I m p r o v e d T r... M y e l o i d L e u...

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Improved Treatment Results in High-Risk Pediatric Acute
M y e l o i d L e u k e m i a P a t i e n t s A f t e r I n t e n s i fi c a t i o n W i t h
High-Dose Cytarabine and Mitoxantrone: Results of Study
A c u t e M y e l o i d L e u k e m i a – B e r l i n - F r a n k f u r t - M u¨ n s t e r 9 3
By U. Creutzig, J. Ritter, M. Zimmermann, D. Reinhardt, J. Hermann, F. Berthold, G. Henze, H. Ju¨rgens, H. Kabisch,
W. Havers, A. Reiter, U. Kluba, F. Niggli, and H. Gadner for the Acute Myeloid Leukemia–Berlin-Frankfurt-Mu¨nster
Study Group
Purpose: To improve outcome in high-risk patients,
high-dose cytarabine and mitoxantrone (HAM) was
introduced into the treatment of children with acute
myelogenous leukemia (AML) in study AML-BFM 93.
Patients were randomized to HAM as either the second
or third therapy block, for the purpose of evaluation of
efficacy and toxicity.
Patients and Methods: A total of 471 children with
de novo AML were entered onto the trial; 161 were at
standard risk and 310 were at high risk. After the
randomized induction (daunorubicin v idarubicin), further therapy, with the exception of HAM, was identical
in the two risk groups and also comparable to that in
study Acute Myeloid Leukemia–Berlin-Frankfurt-Mu
¨nster (AML-BFM) 87.
Results: Overall, 387 (82%) of 471 patients
achieved complete remission, and 5-year survival,
event-free survival (EFS), and disease-free survival
rates were 60%, 51%, and 62%, respectively. Idarubicin induction resulted in a significantly better blast cell
reduction in the bone marrow on day 15. Estimated
survival and probability of EFS were superior in study
AML-BFM 93 compared with study AML-BFM 87 (P ⴝ
.01, log-rank test). This improvement, however, was
restricted to the 310 high-risk patients (remission rate
and probability of 5-year EFS in study AML-BFM 93 v
study AML-BFM 87: 78% v 68%, P ⴝ .007; and 44% v
31%, P ⴝ .01, log-rank test). Probability of 5-year EFS
among standard-risk patients in study AML-BFM 93
was similar to that in study AML-BFM 87 (65% v 63%,
P ⴝ not significant). Whether HAM was placed as the
second or third therapy block was of minor importance.
However, patients who received the less intensive
daunorubicin treatment during induction benefited
from early HAM.
Conclusion: Improved treatment results in children
with high-risk AML in study AML-BFM 93 must be attributed mainly to the introduction of HAM.
J Clin Oncol 19:2705-2713. © 2001 by American
Society of Clinical Oncology.
HE GOAL OF remission and increased overall survival
in acute myelogenous leukemia (AML) is best accomplished through administration of several courses of combination chemotherapy consisting of the antipyrimidine
drug cytarabine (Ara-C) and intercalating agents such as
anthracyclines. Moreover, the addition of etoposide (VP-16)
to standard therapy has improved disease-free survival
(DFS).1 Over the last 15 years, mitoxantrone, an anthracenedione derivative that has activity against AML blasts
when given as a single agent,2 has become more important,
specifically in the treatment of resistant leukemia.3
Another means of improving outcome is intensification
with high-dose Ara-C in either the postremission or induction phase, as demonstrated by several studies in adults4-6
and children.7-9 The dose effect of cytarabine given at a
standard dose of 100 mg/m2, a medium dose of 400 mg/m2,
or the high-dose of 3 g/m2 during postremission treatment
was first shown by the Cancer and Leukemia Group B.6 The
efficacy of high-dose Ara-C in combination with mitoxantrone (HAM) was demonstrated in adult patients with
refractory AML by Hiddemann et al10 and in adult patients
with de novo AML by Arlin et al,11 who reported a higher
complete remission (CR) rate after a single induction course
of the mitoxantrone-based regimen (mitoxantrone 3 ⫻ 12
mg/m2) compared with the standard regimen using daunorubicin (3 ⫻ 45 mg/m2). Bu¨chner et al4,12 demonstrated that
HAM given in a second induction course benefited poorrisk adult patients.
