The role of hydroxyurea in the management of sickle cell disease
The role of hydroxyurea in
the management of sickle
cell disease
Sally C Davies, Annette Gilmore
Imperial College Faculty of Medicine at Central Middlesex Hospital,
Acton Lane, London NW10 7NS, UK
Abstract Sickle cell disease (SCD) is one of the most
common genetic diseases with some 250,000 new births each
year. Most patients suffer intermittent pain crises and
life-threatening events while life expectancy is considerably
reduced. Until the last decade management was purely
preventative or supportive aimed at symptom control. Apart
from stem cell transplant, there is no cure but the oral
chemotherapeutic drug hydroxyurea (HU) has now established a
role in ameliorating the disease and improving life expectancy for
most patients. There are side effects and risks of HU treatment
in SCD but for moderate and severely affected patients, the
benefits can be significant.
c 2003 Elsevier Science Ltd. All rights reserved.
KEY WORDS: sickle; hydroxyurea; crisis; HbF; toxicity
INTRODUCTION
ickle cell disease (SCD) is the family of haemoglobin
disorders inherited in a Mendelian recessive manner in
which a sickle b-globin gene ðbS Þ is inherited. The most
common type is sickle cell anaemia, the homozygote (SS)
situation; while other compound heterozygote conditions
occur featuring the same clinical problems including combinations with other structural variants of the b-chain, e.g.,
SC disease or with a b-thalassaemia mutation giving rise either to Sb0 or Sbþ . SCD is one of the most commonly inherited diseases world-wide with over 250,000 new births
each year resulting in some 70,000 sufferers in North America and in excess of 12,000 in Great Britain. The bS gene, is
widely spread throughout Africa, the Middle East, Mediterranean countries and India and has been carried by population movement to the Caribbean, North America and
Northern Europe. The frequency of sickle cell carriers is up
to one in four in West Africans and 1 in 10 in Afro CaribbeanÕs1 and has reached such high levels in these populations
because the silent carrier state protects against Malaria.2–4
Sickle haemoglobin when not carrying oxygen polymerises distorting the red cells into the classic sickle shape,
which is stiff, deforms poorly and can adhere to the vascular
endothelium.5 The clinical syndrome is a result of chronic
anaemia, and vaso-occlusion, which in turn can give rise to
chronic organ damage. The most common clinical problem is
a painful vaso-occlusive crisis, which causes over 90% of
acute hospital admissions6 and significant morbidity in the
community.7 While the problems are generally the result of
small vessel vaso-occlusion, large vessel disease also occurs
S
resulting in thrombotic cerebral vascular accidents, the acute
sickle chest syndrome and placental infarction. Death generally relates to SCD and is either caused by chronic organ
failure or as a result of an acute catastrophic event such as a
stroke8 acute chest syndrome, splenic sequestration9 or
other complications.10;11 Some 13% of children die before the
age of 20 in the developed world12 while the median survival
for SS has been reported as 42 years in men and 46 years in
women and for SC as 60 and 68 years, respectively.13 Improvements in life expectancy are now being reported which
may represent the milder phenotypes not previously studied
or improved treatment over time.14;15
Standard management of patients, as outlined in Table 1, is
based on infection prophylaxis, prevention of crisis and supportive management for crisis including antibiotics, rehydration and analgesia.16 Life threatening crisis such as the acute
sickle chest syndrome may require inhaled oxygen and transfusion of red cells while new approaches including those
listed in Table 2 are being developed and investigated.17
RATIONALE AND HISTORY OF HYDROXYUREA
High levels of fetal haemoglobin (HbF) have long been recognised to ameliorate or abolish the clinical problems of
SCD.13;18–20 Scientific endeavour has therefore focused on the
determinants of HbF production including: b-globin gene
haplotype and their associated regulatory domains,21–23 DNA
control elements on other chromosomes including the Xlinked F-cell production locus,24 the so-called ‘‘high’’ and
‘‘low’’ HbF alleles,23 and hypomethylation of the gamma
gene.25 After the demonstration by DeSimone et al. that the
cytotoxic 5-azocytidine stimulated HbF production other cytotoxic agents were demonstrated to have similar results.26–29
This led to a number of early clinical studies including a dose
ranging study with hydroxyurea (HU), which had long been
in use for the treatment of neoplasms.26;30–33 In addition,
other studies showed the improved HbF response of patients
on HU when also treated with erythropoetin, haematopoetic
growth factors and, also when treated with sodium butyrate.31;34 The important role of HU in the clinical management of severely affected adult patients with SS was
confirmed by a randomised controlled trial, the Multi Centre
Study of Hydroxyurea in Sickle Cell Anaemia (MSH) in
1995.35
Hydroxyurea is a small molecule that blocks the synthesis
of DNA by inhibiting ribonucleotide reductase, thus arresting
cells in the S-phase. It is in routine use for the management of
many neoplastic diseases, in particular those affecting the
blood cells including chronic myeloid leukaemia and polycythaemia rubra vera. The cytostatic mechanism of HU is
different from the effects of radiation, alkylating agents and
other anti cancer drugs.
