of a new pulmonary infiltrate on chest x-ray films and fever), pri-
apism, and hepatic sequestration (a sudden increase in liver size
associated with pain in the right upper quadrant, a decrease in the
hemoglobin concentration of at least 2 g per deciliter, and more ab-
normal results of liver-function tests not due to biliary tract disease)
was considered a crisis; the occurrence of hematuria and exacerba-
tions of chronic pain was not.
Ascertainment and Classification of Crises
Patients filled out daily pain diaries, recording the severity of pain,
use of analgesics, and visits to medical facilities. These diaries were
reviewed at each clinic visit by members of the clinic staff. The data
coordinating center cross-checked the information obtained during
the clinic visits every two weeks with the information gathered during
monthly telephone inquiries to patients by a coordinator in the central
office who was unaware of the patients’ treatment assignments, and
the clinics were required to resolve discrepancies between the reports.
Site visits were made to each clinic, original medical records were re-
viewed, and medical contacts that were not reported by the clinic
staff were required to be reported to the data coordinating center.
Reports of medical contacts and all associated documents were in-
dependently reviewed by two members of a crisis review committee
(composed of hematologists and general internists), who were un-
aware of patients’ treatment assignments. If they disagreed about
how to classify an event, the records were reviewed by a third com-
mittee member. With respect to the analyses on which the data safety
and monitoring board based its recommendation for early termina-
tion of the study, 97.4 percent of the medical contacts were classified.
Blinding
Neither the patients nor the investigators and staff members at the
clinical sites were aware of the patients’ treatment assignments. Be-
cause knowledge of repeated measurements of a patient’s mean cor-
puscular volume or fetal hemoglobin level might make the treatment
assignments apparent to staff members, such measurements were
made at the central laboratory. Clinic staff members agreed not to
look at the results of tests requested by other clinicians at their insti-
tutions. Treatment assignments could be revealed if knowledge of
the assignment would alter a patient’s subsequent medical care (e.g.,
if a patient or a patient’s partner became pregnant). In such cases,
the study treatments were stopped, but we continued to follow the pa-
tients and to count their crises.
Data Safety and Monitoring Board
A board appointed by the National Heart, Lung, and Blood Insti-
tute approved the protocol, reviewed each clinic’s consent form, pro-
vided advice, and oversaw patient safety and the progress of the
study. The board was composed of four hematologists, two biostatis-
ticians, an ethicist, and an educator–patient advocate. It was empow-
ered to recommend the discontinuation of the study and did so when
interim analyses showed hydroxyurea to be effective.
Statistical Analysis
All patients were included in the primary analysis according to
their original treatment assignments. Treatment groups were com-
pared on the basis of annual crisis rates. The primary end-point
analysis was to be a two-sided comparison at an overall alpha level
of 0.05.
Annual rates were computed by dividing the number of crises by
the number of years elapsed (e.g., 6 crises in 1.9 years 3.16 crises
per year). To test the effect of treatment on the crisis rate, the pa-
tients were ranked according to the number of crises they had had
per year for observed periods of up to two years. Death was consid-
ered the worst outcome, followed by a stroke (defined as a document-
ed new neurologic deficit lasting more than 24 hours, confirmed by a
neurologist) or the institution of long-term transfusion therapy (more
than four months); outcomes for all other patients were ranked ac-
cording to the individual crisis rate. These ranks were used to com-
pare the two treatment groups (Van der Waerden’s test).
13
A rank
statistic was planned for the primary analysis because it was expect-
ed to have more power to detect differences and to be less influenced
by extreme values than a t-test of the means.
Four interim analyses were planned to be conducted every six
months after enrollment began. To take into account multiple exam-
inations of the data,
14
a P value of less than 0.001 was specified for
the differences between groups to reject the null hypothesis at each
of the planned interim analyses, and a P value of less than 0.046 was
required at the final analysis.
In secondary analyses, for discrete variables, chi-square tests were
used to compare the frequency of specific characteristics.
15
For con-
tinuous data, mean values were compared by analysis of variance
and linear regression.