In study AML-BFM 87, an intensive combination chemotherapy regimen including high-dose Ara-C and VP-16
given during postremission treatment produced favorable
results in standard-risk patients, whereas results in high-risk
T
From the Department of Pediatric Hematology/Oncology, University Children’s Hospital, Mu¨nster, Jena, Cologne, Berlin, Hamburg,
Essen, Giessen, and Magdeburg, Germany; St Anna Children’s Hospital, Vienna, Austria; and Department of Pediatric Hematology/
Oncology, University Children’s Hospital, Zurich, Switzerland.
Submitted December 1, 2000; accepted February 9, 2001.
Supported by the Deutsche Krebshilfe.
Address reprint requests to Ursula Creutzig, Prof, Klinik und
Poliklinik fu¨r Kinderheilkunde, Pa¨diatrische Ha¨matologie/Onkologie,
Albert-Schweitzer-Str 33, D-48129 Mu¨nster, Germany; email:
ucreutzig@ aol.com.
© 2001 by American Society of Clinical Oncology.
0732-183X/01/1910-2705
Journal of Clinical Oncology, Vol 19, No 10 (May 15), 2001: pp 2705-2713
Downloaded from jco.ascopubs.org on September 9, 2014. For personal use only. No other uses without permission.
Copyright © 2001 American Society of Clinical Oncology. All rights reserved.
2705
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CREUTZIG ET AL
patients were unsatisfactory. To improve outcome in the
latter group, we introduced HAM in study AML-BFM 93.
Because the dose-intensity of HAM during the first two
treatment courses has been shown to be of prognostic
significance,12 we attempted in the current study to determine whether placing HAM as the first versus second
postinduction treatment block affects prognosis. In view of
reports that this intensification regimen is associated with
increased toxicity and the need for more supportive care,
including transfusion of blood products, especially platelets,13 HAM was restricted to high-risk patients. The regimen was not given to standard-risk patients, with their
estimated survival rate of 70% at 5 years, to avoid impairment of prognosis by severe adverse effects.14
PATIENTS AND METHODS
Eligibility
The entry criteria for studies AML-BFM 93 and 87 included newly
diagnosed AML, patient age 0 to 17 years, and written informed
consent of the patient or parent. Patients with myelosarcoma, secondary
AML, myelodysplastic syndrome, or Down’s syndrome were excluded.
Diagnosis
The initial diagnosis of AML and its subtypes was established using
the French-American-British (FAB) classification.15-17 All initial
smears were routinely studied at the University Children’s Hospital in
Mu¨nster and were reviewed by a panel of hematologists, including
an external investigator (H. Lo¨ffler). The diagnoses of M0 and M7
subtypes always required confirmation by immunologic methods.16,17 Bone marrow aspirates obtained on day 15 were also
reviewed centrally.
Treatment
The treatment protocol of study AML-BFM 93 evolved from that of
study AML-BFM 87.18 At the time of diagnosis, patients in the current
study were randomized to 8-day induction with either daunorubicin
(ADE: Ara-C 100 mg/m2 by continuous infusion on days 1 and 2,
followed by a 30-minute infusion every 12 hours on days 3 through 8;
daunorubicin 30 mg/m2 in a 30-minute infusion every 12 hours on days
3 through 5; and VP-16 150 mg/m2 in a 120-minute infusion on days
Fig 1. Treatment schedules of studies AML-BFM 87 and 93. CNS, central
nervous system; Int, intensification; R1, randomization 1; R2, randomization
2; RT, radiotherapy.
6 through 8) or idarubicin (AIE: idarubicin 12 mg/m2 in a 30-minute
infusion every 24 hours on days 3 through 5; and Ara-C and VP-16 as
in the ADE regimen). For details of the schedules, see Fig 1.
After induction, patients were treated according to risk level. The
risk stratification was based on the initial morphologic parameters and
the blast cell reduction in the bone marrow on day 15 (standard-risk
group: FAB M1 or M2 with Auer rods, FAB M3 [an exception
follows], and FAB M4Eo with ⱕ 5% blasts in the bone marrow on day
15; high-risk group: all others).14 Thus, patients initially allocated to
the standard-risk group on the basis of morphology were shifted to the
high-risk group if they had more than 5% blasts in the bone marrow on
day 15. Patients with FAB M3 were always treated as being at standard
risk, regardless of blast count on day 15.
