Written in Blood
groups (not reached vs. 39.4 months
for favorable-risk [p=0.03] and
33.5 vs. 20.1 for intermediate-risk
[p=0.01]). Although results from
the multivariate analysis (which
adjusted for sex, age, hemoglobin
level, leukocyte count, platelet count,
and cytogenetic profile) suggested
a benefit in those with unfavorable
cytogenetic risk, with the median
OS increasing slightly from 10.2
months to 10.6 months (p=0.22), a
larger study focused on this patient
population is needed to confirm this
benefit, the authors noted.
Patients with the NPM1-,
DNMT3A-, and FLT3-ITD mutations had an improved CR rate with
high-dose daunorubicin, though
no significant CR or OS benefit
could be confirmed in MLL-PTDmutated patients (TABLE 1).
High-dose daunorubicin was
particularly beneficial in patients with NPM1-mutated AML,
increasing the median OS from
16.9 months to 75.9 months and
increasing the four-year OS by
more than 20 percent (from 29%
to 52%). The favorable prognosis
Median Overall Survival Among Patient Subgroups (Multivariable
Analysis)*
TABLE 1.
Standard-Dose Daunorubicin
(45 mg/m2/day)
High-Dose Daunorubicin
(90 mg/m2/day)
p
Value
Hazard Ratio
(95% CI)
CR rate
Median OS in
months
4-year
OS
CR rate
Median OS in
months
4-year
OS
59%
16.6
(n=246/330)
31%
71%
25.4
(n=207/327)
39%
0.001
0.74
(0.61-0.89)
<50 years
61%
20.7
(n=133/188)
35%
73%
44.7
(n=96/172)
48%
0.02
0.67
(0.52-0.88)
≥50 years
56%
12.6
(n=113/142)
25%
68%
17.6
(n=111/155)
28%
0.12
0.82
(0.63-1.07)
Favorable
84%
39.4
(n=24/38)
46%
80%
NR
(n=19/51)
64%
0.02
0.44
(0.24-0.82)
Intermediate
56%
20.1
(n=101/141)
35%
77%
33.5
(n=71/127)
45%
0.01
0.75
(0.55-1.03)
Indeterminate
62%
14.3
(n=66/91)
29%
67%
21.3
(n=62/85)
29%
0.47
0.89
(0.63-1.27)
Unfavorable
44%
10.2
(n=54/59)
14%
57%
10.6
(n=54/63)
19%
0.22
0.66
(0.44-0.98)
NPM1
60%
16.9
(n=50/65)
29%
89%
75.9
(n=31/65)
52%
0.002
0.51
(0.32-0.81)
FLT3-ITD
48%
10.1
(n=74/83)
17%
70%
15.2
(n=44/64)
28%
0.009
0.50
(0.32-0.77)
DNMT3A
61%
14.1
(n=55/61)
13%
79%
16.5
(n=40/58)
33%
0.02
0.67
(0.42-1.05)
MLL-PTD
56%
16.2
(n=16/16)
6%
60%
20.6
(n=10/15)
33%
0.056
0.60
(0.24-1.54)
Subgroup
All patients
Age
Cytogenetic Risk
Gene Mutation
Adjusted for sex, age, hemoglobin level, leukocyte count, platelet count, and cytogenetics
CR = complete remission; OS = overall survival; HR = hazard ratio; CI = confidence interval; NR = not reached
*
associated with the presence of an
NPM1 mutation is uniquely
associated with higher-dose
therapy, the authors added.
“These updated results of the
E1900 trial demonstrate the broad
ability of anthracycline intensification during induction to improve OS
in patients age 60 or younger with
de novo AML, including those with
favorable and intermediate cytogenetics and those with mutations in
FLT3-ITD, NPM1, and DNMT3A,”
Dr. Luskin and colleagues wrote.
In all patients, high-dose daunorubicin was not associated with
additional toxicities, according to
the authors.
“[Given these results] we suggest that high-dose daunorubicin
be the standard for all eligible
adult patients up to 60 years of age
and be the standard of comparison for future clinical trials,” Dr.
Luskin and colleagues concluded.
“As we enter an era of targeted
therapy, including for FLT3ITD-mutant AML in the upfront
setting, it is important that these
agents be tested in the context of
optimal chemotherapy.”
The authors cautioned that
the results of the study should be
interpreted carefully due to the
rarity of these mutation incidences. The study also lacks data
on FLT3-ITD allelic ratio, thus the
benefit of high-dose daunorubicin
in this patient subgroup requires
further investigation. This followup study was also a secondary
analysis of some results that have
been reported previously.
REFERENCE
Luskin MR, Lee JW, Fernandez HF, et al. Benefit of high-dose
daunorubicin in AML induction extends across cytogenetic
and molecular groups. Blood. 2016;172:1551-58.
Thrombocytopenia and Sepsis: A Life-Threatening Combination
Patients with thrombocytopenia
who are admitted to the intensive
care unit (ICU) with sepsis are at
an increased risk for mortality,
compared with patients admitted
to the ICU with normal platelet
levels, according to the results of a
study recently published in Blood.
This study buil ds on findings from
pre-clinical animal trials that have
suggested platelets influence the
host response during sepsis.
Theodora A.M. Claushuis,
MD, from the Center for Experimental and Molecular Medicine at
the University of Amsterdam in the
Netherlands, and colleagues conducted the prospective, observational study to clarify the relation-
32
ASH Clinical News
ship between thrombocytopenia at
ICU admission and biologic and
other clinical variables, outcome,
and host response in patients
with sepsis, as part of the MARS
(Molecular Diagnosis and Risk
Stratification of Sepsis) project.
“Our results provide insight
into how platelets influence the
immune response during sepsis in
humans,” said Dr. Claushuis told
ASH Clinical News.
The researchers evaluated this
association by measuring 17 plasma biomarkers related to activation and dysregulation of pathways
implicated in sepsis pathogenesis
and by conducting whole-genome
blood leukocyte expression profil-
ing. The study included 931 adult
patients who were consecutively
admitted to two teaching hospitals
in the Netherlands between January 2011 and July 2013. Patients
were included in the study if they
had an expected length of stay
longer than 24 hours.
Patients were excluded from
the study if they met any of the
following criteria:
• They had been transferred
from other ICUs (except
when transferred on the day
of ICU admission).
• They had been readmitted to
the ICU at the same hospital
or within 30 days after the
first hospital admission.
• They had a hematologic
malignancy, liver cirrhosis,
splenectomy, thrombocytosis
(≥400x109/L), or unknown
platelet counts in the first 24
hours after ICU admission.
Patients were classified according to
their risk of infection on a four-point
plausibility scale (none, possible,
probable, or definite), with sepsis
defined as the presence of infection
within 24 hours of ICU admission
and at least one other parameter
described in the 2001 International
Sepsis Definitions Conference.
May 2016