16
Cumulative event rates were estimated by the
product-limit (Kaplan–Meier) method,
17
and the log-rank statistic
was used to compare the distributions of events over time.
17
An inter-
action term, testing whether the effect of hydroxyurea changed with
time, was assessed by Cox proportional-hazards models.
18
To adjust
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Vol. 332 No. 20
HYDROXYUREA AND FREQUENCY OF PAINFUL CRISES IN SICKLE CELL ANEMIA
1319
for multiple tests of the data in secondary analyses, two-sided tests
with P values between 0.01 and 0.001 were considered to provide
some evidence of significant differences between groups, and tests
with P values below 0.001 were considered to provide strong evidence
of such differences.
This report is based on events that occurred between the start
of treatment on January 28, 1992, and June 30, 1994, 10 months
before the planned end of the study. The data were obtained from a
file updated in December 1994; analyses were performed with SAS
software.
R
ESULTS
Characteristics of the Patients
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). After
treatment had begun, one patient in the hydroxyurea
group was discovered to have sickle-cell–b -thalasse-
mia (a small amount of hemoglobin A was present).
Results According to Treatment Assignment
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. 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). When only crises severe
enough to cause hospitalization were considered, the
median annual rates were 1.0 and 2.4, respectively
(P 0.001).
The incidence of death, stroke, and hepatic seques-
tration did not differ significantly in the two groups. 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).
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). 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).
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. By the time the study end-
ed, 51 percent of the patients treated with hydroxy-
urea were receiving the maximal tolerated doses, and
doses for the remainder of patients were nearly max-
imal. 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. Capsule counts suggested that about 75 per-
cent of the patients took more than 80 percent of their
capsules. During the dose titration, blood counts consis-
tent with a finding of marrow depression were observed
at least once in 35 percent of the patients who received
placebo.
Hemoglobin levels, mean corpuscular volumes, fetal
hemoglobin levels, and proportions of F cells were high-
er 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. Differ-
ences between the groups in the mean corpuscular vol-
ume 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).
Safety
No deaths were related to treatment with hydroxy-
urea (Table 3). No neoplastic disorders developed dur-
Table 1. Characteristics of the Patients at Base
Line, According to Treatment Group.
C
HARACTERISTIC
H
YDROXYUREA
(N 152)
P
LACEBO
(N 147)
No. of crises in the year before study
entry (% of patients)
3–5
6–9
10
44
26
30
44
21
35
Complications of sickle cell anemia
(% of patients)
Chest syndrome
Ankle ulcer
Aseptic necrosis of bone
66
31
20
65
33
22
Hemoglobin (g/dl)
8.4
8.5
Mean corpuscular volume (mm
3
)
94
93
White cells (10
3
/mm
3
)
12.6
12.3
Platelets (10
3
/mm
3
)
468
457
Reticulocytes (10
3
/mm
3
)
327
325
Fetal hemoglobin (%)
5.0
5.2
F cells (%)
33
33
Dense cells (%)
14.3
14.0
*P 0.001 (by Van der Waerden’s two-sample test).
Table 2. Annual Rates of Painful Crises According
to Treatment Group.
T
YPE OF
C
RISIS
H
YDROXYUREA
P
LACEBO
rate per year
All crises*
Minimal value
25th percentile
Median value
75th percentile
90th percentile
95th percentile
Maximal value
0.0
0.6
2.5
7.0
12.7
16.7
49.5
0.0
2.0
4.5
10.2
16.3
24.0
57.0
Crises requiring hospitalization*
Minimal value
25th percentile
Median value
75th percentile
90th percentile
95th percentile
Maximal value
0.0
0.0
1.0
3.5
7.0
9.5
17.0
0.0
0.6
2.4
5.0
10.8
14.9
52.2
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1320
THE NEW ENGLAND JOURNAL OF MEDICINE
May 18, 1995
ing the study. 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. Treatment was temporarily stopped in almost
all patients in the hydroxyurea group because of mar-
row depression; blood counts usually recovered within
two weeks.
