From www.bloodjournal.org by guest on June 27, 2016. For personal use only.

CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS

Use of glycosylated recombinant human G-CSF (lenograstim) during and/or after

induction chemotherapy in patients 61 years of age and older with acute myeloid
leukemia: final results of AML-13, a randomized phase-3 study
Sergio Amadori, Stefan Suciu, Ulrich Jehn, Roberto Stasi, Xavier Thomas, Jean-Pierre Marie, Petra Muus, Francois Lefre`re, Zwi Berneman,
George Fillet, Claudio Denzlinger, Roel Willemze, Pietro Leoni, Giuseppe Leone, Marco Casini, Francesco Ricciuti,
Marco Vignetti, Filip Beeldens, Franco Mandelli, and Theo De Witte, for the EORTC/GIMEMA Leukemia Groups

The role of glycosylated recombinant human granulocyte colony-stimulating factor (G-CSF) in the induction treatment of
older adults with acute myeloid leukemia
(AML) is still uncertain. In this trial, a total
of 722 patients with newly diagnosed
AML, median age 68 years, were randomized into 4 treatment arms: (A) no G-CSF;
(B) G-CSF during chemotherapy; (C) G-CSF
after chemotherapy until day 28 or recovery of polymorphonuclear leukocytes; and
(D) G-CSF during and after chemotherapy.
The complete remission (CR) rate was

48.9% in group A, 52.2% in group B,

48.3% in group C, and 64.4% in group D.
Analysis according to the 2 2 factorial
design indicated that the CR rate was
significantly higher in patients who received G-CSF during chemotherapy
(58.3% for groups B D vs 48.6% for
groups A C; P .009), whereas no
significant difference was observed between groups A B and C D (50.6% vs
56.4%, P .12). In terms of overall survival, no significant differences were observed between the various groups. Pa-

tients who received G-CSF after

chemotherapy had a shorter time to neutrophil recovery (median, 20 vs 25 days;
P < .001) and a shorter hospitalization
(mean, 27.2 vs 29.7 days; P < .001). We
conclude that although priming with
G-CSF can improve the CR rate, the use
of G-CSF during and/or after chemotherapy has no effect on the long-term
outcome of AML in older patients. (Blood.
2005;106:27-34)
2005 by The American Society of Hematology

Introduction
More than 70% of patients with acute myeloid leukemia (AML) are
older than 60 years, and treatment of these individuals remains a
considerable therapeutic challenge.1 Older adults are less able to
tolerate intensive chemotherapy regimens (associated with higher
remission rates in younger patients), often have pre-existing
hematologic disorders, and are more likely to have poor-risk
cytogenetic abnormalities or expression of the multidrug
resistance phenotype.2-4
Strategies to reduce the toxicity associated with intensive
chemotherapy have involved the use of attenuated doses of
standard regimens and myeloid growth factors.1,5 Although a
decrease in early death rate can be achieved through dose
reduction, response rates are less favorable due to inadequate
antileukemic cytotoxicity.5 Where active treatment is attempted,
standard practice is thus remission induction followed by a

consolidation phase, the latter intended to eliminate residual

leukemia cells. Several trials have investigated the effects of
granulocyte colony-stimulating factor (G-CSF) and granulocytemacrophage colony-stimulating factor (GM-CSF) given after the
completion of standard induction chemotherapy.6-11 Although these
growth factors can consistently reduce the duration of neutropenia
by a few days, they do not modify the overall outcome.12 On the
other hand, attempts to improve the response rate by sensitizing
leukemic cells with hematopoietic growth factors, administered
before or concurrently with remission-induction therapy, have
yielded conflicting results.13-22 In this report, we present the final
results of a multicenter randomized phase-3 study in which
glycosylated recombinant human G-CSF (lenograstim) was given
during and/or after an intensive remission induction regimen in
patients 61 years of age and older with AML. Our aims were to

From the Department of Hematology, University Tor Vergata, Rome, Italy;

European Organisation for Research and Treatment of Cancer (EORTC) Data
Center, Brussels, Belgium; the Department of Hematology, Klinikum
Grosshadern Ludwig-Maximilians, Munich, Germany; the Hematology Unit,
Regina Apostolorum Hospital, Albano Laziale, Italy; the Department of
Hematology, Edouard Herriot Hospital, Lyon, France; the Department of
Hematology, Hotel-Dieu Hospital, Paris, France; the Department of
Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the
Netherlands; the Department of Hematology, Necker Hospital, Paris, France;
the Department of Hematology, University Hospital, Edegem, Belgium; the
Department of Hematology, Sart-Tilman Hospital, Liege, Belgium; the
Department of Hematology, University Hospital, Tubingen, Germany; the
Department of Hematology, University Hospital, Leiden, the Netherlands; the
Department of Hematology, University Hospital, Ancona, Italy; the Department
of Hematology, Catholic University, Rome, Italy; the Department of
Hematology, General Hospital, Bolzano, Italy; the Department of Hematology,
S. Carlo Hospital, Potenza, Italy; Gruppo Italiano Malattie Ematologiche
dellAdulto (GIMEMA) Data Center, Rome, Italy; and the Department of
Hematology, University La Sapienza, Rome, Italy.

Submitted September 27, 2004; accepted February 25, 2005. Prepublished

online as Blood First Edition Paper, March 10, 2005; DOI 10.1182/blood-200409-3728.

BLOOD, 1 JULY 2005 VOLUME 106, NUMBER 1

Supported in part by grants from the National Cancer Institute (grant numbers
2U10-CA11488-25 through 5U10-CA11488-34). Chugai-Aventis provided an
educational grant and GRANOCYTE free of charge.
A list of participating members of the EORTC and GIMEMA Leukemia Groups
appears in Appendix.
An Inside Blood analysis of this article appears at the front of the issue.
Reprints: Sergio Amadori, Department of Hematology, University Tor
Vergata, St Eugenio Hospital, P.le dellUmanesimo, 10, 00144 Rome, Italy;
e-mail: mc7673@mclink.it.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked advertisement in accordance with 18 U.S.C. section 1734.
2005 by The American Society of Hematology

27

From www.bloodjournal.org by guest on June 27, 2016. For personal use only.
28

AMADORI et al

assess the impact of lenograstim on the efficacy and toxicity of

chemotherapy.