EFFECTS OF HYDROXYUREA
Increase of HbF
The impact of HU in SCD was, initially, thought to be attributed to the rise in HbF. Further study has, however, not
c 2003 Elsevier Science Ltd. All rights reserved.
Blood Reviews (2003) 17, 99–109
doi:10.1016/S0268-960X(02)00074-7
99
Davies and Gilmore
Table 1 Routine management of SCD
(A) Maintenance of health
Prophylaxis against infection
Avoidance of precipitating factors
Splenic palpation (infants)
Anti-malarials
(B) Treatment of acute complications
Rehydration
Antibiotics
Analgesia
Symptomatic, e.g., anti-epileptics
Oxygen
Red cell transfusion
(C) Prevention of vaso-occlusion
Red cell transfusion regimens, e.g., 4 weekly
Hydroxyurea
Stem cell transplant
Table 2 Novel approaches to SCD management
1. Induction of HbF, e.g., short chain fatty acids
2. Prevention of red cell dehydration, e.g., hypermagnesaemia,
clotrimazole
3. Normalisation of hypercoagulable state, e.g., warfarin, aspirin
4. Reduction of whole blood viscosity, e.g., flocor
5. Haemoglobin solution or substitutes
6. Inhibition of red cell – endothelium adhesion, e.g., specific monoclonal
antibodies
7. Nitric oxide (or precursor amino acid arginine)
8. Inhibition of bS polymerisation
9. Gene therapy
yet clarified how administration of HU stimulates HbF production nor that the beneficial effects reported by patients
are related solely or even predominantly to increased HbF
synthesis. It is clear that the cyto-reductive effect of hydroxyurea therapy shifts differentiation of erythroid precursors towards macrocytosis with an increased proportion
of F cells, in which polymerisation of HbS is inhibited by
HbF.
While HbF appeared to play a significant role in early
improvement in treated patients, the evidence from the MSH
study was that from three months of treatment the reduction
in neutrophil count was more significantly associated with
clinical response.36 The HbF response did not appear to be
directly related to the haplotype of the b-globin gene cluster,
the a-globin gene genotype nor the phenotype of the F cell
production locus.37 The increase in HbF levels at 2 years of
treatment in the MSH study was greatest in patients with high
baseline reticulocyte counts ( P300 103 llÞ) or neutrophil
counts ( P7500 ll). A good response appeared more likely if
the CAR haplotype was missing.37 Interestingly, after 2 years
of treatment in the MSH study, half of the patients had no
increase or only trivial increments in HbF despite significant
amelioration of the disease in the treatment group.
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c 2003 Elsevier Science Ltd. All rights reserved.
