Hydroxyurea in Sickle Cell Disease

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.

Treatment Details

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.
Limiting effects

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.

Monitoring hydroxyurea

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 been demonstrated.

Contraindications to hydroxyurea Treatment

Pregnancy.
Poor or erratic follow-up.
allergies to hydroxyurea
relative contraindications: - failure to use an accepted mechanism of birth control.

Other Sickle Syndromes

Sickle ß-thalassemia
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.

References:

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.