Context Hydroxyurea increases levels of fetal hemoglobin (HbF)
and decreases morbidity from vaso-occlusive complications in patients
with sickle cell anemia (SCA). High HbF levels reduce morbidity and
mortality.
Objective To determine whether hydroxyurea attenuates mortality in
patients with SCA.
Design Long-term observational follow-up study of mortality in
patients with SCA who originally participated in the randomized,
double-blind, placebo-controlled Multicenter Study of Hydroxyurea in
Sickle Cell Anemia (MSH), conducted in 1992-1995, to
determine if hydroxyurea reduces vaso-occlusive events. In the MSH
Patients' Follow-up, conducted in 1996-2001, patients could continue,
stop, or start hydroxyurea. Data were collected during the trial and in
the follow-up period.
Setting Inpatients and outpatients in 21 sickle cell referral
centers in the United States and Canada.
Patients Two-hundred ninety-nine adult patients with frequent
painful episodes enrolled in the follow-up. Follow-up data through
May 2001 were complete for 233 patients.
Intervention In the MSH, patients were randomly assigned to
receive hydroxyurea (n = 152) or placebo (n = 147).
Main Outcome Measure Mortality, HbF levels, painful episodes,
acute chest syndrome, and blood cell counts. The randomized trial was
not designed to detect specified differences in mortality.
Results Seventy-five of the original 299 patients died, 28% from
pulmonary disease. Patients with reticulocyte counts less than
250 000/mm3 and hemoglobin levels lower than 9 g/dL
had increased mortality (P = .002).
Cumulative mortality at 9 years was 28% when HbF levels were lower
than 0.5 g/dL after the trial was completed compared with 15% when HbF
levels were 0.5 g/dL or higher
(P = .03 ). Individuals who had acute
chest syndrome during the trial had 32% mortality compared with 18%
of individuals without acute chest syndrome
(P = .02). Patients with 3 or more
painful episodes per year during the trial had 27% mortality compared
with 17% of patients with less frequent episodes
(P = .06). Taking hydroxyurea was
associated with a 40% reduction in mortality
(P = .04) in this observational follow-up with
self-selected treatment. There were 3 cases of cancer, 1 fatal.
Conclusions Adult patients taking hydroxyurea for frequent painful
sickle cell episodes appear to have reduced mortality after 9 of years
follow-up. Survival was related to HbF levels and frequency of
vaso-occlusive events. Whether indications for hydroxyurea treatment
should be expanded is unknown.
Acute chest syndrome and painful episodes are the most common precedents
of death in adults with sickle cell anemia (SCA).1 A
randomized, double-blinded, placebo-controlled trial, the Multicenter Study
of Hydroxyurea in Sickle Cell Anemia (MSH), showed that, over 2.5 years, hydroxyurea
diminished the morbidity of SCA in adults with frequent painful episodes by
reducing the incidence of painful episodes and acute chest syndrome by nearly
half.2,3 Hydroxyurea increased
fetal hemoglobin (HbF) concentration while hemolysis was diminished and neutrophil
counts fell.3,4 In SCA, HbF levels
are inversely related to mortality.1 Decreased
morbidity due to hydroxyurea could be associated with reduced mortality. Following
the completion of the MSH, patients enrolled in an observational follow-up
study, selecting with their physicians whether to continue, start, or stop
treatment with hydroxyurea. Follow-up focused on detecting potential complications
of treatment such as neoplasia and cerebrovascular disease, and on ascertaining
the causes of death. Cumulative mortality was analyzed according to exposure
to hydroxyurea and data from the MSH on acute chest syndrome, acute painful
episodes, HbF levels, reticulocyte counts, and neutrophil counts, assessed
both before randomization and at the conclusion of the trial.
The MSH Patients' Follow-up is an observational study of inpatients
and outpatients in 21 sickle cell referral centers in the United States and
Canada who participated from 1992 to 1995 in the MSH to test whether hydroxyurea
could reduce the number of vaso-occlusive events in adults with moderate to
severe SCA.5 Requirements for MSH entry included
a history of more than 3 painful episodes in the 12 months prior to enrollment
and pretreatment hemoglobin levels and reticulocyte counts that would not
contraindicate treatment with hydroxyurea. Definitions of painful episodes
and acute chest syndrome have been published.2 In
the follow-up study, after consultation with their physicians, patients were
free to continue, start, or stop treatment with hydroxyurea. From 1996 through
2001, patients were seen yearly for the purposes of the follow-up study (most
patients were seen more often for medical care) when data on hydroxyurea use
and reportable events including stroke, renal failure, hepatic failure, cancer,
and sepsis were collected. Fatal events and serious illnesses were documented
from medical records. Central review of medical records, and autopsy results
when these were available, were completed to establish causes of death. Patients
provided internal review board–approved written informed consent for
enrollment in the follow-up study.