Erythrocyte alterations
A variety of alterations in the red blood cells of SS patients
taking HU have been described including:
• increase in total haemoglobin and haematocrit;
• increase in mean cell volume (MCV), which is directly
related to the increase in HbF;38
• improved red cell hydration39 which is probably responsible for
s
the increase in red cell life span40 along with
s
reduced haemoglobin polymerisation for the reported
improvement in red cell rheology.40;41
There are also reported alternations in the red cell membrane including reduced expression of adhesion molecules as
discussed below. Reticulocyte counts were directly associated with crisis rate among HU patients but not among
placebo patients (that is the lower the count the lower the
crisis rate).42
Myelosuppression
Clearly HU exerts some of its impact on SCD through
myelosuppression as evidenced by the relationship between not only the reticulocyte count and crisis rate but
also the strong association between neutrophil count and
crisis rate demonstrating evidence of a treatment interaction. While the reduction in neutrophils on treatment is a
result of the cytotoxicity of HU, data from the MSH study
suggests that the association of crisis rate with neutrophil
counts is a biological phenomenon. This is not surprising
as high neutrophil counts are associated with a worse
clinical prognosis and earlier death.13 Neutrophils adhere
to vascular endothelium thus potentially impeding the flow
of the sickle cells43 can increase whole blood viscosity,
release cytokines and are involved in the inflammatory response including the pain pathways.44;45 In addition, adherence of sickle cells to neutrophils followed by
activation and production of toxic oxygen radicals has also
been reported.46
Production of nitric oxide
Hydroxyurea can be oxidised by haeme groups to produce
nitric oxide (NO) in vitro.47–50 While Glover has described
the possible formation of nitrosyl haemoglobin in humans
following an oral dose of HU.51 Thus the NO donor properties of HU may well contribute to its effect.
Ikuta has recently demonstrated that soluble guanylate
cyclase activators and analogues increase fetal haemoglobin
gene expression in primary human erythroblast and erythroleukaemic cells and that the activity of haemin and butyrate on HbF induction was abrogated by inhibiting soluble
guanylate cyclase or cGMP dependent protein kinases, suggesting that one of the mechanisms of HbF induction by HU
may be as a result of NO.52
Nitric oxide plays a major role in maintaining vascular
tone. Production of NO results from the action of nitric oxide
synthetase (NOS) on the non-essential amino acid arginine
and molecular oxygen to form NO and citrulline. The role of
NO is of particular importance in SCD where the vaso-dilatory effect of NO may be critical and constriction can play a
role in the obstruction of the microcirculation by sickle
The role of hydroxyurea in the management of sickle cell disease
Table 3 Additional reported effects of hydroxyurea in SCD
Alterations in the hypercoagulable prothrombotic state of SS66
# Myeloperoxidase of neutrophils62
" TNFa67
" Erythropoetin68
cells.53–56 Further advantages of NO production in SCD include a possible inhibitory role in HbS polymerisation,57 inhibition of platelet aggregation,58 as anti-adhesive therapy for
ischaemia/perfusion injury,59 and by improving endothelial
function.60
Reduction in red cell – endothelial adhesion
Increased NO production as a result of HU treatment may
well be responsible for the reduced expression of VCAM1
reported in SCD patients on HU.61–64 In addition, Hillery
et al.65 have reported a reduction of adhesion of SS red cells
to thrombospondin and laminim with HU treatment.
Other effects of hydroxyurea
A number of other actions of HU have also been reported
which may play a role in ameliorating SCD as shown in Table 3.
RESULTS OF STUDIES OF HU IN SCD
A review of the clinical outcomes of studies of patients on HU
has been published elsewhere bringing together 20 trials and
studies.69 These were assessed according to standard criteria
for quality: concealment, blinding, generation of randomisation sequence, analysis by intention to treat and whether all
randomised patients were included in the analysis.70 Sadly,
only two studies met the criteria for inclusion; the previously
mentioned North American MSH study and a paediatric study
of 25 children and young adults performed in Belgium which
has been recently updated.71;72
The Multi Centre Study of Hydroxyurea in Sickle Cell
Anaemia (MSH)35
This trial involved 299 adults with SS recruited from 21
centres in North America who had a history of three or more
painful crisis in the 12 months prior to enrolment. HU was
started at a low dose (15 mg/kg per 24 h) and increased at 12
weekly intervals by 5 mg/kg per 24 h until mild bone marrow
depression as judged by either neutropenia or thrombocytopenia, at which point treatment was stopped. Treatment was
restarted once blood count had recovered, at 2.5 mg/kg per
24 h less than the toxic dose. The trial was therefore aiming
for the maximum tolerated dose (MTD) for individual patients
within the trial. However, only 53% of patients reached MTD
and HU doses at the time of study closure varying from zero
to the chosen maximum dose of 35 mg/kg per 24 h.