In 12 patients who did not receive transfusions (11
in the hydroxyurea group), hemoglobin levels repeated-
ly exceeded 12.8 g per deciliter, a potentially adverse ef-
fect because of increased blood viscosity (if fetal he-
moglobin levels in red cells were not high enough to
inhibit sickling in vivo). Four patients assigned to hy-
droxyurea and five patients assigned to placebo had
platelet counts of more than 800,000 per cubic millime-
ter. In no case was morbidity associated with a high he-
moglobin concentration or platelet count.
Treatment was interrupted in four patients in the
placebo group because of increased bilirubinemia (bil-
irubin, 10 mg per deciliter [103 mmol per liter]). Hair
loss, rash, fever, and gastrointestinal disturbance were
as common in patients receiving placebo as in those
taking hydroxyurea. In six patients (one in the hydroxy-
urea group) parvovirus B19 infection developed during
treatment; the aplastic crises caused by the virus were
not prolonged, and all the patients recovered unevent-
fully.
Pregnancies occurred in 10 patients or their partners
(Table 3). These patients were informed of their treat-
ment assignments and counseled. Their study treat-
ments were stopped, but they continued to be seen for
follow-up. All live-born babies appeared to be normal.
D
ISCUSSION
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. This result is both
clinically meaningful and statistically significant. Re-
ductions in the frequency of chest syndrome and the
number of transfusions strengthen the conclusion that
hydroxyurea is a useful agent in sickle cell anemia. We
did not address the reversibility of chronic organ dam-
Figure 1. Median Time from the Initiation of Treatment to the First
(Panel A) and Second (Panel B) Painful Crises, According to
Treatment Group.
Painful crises occurred later in patients receiving hydroxyurea
than in those receiving placebo, and the effect was evident in
less than six months.
Figure 2. Measurements of Mean Corpuscular Volume (Panel A)
and F Cells (Panel B) in Patients Who Received Hydroxyurea
(Solid Bars) or Placebo (Open Bars).
At each point, the median value, the 25th and 75th percentiles
(upper and lower limits of boxes), and the maximal and minimal
values (vertical lines) are shown.
Cumulative Event Rate (%)
100
90
80
70
60
50
40
30
20
10
0
0
4
8
12
16
20
24
Placebo
Hydroxyurea
P 0.001
Months of Treatment
Cumulative Event Rate (%)
100
90
80
70
60
50
40
30
20
10
0
0
4
8
12
16
20
24
Placebo
Hydroxyurea
P 0.01
Months of Treatment
B
A
Mean Corpuscular Volume (
m
m
3
)
60
70
80
90
100
110
120
130
140
150
0 8 16 24 32 40 48 56 64 72 80 88 96 104
Weeks of Treatment
A
F Cells (%)
0 8 16 24 32 40 48 56 64 72 80 88 96 104
Weeks of Treatment
100
90
80
70
60
50
40
30
20
10
0
B
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Vol. 332 No. 20
HYDROXYUREA AND FREQUENCY OF PAINFUL CRISES IN SICKLE CELL ANEMIA
1321
age; it is unknown whether the inhibition of sickling
could affect such preexisting lesions.
19
This study was designed to measure clinical respons-
es among patients treated with maximal tolerated dos-
es of hydroxyurea. 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). 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. Our under-
standing of the effect of hydroxyurea is too limited to
permit such a conclusion, but evaluation of alternative
dosage regimens is clearly needed.
The mechanism by which hydroxyurea reduced the
frequency of vaso-occlusive crises is unclear. The pro-
portion of F cells rose between 8 and 24 weeks (Fig. 2),
and changes in the mean corpuscular volume also oc-
curred at this time. 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
20
is only one way in which hydroxyurea can
affect sickle cell anemia. The increase in mean corpus-
cular volume during hydroxyurea treatment is primari-
ly due to an increase in the hemoglobin content of the
cells, but it may also reflect altered properties of red-
cell membranes. Other explanations of the antisickling
effect of hydroxyurea are increased water content of
red cells,
21
with secondarily increased deformability,
22
and decreased adhesion of red cells to endothelium.
23
Used carefully, with frequent monitoring, hydroxy-
urea therapy was safe. Hematopoietic depression did
occur during therapy, as anticipated, but it was short-
lived. Adverse reactions were equally common in both
treatment groups. In no instance could the death of a
study patient be related to treatment with hydroxyurea.