Methods for blood cell counts and measurement of HbF levels have been
previously reported.2,3,5,6 A
single pretreatment value for each laboratory determination was computed by
averaging all pretreatment values of that measurement for each patient. A
single 2-year value was computed by averaging available data during the final
18 to 24 months of study treatment.2 Levels
of HbF were expressed as absolute levels of HbF in g/dL (HbF [g/dL] = HbF
[%] × hemoglobin concentration [g/dL]) because no biological mechanism
of HbF production exists that would regulate HbF as a percentage of total
hemoglobin.
Patients were grouped for comparisons in a variety of ways, including
the treatment group (hydroxyurea or placebo) to which they were originally
assigned, and according to characteristics measured later during the MSH,
such as HbF level and painful crisis rate at 2 years. For discrete variables, χ2 tests were used to compare the frequency of patient characteristics.7 Continuous measurements are presented as mean (SD)
and compared using analysis of variance.8
Mortality in 3-month intervals was assessed using general estimating
equation logistic models based on hydroxyurea usage (yes or no) during each
interval.9 Analyses were performed using SAS
v7.6 (SAS Institute Inc, Cary, NC). Mortality is also reported as cumulative
9-year event rate from Kaplan-Meier survival curves.10 Differences
in mortality between patients randomly assigned to receive hydroxyurea and
those assigned to receive placebo (ie, intention-to-treat analyses) and between
post hoc groups (eg, HbF levels at 2 years) were tested with the log-rank
statistic.10 Patients were censored at the
time they were last documented to be alive by clinical center staff. Hydroxyurea
usage was measured as taken, not taken, or unknown for each month during the
trial and follow-up period until the patient died or was censored, and was
summarized as total months of taking hydroxyurea (never, <1 year, or ≥1
year).
The MSH was not designed to detect specified differences in mortality.
Because of multiple testing that has occurred in secondary analyses of data
from these patients, the strength of statistical evidence for differences
between the original treatment groups was predetermined at a more stringent
level than the primary end point trial design of α = .05.5 Observed
differences carrying a nominal P value of less than
.05 should not be taken as conclusive evidence of a difference. Because inference
is not formal with the comparisons presented now—most of which are observational
and not randomized—the nominal P values should
be regarded as indicators of association, not tests of a priori hypotheses,
and should be interpreted cautiously.
Follow-up data for up to 9 years through May 2001 were complete for
233 (77.9%) of the 299 patients enrolled in the long-term follow-up. Eight
patients died during the randomized trial (2 receiving hydroxyurea, 6 receiving
placebo). Hydroxyurea use in follow-up is unknown for 13 patients (4.3%) originally
randomly assigned to receive hydroxyurea and for 15 patients (5.0%) assigned
to receive placebo. Vital status was not entered into our database for 27
patients (9.0%).
Many patients were treated with hydroxyurea for at least 1 year since
the start of the trial (Table 1).
Ninety-six (32%) patients never received hydroxyurea; 48 (16%) received hydroxyurea
for less than 1 year and 156 (52%) received hydroxyurea for 1 or more years.
Twenty-five percent of patients (n = 75) who volunteered for the MSH died
during the trial or follow-up, reflecting the severity of disease, which was
a criterion for enrollment, and the high death rate in adult SCA.1 Twenty-eight percent of these deaths were due to pulmonary
complications (Table 2).