Pain crisis was described as a visit to a medical facility
lasting four or more hours requiring opiate analgesia. There
was an impressive reduction in the annual rate of crisis in the
treatment group with the total crisis rate 5.1 (SD 7.3) as
compared with 7.9 (SD 9.6) in the placebo group, WMD – 2.8
(95% CI – 4.74,)0.86). There was also significant improvement (p 6 0:001) in the medium time interval to first crisis
(2.76 versus 1.35 months) and second crisis (6.58 versus 4.13
months) after starting treatment. Other markers of clinical
improvement included the reduction in the incidence of the
acute sickle chest syndrome (23 in the HU group versus 51 in
the controlled group [relative risk 0.44 at 95% CI 0.28, 0.68]).
This is particularly important as the majority of sickle related
deaths in adolescence and young adults relate to the sickle
chest syndrome.10;11;13 It is important to note that the transfusion requirement in the HU treated group was also significantly lower than the placebo group (48 events versus 73,
p ¼ 0:001).
The final HbF levels in the HU group did not differ
markedly from their pre-treatment levels (5% versus 9%) and,
although higher HbF levels were associated with lower crisis
rates, the association was not statistically significant.37 Neutrophil counts appeared to have the most impact being associated with lower crisis rates throughout the whole study
as previously discussed.35;42
The MSH study suggests some improvement in quality of
life over start of study baseline in the HU group as compared
with the placebo group. Weight gain after 2 years was reported in the MSH study as a mean rise of 3% in the HU group
and 6% in the placebo group, which is not significantly different. Nor were there significant differences reported between the two groups in the symptoms of hair-loss, skin rash,
fever, gastrointestinal disturbance or other self-reported
symptoms. The incidence of new leg ulcers and new diagnoses of aseptic necrosis of the humerus or femur was similar
in both groups.
There was no significant difference in the reported
deaths (two in the treatment group and five in the placebo
group, including one homicide). Also non-significant was the
incidence of stroke occurring in two of the treated and
three of the placebo group, (relative risk 0.64 at 95% CI
0.11, 3.8).
Studies in children
A mean hospital stay of 5.3 days in the HU group and 15.2 in
the placebo group was reported in the Belgian study.71 A
later publication from Ferster based on the Belgian SCD HU
treatment registry72 along with 12 other paediatric Phase I/II
studies in the literature support the overall findings of the
MSH.73–86 Marked increases in HbF and MCV with reduction
in white cells and reticulocytes are reported with a comcomitent reduction in measurements of pain and hospital
admissions as well as a reduced frequency of the acute sickle
chest syndrome.
If HU is started very young in SCD it may prevent end
organ damage, which is closely associated with morbidity
and mortality. Hydroxyurea was reported to result in the
reversal of splenic disfunction in two young adults.87 This
finding was not however confirmed in a larger study.79
Two studies using HU in young children have been reported. The first of eight children aged 2–5 years followed for
1–5 years showed a reduction in hospital admissions and the
acute sickle chest syndrome as well as in the use of transfusion.84 However, one child aged 3.5 years had an infarctive
stroke after 56 weeks of therapy. In the second study, 28
c 2003 Elsevier Science Ltd. All rights reserved.
Blood Reviews (2003) 17, 99–109
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Davies and Gilmore
infants of a median age of 15 months were treated with
20 mg/kg per 24 h over 2 years.85 Radionuclide splenic uptake was absent in 47% of patients at study completion
compared with predictive functional asplenia in 80% of the
patients, suggesting some improvement. However, while
haematologic responses to HU mimicked the responses observed in older patients and the HU appeared to prevent or
slow the expected decline of HbF in these infants, they experienced a number of clinical adverse events including a
death. Seven of the 28 patients exited the study early: five for
non-compliance or refusal to continue, one because of a mild
stroke and one for fatal splenic sequestration. The adverse
clinical events experienced during the study included: two
patients developing splenic sequestration, one with a cerebro-vascular accident and a second with a transient ischaemic
attack and three patients who had a total of seven episodes of
acute sickle chest syndrome. A further two patients had
priapism and three suffered dactylitis. Of those suffering
infection, one had penicillin sensitive pneumococcal meningitis.