High-risk patients were randomized to either HAM (high-dose
Ara-C 3 g/m2 every 12 hours for 3 days and mitoxantrone 10 mg/m2
days 4 and 5) followed by consolidation therapy (early HAM) or
consolidation therapy followed by HAM (late HAM). Consolidation
therapy consisted of 6 weeks of treatment with seven drugs
(thioguanine 60 mg/m2 PO days 1 to 43; prednisolone 40 mg/m2 PO
days 1 through 28; vincristine 1.5 mg/m2 days 1, 8, 15, and 22;
doxorubicin 30 mg/m2 days 1, 8, 15, and 22; Ara-C 75 mg/m2 days
3 through 6, 10 through 13, 17 through 20, 24 through 27, 31
through 34, and 38 through 41; intrathecal Ara-C standard dose ⱖ
3 years 40 mg days 1, 15, 29, and 43; and cyclophosphamide 500
mg/m2 days 29 and 43.) Standard-risk patients received consolidation therapy only, without HAM.
Subsequently, all patients were treated with an intensification block
of high-dose Ara-C and VP-16 (high-dose Ara-C 3 g/m2 every 12 hours
for 3 days and VP-16 125 mg/m2 days 2 through 5). This was followed
by cranial irradiation with 18 Gy (standard dose in children ⱖ 3 years)
and maintenance therapy with daily thioguanine 40 mg/m2 PO and
Ara-C 40 mg/m2 subcutaneously ⫻ 4 days monthly for a total of 18
months. Allogeneic stem-cell transplantation (SCT) was recommended
for high-risk children in first CR (after the second treatment course), if
a sibling donor was available.
The main difference between studies AML-BFM 87 and 93 was that
in the earlier study, there were two blocks of intensification after
consolidation treatment with high-dose Ara-C and VP-16. Also in study
AML-BFM 87, patients without CNS involvement were randomized to
cranial irradiation with 18 Gy or no irradiation, during the first part of
the study.
Definitions and Statistics
CR was defined according to Cancer and Leukemia Group B
criteria19 and was to be achieved by the end of intensification treatment.
Early death was death before treatment or within the first 6 weeks of
treatment. Response after induction was evaluated on day 15 by blast
count (ⱕ or ⬎ 5% blasts in the bone marrow).
Randomization of high-risk patients was carried out after the bone
marrow evaluation on day 15, when risk classification of all patients
was possible. The planned sample size was 160 for each group. The end
point was event-free survival (EFS). The power to detect an increase in
probability of EFS (pEFS) from 50% to 66% was 80%. All patients
were randomized to AIE or ADE immediately after diagnosis. Both
randomizations were done with permuted blocks. EFS was calculated
from the date of diagnosis to last follow-up or first event (failure to
achieve remission, early death, resistant leukemia, relapse, second
malignancy, or death from any cause). For patients who failed to
achieve remission, EFS was set at zero. Survival was calculated from
the date of diagnosis to death from any cause or last follow-up. DFS
of patients achieving remission was calculated from the date of
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IMPROVED SURVIVAL IN HIGH-RISK PEDIATRIC AML
remission to first event (relapse or death from any cause). The end
point for determining the efficacy of early versus late HAM was
EFS. Toxicity was assessed using National Cancer Institute common
toxicity criteria.20
Univariate analysis was conducted using the Wilcoxon test for
quantitative variables and Fisher’s exact test for qualitative variables.
When frequencies were sufficiently large, the ␹2 statistic was used. For
testing trends in frequency tables for toxicity scales, the CochranArmitage test was applied, which takes into account the ordered nature
of the scales. Analysis of efficacy data was performed according to the
intent-to-treat principle. Toxicity data were evaluated by treatment
group. Computations were performed using SAS, Version 6.12 (SAS
Institute, Cary, NC).
Eleven patients allocated to early HAM received late HAM, and
three children allocated to late HAM received early HAM. However,
for the intent-to-treat analysis, these patients remained in their randomization groups. Allogeneic matched related-donor SCT was performed
in 14 patients each in the early and late HAM groups.
