|Arsenic Compound Improves Survival of Adults
with Uncommon Form of Leukemia
Positive results of a phase III cancer clinical trial in an uncommon
form of leukemia were released today. The results showed that adult
patients with previously untreated acute promyelocytic leukemia
(APL) who had standard chemotherapy to induce remission of their
disease, and then received the chemotherapy drug arsenic trioxide
to maintain remission, had a significantly better event-free survival
(more patients free of leukemia) and better overall survival than
those who received only standard chemotherapy . The trial was sponsored
by the National Cancer Institute (NCI), part of the National Institutes
of Health, and was led by one of its Cooperative Clinical Trials
Groups — the Cancer and Leukemia Group B (CALGB).
“The positive result in a clinical trial of a common element holding
an uncommon disease in remission for a significant period of time
is very encouraging,” said NIH Director Elias A. Zerhouni, M.D.
Acute promyelocytic leukemia, an uncommon subtype of acute myeloid
leukemia (AML), accounts for approximately 10 percent of AML cases,
or about 1,500 cases per year, in the United States. It is most
often diagnosed in young and middle aged adults, but it also occurs
in children and older adults. Standard chemotherapy regimens produce
complete remission rates of approximately 70 percent and show a
five-year survival without the recurrence of disease in 35 to 45
percent of patients.
"Achieving success in a clinical trial for a rare cancer is a
difficult task due to the limited number of patients eligible to
enroll in the trial, so this is very encouraging news for all patients
with this form of leukemia," said NCI Director John Niederhuber,
M.D. "This positive outcome demonstrates, yet again, the benefits
of clinical trials and will hopefully serve as encouragement for
others to join such trials."
This particular type of leukemia is often accompanied by life-threatening
bleeding at diagnosis that typically worsens, even as initial treatment
is administered. Treatment has improved dramatically in recent
years with the addition of all-trans retinoic acid (ATRA, or tretinoin)
to chemotherapy. More recently, arsenic trioxide (Trisenox ®)
was shown to be an effective drug for producing a second remission
in patients who had a relapse or recurrence of their APL after
initial treatment. Both ATRA and arsenic trioxide are approved
by the U.S. Food and Drug Administration for the treatment of APL.
The CALGB-coordinated study tested the effectiveness and side
effects from adding two 25-day courses of intravenous arsenic trioxide
to the combination of ATRA and chemotherapy. Patients with newly
diagnosed APL were randomly assigned to receive either (1) the
standard remission treatment with ATRA twice daily, daunorubicin
for four days, and cytarabine for seven days, both of which are
standard chemotherapy drugs for this disease, followed by a standard
post-remission regimen with two more courses of ATRA plus daunorubicin,
or (2) the experimental treatment where patients received the same
standard treatment with the addition of two courses of arsenic
trioxide given immediately after the patient entered a complete
or partial remission and before the standard post-remission regimen.
The arsenic trioxide course was a two hour intravenous infusion,
Monday through Friday, on an outpatient schedule for five weeks.
Patients who remained free of visible leukemia after completion
of the remission therapy then received an additional year of treatment
with oral chemotherapy drugs to prevent the leukemia from relapsing.
Between June, 1999 and March, 2005, 582 patients enrolled on this
study. Patients participated through one of five NCI-sponsored
North American Cooperative Oncology Groups, including CALGB, Eastern
Cooperative Oncology Group (ECOG), Southwest Oncology Group (SWOG),
Children's Oncology Group (COG) and the National Cancer Institute
of Canada, Clinical Trials Group (NCIC-CTG). By study design, patients
less than 15 years of age (11 percent of the entire group) were
not assigned to the treatment that contained arsenic trioxide.
The percentage of adult patients who remained alive and in remission — free
of relapse of their leukemia — three years after diagnosis
was 77 percent on the treatment arm that included arsenic trioxide
compared to 59 percent on the standard treatment arm. This difference
was highly statistically significant. The greater effectiveness
of the experimental combination also resulted in better overall
survival after three years of 86 percent for the patients who received
the arsenic trioxide compared to 77 percent for patients on the
standard treatment arm.
Patients were followed for a median period of 29 months. After
reviewing the study results, a data safety monitoring board notified
the investigators and the NCI of the positive results, and the
findings are being released so that all APL patients will have
a chance to benefit from this therapy.
Bayard Powell, M.D., Wake Forest University, Winston-Salem, N.C.,
principal investigator of the study, said, “The willingness of
patients with leukemia and their physicians to participate in this
important clinical trial has markedly improved the outcome for
these and future patients with APL.”
The side effects from treatment were reported at the annual meeting
of the American Society of Hematology in Orlando, Fla., in December
2006. There was no difference in hematologic (blood count) toxicities
between the group who received arsenic and those who did not, but
there was a slightly higher incidence of headache and infection
in the group who received arsenic trioxide. A complete scientific
presentation of these study results is planned for the annual meeting
of the American Society of Clinical Oncology in Chicago, Ill.,
in June 2007.
Richard Larson, M.D., University of Chicago, Ill., a co-investigator
of the study, noted, “These results indicate that arsenic trioxide
should be considered as part of the initial treatment of patients
with acute promyelocytic leukemia.”
The study was sponsored by the Division of Cancer Treatment and
Diagnosis (DCTD), NCI, under a Clinical Trials Agreement between
DCTD, NCI and Cephalon, Inc., Frazer, Pa. (marketers and sellers
of Trisenox®) and monitored by an independent Data and Safety
Monitoring Board that recommended release of the results.
For more information about cancer, please visit the NCI Web
site at http://www.cancer.gov,
or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.