The reports published for treatment in children to date
suggest that growth and development are unaffected even in
the very young, although this needs to be kept under review.84;86;88;89
These early studies suggest that while HU has a role to
play in the prevention of acute painful events and some of
the other consequences of vaso-occlusion, even when started
young it appears unlikely that the children will be fully protected against all the consequences of SCD. A further issue of
concern is the impact that HU may have on the developing
brain in the first two years of life. A study of the brain in small
numbers of mice, given massive doses of HU (50–1000 mg/kg
per 24 h) starting three days after birth, showed dramatic
changes which appeared age and dose dependent.89 A
French study of 34 HU treated children however, compared
with 30 not given HU found the treated patients performed
significantly better than the non-treated on full scale IQ.90
The issues relating to brain development and subsequent
function with HU treatment, particularly given during the
critical period of brain development are therefore unresolved.
ROLE OF HU IN THE MANAGEMENT OF STROKE
Cerebo-vascular events occur in around 10% of children and
have been reported in children taking HU.35;85 Whether HU
treatment can therefore prevent some cases of primary
cerebro-vascular occlusion is as yet undetermined. However,
it may have a role, in selected patients, in the longer-term
management of prevention of stroke recurrence in those
who have already suffered one or more events. Ware et al.83
have reported 16 paediatric patients with SCD and stroke
where transfusion was discontinued for reasons including
red cell alloimmunisation or antibodies, recurrence of stroke
on transfusion, iron overload, non-compliance and desferioxamine allergy. Over a 22 month period (range 3–52)
three patients had neurological events, considered recurrent
stroke, each three to four months after discontinuing transfusions but before maximal HU affects. The concern with this
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c 2003 Elsevier Science Ltd. All rights reserved.
approach is that of raising the total haemoglobin and thus the
blood viscosity. So 14 of their patients underwent venesection, which was also effective in reducing iron overload.
ADVERSE EFFECTS OF HU IN SCD
Short term effects generally relate to the myelosuppression,
so all patients on treatment should be monitored carefully as
cytopenias are to be expected, in particular while seeking the
MTD. Despite a cautionary note sounded by Vichinsky91 with
careful laboratory monitoring and appropriate patient education, such cytopenias rarely represent a major issue as
demonstrated by the studies discussed earlier.35;71
Other toxicities often related to chemotherapeutic agents
such as hair loss, skin rash, gastrointestinal disturbance and
fever have also been shown by the MSH study not to be
significantly more frequent in the treated group as compared
with the placebo group, as mentioned earlier. The cutaneous
side effects of HU are however, increasingly recognised including melanonychia92 , squamous cell carcinoma, solar
keritosis and rarely dermopathy likened to dermatomyositis
without the myositis.93 While some physicians have used HU
in SCD in order to treat leg ulcers, it is important to be aware
that leg ulcers are also a reported complication of HU therapy
itself.94;95
PREGNANCY AND HU IN SCD
The safety of HU therapy in pregnancy remains unclear. Very
large doses (above 250 mg/kg per 24 h) have been reported
as teratogenic.96;97 Three babies born to parents on hydroxyurea during the MSH study showed no evidence of
birth defects or developmental abnormalities during early
follow-up. A recent summary of the case reports in the
published literature of hydroxyurea used during pregnancy
reports 15 additional cases.98 The outcomes were two therapeutic abortions, one normal phenotype still-born at 26
weeks gestation when the mother suffered from eclampsia
and 12 normal term infants born to mothers on HU during
pregnancy for periods of six weeks of gestation to throughout pregnancy on doses of 0.5–3.0 g per 24 h.