Patients, materials, and methods

Study design
The AML-13 was a randomized, open-label, active-controlled, phase-3
study carried out by the European Organisation for Research and Treatment
of Cancer and Gruppo Italiano Malattie Ematologiche dellAdulto (EORTC/
GIMEMA) leukemia groups in 53 European centers. The final protocol was
approved by the EORTC Protocol Review Committee and by the Ethical
Committee of each participating center. Each patient had to sign an
informed consent before randomization.
The main objective of the study was to determine the efficacy and
toxicity of adding G-CSF to induction chemotherapy. The primary end
point was the overall survival (OS). Secondary end points included the
complete remission (CR) rate after induction, disease-free survival (DFS),
duration of remission, incidence of death in CR, event-free survival (EFS),
the number of days to hematopoietic recovery, and the duration of
hospitalization. Other objectives were (1) to assess the role of oral mini-ICE
as consolidation relative to intravenous idarubicin-cytarabine-etoposide
(mini-ICE); (2) to evaluate the feasibility of myeloablative chemotherapy
with autologous peripheral blood stem cell (autoPBSC) support as second
consolidation course in patients with a good performance status (PS) and
age of 70 years or younger. A detailed analysis of postinduction treatment
will be reported in full elsewhere.
Eligibility
Eligibility requirements were as follows (1) age 61 years and older, with an
upper age limit of 80 years; (2) diagnosis of primary or secondary AML
(sAML, including AML after myelodysplastic syndrome [MDS]) other than
French-American-British (FAB) M3 and 30% or more blast cells in bone
marrow smears; (3) no prior chemotherapy; (4) World Health Organization
(WHO) PS of 2 or more; (5) normal cardiac left ventricular ejection
fraction; (6) no evidence of severe concurrent cardiac, pulmonary, neurologic, or metabolic disease; and (7) adequate liver (serum bilirubin
level 2 upper normal limit) and renal (serum creatinine 2
upper normal limit) function tests. Exclusion criteria included blast
crisis of chronic myeloid leukemia and AML supervening after other
myeloproliferative diseases, other progressive malignant diseases, and
uncontrolled infections.
Treatment
The overall study plan is represented in Figure 1. Enrolled patients were
first randomized to receive G-CSF or no G-CSF in combination with
induction chemotherapy according to a 2 2 factorial design (yes or no
G-CSF during chemotherapy; yes or no G-CSF after chemotherapy). The
cytokine was applied as follows: no G-CSF (/, group A); G-CSF during
chemotherapy only (/, group B); G-CSF after chemotherapy only
(/, group C); G-CSF during and following chemotherapy (/,
group D). G-CSF (lenograstim, GRANOCYTE; Chugai-Aventis, Antony,

Figure 1. AML-13 schema. *After the first consolidation, patients 61 to 70 years old
who were WHO PS 0 or 1 were eligible to receive autoPBSC transplantation instead
of a second consolidation.

BLOOD, 1 JULY 2005 VOLUME 106, NUMBER 1

France) was given at the dose of 150 g/m2 daily by 30-minute intravenous
infusion. The cytokine was discontinued earlier if (1) the number of
circulating blast cells increased more than 2-fold during the chemotherapy
course (in that case, G-CSF could be reinstituted during the induction
period when the circulating blast cells had disappeared); (2) circulating
blast cells persisted at a significant level ( 1 109/L) for more than 3 days
after the chemotherapy course; (3) circulating blast cells ( 1 109/L)
reappeared after the chemotherapy course; and (4) the white blood cell
(WBC) count after treatment reached 10 109/L. G-CSF was also to be
discontinued in case of serious toxicity considered to be attributable to the
growth factor. Induction chemotherapy consisted of the MICE regimen:
mitoxantrone 7 mg/m2 intravenously on days 1, 3, and 5; cytarabine 100
mg/m2 per day intravenous continuous infusion on days 1 to 7; and
etoposide 100 mg/m2 as a 1-hour intravenous infusion on days 1 to 3.
Patients who achieved a partial remission (PR) received a second, identical
induction course. Patients who achieved CR were randomized to receive 2
courses of consolidation therapy with either the intravenous or the oral
mini-ICE regimen. Before the start of the trial, centers were asked to choose
between the use of a second mini-ICE consolidation course in all patients
who were in good clinical condition (WHO PS 0-1), or to administer
myeloablative chemotherapy with autoPBSC support in the younger cohort
( 70 years of age). Centers that chose to use the autografting strategy had
to register this intent by the official trial start date, and were strongly
advised to obey the following directives: ages 61 to 70 years and WHO PS
0 to 1, eligible for high-dose chemotherapy with autoPBSC support; ages 71
to 80 years and WHO PS 0 to 1, second mini ICE consolidation course;
WHO PS 2 or more after the first consolidation course, no further treatment.
If the transplantation procedure was not feasible, the patient was to receive
a second, identical mini-ICE course as assigned by the second randomization. The directives for centers not choosing to undertake autoPBSC
transplantation were as follows: age 61 to 80 years and WHO PS 0 to 1,
second mini-ICE consolidation course; WHO PS 2 or more after first
consolidation course, no further treatment.
The prescribed dosage and scheduling of intravenous mini-ICE was as
follows: idarubicin 8 mg/m2 per day intravenously on days 1, 3, and 5;
cytarabine 100 mg/m2 per day on days 1 to 5, as an intravenous continuous
infusion; etoposide 100 mg/m2 on days 1 to 3, as a 1-hour intravenous
infusion. The prescribed dose and scheduling of oral mini-ICE was as
follows: idarubicin 20 mg/m2 per day on days 1, 3, and 5 orally (after
breakfast); cytarabine 50 mg/m2 on days 1 to 5, as twice-daily subcutaneous
injections (total daily dose 100 mg/m2); etoposide 100 mg/m2, twice daily
(total daily dose 200 mg/m2), on days 1 to 3 orally (after breakfast and
dinner). The use of G-CSF was contemplated neither during nor after the
consolidation courses.
Criteria of response and evaluation of outcome
The Cancer and Leukemia Group B (CALGB) criteria for response to
treatment and relapse were used.23 A CR was defined as a morphologic
normal marrow with less than 5% blasts, no evidence of extramedullary
leukemia, and recovery of peripheral blood values to platelet counts of at
least 100 109/L and polymorphonuclear leukocytes (PMNs) 1.5 109/L
or more. A PR was defined by bone marrow smears containing between
5.1% and 25% blasts and less than 5% circulating blast cells. Failures of
response were classified as treatment resistance when there was no
reduction of the leukemic cell infiltration in the marrow or a reduction that
would not meet the criteria of PR or CR. Hypoplasia followed by leukemic
regrowth was also classified as resistant disease. Early death was defined as
death before the completion of the first cycle of induction therapy, and
hypoplastic death was defined as death after the completion of induction
cycle (1 or 2) before hematologic recovery. Relapse was defined as
recurrence of leukemia after initial CR as documented by cytologic or
pathologic evaluation of bone marrow or blood smears, or pathologic
diagnosis of extramedullary leukemia.
Morphologic classification followed the FAB group proposals.24,25
Standard cytogenetic techniques were used at diagnosis to karyotype the
leukemia. Normal cytogenetics (NN), abnormal cytogenetics (AA),