When analyzed according to the original assignment (regardless of the
patient's choice of treatment after the randomized phase of the study was
completed), mortality was similar in the original 2 treatment groups (P = .35; Figure 1,
A). Cumulative mortality analyzed according to clinical events and laboratory
measurements at the conclusion of randomized treatment is shown in Figure 1 (panels B-F). Of 276 patients who
had HbF levels measured approximately 2 years into the MSH, patients with
HbF levels lower than 0.5 g/dL had a 28% cumulative mortality through 9 years
compared with 15% mortality in patients whose HbF levels were 0.5 g/dL or
higher (P = .03 by log-rank test; Figure 1, B). The effect on mortality was similar when HbF levels
lower than 0.75 g/dL and those 0.75 g/dL or higher were analyzed. Cumulative
mortality through 9 years in the 199 patients with pretreatment HbF levels
lower than 0.5 g/dL was 32% compared with 15% mortality in patients whose
pretreatment HbF levels were 0.5 g/dL or higher (P =
.01). Before treatment, 68% of patients randomly assigned to receive hydroxyurea
and 65% of those assigned to receive placebo had HbF levels of lower than
0.5 g/dL. When the trial was completed, 38% of the patients assigned to receive
hydroxyurea with initial HbF levels lower than 0.5 g/dL had HbF levels 0.5
g/dL or higher. In contrast, only 8% of patients receiving placebo with baseline
HbF levels lower than 0.5 g/dL had final HbF levels 0.5 g/dL or higher.
Neutrophil counts before random assignment and treatment were not associated
with differences in mortality. Neutrophil counts above or below 5000/mm3 at the end of the clinical trial also did not predict mortality (P = .70 by log-rank test; Figure 1, C), although aggressive titration with hydroxyurea affects
neutrophil counts. Similarly, neutrophil counts above or below 7000/mm3 did not affect mortality. Reticulocyte counts before randomization
did not predict mortality. Patients with absolute reticulocyte counts less
than 250 000/mm3 after 2 years of treatment had a cumulative
mortality of 37% compared with 18% for individuals with 250 000/mm3 or more (P = .001). A subgroup of 63 patients
with reticulocyte counts less than 250 000/mm3 and hemoglobin
concentrations lower than 9 g/dL had increased cumulative mortality up to
9 years of observation (38% dead at 9 years, P =
.002 by log-rank test; Figure 1,
D) They also had lower HbF levels (0.42 g/dL vs 0.62 g/dL; P = .005), higher mean (SD) serum creatinine levels (1.49 [1.77] vs
0.96 [0.23] mg/dL [131.7 {156.5} vs 84.9 {20.3} µmol/L]; P = .02) and received lower doses of hydroxyurea compared with other
patient groups (Table 3).
Patients with no episodes of acute chest syndrome during the trial had
a mortality of 18% compared with 32% in patients who had 1 or more episodes
(P = .02; Figure
1, E). Individuals with fewer than 3 annual painful episodes during
the clinical trial had a mortality of 17% compared with 27% in patients with
3 or more episodes annually (P = .06; Figure 1 1F).
As shown in Table 4, total
months of exposure to hydroxyurea were related to original treatment assignment,
duration of survival in follow-up, and choice of treatment in follow-up. By
analyzing mortality in 3-month intervals according to hydroxyurea usage in
the interval, death rates were reduced 40% during 3-month intervals when patients
were taking hydroxyurea [2.6 (5.8) deaths per 3-month period vs 1.5 (7.9)
deaths per 3 months; P = .04)].
Three patients developed cancer. One individual who was randomly assigned
to receive placebo, but who subsequently received hydroxyurea for 63 months,
had carcinoma in situ of the uterine cervix at 7 years after randomization.
A patient randomly assigned to hydroxyurea had 47 months of exposure to hydroxyurea
in 3 periods: for less than 1 year during the MSH, after the clinical trial,
and after mastectomies 3 years later. She had a history of fibrocystic disease
of the breast and had had prophylactic bilateral mastectomies. Histological
examination showed multifocal carcinoma in situ in the left breast. Both patients
died of causes unrelated to carcinoma. A third patient randomly assigned to
hydroxyurea who received long-term treatment was diagnosed with and died from
endometrial carcinoma after the completion of 9 years of follow-up.
Fourteen patients had stroke; 8 in the original hydroxyurea group and
6 in the original placebo group (Table 1). Eleven of these patients had more than 1 year of exposure to
hydroxyurea, 2 had less than 1 year of exposure, and one had unknown exposure
prior to the event—results consistent with the number of years of hydroxyurea
treatment accumulated across the MSH Patient's Follow-up.
The MSH was designed to test whether hydroxyurea reduced the incidence
of vaso-occlusive episodes in SCA and not to detect differences in mortality
between treatment groups. However, our follow-up studies suggest that adults
with moderate to severe SCA who take hydroxyurea have reduced mortality compared
with patients not taking this drug. Our estimated overall reduction in mortality
up to 9 years of observation is 40%. These results must be interpreted cautiously.