In a study of HU treated mice the cytological appearance
of sperm was altered by doses exceeding 25 mg/kg per 24 h
although no abnormalities were described in the offspring of
HU treated male mice.99 It is clear however, that every attempt should be made to prevent pregnancy in patients and
their partners as the magnitude of the risk is unknown.
THE RISK OF MALIGNANCY WITH HU TREATMENT
IN SCD
As a chemotherapeutic agent the cytostatic affects of HU are
different from those of radiation, alkylating agents and other
anti-cancer drugs, many of which are known to increase the
risk of development of either leukaemia or cancer. The MSH
patients continued to be followed up after closure of the
study and, apart from one woman with unrelated carcinoma
in situ of the cervix no cases of malignancy were reported.100
The role of hydroxyurea in the management of sickle cell disease
Meanwhile, five cases of haematological malignancy have
been reported of which two are clearly unrelated: a Philadelphia positive acute lymphoblastic leukaemia in a child
after seven weeks of treatment and a HodgkinÕs lymphoma
after six months of treatment.101;102 A further three cases in
adults after 6–8 years of treatment could be related, although
there is no clear relationship. The reports are of acute myeloblastic leukaemia, acute myeloblastic leukaemia on a
background of myelodysplastic syndrome and an acute
promyelocytic leukaemia.103–105
The instance of leukaemia in patients treated with HU
for the unrelated condition polycythaemia rubra vera has
been reported by the Polycythaemia Vera Study Group
demonstrating an incidence of acute leukaemia after median follow up of 8.6 years of 5.9% in the HU group as
compared with 1.5% of the phlebotomy group (p ¼ 0:18 by
the log rank test).106;107 A French study of 292 polycythaemia patients comparing HU and pipobroman therapy reported a risk of leukaemia of 10% in the 13th year with
no significant differences between the two arms94 , while
essential thrombocythaemia patients treated with HU also
have been reported to be associated with a leukaemic risk
of approximately 3.5%, many with a morphologic, cytogenetic and molecular characteristics of the 17p-syndrome.108
The relevance of these and similar reports in the literature
to SCD is unclear as in these diseases there is a well documented tendency to evolve into acute leukaemia. While
apart from the erythroid hyperplasia, the bone marrow of
people with SCD is normal with no recognised increased
tendency to develop leukaemia over that of the general
population.
There is one report of a group of patients with high red
cell counts, relating to cyanotic congenital heart disease who
were treated with similar doses of HU to those of the MSH
study for periods of between 2 and 15 years.109 None of these
patients developed a malignancy during the observation
period reported.
Somatic DNA mutations in peripheral blood monocytes
of patients with SCD treated with HU have also been
studied.110 Comparing 36 patients not exposed to HU and
32 treated, Hanft and colleagues found that adults with SCD
had equivalent numbers of DNA mutations regardless of HU
treatment. In the children, however, while exposure did
not alter the range of hprt-mutations, the treated children
had significantly more VDJ mutations. The authors conclude
that these data suggest that the mutagenic and carcinogenic
potential of HU therapy for SCD patients is therefore
low.
IMPACT OF HYDROXYUREA ON LIFE EXPECTANCY
IN SCD
The MSH patients continue on long-term follow up and all
patients were offered HU therapy at the end of the
randomised study. The study co-ordinators recently reported cumulative mortality at 8 years of follow up
showing patients who had taken HU in a given quarter had
a lower mortality rate compared with patients not taking
HU during this interval.100 The risk ratio reported of 0.58 is
equivalent to a 40% reduction in mortality over an observation period of 6–8 years (p ¼ 0:04). After 8 years of
Fig. 1a Monitoring schedule for hydroxy urea treatment in sickle cell disease.
c 2003 Elsevier Science Ltd. All rights reserved.
Blood Reviews (2003) 17, 99–109
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Davies and Gilmore
follow up 58 of the original 299 patients are known to
have died, with pulmonary disease remaining the most
common cause of death. Six strokes have occurred in the
original HU group (three fatal) and five strokes in the
original placebo group (none fatal). The authors further
note no unexpected adverse events since the start of the
randomised treatment. A further long-term report from
North America of 149 patients treated for up to 10 years
lists 12 deaths and no malignancies while on HU
therapy.92
Fig. 1b Hydroxy urea treatment data collection/monitoring form.
