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HICNet Medical News Digest Tue, 21 Mar 1995 Volume 08 : 
Issue 09

Today's Topics:

 Drug Treatment for Sickle Cell Anemia Announced

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CLINICAL ALERT: Drug Treatment for Sickle Cell Anemia Announced

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) 496-6931.

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.



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End of HICNet Medical News Digest V08 Issue #09
***********************************************


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