Comparisons of patients receiving and not receiving hydroxyurea were no longer
randomized after the initial treatment period of the MSH, so patients who
might receive more medical care and better follow-up while taking hydroxyurea
might live longer for reasons other than treatment. Moreover, assessment of
the effect of hydroxyurea on mortality in an observational study is complex.
The ability to take hydroxyurea (a predictor) is dependent on being alive
(an outcome). Also, patients in the MSH were not typical of all adults with
SCA; their average age was 32 years and they were selected for the trial because
of frequent painful episodes, a predictor of mortality.1,5 However,
it is compelling that patients who had marked clinical benefit, reduced crises,
reduced chest syndrome, and a good bone marrow reserve after 2 years of receiving
hydroxyurea as randomized were the ones with reduced mortality in follow-up
(Figure 1). This, coupled with the
more direct, albeit observational, comparison of 3 months receiving hydroxyurea
vs 3 months not receiving the drug is consistent with a long-term salutary
effect of hydroxyurea on mortality.
How hydroxyurea affects morbidity and mortality in young children or
individuals with less severe disease is unknown. Clinical trials of hydroxyurea
have not been conducted in patients with HbSC disease, another clinically
important sickle hemoglobinopathy.11
There were no appreciable differences for mortality or the clinical
events reported here in follow-up between the 2 initial treatment groups.
The clearest test of whether hydroxyurea has an impact on mortality in SCA
would be a controlled study in children that could provide definitive data
on long-term mortality effects. However, the death rate in children is lower
than in older adults. Since hydroxyurea is likely to have similar short-term
beneficial effects in children and adults, prolonged follow-up of a group
of children receiving placebo may not be acceptable to families. In 93 patients
with SCA, 87 of whom were younger than 20 years at the start of treatment,
no severe adverse effects of treatment were found after a median of 3.5 years
of observation.12
Hydroxyurea reduces some vaso-occlusive complications of SCA.2 While its mechanism of action is incompletely understood,
hydroxyurea is associated with increased levels of HbF in SCA; increased levels
of HbF are known to improve survival.1 In the
MSH and other studies, hydroxyurea reduced the incidence of acute chest syndrome
and acute painful episodes, events associated with increased mortality and
influenced by HbF concentrations.13-16 Levels
of HbF 0.5 g/dL or higher, absence of acute chest syndrome, and fewer than
3 painful episodes annually during the trial were each associated with nearly
a 50% reduction in mortality. Almost half of the classified deaths in our
study were due to pulmonary disease or sudden death during a painful episode.
Our observation of reduced mortality associated with hydroxyurea is consistent
with hydroxyurea reducing the incidence of these morbid events by nearly half
in the MSH.2 These observations also confirm
the link of HbF to mortality in sickle cell disease1 and
suggest that the ability of hydroxyurea to increase levels of HbF may be associated
with reduced mortality.
Besides HbF, proposed mediators of the clinical effectiveness of hydroxyurea
include reductions in adherent reticulocytes that may help initiate vaso-occlusion
and in leukocytes that might release proinflammatory cytokines.3,17 Neutrophil
counts have been associated with mortality in other diseases besides sickle
cell disease. Leukocytosis is a predictor of the extent of and sudden death
from coronary artery disease.18,19 Some
beneficial effects of hydroxyurea in SCA have been associated with reduction
in neutrophil counts during treatment.1,3 We
found no relationship between decrements in neutrophil counts—also a
predictor of HbF concentration in patients treated with hydroxyurea6—and mortality, but the Cooperative Study of
Sickle Cell Disease (CSSCD) found that lower leukocyte counts were associated
with longevity.1 In the MSH, hydroxyurea was
titrated to maximum tolerated doses that most often were the largest doses
that could be taken without neutropenia. Consequently, most patients taking
hydroxyurea developed some level of potentially dangerous neutropenia. Since
hydroxyurea was associated with a strong beneficial effect on painful crisis
frequency in the MSH, this design forced an association between neutropenia
and painful crisis frequency—low white blood cell counts being associated
with fewer crises. Since neutrophils are acute-phase reactants, the association
in the MSH is in the same direction as the association of neutrophil counts
with mortality in the CSSCD, but for a different reason. In the follow-up
study, doses of hydroxyurea used by the patients' physicians were less than
the maximum tolerated doses in the MSH. During the follow-up, hydroxyurea
effects, like increases in concentrations of HbF and total hemoglobin and
decreases in bilirubin levels, were observed without notable effects on leukocyte
counts (F.B., unpublished data). Although induction of neutropenia may play
some role in the beneficial effects of hydroxyurea for SCA, the follow-up
study data suggest that neutropenia is not a main mechanism of action.