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The role of hydroxyurea in the management of sickle cell disease
HU FOR THE NON-SS SICKLE SYNDROMES
Hydroxyurea has been widely used in sickle b-thalassaemia
with reportedly good response.111–113 While the initial results
in adults with SC disease, from a small study of six patients,
were disappointing;114 more recently, six children with SC
are reported to have shown a good clinical response with
marked reduction in hospital admission rates and a significant
rise in HbF.115 There are also case reports documenting
clinical improvement in patients with SD, who are treated
with HU.116
In the anaemic SCD syndromes it is likely that the responses will be similar to SS. In those that are not anaemic
yet severely affected, a trial of therapy should not be precluded on the grounds of present published data but based
on present understanding of the outcome is likely to be less
favourable.
THE PRESENT ROLE OF HYDROXYUREA IN THE
TREATMENT OF SCD
The published literature as described in this article demonstrates that adults and probably children with moderately
severe to severe SCD can respond well to HU treatment improving their quality of life, reducing hospital admissions and
for many extending their life expectancy, perhaps by reducing long-term end organ damage. There are descriptions
in the literature, and we have personal experience, of a small
number of patients who do comply with HU treatment, yet
do not respond despite high doses of HU. The reasons for
non-response are unclear. It is our experience that a minimum of three months and generally six months of treatment
and doses at MTD should be tried for effectiveness before
labelling a patient as a ‘‘non-responder’’. Conversely, there
are reports, including in the MSH of patients with poor bone
marrow reserves who are exquisitely sensitive to HU therapy
resulting in cytopenias and necessitating low doses or even
rarely precluding treatment.
It is impossible as yet to predict a patientÕs response to HU
either as a change in crisis rate from baseline or as changes
from baseline laboratory measurements, making it difficult to
select ‘‘good responding’’ patients. In particular, the MSH
study showed no relationship between baseline characteristics and outcome for gender, age, a-globin gene number,
number of high FCP genes or the b-globin haplotype. Pretreatment crisis rate was very strongly associated with crisis
rate during treatment (p < 0:0001) for all patients in the MSH
study. However, the MSH study did not show a clear relationship between reduction in crisis frequency and increase
in F cells (F cell counts and HbF levels have been demonstrated to show a very close relationship).37 A study in children looking at predictors of HbF response in children with
SS on HU (HUG-Kids) demonstrated a significant association
between a higher HbF percentage at MTD and higher baseline HbF values (p ¼ :001), higher baseline haemoglobin
concentration (p ¼ :01), MTD dose (p ¼ :02) and compliance (p ¼ :02).76 After adjusting for variations in baseline
HbF%, the baseline reticulocyte count (p ¼ :05) and baseline
white cell count (p ¼ :05) were also significantly associated
with higher HbF levels at MTD. The HbF response and
therefore in part the clinical response to HU is however,
variable and complex and even children with a low baseline
HbF can develop substantial increases in HbF at MTD.117
It is clear that the best results occur in patients who have
good bone marrow reserves and are given MTD. However,
there are no randomised controlled trials comparing MTD
with lower doses to evaluate the long-term outcomes and
general cost effectiveness to help decide whether patients
should be on MTD or may reasonably stay at a lower dose.
Management protocol
When treating SCD patients with HU we start by two full
counselling sessions at least one week apart addressing the
present knowledge as discussed here and the importance of
regular routine monitoring. HU is only started following
signed consent, as it is not licensed for this use in Britain,
with agreement by the patient to the monitoring regime and
to data collection into our electronic registry.
Our aim is to achieve maximum tolerated dose (MTD) or
30 mg/kg per 24 h, whichever is lower. We monitor regularly
by full blood count for safety and only prescribe sufficient
HU for the period until the next scheduled monitoring visit.
Our routine dosing schedule is shown in Figure 1a and our
clinic monitoring sheet for both the clinical notes and
registry database in Figure 1b.