Table 1 lists the characteristics of the patients as a whole and by
group. Nonrandomized and randomized patients showed no major
difference in age (P ⫽ .75, Wilcoxon test) or initial WBC count (P ⫽
.16, Wilcoxon test). The FAB classification distribution was similar for
nonrandomized and randomized patients (P ⫽ .71, ␹2 test). Comparing
initial patient data for the randomized groups revealed no clinically
important differences, nor was there any significant difference in initial
patient data between high-risk patients in study AML-BFM 87 and
high-risk patients in study AML-BFM 93.
Patient Characteristics
Between January 1993 and June 1998, 471 patients were enrolled
onto study AML-BFM 93. (Accrual of patients for randomization 1
ended on December 31, 1997, and accrual for randomization 2
continued for 6 months more.) Follow-up was as of March 2000. Figure
2 shows the numbers of patients according to treatment and randomization. Of the 471 patients, 161 were at standard risk and 310 were
high-risk patients.
One hundred ninety-six (63%) of 310 high-risk patients were
randomized to early or late HAM (Fig 2). Of the 114 high-risk patients
who were not randomized, 25 did not receive HAM (18 died before
randomization, mainly because of initial complications related to
leukostasis or hemorrhage; five patients experienced severe toxicity
that necessitated therapy reduction or modification; and two children
had been assigned to the wrong risk group) and 89 patients were
allocated to either early HAM (n ⫽ 12) or late HAM (n ⫽ 77) by
choice. Late HAM was often selected by parents or physicians, because
it was presumed to be less toxic. Four of these patients had initially
been allocated to the wrong risk group (standard risk).
RESULTS
Study AML-BFM 93
Overall outcome. In study AML-BFM 93, 387 (82%) of
471 patients achieved CR. Estimated probabilities of 5-year
survival, EFS, and DFS (⫾ SE) were 60% ⫾ 3%, 51% ⫾
2%, and 62% ⫾ 3%, respectively. Overall results were
significantly better than those of study AML-BFM 87
(Table 2, Fig 3).
Outcome by risk group. Five-year survival, EFS, and
DFS rates (⫾ SE) were 74% ⫾ 4%, 65% ⫾ 4%, and 73%
⫾ 4%, respectively, among the 161 standard-risk patients;
and 52% ⫾ 3%, 44% ⫾ 3%, and 56% ⫾ 3%, respectively,
among the 310 high-risk patients. Outcome among the 28
high-risk patients who underwent allogeneic matched relat-
Fig 2. Flow of
patients entered onto
study AML-BFM 93.
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CREUTZIG ET AL
Table 1.
Patient Characteristics
High Risk
Sex
Male
Female
Age, years
Median
Range
Leukocytes, cells/␮L
Median
Range
Favorable karyotypes* (%)
FAB classification
M0
M1/M2
M3
M4/M5
M6/M7
Other
Follow-up during CCR, years
Median
Range
AML-BFM 93
AML-BFM 87
(n ⫽ 307)
AML-BFM 93
(n ⫽ 471)
AML-BFM 87
(n ⫽ 208)
AML-BFM 93
(n ⫽ 310)
Nonrandomized
(n ⫽ 114)
Early HAM
(n ⫽ 98)
Late HAM
(n ⫽ 98)
166
141
253
218
111
97
173
137
63
51
56
46
54
44
7.9
7.8
5.36
0.0-16.5
5.39
0.0-17.8
5.74
0.0-16.8
5.07
0.3-16.5
5.3
0.2-17.8
27,000
450-528,000
42/146 (29)
18,200
300-520,000
62/274 (23)
27,750
450-528,000
7/96 (7.3)
18,040
300-500,000
13/200 (6.5)
22,000
1,200-360,000
6/77 (7.8)
15,450
300-433,000
3/62 (4.8)
17,500
500-500,000
4/61 (6.6)
17
114
15
135
25
1
26
180
23
192
47
3
17
62
—
103
25
1
26
76
—
158
47
3
10
27
—
56
19
2
11
27
—
50
10
0
5
22
—
52
18
1
8.12
2.6-12.6
3.94
0.9-7.0
8.70
3.6-12.4
3.95
1.1-6.9
4.11
1.5-6.7
3.84
1.1-6.9
3.75
1.3-6.5
NOTE. The distribution of initial parameters was tested for differences between all patients in each study, high-risk patients in each study, randomized and
nonrandomized high-risk patients in the later study, and between randomized groups. For all tests, P ⬎ .05. For leukocytes, there was a trend toward a difference
between randomized and nonrandomized patients.
