CLINICAL NEWS
Similar Outcomes with Different Daunorubicin
Doses in Acute Myeloid Leukemia
The combination of cytosine arabinoside (Ara-C)
and an anthracycline has held its ground as the
standard induction therapy for acute myeloid
leukemia (AML) for more than 30 years, with a
variety of modifications yielding no differences
in outcomes. While doubling the dose of the
anthracycline daunorubicin (from the standard of
45 mg/m2 up to 90 mg/m2) has led to improved
overall survival in younger adults (<60 years)
adults, is it possible to gain the same survival
advantage with less?
Investigators from the United Kingdom, led
by Alan K. Burnett, MD, of Cardiff University in
Wales, believe they have found an optimal dose of
daunorubicin to provide the greatest benefit with a
lower risk of adverse effects: 60 mg/m2. According
to the results of a prospective, randomized trial
of more than 1,000 AML patients, the lower dose
performed favorably compared with the higher
dose – 90 mg/m2.
“Fairly recently, three randomized trials showed
that a 90 mg/m2 dose was better than 45 mg/m2,” Dr.
Burnett told ASH Clinical News. “Although open to
criticism, this provided evidence that the 45 mg/m2
should not continue. However, many clinicians use a
60 mg/m2 dose, and it has never been prospectively
compared in randomized trials.”
The current UK NCRI AML 17 Trial enrolled
1,206 adults (median age = 53 years) with
untreated AML or high-risk myelodysplastic
syndromes. Patients received two rounds of
induction chemotherapy: In the first round, they
were randomized to 90 mg/m2 or 60 mg/m2 of
daunorubicin and cytosine arabinoside on days
1, 3, and 5; in the second round of induction, all
patients received another daunorubicin-containing
course (50 mg/m2 on days 1, 3, and 5). So, patients
received either a total daunorubicin dose of 420
mg/m2 (in the 90 mg/m2 arm) or 330 mg/m2 (in
the 60 mg/m2 arm).
Ultimately, the authors found very little difference
between the two doses of daunorubicin, with respect
to both complete remission rates, induction death,
and overall survival (TABLE 1).
The causes of death at 60 days included infection,
hemorrhage, and resistant disease – all of which
occurred more often in the 90 mg/m2 group. In terms
of toxicity, there were more high-grade cases of
nausea and diarrhea in the higher-dose arm during
the first treatment course, but not during the second
therapy course, the authors pointed out.
In an exploratory subgroup analysis, Dr. Burnett
and investigators found only one factor that had
a significant association with worse outcome: the
presence of an FLT3-ITD mutation. The 462 FLT3ITD wild-type patients who received the 90 mg/
m2 dose experienced significantly worse outcomes
than non–FLT3-ITD patients (HR=1.30 [1.02-1.66];
p=0.03). There was, however, a nonsignificant trend
for benefit beyond 12 months in FLT3-ITD mutant
patients who received the 90 mg/m2 dose (HR=0.74
[0.47-1.17]; p=0.2).
“Taken altogether, the mean survival, truncated
at 24 months, was 16.5 months [for the 90 mg/m2
dose] and 16.0 months [for the 60 mg/m2 dose],” the
authors wrote. “There was no evidence of benefit for
the 90 mg/m2 arm in any cytogenic subgroup, and
there was no significant difference between the arms
in survival 12 months after relapse.”
The overall take-home message from this trial?
“There is no need to go to 90 mg/m2 dose,” Dr.
Burnett said. “A 60 mg/m2 dose is fine, but if you use
45 mg/m2, change to 60 mg/m2.”
However, that message may carry less weight
in the United States, according to Harry Erba, MD,
PhD, of the University of Alabama at Birmingham
and chair of the Southwest Oncology Group (SWOG)
Leukemia Committee. The design of the trial has a lot
to do with that.
The U.S. standard of practice – based largely on
results from the Eastern Cooperative Oncology Group
E1900 trial – for younger AML patients is to give one
round of induction therapy containing daunorubicin
at 60 mg/m2. In the E1900 trial, a second round
was given only to patients with persistent disease at
day 14, but most of the participants opted out of the
second round of daunorubicin.
“With the U.K. trial results, we are looking at
the long-term outcomes in terms of survival of
a cumulative dose of daunorubicin during two
rounds of induction, not just that first cycle,” Dr.
Erba told ASH Clinical News. “It is possible that
there really was a benefit with the 90 mg/m2
dose, but, because all patients received a second
round of an anthracycline-containing regimen, it is
difficult to know for certain that the 60 mg/m2 is
as effective as the higher dose.”
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Deficits
60 mg/m2 dose
90 mg/m2 dose
Odds ratio or
hazard ratio
(95% CI)
Complete remission
75%
73%
1.07 (0.83-1.39)
0.6
Induction death
4%
6%
1.63 (0.97-2.73)
0.07
Resistant disease
12%
13%
1.04 (0.74-1.47)
0.8
30-day mortality
4%
6%
1.56 (0.94-2.61)
0.09
60-day mortality
5%
10%
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