COMPARISON OF HYDROXYUREA THERAPY WITH
OTHER NOVEL THERAPIES FOR SCD
A number of new therapeutic agents are under investigation
in the laboratory or in early phase studies with patients; some
approaches are listed earlier in Table 2. Meanwhile any
therapy has to be judged against the natural history of the
disease and active management by regular and routine blood
transfusions to maintain haemoglobin levels and suppress
sickle haemoglobin production with associated iron chelation therapy.
The most successful alternative therapy is that of stem cell
transplantation (SCT) in SCD.118 In the three major series of
patients transplanted for SCD, which have been predominantly children and adolescents and a few young adults (<25
years), there has been no recurrence of painful crisis in those
with stable engraftment.119–121 However, some 10–20% of
patients reject their bone marrow with autologous reconstitution although, there may be amelioration of the disease for
several years.122 Against these good outcomes should be
balanced a transplant related mortality of around 8%, the risk
of a chronic graft versus host disease of around 6% and a
likelihood with current conditioning regimes of impaired
fertility.
It is now generally accepted practice that severely affected patients should have a trial of treatment with HU and
only if the response is unsatisfactory is SCT seriously contemplated. The best outcomes are those from a matched
sibling donor and no volunteer unrelated donor transplants
have been reported. However, a number of SCD children
have now had stem cell transplants from cord blood stem
cells both directed from siblings and unrelated.121;123;124
This is still an experimental approach and should only be
c 2003 Elsevier Science Ltd. All rights reserved.
Blood Reviews (2003) 17, 99–109
105
Davies and Gilmore
performed in the context of clinical trials although there may
be advantages in a lower incidence of graft versus host disease. Experience in other diseases suggest that when the
cord blood cell dose is low there is a high risk of graft rejection and slow engraftment.125
Correspondence to: Sally C. Davies, F MedSci., FRCP, FRC Path FRCPCh, FFPHM,
Imperial College Faculty of Medicine at Central Middlesex Hospital, Acton
Lane, London NW10 7NS, UK. Tel.: +020-7725-5408. Fax: +020-7725-5467;
E-mail: [email protected]
CONCLUSION
Many patients with sickle cell disease derive clinical benefit
from treatment with HU. The impact is unlikely to be
simply the result of the rise in HbF seen in most patients,
and exploration of the other effects of HU may open up
new therapeutic avenues. The reason for non-response in a
small number of patients is unclear. Hydroxyurea is now
considered by most physicians in the developing world as
the treatment of choice for severe SCD, although there are
risks associated with its use.
Practice points
HU has a role in the management of moderate to severe SCD
HU does not cure SCD rather ameliorates
Some SCD patients do not respond to HU
Best outcomes are probably achieved with MTD
Patients must be fully counselled prior to HU therapy
Routine and regular monitoring by FBC is essential
Research Agenda
Randomised controlled trials of appropriate power to study
The role of HU in children
The role of HU in non-SS syndromes
The cost benefit of low/medium dose compared with maximum tolerated
The role of HU in the developing world
Long-term studies to assess
The impact of HU therapy on chronic organ damage
Leukaemogenic and carcinogenic risk of HU in SCD
Population survival alterations resulting from HU treatment
Scientific study to unravel the mechanisms of action of HU in SCD and
their relative roles and to
Understand the reasons for non-response
The impact of HU on brain development in primates as well as infants and
children with SCD
The neuropsychometric outcomes of infants and children treated with
HU
Acknowledgments
One of the authors (Annette Gilmore) was funded on a
grant (No. RFG 597) from the NHS R&D, London Region.
The clinical trials were reviewed in The Systematic Review
of the Role of Hydroxyurea in Sickle Cell Disease of the
International Cochrane Collaboration. Our thanks to Professor R. Smyth, co-ordinating editor, Tracey Remmington,
group co-ordinator and Dr. Ade Olujohungbe as co-reviewer.
106
Blood Reviews (2003) 17, 99–109
c 2003 Elsevier Science Ltd. All rights reserved.
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