Patients with reticulocyte counts less than 250 000/mm3 and
hemoglobin concentrations lower than 9 g/dL had increased mortality. These
individuals also had lower HbF levels, higher serum creatinine levels, and
received lower doses of hydroxyurea.20 This
combination of findings suggests that these patients had more severe disease
and perhaps reduced marrow reserve and that, as a result, they were unable
to tolerate sufficient hydroxyurea treatment to increase HbF levels.6 Anemia and reticulocytopenia may also be indications
of early renal failure that is associated with a poor prognosis.20
During the 9-year observation period we found little risk associated
with the careful use of hydroxyurea in SCA. Yet, hydroxyurea must be taken
indefinitely to be effective and is potentially mutagenic and carcinogenic.
Other investigators have reported that 5% to 10% of patients with polycythemia
vera and essential thrombocythemia, both preneoplastic myeloproliferative
diseases, who received hydroxyurea developed acute leukemia.21-28 Whether
or not this risk can be extrapolated to patients with SCA is uncertain. Three
reports of patients with SCA treated with hydroxyurea who developed acute
leukemia have been published, but the total number of patients treated is
unknown.29-31Our
data suggest that the risk of leukemia in patients with SCA treated with hydroxyurea
is much less than that observed in myeloproliferative disorders and that the
risk of death from the complications of sickle cell disease is at least 10
times greater than the incidence of leukemia in these patients.
Intracerebral hemorrhage, the main cause of stroke in adult SCA, occurs
at a rate of about 1 per 400 patient-years.32,33 Given
our number of patients under observation, we should have been able to detect
a doubling in the incidence of intracerebral hemorrhage, but no association
of stroke with hydroxyurea was found. Cerebrovascular mortality occurred more
frequently among patients originally assigned to hydroxyurea than placebo,
but was not related to use of hydroxyurea in follow-up.
Hydroxyurea increased HbF concentrations and diminished vaso-occlusive
complications in adults with moderate to severe SCA and these effects were
associated with decreased mortality. After up to 9 years of follow-up, unexpected
serious adverse effects of this treatment were not observed. Whether hydroxyurea
should be given to patients with SCA and fewer vaso-occlusive events or to
patients with HbSC disease remains to be determined. We conclude that underlying
disease severity remains critical to determining the prognosis of adult SCA,
but hydroxyurea may mitigate disease severity.
1.Platt OS, Brambilla DJ, Rosse WF.
et al. Mortality in sickle cell disease: life expectancy and risk factors
for early death.
N Engl J Med.1994;330:1639-1644.Google Scholar 2.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.Google Scholar 3.Charache S, Barton FB, Moore RD.
et al. Hydroxyurea and sickle cell anemia.
Medicine (Baltimore).1996;75:300-326.Google Scholar 4.Ballas SK, Marcolina MJ, Dover GJ, Barton FB. Erythropoietic activity in patients with sickle cell anaemia before
and after treatment with hydroxyurea.
Br J Haematol.1999;105:491-496.Google Scholar 5.Charache S, Terrin ML, Moore RD.
et al. Design of the multicenter study of hydroxyurea in sickle cell anemia.
Control Clin Trials.1995;16:432-446.Google Scholar 6.Steinberg MH, Lu Z-H, Barton FB.
et al. Fetal hemoglobin in sickle cell anemia: determinants of response to
hydroxyurea.
Blood.1997;89:1078-1088.Google Scholar 7.Feinberg SE. The Analysis of Cross-Classified Categorical Data. 2nd ed. Cambridge, Mass: The MIT Press; 1980.
8.Draper NR, Smith H. Applied Regression Analysis. New York, NY: John Wiley; 1966.
9.Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models.
Biometrika.1986;73:13-22.Google Scholar 10.Kaplan EL, Meier P. Non parametric estimation from incomplete observations.
J Am Stat Assoc.1958;53:457-481.Google Scholar 11.Steinberg MH, Nagel RL, Brugnara C. Cellular effects of hydroxyurea in Hb SC disease.
Br J Haematol.1997;98:838-844.Google Scholar 12.Ferster A, Tahriri P, Vermylen C.
et al. Five years of experience with hydroxyurea in children and young adults
with sickle cell disease.
