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Clinical Alert: Drug Treatment for Sickle_cell Anemia 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_understood not completely, 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_approved not currently 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_understood not completely, 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_used not routinely to treat crises); or,(3) parenteral nonsteroidal_anti-inflammatory_drugs (NSAID's). Episodes of acute chest syndrome, hepatic sequestration, and priapism were_considered also to be crises, but surgical_procedures and pain due_to acute exacerbations of chronic conditions (e_g. ankle ulcer, hip necrosis, or osteomyelitis) were_considered not 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_monitored carefully 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 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_approved not 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. U_s. National Library of Medicine, 8600 Rockville Pike, Bethesda, MD 20894 National_institutes_of_health, Department_of_health & Human Services Copyright Privacy, Accessibility Last updated: 30 October 1998