Abbreviation: CCR, continuous complete remission.
*t(8;21); t(15;17); inv(16).
ed-donor SCT during first CR was in the same range (DFS
rate, 64% ⫾ 9%) as that among the high-risk patients who
did not undergo SCT.
Outcome by induction treatment. Overall, patients initially treated with idarubicin had significantly better blast
cell reductions in the bone marrow on day 15 (17% patients
with ⬎ 5% blasts compared with 31% of patients on the
daunorubicin arm; P ⫽ .01, ␹2 test). However, probabilities
of 5-year EFS and DFS were similar for the two arms.21,22
The infection rate in the AIE group was slightly higher than
that in the ADE group (P trend ⫽ .016), and the duration of
aplasia (until neutrophil recovery to 500/␮L) was also 2
days longer for the AIE patients.
Outcome by HAM group. One hundred ninety-six highrisk patients were randomized to either early HAM (n ⫽ 98)
or late HAM (n ⫽ 98). Overall results in terms of response
and relapse rate were similar on the two arms (5-year
survival, EFS, and DFS rates [⫾ SE] in the early-HAM
group compared with the late-HAM group were 58% ⫾ 5%
v 57% ⫾ 6%; 52% ⫾ 5% v 45% ⫾ 5%; and 59% ⫾ 5% v
53% ⫾ 6%, respectively [Fig 4]). Results of the treatment
actually administered were in the same range (5-year EFS
rate, 48% ⫾ 5% [both groups]).
The pEFS was slightly higher among patients initially
treated with daunorubicin who received early HAM compared with patients who received daunorubicin and late
HAM (Table 3 and Fig 5), whereas results associated with
early or late HAM were similar for patients initially treated
with idarubicin. This finding was confirmed by tests for
interaction in a Cox regression model, which showed a
tendency for a worse outcome only in patients randomized
to daunorubicin followed by late HAM (risk ratio, 1.52;
95% confidence interval, 0.99 to 2.32; P ⫽ .054).
Toxicity. Fatal events occurred in four (4%) of 110
patients during or after early HAM and in nine (5%) of 186
in connection with late HAM. One of the latter patients who
met standard-risk criteria died after having achieved remission. All four patients who died during or after early HAM
had severe sepsis or pneumonia in aplasia; these conditions
were resistant to therapy in two cases. Eight of the nine
patients whose deaths were related to late HAM had
infections (fungal sepsis or aspergillosis in five cases), and
one patient had cardiac insufficiency and alveolar proteinosis. Three of the nine children were nonresponders.
Toxicities, namely bleeding, hepatotoxicity and nephrotoxicity, peripheral and central neurotoxicity, and cardio-
2709
Table 2.
Overall Results of Studies AML-BFM 87 and 93
AML-BFM 87 (n ⫽ 307)
Early death
No or partial response
CR
Allogen SCT during 1st CR†
Relapse
Death during CCR
Secondary malignancy
LFU during CCR
Probability of 5-year survival‡
Probability of 5-year EFS‡
Probability of 5-year DFS‡
AML-BFM 93 (n ⫽ 471)
No. of
Patients
%
28
49
230
17
98
9
1
5
9
16
75
6
32
3
0.3
2
49 ⫾ 3
41 ⫾ 3
55 ⫾ 3
No. of
Patients
%
35
49
387
42
122
18
7
10
82
9
26
4
1
P
.01*
0.2
60 ⫾ 3
51 ⫾ 2
62 ⫾ 3
.01§
.01§
.26§
Abbreviation: LFU, lost to follow-up.
*␹2 test.
†See text for outcome after SCT (31 patients in the later study, including 3 standard-risk patients, underwent matched related-donor SCT).
‡Median ⫾ SE.
§Log-rank test.
toxicity, were similar in the early-HAM and late-HAM
groups. However, the late-HAM group, compared with the
early-HAM group, showed a tendency toward a higher
infection rate during the third treatment block (no infection
v infection: 43 of 62 v 50 of 58 patients; P ⫽ .03, ␹2 test).