Patients known to have antibodies to HIV were ex-
cluded from the study, but there is no evidence that hy-
droxyurea is harmful to such persons. A recent report
suggests that hydroxyurea can inhibit the replication of
HIV in vitro, but the clinical implications of those find-
ings are unknown.
24
The safety of hydroxyurea therapy in pregnancy is
unclear. In animals, very large doses ( 250 mg per kil-
ogram) are teratogenic,
25,26
possibly as a result of in-
terference with uterine blood flow.
27,28
The cytologic ap-
pearance of mouse sperm is altered by doses exceeding
25 mg per kilogram,
29
but no abnormalities have been
described in the offspring of male mice treated with
hydroxyurea. Normal pregnancies have been reported
in five women who took hydroxyurea for chronic mye-
locytic leukemia,
30
and there have been no reports of
teratogenesis or mutagenesis in humans. The children
born to our patients have shown no evidence of birth
defects or developmental abnormalities to date.
There is concern that long-term hydroxyurea thera-
py may be carcinogenic or leukemogenic, because some
other antineoplastic agents have such effects. Hydroxy-
urea blocks the synthesis of DNA by inhibiting ribonu-
cleotide reductase. Its cytostatic effects thus differ from
those of radiation, alkylating agents, and other antican-
cer drugs.
31,32
The incidence of leukemia in patients
treated with hydroxyurea for polycythemia vera has
been reported by the Polycythemia Vera Study Group.
33
They compared 51 hydroxyurea-treated patients who
had received no prior therapy with 134 previously un-
treated patients who were treated by phlebotomy alone.
In the most recent report,
34
the incidence of acute leu-
kemia 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). Reports of leukemia in smaller groups of
hydroxyurea-treated patients with polycythemia vera
continue to arouse concern about the leukemogenic ef-
fect of the drug.
35,36
However, the relevance of these re-
ports to sickle cell anemia is unclear because of the in-
herent tendency of myeloproliferative diseases to evolve
into acute leukemia.
Perhaps more relevant to our study is the report on
a group of 64 patients with erythrocytosis due to inop-
erable cyanotic congenital heart disease who were treat-
ed 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).
37
Cancer or leukemia did not develop in
any of the patients during the period of observation.
The uncertain safety of long-term hydroxyurea therapy
with respect to leukemogenesis must be carefully bal-
anced against its anticipated benefit.
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 prog-
ress. It is not approved by the Food and Drug Admin-
istration for the prevention of crises, and short-term
and long-term use of this drug is potentially dangerous.
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 moni-
toring and can appreciate the still unclear long-term
risks of such treatment.
Table 3. Number of Deaths, Reasons for Stopping
Treatment Permanently, and Pregnancies in the
Two Groups of Patients as of June 30, 1994.
H
YDROXYUREA
P
LACEBO
number
Death
Intracranial bleeding
Cardiorespiratory arrest
Acute renal failure
Pulmonary edema
Homicide
2
1
1
0
0
0
5
0
1
1
2
1
Permanent cessation of treatment
Long-term transfusion therapy
Acute renal failure
Fulminant hepatitis
Myelotoxicity at a dose of 2.5 mg
of hydroxyurea/kg/day
Overdose by patient
14
2
1
1
2
2
6
2
0
0
—
0
Pregnancy
Patients
Normal full-term delivery
Elective termination
Partners of patients
Normal full-term delivery
Spontaneous abortion
Still pregnant
1
2
2
1
0
2
1
0
0
1
Copyright © 1995 Massachusetts Medical Society. All rights reserved.
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Page 6

1322
THE NEW ENGLAND JOURNAL OF MEDICINE
May 18, 1995
We are indebted to the study patients and their families for their
enthusiasm and cooperation.
