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Clinical Alert: Drug Treatment for Sickle Cell Anemia

National Heart, Lung, and Blood Institute (NHLBI)
January 30, 1995

Abstract:

The National Heart, Lung, and Blood Institute (NHLBI) today announced a drug treatment for sickle cell anemia. Findings from a multicenter clinical trial show that daily administration of the drug hydroxyurea reduced by about 50% the frequency of painful episodes and hospital visits for those episodes. The treatment also reduced the frequency of acute chest syndrome and the number of blood transfusions for patients in the study.

Hydroxyurea has been used primarily to treat myeloproliferative disorders such as polycythemia vera. Although the exact mechanism of action in sickle cell anemia is not completely understood, it is believed that hydroxyurea works by increasing the production of fetal hemoglobin in red blood cells. This may prevent the cells from becoming rigid and clogging the blood vessels. Hydroxyurea is not currently approved by the U.S. Food and Drug Administration to treat sickle cell anemia although physicians can prescribe it for that purpose.

Hydroxyurea may not be appropriate for all patients with sickle cell anemia, and this study only enrolled adults with severe recurrent painful episodes. It is a cytotoxic agent, and has the potential to cause life-threatening cytopenia. In addition, this drug should not be used in patients likely to become pregnant or those unwilling or unable to follow instructions regarding treatment. Hydroxyurea is a treatment, not a cure, and any beneficial effects experienced will last only as long the patient continues to take the prescribed dose.

These findings are the results of data analyzed from the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), which was a double-blind, placebo-controlled trial. The data were so compelling that the trial's Data and Safety Monitoring Board recommended that the trial be terminated before the scheduled date of May 1995. NHLBI contact: Dr. Duane Bonds, (301) 435-0055 [corrected October 30, 1998].

Full Text:

The National Heart, Lung, and Blood Institute (NHLBI) announced today a treatment which reduces the frequency of painful episodes or crises in patients with sickle cell anemia. Recurrent painful episodes are the most disabling feature of sickle cell anemia, interfering with education, vocational training, job retention and psychosocial development. The treatment, daily administration of the drug hydroxyurea, reduced the frequency of painful episodes and hospital admissions for painful episodes by approximately 50 percent. In addition, hydroxyurea therapy significantly reduced the frequency of acute chest syndrome, a life-threatening complication of sickle cell anemia characterized by chest pain, fever, prostration, and an abnormal chest x ray. The patients treated with hydroxyurea required fewer blood transfusions during the study, an outcome which has important public health implications.

Hydroxyurea is a drug which up until this trial had primarily been used to treat myeloproliferative disorders such as polycythemia vera. Although the exact mechanism of action in sickle cell anemia is not completely understood, it is believed that hydroxyurea works by increasing the production of fetal hemoglobin in red blood cells. Sickle hemoglobin forms long strands or polymers inside of red blood cells that have released their oxygen into the circulation, causing the red blood cells to become rigid. Rigid sickle red blood cells clog the blood vessels, causing vaso-occlusion and painful episodes, which are the hallmarks of sickle cell anemia. Increased levels of fetal hemoglobin inside sickle red blood cells may prevent the cells from becoming rigid, thereby preventing vaso-occlusion.

These findings are the results of data analyzed from the Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH), which was a double-blind, placebo-controlled trial in which half of the patients received hydroxyurea and half received a placebo capsule. The primary analysis compared annual crisis rates of patients assigned to receive hydroxyurea to rates of patients assigned to receive placebo. A painful or vaso-occlusive crisis was defined as a visit to a health care facility lasting more than 4 hours for treatment of an acute painful event which required treatment with either (1) parenteral narcotics; or, (2) an equianalgesic dose of oral narcotics, (if the episode was treated at a facility in which parenteral narcotics were not routinely used to treat crises); or, (3) parenteral non-steroidal anti-inflammatory drugs (NSAID's). Episodes of acute chest syndrome, hepatic sequestration, and priapism were also considered to be crises, but surgical procedures and pain due to acute exacerbations of chronic conditions (e.g. ankle ulcer, hip necrosis, or osteomyelitis) were not considered to be crises. Between January 1992 and April 1993, the NHLBI-sponsored trial headquartered at Johns Hopkins University (Dr. Samuel Charache) and the Maryland Medical Research Institute (Dr. Michael Terrin) enrolled 299 adult sickle cell anemia (Hb SS) patients who had experienced at least 3 painful crises in the previous year. The patients were drawn from 21 clinical centers around the United States (list attached). Only patients with moderate-to-severe disease who were age 18 and older were allowed to participate. The drug was supplied by Bristol-Meyers Squibb.