Studies AML-BFM 87 and 93
Results in standard-risk patients were in the same
range in both studies (study AML-BFM 93 v study
AML-BFM 87: CR rate, 89% v 90%; pEFS [⫾ SE], 65%
⫾ 4% v 63% ⫾ 5%), whereas high-risk patients in study
AML-BFM 93 fared significantly better than high-risk
patients in study AML-BFM 87 (study AML-BFM 93 v
study AML-BFM 87: probability of 5-year EFS, 44% ⫾
3% v 31% ⫾ 3%; P ⫽ .01, log-rank test) (Fig 6). This
Fig 3. Estimated pEFS among patients in studies AML-BFM 93 and 87.
Slash indicates last patient in CCR entering the trial.
was mainly due to a higher response rate (study AMLBFM 93 v study AML-BFM 87: CR rate, 78% v 68%; P
⫽ .007) (Table 4).
In study AML-BFM 87, fatal events occurred in 17
(8%) of the 208 high-risk patients between days 15 and
90, the exact time in the treatment course of study
AML-BFM 93 when assessment of early- versus lateHAM toxicity was performed. Nine of the 17 events
occurred in nonresponders and were mostly due to
infections. Seven of the remaining patients died during
the first 6 weeks of treatment, because of infections (n ⫽
6) or bleeding (n ⫽ 1). One patient had severe sepsis and
died shortly after achieving remission.
Fig 4. Estimated pEFS among high-risk patients randomized to early
HAM or late HAM in study AML-BFM 93. Slash indicates last patient in CCR
entering the trial.
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CREUTZIG ET AL
Fig 5. Estimated pEFS among high-risk patients in study AML-BFM 93
who were treated initially with ADE or AIE and subsequently randomized to
early HAM or late HAM. Slash indicates the last patient in CCR entering the
trial. HR1, early HAM; HR2, late HAM.
DISCUSSION
The results of study AML-BFM 93 in terms of estimated
5-year survival rate (60% ⫾ 3% [SE]) and EFS rate (51% ⫾
2%) for the total group of patients are significantly better
than those of our previous study (AML-BFM 87) and
similar to those of the successful Medical Research Council
(MRC) AML 10 trial in children.7 This improvement is
most probably due to the intensification with HAM in
high-risk patients (two thirds of our patients). The new
treatment course with HAM had been shown to be an
effective, though toxic, therapy element in adults with
AML.5,11,12
In children, the impact of high-dose Ara-C was demonstrated in the Nordic Society of Pediatric Haematology and
Oncology’s AML 93 trial: outcome was improved after four
Fig 6. Estimated pEFS among high-risk patients in study AML-BFM 93
compared with high-risk patients in study AML-BFM 87. Slash indicates the
last patient in CCR entering the trial.
intensification blocks of high-dose Ara-C.8 The MRC AML
10 protocol, which specified two highly intensive courses,
one of them including mitoxantrone and high-dose Ara-C,
resulted in a significantly better outcome than in previous
MRC studies.7
The effect of dose scheduling and dose-intensity during
postremission treatment was demonstrated in the Children’s
Cancer Group 213P study. Two courses of high-dose Ara-C
and asparaginase administered at 7-day intervals resulted in
superior survival rates compared with administration at
28-day intervals.9 Furthermore, in the Children’s Cancer
Group study, 2,861 patients receiving intensive-timing induction chemotherapy (second cycle 10 days after the first
cycle) had a significantly better DFS than did patients
receiving standard-timing induction therapy (second cycle 14 days or more after the first cycle, depending on
bone marrow status).23 A study involving adults demonstrated that the time to achievement of remission is an
important predictor of survival and DFS.24 This supports
the hypothesis that rapid blast clearance may prevent
development of resistance.
The main difference between studies AML-BFM 93 and
87 related to the introduction of the HAM combination and
the scheduling of HAM, rather than to administration of
high-dose Ara-C, which in study AML-BFM 87 was given
as intensification after consolidation therapy in combination
with VP-16. Furthermore, all patients in study AML-BFM
87 received daunorubicin as induction therapy.