A
PPENDIX
The following institutions and investigators participated in the
Multicenter Study of Hydroxyurea in Sickle Cell Anemia:
Clinical Centers (the numbers in parentheses are the numbers of
patients enrolled at each center) — University of North Carolina, Chapel
Hill (19): E. Orringer, S. Jones, and D. Strayhorn; Duke University,
Durham, N.C. (16): W. Rosse, G. Phillips,* D. Peace, and A. Johnson-
Telfair; Medical College of Georgia, Augusta (15): P. Milner, A. Kutlar,
and A. Tracy; Thomas Jefferson University, Philadelphia (21): S.K. Bal-
las, G.E. Allen, J. Moshang, and B. Scott; University of Mississippi,
Jackson (19): M. Steinberg, A. Anderson, and V. Sabahi; University of
Miami, Miami (12): C. Pegelow, D. Temple, E. Case, R. Harrell, and
S. Childerie; San Francisco General Hospital, San Francisco (6): S. Em-
bury, B. Schmidt, and D. Davies; University of Illinois, Chicago (57):
M. Koshy, N. Talischy-Zahed, L. Dorn, G. Pendarvis, and M. McGee;
Michael Reese Hospital, Chicago (11): M. Telfer and A. Davis; Howard
University, Washington, D.C. (20): O. Castro, H. Finke, E. Perlin, and
J. Siteman; University of Medicine and Dentistry of New Jersey, Newark
(10): P. Gascon, P. di Paolo, and S. Gargiulo; Emory University, Atlanta
(14): J. Eckman, J.H. Bailey, A. Platt, and L. Waller; St. Luke’s–
Roosevelt Medical Center, New York (18): G. Ramirez, V. Knors, S. Her-
nandez, E.M. Rodriguez, and E. Wilkes; Children’s Hospital of Oak-
land, Oakland, Calif. (5): E. Vichinsky, S. Claster, A. Earles, K. Kle-
man, and K. McLaughlin; Medical College of Virginia, Richmond (19):
P. Swerdlow, W. Smith, B. Maddox, L. Usry, A. Brenner, K. Williams,
R. O’Brien, and K. Genther; Case Western Reserve University, Cleveland
(5): S. Shurin, B. Berman, K. Chiarucci, and L. Keverline; Hospital
for Sick Children, Toronto (6): N. Olivieri, D. Shaw, and N. Lewis;
Brigham and Women’s Hospital, Boston (5): K. Bridges, B. Tynan, and
C. Winograd; Interfaith Medical Center, Brooklyn, N.Y. (8): R. Bellevue,
H. Dosik, M. Sheikhai, P. Ryans, and H. Souffrant; University of Ala-
bama, Birmingham (8): J. Prchal, J. Braddock, and T. McArdle; and
University of Pittsburgh, Pittsburgh (5): T. Carlos, A. Schmotzer, and
D. Gardner.
Central Office Staff (Johns Hopkins University, Baltimore) —
S. Charache, R. Moore, G. Dover, M. Bergner,* C. Ewart, S. Eckert,
C. Lent, J. Ullrich, L. Fishpaw, G. Tirado, J. Gibson, T. Moeller, and
T. Nagel.
Data Coordinating Center (Maryland Medical Research Insti-
tute, Baltimore) — M. Terrin, F.B. Barton, R.P. McMahon,
C. Handy, D. Harris, M. Canner, J. Depkin, N. Meinert, M. Carroll,
R. Giro, S. Karabelas, and C. Kelly.
Crisis Review Committee — Active Members: M. Heyman, P. Bei-
linson, M. Druskin, P. Ellis, W.A. Flood, S. Kravitz, S. Lanzkron,
V. Lorica, A. Moliterno, A. Nahum, J.A. Nesbitt III, L. Rosenthal,
W. Sharfman, M. Streiff, and M. Wachsman; Former Members: P. Bray,
C. Van Dang, J. Casella, M. McGuire, L. Patrick, H. Schaad, and
C. Steiner.
Data and Safety Monitoring Board — C. Johnson, A. Bank,
G. Cutter, C.E. Davis, O. Huntley, L. Lessin, O. Platt, and M. Gray-
Secundy.
Project Office (National Heart, Lung, and Blood Institute, Be-
thesda, Md.) — D. Bonds, C. Reid, N. Geller, and M. Waclawiw.
*Deceased.
R
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