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BLOOD, 1 JULY 2005 VOLUME 106, NUMBER 1

G-CSF IN OLDER PATIENTS WITH AML

Table 1. Patient characteristics by randomized treatment group

and a mosaicism of abnormal and normal karyotypes (AN) were recorded.

The NN score was applied only when a minimum number of 20 mitoses had
been evaluated; in case of an examination of fewer metaphases, the analysis
was considered inadequate. Abnormalities 16q(22) and t(8;21) were
considered favorable risk abnormalities, whether other abnormalities were
present or not. NN karyotypes or those with only Y were classified as
intermediate risk. Deletions of the long arm of chromosomes 5 (5q)
and/or 7 (7q), or of the entire chromosomes (5, 7), and complex
abnormalities ( 3 abnormalities) were considered to have an unfavorable
prognosis. Patients with other abnormalities were pooled into a separate
cytogenetic risk group (other).
The patients with unknown, not done, or unsuccessful cytogenetics
were grouped together as unknown risk. Cytology, immunology, and
cytogenetics were each reviewed by central reviewers.

No. of patients (%)

Group A,
G-CSF/

Group B,
G-CSF/

Group C,
G-CSF/

Group D,
G-CSF/

182

180

180

180

EORTC

105 (57.7)

111 (61.7)

110 (61.1)

114 (63.3)

GIMEMA

77 (42.3)

69 (38.3)

70 (38.9)

66 (36.7)

61 to 70

112 (61.5)

116 (64.4)

124 (68.9)

127 (70.6)

71 to 80

70 (38.5)

64 (35.6)

56 (31.1)

53 (29.4)

Male

97 (53.3)

91 (50.6)

86 (47.8)

111 (61.7)

Female

82 (45.1)

86 (47.8)

89 (49.4)

67 (37.2)

Missing

3 (1.6)

3 (1.7)

5 (2.8)

2 (1.1)

PS 0

59 (32.4)

52 (28.9)

51 (28.3)

54 (30.0)

PS 1

81 (44.5)

91 (50.6)

87 (48.3)

83 (46.1)

PS 2

37 (20.6)

Total
Group

Age, y

Sex

Statistical analysis

Performance status*

38 (20.9)

34 (18.9)

38 (21.1)

PS 3 to 4

1 (0.5)

0 (0.0)

0 (0.0)

3 (1.7)

Missing/unknown

3 (1.6)

3 (1.7)

4 (2.3)

3 (1.7)

140 (76.9)

139 (77.2)

140 (77.8)

145 (80.6)

42 (23.1)

41 (22.8)

40 (22.2)

35 (19.4)

M0

12 (6.6)

18 (10.0)

15 (8.3)

8 (4.4)

M1

42 (23.1)

35 (19.4)

29 (16.1)

34 (18.9)

M2

58 (31.9)

47 (26.1)

58 (32.2)

56 (31.1)

M3

0 (0.0)

1 (0.6)

0 (0.0)

0 (0.0)

M4

29 (15.9)

25 (13.9)

29 (16.1)

40 (22.2)

M5

22 (12.1)

32 (17.8)

29 (16.1)

32 (17.8)

M6

6 (3.3)

10 (5.6)

4 (2.2)

4 (2.2)

M7

1 (0.5)

2 (1.1)

2 (1.1)

1 (0.6)

12 (6.5)

10 (5.6)

14 (7.8)

5 (2.8)

Type of AML
De novo
Secondary
FAB subtype

Missing/unknown
WBC, 109/L
Less than 25

113 (62.1)

123 (68.3)

118 (65.6)

124 (68.9)

25 to 99.9

45 (24.7)

35 (19.4)

39 (21.7)

38 (21.1)

100

17 (9.3)

16 (8.9)

16 (8.9)

16 (8.9)

7 (3.8)

6 (3.3)

7 (3.9)

2 (1.1)

Missing/unknown
Cytogenetics
Favorable

29

2 (1.1)

3 (1.7)

1 (0.6)

8 (4.4)

Intermediate

43 (23.6)

37 (20.6)

52 (28.9)

58 (32.2)

Unfavorable

16 (8.8)

31 (17.2)

21 (11.7)

21 (11.7)

Other

31 (17.0)

26 (14.4)

31 (17.2)

24 (13.3)

Missing/unknown

90 (49.5)

83 (46.1)

75 (41.7)

69 (38.3)

Results are presented as absolute numbers, with percentages shown in parentheses.

/ indicates not administered; /, administered on days 1 to 7; /,
administered on days 8 to 28; and /, administered on days 1 to 28.
*WHO scale.
This case was considered morphologically as FAB M3, but lacked both the
t(15;17) translocation at conventional cytogenetics and the promyelocytic leukemiaretinoic acid receptor (PML /RAR-) rearrangement at a molecular level.
NN, Y.
Presence of 5, 7, 5q, 7q, complex abnormalities.