In study AML-BFM 93, the efficacy of idarubicin and
daunorubicin as induction treatments was compared by
randomized allocation; standard-risk patients were included. The results indicated a significantly better blast cell
reduction in the bone marrow on day 15 in the idarubicintherapy group, whereas long-term outcome was similar on
both treatment arms22 and was also comparable to that of
standard-risk patients in study AML-BFM 87. Treatment
intensity for standard-risk patients, who in study AMLBFM 87 received two late courses with high-dose Ara-C
and VP-16, was similar in the two studies. CNS irradiation
was not generally performed.
In the second randomization, high-risk patients were
assigned to early or late HAM. Through early administration of HAM, we tried to enhance cytotoxic activity and
thus achieve higher efficacy. It was suggested that this
approach, compared with a treatment course with lower
dose-intensity, might overcome resistance by more rapid
blast cell clearance and a reduction in the rate of minimal
residual disease.
The randomization to early versus late HAM was necessary to evaluate whether a possibly improved blast cell
reduction owing to early administration might be com-
2711
Table 3.
Results of Study AML-BFM 93, by HAM Group and Induction Treatment
⬍ 5% Blasts on Day 15
HAM
Induction
Total No. of
Patients
Early
Daunorubicin
Idarubicin
Daunorubicin
Idarubicin
46
52
46
52
Late
No. of
Patients*
10/21
21/29
14/28
18/28
CR
%
No. of
Patients
%
pEFS ⫾ SE (%)
48
72
50
64
40
46
37
46
87
89
80
89
51.9 ⫾ 7.4
51.3 ⫾ 7.0
35.6 ⫾ 7.3†
53.6 ⫾ 7.0
*No. of patients with ⬍ 5% blasts/total no. of patients with data available.
†Late HAM after daunorubicin induction versus other groups: P ⫽ .05, log-rank test.
pounded by more toxicity after the course. HAM treatment,
however, was not offered to standard-risk patients, because
of the expected higher rate of acute adverse events and
possible late cardiotoxicity associated with administration
of additional cardiotoxic drugs. The cumulative dose of
anthracyclines, including the anthracycline analog mitoxantrone (assuming a dose ratio of daunorubicin to mitoxantrone of 5:1), was 300 mg/m2 in standard-risk patients and
400 mg/m2 in high-risk patients.
Results of the randomized scheduling of HAM as the
second or third treatment course after induction did not
reveal major differences in outcome. However, the induction treatment must be considered as well. Induction with
idarubicin, as opposed to daunorubicin, was more effective
in reducing the blast cell count in the bone marrow by day
15.25 Patients who received the less intensive daunorubicin
treatment during induction benefited from early HAM. This
was in contrast to the effects of late HAM after daunorubicin induction (Table 3).
Moreover, when we compared high-risk patients in study
AML-BFM 87 (the historical control group) with high-risk
Table 4.
patients treated initially with daunorubicin and then with
late HAM, we found that results were similar: the probability of 5-year EFS [⫾ SE] in the former group was 31.1% ⫾
3.2%, v 35.6% ⫾ 7.3% for the latter group (P ⫽ .54). This
finding suggests that induction with idarubicin followed by
HAM might have a cumulative effect in high-risk patients.
The results are in line with those of a German AML
Cooperative Group trial in adults, which showed that
mainly poor-risk patients benefited from a two-course
induction combining thioguanine, Ara-C, and daunorubicin,
with HAM as the second course, rather than two courses of
that induction therapy.12
In several studies, the rate of toxicity associated with
HAM treatment was increased, and more severe neutropenia, thrombocytopenia, nausea, vomiting, and eye toxicity
were noted compared with standard induction treatment,5
indicating that not only HAM treatment per se but also the
placement of HAM within the sequence of treatment
courses might influence tolerability. This led to a higher
selection on the late-HAM arm in study AML-BFM 93,
presuming a higher rate of toxicity with early HAM.
Results of Studies AML-BFM 87 and 93 (high-risk and nonrandomized patients, and HAM recipients)
AML-BFM 93
No.
