Chemotherapy Significantly Prolongs Survival
for
Patients with Acute Myeloid Leukemia
Preliminary results from a large, randomized clinical trial
for patients ages 16 to 60 with previously untreated acute
myeloid leukemia (AML), a cancer of the blood and bone marrow,
show that patients who received a high dose of a commercially
available chemotherapy drug, daunorubicin, during initial
therapy lived longer than patients who received a standard
dose of the same drug. Daunorubicin, a drug originally approved
for use by the U.S. Food and Drug Administration in 1979,
inhibits DNA replication and repair and leads to cell death.
The clinical trial was sponsored by the National Cancer Institute
(NCI), part of the National Institutes of Health, and conducted
by a network of researchers led by the Eastern Cooperative
Oncology Group (ECOG).
The Data Monitoring Committee overseeing the trial (known
as E1900, clinical trial registry number NCT00049517) recommended
that the results of a recent interim analysis be made public
because the study had met its primary endpoint of demonstrating
improved overall survival. Researchers found that the patients
in the trial who received the higher dose of daunorubicin
(90 milligrams per square meter of body surface area, or 90mg/m²,
given on each of the first three days of treatment) in combination
with standard treatment of a chemotherapy drug used for AML
since the 1960s, ara-C (cytarabine), had a median overall
survival of 23.7 months compared to patients treated with
the standard dose of daunorubicin (45 mg/m² given on
each of the first three days of treatment) in combination
with ara-C, who had a median overall survival of 15.1 months.
This survival difference was highly statistically significant.
Also of importance, the frequency of serious treatment toxicities
observed in this study was similar between the high-dose and
standard-dose daunorubicin treatment groups.
"The findings of this large clinical trial are important
because they will likely change practice and improve the outcome
for many patients with AML," said Martin Tallman, M.D.,
chair of the ECOG Leukemia Committee and professor of Medicine
at Northwestern University Feinberg School for Medicine and
the Robert H. Lurie Comprehensive Cancer Center, Chicago.
The trial's study chair was Hugo Fernandez, M.D., associate
professor of Medicine and Oncology and associate chief of
the Blood & Marrow Transplantation Division at the H.
Lee Moffitt Cancer Center and Research Institute, Tampa, Fla.
A total of 633 patients with non-promyelocytic AML who had
not previously received chemotherapy were enrolled in this
study between December 2004 and September 2008. Patients were
randomly assigned to one of two treatment groups to receive
initial, or induction, chemotherapy with either high-dose
or standard-dose daunorubicin with ara-C. Patients who were
assessed as having a complete, positive response to induction
therapy were then treated with additional therapy. As of September
2008, 334 patients proceeded to the next, or consolidation
step of the study.
Bone marrow transplantation and peripheral blood stem cell
transplantation are procedures that restore stem cells that
have been destroyed by high doses of chemotherapy and/or radiation
therapy and are common procedures for patients with AML. In
this trial, those patients with unfavorable prognostic factors
and/or matching sibling donors were treated with an allogeneic
(donor) transplant whenever possible. Among those who received
standard-dose daunorubicin, 4.7 percent underwent allogeneic
hematopoietic stem cell transplantation (HSCT). For those
randomized to high-dose daunorubicin, 5.7 percent underwent
allogeneic HSCT. There were no differences between the treatment
groups in terms of subsequent chemotherapy or autologous transplantation
that affect the results of the trial.
Because daunorubicin is an FDA-approved drug for AML, patients
with this disease can potentially gain immediate benefit from
the results of this trial. "This trial is a prime example
of a study question that would only have been carried out
by an NCI-sponsored oncology Cooperative Group because the
agent tested in the trial has been in common use for this
disease for more than three decades and there's little incentive
for commercial concerns to test an already approved product,"
said James H. Doroshow, M.D., director of NCI's Division of
Cancer Treatment and Diagnosis.
An estimated 13,290 people will be diagnosed with AML in
the United States in 2008. Most cases are in adults with half
the cases being under 60 years of age. Overall, only about
33 percent of those with AML survive the disease, and survival
is less likely with increasing age. Advances in AML therapy
depend in large part on the ability to increase the initial
response to induction therapy.
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