Randomization was performed centrally (EORTC Data Center, Brussels)

and patients were stratified according to center, age (61-70 vs 71-80 years),
and type of AML (de novo AML vs sAML), using the minimization
technique. OS was defined as the time interval from randomization until
death, whatever the cause. DFS was defined as the time from CR until the
first relapse or death, whatever the cause. EFS was defined as the time from
the evaluation of the induction to the date of death or relapse, whichever
occurred first. The duration of recovery was defined as the time from start of
induction until PMN recovery or platelet recovery; patients without
recovery were censored at day 90. Toxicity was evaluated according to the
National Cancer Institute (NCI) Common Toxicity Criteria version 2.0.
(National Cancer Institute, http://ctep.cancer.gov/reporting/CTC-3.html).
The sample size of the whole study was derived based on the primary
end point of OS. According to the EORTC database for elderly AML, the
median survival of patients treated with conventional chemotherapy is
approximately 9 months and the 3-year survival rate is about 10%. In a
2-arm randomized study in order to detect an increase of 8% at 3 years,
representing a reduction of the death rate of 26% (hazard ratio [HR] 0.74),
a total of 500 patients are required to be randomized and 425 followed until
death (log-rank 2-tailed test, alpha 0.05, beta 0.15).26 This 2 2
factorial design, based on the assumption that no interaction exists between
the impact of the 2 questions (yes or no G-CSF during MICE; yes or no
G-CSF after MICE) on treatment outcome, did not require additional
patients to be randomized. As the second randomized question (oral vs
intravenous mini-ICE for consolidation) required a minimum of 330
patients, more than 720 patients were ultimately randomized in this study to
determine the value of G-CSF during and/or after remission induction. This
number of patients allowed the detection of differences in the CR rate (odds
ratio [OR], 1.86) between the individual groups (A vs B, C vs D, A vs C, B
vs D) with roughly 70% power (alpha 2.5%), and of the impact on CR
rate (OR, 1.83) of G-CSF given during (group B D vs A C) or after
chemotherapy (group C D vs A B) with a power of 90% (alpha 5%).
At the time of the final analysis, 613 deaths were reported, providing a
power more than 90% for the detection of significant differences between
the treatment groups (B D vs A C and C D vs A B). For the
time-to-events end points (OS, DFS, EFS), the actuarial curves were
computed using the Kaplan-Meier technique and the standard errors (SEs)

Table 2. Response to induction chemotherapy by treatment group

Group A,
G-CSF/
No. patients
Overall complete response
Partial response
Resistant disease
Early death
Death in hypoplasia
Unknown/missing data

Group B,
G-CSF/

Group C,
G-CSF/

Group D,
G-CSF/

Total,
Groups
A-D

Groups
A C,
G-CSF/

Groups
B D,
G-CSF/.

Groups
A B,
G-CSF./

Groups
C D,
G-CSF./

182

180

180

180

722

362

360

362

360

89 (48.9)

94 (52.2)

87 (48.3)

116 (64.4)

386 (53.5)

176 (48.6)

210 (58.3)

183 (50.6)

203 (56.4)

1 (0.5)

9 (5.0)

6 (3.3)

7 (3.9)

23 (3.2)

7 (1.1)

16 (4.4)

10 (2.7)

13 (3.6)

64 (35.1)

49 (27.2)

46 (25.5)

33 (18.4)

192 (26.6)

110 (30.3)

82 (22.7)

113 (31.2)

79 (21.9)

4 (2.2)

2 (1.1)

5 (2.8)

6 (3.3)

17 (2.3)

9 (2.5)

8 (2.2)

6 (1.7)

11 (3.1)

21 (11.5)

18 (10.0)

27 (15.0)

15 (8.3)

81 (11.2)

48 (13.3)

33 (9.2)

39 (10.8)

42 (11.7)

3 (1.6)

8 (4.4)

9 (5.0)

3 (1.6)

23 (3.2)

12 (3.3)

11 (3.0)

11 (3.0)

12 (3.3)

Results are presented as absolute numbers, with the percentages in parentheses. / indicates not administered; /, administered on days 1 to 7; /, administered
on days 8 to 28; /, administered on days 1 to 28; /., not administered on days 1 to 7; /., administered on days 1 to 7; ./, not administered on days 8 to 28; and ./,
administered on days 8 to 28.

From www.bloodjournal.org by guest on June 27, 2016. For personal use only.
30

BLOOD, 1 JULY 2005 VOLUME 106, NUMBER 1

AMADORI et al

Table 3. Estimated ORs and the corresponding confidence intervals for CR rates

Analysis

Group B vs
group A
(97.5% CI)

Group D vs
group C
(97.5% CI)

Groups B D
vs groups
A C (95% CI)

Group C vs
group A
(97.5% CI)

Group D vs
group B
(97.5% CI)

Groups C D
vs groups
A B (95% CI)

1.14 (0.71-1.83)

1.94 (1.20-3.14)

1.48 (1.10-1.99)

0.98 (0.61-1.57)

1.66 (1.02-2.69)

1.27 (0.94-1.70)

.53

.003

.009

.92

.024

.12

1.11 (0.67-1.83)

1.76 (1.05-2.94)

1.43 (1.05-1.94)

0.98 (0.59-1.60)

1.44 (0.86-2.42)

1.15 (0.84-1.56)

.65

.01

.025

.90

.12

.38

Uni/bivariate
OR
P
Multivariate
OR
P

Multivariate indicates adjustment for cytogenetics (unknown/not done, favorable, intermediate, unfavorable, other), WBC ( 5, 5-24.9, 25-99.9, 100 109/L), age
(61-65, 66-75, 75 years), and disease (de novo AML, sAML).

of the estimates were obtained via the Greenwood formula.27 The differences between curves were tested for statistical significance using the
stratified 2-tailed log-rank test.27 The estimate of the cumulative incidence
of relapse and of the incidence of death in CR and their corresponding SEs
were obtained using competing risk methods.27 The reflected method was
used to determine the 95% confidence interval (CI) of the median survival
time.28 The Cox proportional hazards model has been used to obtain the
estimate and the 95% CI of the HR of the instantaneous event rate in one
treatment group versus the control group; this required the inclusion of 2
binary variables in the model, corresponding to the presence or absence of
G-CSF during and after chemotherapy.27
For the treatment comparison in terms of CR rate, the Fisher exact test
was used.29 The usual logistic regression model has been used for the
estimates of the OR of the CR rates between 2 treatment groups and the
corresponding confidence interval (95% for each question, B D vs A C
and C D vs A B; 97.5% for individual groups); this model was used to
perform adjustments of the treatment comparisons for those factors that
appeared to be of prognostic importance and/or in assessing the interaction
between the 2 questions on the CR rates.29 In the multivariate analysis,
adjustments were made for cytogenetics (favorable, intermediate,
unfavorable, other, not done/unknown), WBC ( 5, 5-24.9, 25-99.9,
100 109/L), age (61-65, 66-75, 75 years), and type of AML (de
novo vs sAML).
All the efficacy analyses were performed according to the intent-to-treat
principle. The durations of hospitalization, intravenous antibiotics, and
intravenous antifungals were compared using the Wilcoxon test.29 The
database was frozen on September 2003. SAS 8.2 software (SAS Institute,
Cary, NC) has been used for the statistical analyses.