Blood.2001;97:3628-3632.Google Scholar 13.Vichinsky EP, Neumayr LD, Earles AN.
et al. Causes and outcomes of the acute chest syndrome in sickle cell disease.
N Engl J Med.2000;342:1855-1865.Google Scholar 14.Vichinsky EP, Styles LA, Colangelo LH.
et al. Acute chest syndrome in sickle cell disease: clinical presentation
and course.
Blood.1997;89:1787-1792.Google Scholar 15.Castro O, Brambilla DJ, Thorington B.
et al. The acute chest syndrome in sickle cell disease: incidence and risk
factors.
Blood.1994;84:643-649.Google Scholar 16.Platt OS, Thorington BD, Brambilla DJ.
et al. Pain in sickle cell disease-rates and risk factors.
N Engl J Med.1991;325:11-16.Google Scholar 17.Bridges KR, Barabino GD, Brugnara C.
et al. A multiparameter analysis of sickle erythrocytes in patients undergoing
hydroxyurea therapy.
Blood.1996;88:4701-4710.Google Scholar 18.Kostis JB, Turkevich D, Sharp J. Association between leukocyte count and the presence and extent of
coronary atherosclerosis as determined by coronary arteriography.
Am J Cardiol.1984;53:997-999.Google Scholar 19.Friedman GD, Klatsky AL, Siegelaub AB. Predictors of sudden cardiac death.
Circulation.1975;52(suppl 6):III164-III169.Google Scholar 20.Powars DR, Elliott Mills DD, Chan L. Chronic renal failure in sickle cell disease: risk factors, clinical
course, and mortality.
Ann Intern Med.1991;115:614-620.Google Scholar 21.Weinfeld A, Swolin B, Westin J. Acute leukaemia after hydroxyurea therapy in polycythemia vera and
allied disorders.
Eur J Haematol.1994;52:134-139.Google Scholar 22.Nand S, Stock W, Godwin J, Fisher SG. Leukemogenic risk of hydroxyurea therapy in polycythemia vera, essential
thrombocythemia, and myeloid metaplasia with myelofibrosis.
Am J Hematol.1996;52:42-46.Google Scholar 23.Najean Y, Rain JD. Treatment of polycythemia vera: the use of hydroxyurea and pipobroman
in 292 patients under the age of 65 years.
Blood.1997;90:3370-3377.Google Scholar 24.Najean Y, Rain J-D. Treatment of polycythemia vera: use of
32P alone or in combination
with maintenance therapy using hydroxyurea in 461 patients greater than 65
years of age.
Blood.1997;89:2319-2327.Google Scholar 25.Fenaux P, Preudhomme C, Laï JL, Sterkers Y. Is hydroxyurea leukemogenic in essential thrombocythemia?
Blood.1998;92:1460-1461.Google Scholar 26.Sterkers Y, Preudhomme C, Laï JL.
et al. Acute myeloid leukemia and myelodysplastic syndromes following essential
thrombocythemia treated with hydroxyurea.
Blood.1998;91:616-622.Google Scholar 27.Liozon E, Brigaudeau C, Trimoreau F.
et al. Is treatment with hydroxyurea leukemogenic in patients with essential
thrombocythemia?
Hematol Cell Ther.1997;39:11-18.Google Scholar 28.Barbui T, Finazzi G, Ruggeri M, Rideghiero F. Secondary leukemia following hydroxyurea in patients with essential
thrombocythemia.
Blood.1998;92:489.Google Scholar 29.Wilson S. Acute leukemia in a patient with sickle-cell anemia treated with hydroxyurea.
Ann Intern Med.2000;133:925-926.Google Scholar 30.Rauch A, Borromeo M, Ghafoor A. Leukemogenesis of hydroxyurea in the treatment of sickle cell anemia.
Blood.1999;94:415.Google Scholar 31.Al Jam'a AH, Al Dabbous IA, Al Khatti AA, Esan FG. Are we underestimating the leukemogenic risk of hydroxyurea.
Saudi Med J.2002;23:1411-1413.Google Scholar 32.Anson JA, Koshy M, Ferguson L, Crowell RM. Subarachnoid hemorrhage in sickle-cell disease.
J Neurosurg.1991;75:552-558.Google Scholar 33.Ohene-Frempong K, Weiner SJ, Sleeper LA.
et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors.
Blood.1998;91:288-294.Google Scholar