The dosing of hydroxyurea was achieved as follows: patients were begun on 15 mg/kg, and the dose was increased by 5 mg/kg every 12 weeks unless toxicity was observed or the maximum dose of 35 mg/kg/day was reached. If toxicity occurred, treatment was stopped until the bone marrow recovered, and then was restarted at a lower dose (2.5 mg/kg less than the previous dose). If no toxicity occurred after 12 weeks on the lower dose, the subsequent dose was increased by 2.5 mg/kg/day. The maximum tolerated dose was a dose just less than that which produced toxicity. Patients were carefully monitored every 2 weeks. Toxic bone marrow depression was defined as absolute neutrophil counts less than 2,000/cubic millimeters, absolute reticulocytes less than 80,000/cubic millimeters (if the hemoglobin concentration is below 9 gm/dL), platelet counts less than 80,000/cubic millimeters, or a fall in hemoglobin concentration from > or = 7.0 gm/dL (pre-enrollment) to 4.5 - 5.0 if reticulocytes < 320,000, or hemoglobin concentration < 4.5 gm/dL. The only evidence of toxicity noted was reversible bone marrow suppression.

Hydroxyurea may not be appropriate for all patients with sickle cell anemia, and this study only enrolled adults with severe recurrent painful episodes. It is a cytotoxic agent, and has the potential to cause life-threatening cytopenia. In addition, this drug should not be used in patients likely to become pregnant or in those unwilling or unable to follow instructions regarding treatment. Therefore, each sickle cell anemia patient must be evaluated carefully before hydroxyurea therapy is begun, and careful monitoring must continue while the patient is on this agent. Patients must also understand that hydroxyurea treatment is not a cure. If hydroxyurea therapy has any beneficial effects, they last only as long as the patient continues to take the prescribed dose.

Hydroxyurea is used for treatment of polycythemia vera, a disease in which too many red blood cells are produced. In an open label study of polycythemia vera now entering its 15th year, patients treated with hydroxyurea have a higher rate of leukemia that is not statistically significant when compared to those treated with phlebotomy alone. Because the long term side effects of hydroxyurea are unknown, the patients participating in the MSH clinical trial will be followed and examined annually to ascertain rates of malignancies and other health problems. Safety of this agent for children with sickle cell anemia must be determined.

Physicians can prescribe hydroxyurea for the treatment of sickle cell anemia in their patients, although the drug is not approved for this use by the U.S. Food and Drug Administration (FDA). The FDA will consider approval of this use of the drug following the submission of the data by the manufacturer.

The MSH clinical trial was scheduled to continue until May 1995. The results found during interim analyses were so compelling that the study's Data and Safety Monitoring Board, composed of independent, outside experts in the fields of hematology, biostatistics, and ethics, recommended that the study be terminated early. The Data and Safety Monitoring Board felt that the patients who had been receiving the placebo should immediately be offered an effective treatment. On January 14, 1995, the study was stopped, and the clinical investigators in the 21 participating centers were notified of the study's results and the efficacy and safety of hydroxyurea therapy. During the last two weeks, the results were discussed with patients in both treatment arms.

NHLBI contact: Dr. Duane Bonds, (301) 435-0055 [corrected October 30, 1998].


MSH Principal Investigators:

Samuel Charache, M.D., The Johns Hopkins Hospital, (410) 955-6315;
Michael L. Terrin, M.D., C.M., M.P.H., Maryland Medical Research Institute, (410) 435-4200.


MSH Clinic Directors:

Eugene Orringer, M.D., University of North Carolina School of Medicine, (919)966-2467.
Wendell Rosse, M.D., Duke University Medical Center (919) 684-6464.
Paul Milner, M.D., Medical College of Georgia, (706) 721-2171.
Samir K. Ballas, M.D., Thomas Jefferson University, (215) 955-8485.
Martin Steinberg, M.D., Veterans Administration Medical Center, (601) 364-1315.
Charles H. Pegelow, M.D., University of Miami School of Medicine, (305) 585-7752.
Stephen H. Embury, M.D., San Francisco General Hospital, (415) 206-8573.
Mabel Koshy, M.D., University of Illinois Hospital, (312) 996-5680.
Oswaldo Castro, M.D., Howard University, (202) 806-7930.

Pedro Gascon, M.D., University of Medicine and Dentistry of New Jersey, (201) 456-5256.
James R. Eckman, M.D., Emory University School of Medicine, (404) 616-3572.
Gloria Ramirez, M.D., St. Luke's/Roosevelt Hospital Center, (212) 523-3116.
Elliott Vichinsky, M.D., Children's Hospital of Oakland, (510) 428-3651.
Paul Swerdlow, M.D., Medical College of Virginia, (804) 230-1364.
Susan B. Shurin, M.D., Rainbow Babies & Children's Hospital, (216) 844-3345.
Nancy Olivieri, M.D., The Hospital for Sick Children, Toronto, (416) 813-6823.
Kenneth Bridges, M.D., Brigham and Women's Hospital, (617) 732-7288.
Rita Bellevue, M.D., Interfaith Medical Center, (718) 935-7888.
Josef Prchal, M.D., University of Alabama at Birmingham, (205) 934-2721.
Timothy Carlos, M.D., University of Pittsburgh, (412) 648-6776.
Margaret Telfer, M.D., Michael Reese Hospital Medical Center, (312) 791-3123.

The full text of this alert has been mailed to all libraries that are members of the National Network of Libraries of Medicine.