Results
Patient characteristics

Between December 1995 and February 2001, a total of 722 patients

were randomized in the trial. Their median age was 68 years (range,
61-80 years); 53.3% were males. The median WBC count was
8.1 109/L (range, 0.2-360 109/L). The 4 treatment groups were
evenly matched with respect to various baseline characteristics,
with the only exception of cytogenetics, which showed a slight
preponderance of favorable and intermediate karyotypes in group
D (Table 1). A total of 35 patients were considered ineligible: 5 in
group A, 10 in group B, 10 in group C, and 10 in group D. Reasons
for ineligibility included insufficient data in 13, concomitant
malignant diseases in 11, prior chemotherapy in 4, inadequate
performance status in 3, leukemia supervening after a myeloproliferative disorder in 2, and other causes in 2. Ineligible patients were
also included in the intention-to-treat analysis.

(95%), this response was obtained after the first induction cycle. As
shown in Table 2, CR rates were as follows: 48.9% (group A),
52.2% (group B), 48.3% (group C), and 64.4% (group D). In
Table 3, the estimated ORs for the pairwise comparisons (B vs A, D
vs C, C vs A, and D vs B) along with the 97.5% CIs are given.
Higher ORs were obtained for the comparison group D vs group C
than for group B vs group A, and for group D vs group B than for
group C vs group A, suggesting a possible interaction between the 2
questions (yes or no G-CSF during chemotherapy; yes or no G-CSF
after chemotherapy). However, this interaction was found to be not
significant (P .08). Multivariate analysis showed that the superiority of group D was in fact of lower magnitude for each
comparison (group D vs group C: OR, 1.76 [P .01]; group D vs
group B: OR, 1.44 [P .12]), and confirmed that the interaction
between the 2 questions was not significant (P .23).
Analysis according to the 2 2 factorial design indicated that
the CR rate was significantly higher in patients who received
G-CSF during chemotherapy (58.3% for groups B D vs 48.6%
for groups A C; Fisher exact test, P .009; OR, 1.48; 95% CI,
1.10-1.99; Tables 2-3). This was related mostly to the lower
percentage of resistant disease in patients receiving G-CSF with
chemotherapy compared with controls (22.7% vs 30.3%, P .019,
Table 2). Conversely, G-CSF administered after chemotherapy did
not influence significantly the CR rate (56.4% for groups C D vs
50.6% for groups A B; Fisher exact test, P .12; OR, 1.27; 95%
CI, 0.94-1.70; Tables 2-3). Adjustment for factors that appeared to
be of prognostic importance (secondary vs de novo AML, age,
cytogenetics, WBC count) in a linear logistic model confirmed
these findings (Table 3), although the adjusted estimates of the OR
were slightly lower (1.43 and 1.15).

Response to induction treatment

A complete response after 1 or 2 courses of induction chemotherapy was achieved in 53.5% of patients (Table 2). In most cases

Figure 2. Duration of overall survival according to randomized treatment

group. N indicates the number of patients in each group; O, the observed number of
deaths.

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BLOOD, 1 JULY 2005 VOLUME 106, NUMBER 1

G-CSF IN OLDER PATIENTS WITH AML

Table 4. Estimates of the 3-year rates or incidences by treatment

group
Group A,
G-CSF/

Group B,
G-CSF/

Group C,
G-CSF/

Group D,
G-CSF/

OS rate

15.2 (2.8)

18.3 (3.0)

14.4 (2.7)

7.6 (2.9)

EFS rate

10.5 (2.3)

9.2 (2.2)

9.0 (2.2)

9.3 (2.2)

End point

DFS rate*

21.5 (4.4)

17.6 (4.0)

18.6 (4.2)

14.5 (3.3)

Relapse incidence*

63.6 (5.2)

73.9 (4.7)

72.2 (4.9)

72.6 (4.2)

Death in CR incidence*

14.9 (3.9)

8.6 (2.9)

9.3 (3.2)

12.9 (3.1)

Survival from CR rate*

26.6 (4.8)

30.4 (4.9)

25.1 (4.7)

24.8 (4.0)

Numbers in parentheses are the standard errors.

*Only patients who achieved a complete remission were considered (the number
of patients in each group is given in Table 2).

Consolidation treatment

A total of 346 patients were randomized to receive either the intravenous

mini-ICE (n 172) or the oral mini-ICE (n 174). Baseline characteristics were evenly matched between treatment groups (data not shown).
Of the patients, 15 were not evaluable: 6 in the intravenous and 9 in the
oral arm. Among 331 evaluable patients, 114 received one consolidation
course only; 182, 2 consolidation courses; and 35, one consolidation
course followed by myeloablative chemotherapy with autoPBSC support. Withdrawals due to toxicity or treatment refusal were similar
between the 2 groups. The instantaneous risk of death or relapse was
17% (95% CI, 7%-48%) higher in the oral group than in the
intravenous group. The corresponding HR in the intention-to-treat
population was 1.18 (95% CI, 0.94-1.49).
Duration of survival

31

leukemia at 3 years. The 3-year incidence of relapse was comparable among the treatment groups (Table 4).
G-CSF treatment, hematopoietic recovery, and hospitalization

