revised April 22, 1998
Use of Hydroxyurea in Patients with Sickle Cell Disease
The Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH)
The MSH study included patients
and investigators from 22 sickle cell anemia treatment centers in the U.S.
and Canada. The study included over 290 patients in the in the placebo-controlled,
double-blind investigation. The Independent Oversight Committee, charged
by the National Heart, Lung, and Blood Institute (NHLBI) to guard the welfare
of the patients, terminated the study on January 31, 1995 because the patients
on the hydroxyurea (HU) arm had significantly fewer episodes of vaso-occlusive
painful crises, fewer hospitalizations, and fewer episodes of acute chest
syndrome. The initial results were reported in the New England Journal
of Medicine, May 18, 1995 (1). Hydroxyurea is the first agent
that can prevent above-mentioned complications of sickle cell anemia.
Certain groups of patients with sickle syndromes who might benefit
from treatment with hydroxyureawere excluded from the MSH study to reduce
the baseline variability in the patient population. Among the excluded
patients were compound heterozygotes with sickle ß-thalassemia, as
well as patients with hemoglobin SC disease. Patients under 18 years of
age were excluded, as well as people on chronic transfusion therapy for
any reason. Reasonable guidelines for the use of hydroxyureain patients
with sickle cell disease can be constructed from the data gathered in the
MSH study. Nonetheless, a number of important issues remain unresolved.
Hydroxyurea is a chemotherapy agent with potent effects on the
bone marrow. The agent was used for many years to treat people with certain
malignancies before being used for sickle cell disease. The primary side-effect
of hydroxyurea is suppression of blood counts, particularly the white blood
cells (neutropenia) and platelets (thrombocytopenia). Neutropenia and thrombocytopenia
respectively place patients at risk for infection and bleeding. Patients
with sickle cell disease who require hydroxyurea therapy are best served
by having their treatment coordinated by specialists familiar with the
use of this drug.
Logistics of hydroxyurea in patients with SCD
When is hydroxyurea a Reasonable Considerations?
Recurrent painful vaso-occlusive crises.
Most patients with sickle cell disease have painful vaso-occlusive crises.
The frequency, severity , and duration of these crises vary
tremendously, however. No magic number exists to trigger treatment with
hydroxyurea. The MSH study used a baseline of 3 painful vaso-occlusive
crises per year as an enrollment criterion. This number is probably low
for practical purposes. Patients who are hospitalized more than 4 or 5
times per year with painful vaso-occlusive crises are good candidates for
hydroxyurea therapy. Some patients have frequent painful crises that are
managed at home with rest and analgesia. In some instances, this pattern
of illness may interfere with normal activities, such as work or school.
Hydroxyurea should be considered as an option in the management of these
patients as well.
Acute Chest Syndrome.
The acute chest syndrome (ACS) is a significant
cause of morbidity and mortality in patients with sickle cell disease.
Patients who survive the syndrome are more likely to suffer a recurrent
episode than are people who have never been affected. About half the patients
in the MSH study were ACS survivors. Hydroxyurea reduced by half the number
of episodes of ACS in the patients in the treatment arm. Given the life-threatening
nature of this condition, patients who survive acute chest syndrome should
be considered for hydroxyureatherapy.
Other complications of SCD.
The effect of hydroxyurea on other serious complications of SCD is unknown.
Stroke is a complication of sufficient severity and risk of recurrence
that some children are treated with drastic measures, such as bone
marrow transplantation. Chronic transfusion therapy is mandated for
all patients who do not receive a bone marrow transplant. Whether hydroxyurea
would alter the rate of stroke recurrence in children is unknown. Other
serious complications of SCD in which the standard therapy is relatively
ineffective are leg ulcers, aseptic necrosis of bone, and priapism. The
effect of hydroxyureaon these conditions is unknown.
Baseline measurements- At least two months of baseline information on the
hematologic status of patients with sickle cell disease should be available
before starting treatment.
Starting dose- hydroxyurea can be started at a dose of 10 mg/kg orally,
on a daily basis. The patient's hematologic status should be monitored
to rule-out falls in the neutrophil count to less than 2,500 per cubic
millimeter or platelet count to less than 80,000 per cubic millimeter.
Dose escalation- The dose of hydroxyurea can be increased at a rate of
5 mg/kg/wk as long as the hematologic values remain in an acceptable range,
and the patient shows no other evidence of side-effect from the HU.
