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Text File | 1995-01-29 | 11KB | 237 lines

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,
[phone].


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, [phone].
--------------------------------------------------------
MSH Principal Investigators:

Samuel Charache, M.D., The Johns Hopkins Hospital, [phone];

Michael L. Terrin, M.D., C.M., M.P.H., Maryland Medical
Research Institute, [phone].

--------------------------------------------------------
MSH Clinic Directors:

Eugene Orringer, M.D., University of North Carolina School of
Medicine, [phone].

Wendell Rosse, M.D., Duke University Medical Center [phone].

Paul Milner, M.D., Medical College of Georgia, [phone].

Samir K. Ballas, M.D., Thomas Jefferson University, [phone].

Martin Steinberg, M.D., Veterans Administration Medical Center,
[phone].

Charles H. Pegelow, M.D., University of Miami School of Medicine,
[phone].

Stephen H. Embury, M.D., San Francisco General Hospital, (415)
206-8573.

Mabel Koshy, M.D., University of Illinois Hospital, [phone].

Oswaldo Castro, M.D., Howard University, [phone].

Pedro Gascon, M.D., University of Medicine and Dentistry of New
Jersey, [phone].

James R. Eckman, M.D., Emory University School of Medicine,
[phone].

Gloria Ramirez, M.D., St. Luke's/Roosevelt Hospital Center,
[phone].

Elliott Vichinsky, M.D., Children's Hospital of Oakland, (510)
428-3651.

Paul Swerdlow, M.D., Medical College of Virginia, [phone].

Susan B. Shurin, M.D., Rainbow Babies & Children's Hospital,
[phone].

Nancy Olivieri, M.D., The Hospital for Sick Children, Toronto,
[phone].

Kenneth Bridges, M.D., Brigham and Women's Hospital, (617)
732-7288.

Rita Bellevue, M.D., Interfaith Medical Center, [phone].

Josef Prchal, M.D., University of Alabama at Birmingham, (205)
934-2721.

Timothy Carlos, M.D., University of Pittsburgh, [phone].

Margaret Telfer, M.D., Michael Reese Hospital Medical Center,
[phone].

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