G-CSF was administered for a median of 7 days (range, 2-18 days)

in group B, 18 days (range, 1-36 days) in group C, and 24 days
(range, 1-38 days) in group D. Treatment with G-CSF was
interrupted or not administered in 174 (34.1%) of 510 patients. The
primary reasons were granulocyte recovery (93 patients), and
persistence or reappearance of circulating blast cells (19 patients).
Other reasons, based on decisions by local physicians, were usually
related to medical problems (eg, liver function abnormalities
and allergy).
The median times to neutrophil recovery of 0.5 109/L in
groups C D versus groups A B were 20 days (range, 1-83
days) and 25 days (range, 1-55 days), respectively (P .001). The
median times of recovery to a platelet value of 20 109/L were 20
days (range, 1-67 days) in the C D groups and 21 days (range,
1-55 days) in the A B groups (P .93). The mean ( SD)
number of days spent in the hospital during induction cycle 1 were
27.2 ( 12.4) days in groups C D and 29.7 ( 14.2) days in
groups A B (P .001). Intravenous antibiotics were administered for significantly fewer days in patients who received G-CSF
after chemotherapy: mean ( SD) of 19.0 ( 11.3) days in groups
A B versus 16.2 ( 10.2) days in groups C D (P .001). The
duration of intravenous antifungal therapy in group C D was also
significantly shorter than in groups A B: mean ( SD) of 6.4
( 8.9) versus 8.5 ( 10.5) days (P .007).
Toxicity

Patients have been followed for a median of 4.7 years after the first
randomization. The median OS time for all patients was 9.1
months; in particular, the estimated median values (97.5% CI) were
7.9 months (5.8-10.4) in group A, 9.2 months (6.7-12.6) in group B,
8.4 months (6.1-10.9) in group C, and 11.5 months (8.3-14.9) in
group D (Figure 2). The 3-year OS rates were similar in the
different groups (Table 4), and the estimated HRs were close to 1
(Table 5).
A Cox model showed that the results remained practically
unchanged after the adjustment for several presenting factors
(disease, age, cytogenetics, WBC); for the comparison B D
versus A C, the estimated HR was 0.91 (95% CI, 0.78-1.07;
P .26), and for the comparison C D versus A B, the
estimated HR was 1.03 (95% CI, 0.88-1.21; P .73). This is also
true for the individual comparison D versus C (HR, 0.90; 97.5% CI,
0.69-1.17; P .37) and B versus A (HR, 0.91; 97.5% CI,
0.70-1.18; P .41).
EFS and DFS

Likewise, the 3-year EFS and DFS rates were similar between the
different treatment groups (Figures 3-4; Tables 4-5). Of the 386
complete responders, 44 died in first CR and 271 had recurrence of

The frequencies of various grade 3 or grade 4 adverse effects after

induction cycles 1 and 2 were similar between the groups except
for severe hypotension, which was more frequent in patients who
received G-CSF after chemotherapy (4.3% for groups C D vs
1.2% for groups A B; Table 6).
The mean SD number of days of fever (axillary temperature,
38.5C) in association with induction chemotherapy was
8.8 6.7 days in groups A B and 8.0 6.7 days in groups
C D. The incidence of microbiologically documented infections
(63.7% vs 60.4%) as well as of fatal infections (6.6% vs 6.7%) was
also similar between groups A B and groups C D. There were
no differences regarding the frequency and types of both bacterial
and fungal infections (data not shown).

Discussion
This randomized study considered the role of lenograstim as an
adjunct to chemotherapy in older patients with AML. Based on in
vitro data showing that exposure to myeloid growth factors
increases the susceptibility of blast cells to cell cyclespecific

Table 5. Estimated HRs and the corresponding confidence intervals for the main end points

End point

Group B vs
group A
(97.5% CI)

Group D vs
group C
(97.5% CI)

Groups B D
vs groups
A C (95% CI)

Group C vs
group A
(97.5% CI)

Group D vs
group B
(97.5% CI)

Groups C D
vs groups
A B (95% CI)

OS

0.95 (0.74-1.23)

0.87 (0.67-1.12)

0.91 (0.78-1.02)

1.03 (0.79-1.32)

0.94 (0.72-1.21)

0.98 (0.84-1.15)

EFS

0.98 (0.76-1.25)

0.86 (0.67-1.10)

0.92 (0.79-1.07)

1.00 (0.78-1.28)

0.88 (0.69-1.13)

0.94 (0.81-1.09)

DFS from CR

1.03 (0.72-1.48)

1.05 (0.75-1.48)

1.04 (0.84-1.30)

0.99 (0.68-1.44)

1.01 (0.72-1.41)

1.00 (0.81-1.24)

Survival from CR

1.00 (0.68-1.46)

1.01 (0.71-1.44)

1.00 (0.80-1.26)

1.08 (0.73-1.58)

1.11 (0.78-1.57)

1.09 (0.87-1.37)

*Only patients who achieved CR were considered (the number of patients in each group is given in Table 2).

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32

BLOOD, 1 JULY 2005 VOLUME 106, NUMBER 1

AMADORI et al

Figure 3. Event-free survival according to randomized treatment group. N

indicates the number of patients in each group; O, the observed number of events
(lack of CR after induction, relapse, or death in CR).

agents such as cytarabine,30-34 it was hypothesized that priming

with G-CSF might improve the outcome of chemotherapy for
AML. It also was assumed that G-CSF might possibly reduce the
duration of neutropenia after chemotherapy, thereby reducing
morbidity and mortality from bacterial and fungal infections.
Our data indicate that G-CSF administered concomitantly with
standard induction chemotherapy results in a higher CR rate than
chemotherapy alone in patients with AML who are 61 years and
older, but has no significant impact on OS. In particular, the CR rate
was 52.2% in patients randomized to receive G-CSF during
chemotherapy only (group B), while it reached 64.4% in those
assigned to receive the cytokine both during and after chemotherapy (group D), suggesting that the magnitude of the effect of
G-CSF on the rate of response might be further enhanced by
extending its administration after chemotherapy. This latter result,
however, should be interpreted with caution for a number of
reasons: (1) multivariate analysis showed no significant interaction
between the use of concurrent and postchemotherapy G-CSF;
(2) the higher, although not significantly, proportion of patients
with favorable/intermediate cytogenetics may at least in part have
contributed to the greater response rate in group D; and (3) even in
this group of patients with the highest CR rate, there was no
significant improvement of survival parameters. A plausible explanation for these findings is that the quality of induced complete
responses in terms of minimal residual disease could be lower in
patients treated with G-CSF, in whom the residual blast count may
be confounded by granulocytic hyperplasia.35 Nevertheless, the
poor outcome may also result from inadequate postremission
therapy. In fact, AML in older patients often presents with high-risk
features (poor cytogenetics, expression of multidrug resistance