Maximum dose- At BWH, the maximum dose of hydroxyurea used in most patients
is 25 mg/kg/day. Patients at some institutions receive doses of hydroxyurea
as high as 35 mg/kg/day. The minimum effective dose of hydroxyurea is one
of the unanswered questions from the MSH study. The patients received "maximum
tolerated doses" (MTD) in the study. To achieve this, the dose of hydroxyurea
was advanced until evidence of BM suppression appeared. At this time the
dose was reduced slightly to achieve the MTD. The chances are slight that
very low doses of hydroxyurea, such as 10 mg/kg will benefit patients.
However, no evidence indicates that the MTD, which is close to toxicity,
is more likely to be beneficial. In a recent publication in Blood, Bridges,
et al. showed significant positive changes in the red cells of patients
treated with hydroxyurea at a dose of 25 mg/kg/day (2).
Trial period- Patients should remain on hydroxyurea for six to nine months
before any decision is made on the efficacy of the treatment. The pattern
of vaso-occlusive pain is sufficiently variable that cause-and-effect with
hydroxyurea treatment of a single patient is difficult to assess. The infrequency
of ACS means that even longer periods of assessment are necessary when
treating this condition.
platelet count of less than 80,000.
neutrophil count (not white count) of less that 2,500
hemoglobin of less than 6 g/dl.
hair loss, GI upset, rash.
Contraindications to hydroxyurea Treatment
hydroxyurea blood levels- Blood levels of hydroxyurea are difficult to
interpret because of fluctations that reflect, among other things, the
pattern of drug use (e.g., once a day versus twice a day) and the timing
of the blood test relative to ingestion of the HU.
MCV- The MCV rises in many patients treated with hydroxyurea. The response
varies significantly between patients, making it unreliable as a measure
of hydroxyurea efficacy or patient compliance with the drug.
Fetal hemoglobin levels- Fetal hemoglobin levels rise in many patients
treated with hydroxyurea, but the response is variable. A correlation between
patient clinical response and a rise in fetal hemoglobin levels has not
Poor or erratic follow-up.
allergies to hydroxyurea
relative contraindications: - failure to use an accepted mechanism of birth
Other Sickle Syndromes
Patients with this compound heterozygous condition were excluded
from the MSH study. Therefore, no firm data exists on their response to
hydroxyurea. Since patients with sickle ß-thalassemia often have
a substantial quantity of HbA, clinical amelioration for a given degree
of elevation of Hb F might be greater than that seen in patients with homozygous
sickle cell anemia. Symptomatic patients with sickle ß-thalassemia
should be considered for hydroxyurea therapy.
Hemoglobin SC disease
The clinical course of Hb SC disease is extremely variable. Some
patients are almost completely free of vaso-occlusive pain crises, while
others have a clinical course that is indistinguishable from that of patients
with homozygous sickle cell anemia. Only a small cohort of patients with
Hb SC disease will fit the criteria used to select patients for hydroxyurea
therapy. No controlled data exist on the efficacy of hydroxyurea in the
treatment of Hb SC disease. Anecdotal experience at BWH and other institutions
has been disappointing.
Hydroxyurea in Children
One of the most difficult issues with hydroxyurea is use in children.
Only people 18 years and older were included in the MSH. Investigators
and physicians are concerned about possible effects of hydroxyurea on growth
and development in children since the drug blocks cells division. Although
hydroxyurea is used at a lower dose in patients with sickle cell disease
compared to other conditions (e.g., polycythemia vera), some suppression
of cell growth almost certainly occurs.
To address these and other issues, the NHLBI launched the Pediatric
Study of Hydroxyurea in Sickle Cell Disease (HUG) at four centers: Children's
Hospital, Boston; Children's Hospital of Philadelphia; Duke University
Hospital; and Children's Hospital of Oakland. Enrollment in the study is
closed and the patients are currently being carefully monitored. Should
hydroxyurea prove to be safe and effective in children, a major inroad
will have been made in the treatment of this disorder.
Charache S, et al. 1995. Effect of
hydroxyurea on the freqency of painful crises in sickle cell anemia. Investigators
of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia.
N. Engl. J. Med. 322:1317.
Goldberg, M., Brugnara, C., Dover, G., Schapira, L., Charache ,S., and
Bunn, H. (1990. Treatment of sickle cell anemia with hydroxyurea and erythropoietin.
N Eng J Med 323, 366-372.
Goldberg, M., Brugnara, C., Dover, G., Schapira, L., Lacroix, L., and Bunn,
H. (1992). Hydroxyurea and erythropoietin therapy in sickle cell anemia.
Seminarys in Oncology 19, 74-81.
Bridges KR, et al. 1996. A multiparameter analysis of sickle erythrocytes
in patients undergoing hydroxyurea therapy. Blood 88:4701.