phenotype, etc) that would require very aggressive strategies

generally not applicable to these individuals.
Previous controlled trials have failed to show a beneficial effect
on the response rate of priming with either G-CSF or GM-CSF in
patients with AML.13,14,16-18,20-22,36,37 However, a careful analysis
reveals a great variability in study conditions, with very few
identical study designs (Table 7). When analyzing different clinical
trials addressing similar questions, it is particularly important to
compare patients age, disease state (whether de novo AML or
sAML), and the induction regimen used. It is theoretically possible
that the more intensive induction regimens, with a more profound
suppression of the bone marrow, may have a greater potential for a
beneficial effect from cytokine priming. In this regard, the 3-drug
regimen (mitoxantrone, cytarabine, etoposide) that we used for
induction treatment may have some bearing on the results, because
other trials have predominantly used 2-drug regimens (an anthracycline or mitoxantrone plus cytarabine). Only a recent Swedish
study used an induction chemotherapy with the same 3 agents used
in our trial, although delivered with a different schedule.22 In that
study, the administration of GM-CSF prior to and in combination
with induction treatment did not improve either the response rate or
OS. However, it should be underlined that the response rates in
both arms were very high (64% in patients without GM-CSF, and
65% in patients who received GM-CSF), despite the fact that the
median age was considerably higher (77 years) than the average of
the other studies. Selection biases (exclusion of patients with
leukocyte counts more than 50 109/L, and with sAML) can
account for these findings.
Timing of growth factor administration, used as priming,
may represent another critical issue. However, the discrepant
results of published studies do not help to clarify whether the
priming cytokine should be administered prior to, or concomitantly with, the administration of chemotherapy. In fact, it has
been suggested that some detrimental effect might occur
following blast cell stimulation without simultaneous cytotoxic
therapy.38 Another variable to be considered is the use of
different study products, since there may be pharmacologic
differences even among different cellular preparations of the
same cytokine. The statistical end points used in the design of
many of these studies also need to be very carefully evaluated.
Some of the studies were part of larger studies designed and
sized to evaluate differences in hematopoietic recovery, for
example, but not to detect differences in complete response rate,
Table 6. Incidence of WHO grade-3 to grade-4 side effects
during induction therapy
Group A,
G-CSF/
N
Hemorrhage

Group B,
G-CSF/

Group C,
G-CSF/

Group D,
G-CSF/

178

172

173

177

9 (5.0)

15 (8.8)

13 (7.5)

7 (4.0)

Hepatic

14 (7.9)

13 (7.5)

21 (12.1)

22 (12.4)

Cardiovascular*

23 (12.9)

11 (6.4)

15 (8.7)

20 (11.3)
7 (4.0)

Hypotension

2 (1.1)

2 (1.2)

8 (4.6)

Diarrhea

10 (5.6)

3 (1.8)

8 (4.6)

7 (4.0)

Nausea

38 (21.4)

40 (23.3)

30 (17.4)

28 (15.8)
1 (0.6)

Rigors/chills

0 (0)

0 (0)

2 (1.2)

Bone pain

1 (0.6)

0 (0)

1 (0.6)

2 (1.1)

Rash/itch

2 (1.1)

4 (2.3)

6 (3.5)

7 (4.0)

Infection

48 (27.0)

57 (23.1)

54 (31.2)

45 (25.4)

Results are presented as absolute numbers, with the percentages in parentheses.

Figure 4. Disease-free survival according to randomized treatment group. N
indicates the number of patients in each group; O, the observed number of events
(relapse or death in CR).

/, indicates not administered on days 1 to 7; /, administered on days 1 to 7;

/, not administered on days 8 to 28; and /, administered on days 8 to 28.
*Includes nonspecific cardiac events and dysrhythmias.

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BLOOD, 1 JULY 2005 VOLUME 106, NUMBER 1

G-CSF IN OLDER PATIENTS WITH AML

33

Table 7. Randomized studies of growth factors as priming therapy for acute myeloid leukemia

Reference

No. of
patients

Median
age, y

AML state

Growth
factor/control

Day of first
administration*

Growth factor vs control

group
% CR

% overall survival

58

43-47

Relapsed/refractory

Filgrastim/placebo

50/37

Same

197

58-61

De novo/secondary

Filgrastim/control

63/54

Same

Heil et al15

80

55

De novo

Molgrastim/placebo

81/79

45/49 (at 43 mo)

Zittoun et al16

51

54

Previously untreated

Molgrastim/control

72/77

Same

Lowenberg et al17

318

68

De novo/secondary

Molgrastim/control

56/55

22/22 (at 24 mo)

Witz et al18

240

66

De novo

Molgrastim/placebo

62/61

44/19 (at 24 mo)

Thomas et al19

192

46-47

Relapsed/refractory

Molgrastim/placebo

65/59

Same

Lowenberg et al20

640

44

De novo/secondary

Lenograstim/control

79/83

40/35 (at 48 mo)

Rowe et al21

245

67-69

Previously untreated

Sargramostim/placebo

38/40

Same

Lofgren et al22

110

77

De novo

Sargramostim/control

65/64

8/10 (at 72 mo)

Ohno et

al13

Estey et al14

Filgrastim indicates Escherichia coliderived recombinant human granulocyte colony-stimulating factor; Lenograstim, Chinese hamster ovaryderived recombinant
human G-CSF; Molgrastim, Escherichia coliderived recombinant human GM-CSF; and Sargramostim, yeast-derived recombinant human granulocyte-macrophage
colony-stimulating factor.
*Day of first administration of the growth factor in relation to the start of chemotherapy.
Including 74 patients with myelodysplastic syndrome.
P .003.
P .16; DFS 45/33, P .02.
P .07.

DFS, or survival. In fact, a lack of the statistically significant

improvement in response rate does not necessarily indicate a
lack of efficacy, but rather the inability to make any substantive
conclusions because of the intrinsic study design.
Contrary to the findings of Lowenberg et al,20 showing that
G-CSF given concurrently with chemotherapy produced an improvement of DFS in AML patients 18 to 60 years of age who were
considered to be in a standard risk prognostic category, the
results of our study indicated that no particular subgroup identified
by cytogenetics benefited from G-CSF priming. Nevertheless, we
have to acknowledge that our study was underpowered in this respect,
and, in addition, 44% of the patients from our series did not have
evaluable cytogenetics. It is noteworthy that the glycosylated G-CSF
used in the Hemato-Oncologie voor Voolwassenen Nederland (HOVON) trial had the same cellular origin and was manufactured by the
same company as in our study. Thus, the differences in the results are not
attributable to different growth factor properties, but rather to differences
in the patient population under study (older age in our series) and in the
intensity of treatment.
Preliminary data of a German multicenter trial in AML patients
16 to 83 years of age are consistent with our results, showing no
significant difference in OS or DFS between patients assigned to
G-CSF and those assigned to no G-CSF, irrespective of the
cytogenetic category.39
In our study, the use of G-CSF after chemotherapy resulted in a shorter
duration of neutropenia by 5 days, but it did not prevent the infectious
complications during the hypoplastic phase to any significant extent. As a
result, morbidity or mortality was not reduced. These results are largely in
line with other trials conducted to date.6-10,13,14,17,18,22 The shortened period
of neutropenia was probably the reason for less antibiotic and antifungal
use as well as shorter hospitalization in this group of patients. These
positive clinical findings definitely encourage the use of G-CSF as an
adjunct to standard supportive care in AML. We are aware that economic
considerations are important when evaluating a supportive care treatment.
In this regard, 2 major health-economic studies of myeloid growth factors
as adjunct therapy in older patients with AML have been conducted, and
both demonstrated no significant increment in costs of care associated
with the use of G-CSF or GM-CSF.40,41 Besides, it has been argued that
the short-term outcomes of these economic studies may inappropriately penalize the growth factors, when strict economic analyses
are carried out.42 For example, if G-CSF were to prevent delays

in therapy, health care costs might be less and clinical outcomes

might ultimately be improved.
The use of priming with growth factors has aroused concern that
the stimulation of residual normal precursors could increase their
sensitivity to chemotherapy, with consequent delays in the return of
blood counts to normal. This has not occurred in our trial, which
opens the question of the nature of the protective mechanisms that
allow normal stem cells to regenerate rapidly when the leukemia
clone is suppressed.
In conclusion, the results of our trial suggest that neither G-CSF
priming nor G-CSF administration after induction chemotherapy
has any impact on the long-term outcome of AML in older patients.
At the present time, G-CSF should be offered to these patients only
as a supportive care measure.

Acknowledgments
We acknowledge St Jude Childrens Research Hospital for providing an SAS macro allowing the computation of the cumulative
incidences of relapse and of death in CR. We thank the cytogeneticists of the different institutions, in particular A. Bernheim
(Villejuif), M. Mancini (Rome), D. Olde-Weghuis (Nijmegen), and
A. Hagemeijer (Leuven), for the review of karyotypes.
The contents of this paper are solely the responsibility of the
authors and do not represent the official views of the National
Cancer Institute (Bethesda, MD).

Appendix
The following members of the EORTC or GIMEMA Leukemia Groups
participated in this study: Dr Sinnige (Den Bosch), Dr Vreugdenhil
(Veldhoven), Dr Bron (Brussels), Dr De Bock (Antwerpen), Dr Berneman
(Antwerpen), Dr Vermeulen (Verviers), Dr Feremans (Brussels), Dr Fillet
(Lie`ge), Drs Schneider and Thyss (Nice), Dr Bourhis (Villejuif), Drs
Archimbaud, Chelghoum, Fie`re, and Thomas (Lyon), Drs Vekhouff and
Marie (Paris), Drs Delarue, Lefre`re, and Varet (Paris), Dr Dreyfus (Paris),
Dr Baumelou (Suresnes), Drs de Witte and Muus (Nijmegen), Dr Willemze
(Leiden), Dr Jehn (Munich), Dr Denzlinger (Tubingen), Dr Stauder
(Innsbruck), Dr Labar (Zagreb), Dr Jaksic (Zagreb), Dr Indrak (Olomouc),
Dr Ribeiro (Porto), Dr Nobile (Reggio Calabria), Drs Amadori, Stasi, and

From www.bloodjournal.org by guest on June 27, 2016. For personal use only.
34

BLOOD, 1 JULY 2005 VOLUME 106, NUMBER 1

AMADORI et al

Venditti (Rome), Dr Citarella (Palermo), Dr Rizzoli (Parma), Dr Gabbas

(Nuoro), Dr Leoni (Ancona), Drs Mandelli, Petti, and Vignetti (Rome), Drs
Leone and Pagano (Rome), Dr Defazio (Lodi), Dr Greco (San Giovanni
Rotondo), Dr Lucarelli (Pesaro), Dr Mirto (Palermo), Dr Rotoli (Napoli),
Dr Broccia (Cagliari), Dr Fioritoni (Pescara), Dr Mariani (Palermo), Dr

Ricciuti (Potenza), Dr Ferrara (Napoli), Dr Torelli (Modena), Dr Longinotti

(Sassari), Dr Morandi (Cremona), Dr Mazza (Taranto), Dr Levis (Alessandria), Drs Coser, Casini, and Cassibba (Bolzano), Dr Quarta (Brindisi), Dr
Montanaro (Montefiascone), and Dr Boccadoro (Torino).
Dr Archimbaud is deceased.

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From www.bloodjournal.org by guest on June 27, 2016. For personal use only.

2005 106: 27-34

doi:10.1182/blood-2004-09-3728 originally published online
March 10, 2005

Use of glycosylated recombinant human G-CSF (lenograstim) during

and/or after induction chemotherapy in patients 61 years of age and
older with acute myeloid leukemia: final results of AML-13, a randomized
phase-3 study
Sergio Amadori, Stefan Suciu, Ulrich Jehn, Roberto Stasi, Xavier Thomas, Jean-Pierre Marie, Petra
Muus, Francois Lefrre, Zwi Berneman, George Fillet, Claudio Denzlinger, Roel Willemze, Pietro
Leoni, Giuseppe Leone, Marco Casini, Francesco Ricciuti, Marco Vignetti, Filip Beeldens, Franco
Mandelli and Theo De Witte

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