Early death before day 15
Early death after day 15
⬍ 5% blasts in bone
marrow on day 15
No or partial response
CR
Relapse
Death during CCR
Secondary malignancy
LFU during CCR
Probability of 5-year EFS,
% ⫾ SE
Late HAM
Patients
(n ⫽ 98)
Early HAM
Patients
(n ⫽ 98)
Nonrandomized
Patients
(n ⫽ 114)
High-Risk
Patients
(n ⫽ 310)
AML-BFM 87 HighRisk Patients
(n ⫽ 208)
%
No.
%
No.
%
No.
%
No.
%
15
7
96
7.2
3.4
54.5
18
8
164
5.8
2.6
65.6
18
5
58
15.7
4.4
72.5
2
52
2
65.0
1
54
1
61.4
45
141
71
6
1
4
21.6
67.8
34.1
2.9
0.5
1.9
41
243
92
12
13.2
78.4
29.7
3.9
17
74
28
2
14.9
64.9
24.6
1.8
10
86
31
4
10.2
87.8
31.6
4.1
14
83
33
6
14.3
84.7
33.7
6.1
31 ⫾ 3
44 ⫾ 3
38 ⫾ 5
52 ⫾ 5
45 ⫾ 5
2712
CREUTZIG ET AL
However, the rate of infections was only slightly increased
in the early-HAM group compared with late HAM and with
study AML-BFM 87. The incidence of therapy-related
deaths was similar, indicating that this therapy is feasible in
children with AML.
We have demonstrated the efficacy of HAM treatment,
with a tolerable rate of toxicity, in high-risk children. As
a consequence, in the ongoing study AML-BFM 98,
HAM has been introduced into the second therapy course
of all pediatric patients with AML, our aim being to
improve the survival rate among standard-risk patients as
well.
ACKNOWLEDGMENT
We thank P. Stappert, E. Kurzknabe, and J. Meltzer for their
excellent technical assistance, Enno Mu¨ller for his competent data
management, and Christa Lausch for her valuable assistance in the
management of the AML Trial Office in Mu¨nster.
APPENDIX
The following individuals participated in the study: Principal investigators in Germany: R. Mertens, Kinderklinik RWTH, Aachen; A. Gnekow,
I. Kinderklinik des Klinikums, Augsburg; G.F. Wu¨ndisch, Universita¨ts-Kinderklinik, Bayreuth; G. Henze, CCVK-Kinderklinik, Berlin; E.
Hilgenfeld, Charite´-Kinderklinik; W. Do¨rffel, II. Kinderklinik Berlin-Buch, Berlin; N. Jorch, Kinderklinik Gilead, Bielefeld; U. Bode,
Universita¨ts-Kinderklinik, Bonn; H.-J. Spaar, Th. Lieber, Prof.-Hess-Kinderklinik, Bremen; W. Eberl, Sta¨dtische Kinderklinik, Braunschweig; I.
Krause, Sta¨dtische Kinderklinik, Chemnitz; E. Holfeld, Kinderklinik d. Carl-Thiem-Klinikums, Cottbus; W. Andler, Th. Wiesel, Vestische
Kinderklinik, Datteln; I. Lauterbach, Kinderklinik d. TU, Dresden; V. Scharfe, Sta¨dtische Kinderklinik Dresden-Neustadt, Dresden; G. Weinmann,
Universita¨ts-Kinderklinik, Erfurt; J.D. Beck, Universita¨ts-Kinderklinik, Erlangen; W. Havers, Universita¨ts-Kinderklinik, Essen; B. Kornhuber,
Universita¨ts-Kinderklinik, Frankfurt; C.M. Niemeyer, Universita¨ts-Kinderklinik, Freiburg; A. Reiter, R. Blu¨tters-Sawatzki, Universita¨ts-Kinderklinik, Giessen; M. Lakomek, A. Pekrun, Universita¨ts-Kinderklinik, Go¨ttingen; J.F. Beck, H. Weigel, Universita¨ts-Kinderklinik, Greifswald; V.
Gerein, Kinderklinik, Gummersbach; S. Burdach, T. Rie␤, Universita¨ts-Kinderklinik, Halle; H. Kabisch, R. Schneppenheim, Universita¨tsKinderklinik, Hamburg; B. Selle, Universita¨ts-Kinderklinik, Heidelberg; N. Graf, Universita¨ts-Kinderklinik, Homburg/Saar; J. Hermann,
Universita¨ts-Kinderklinik, Jena; G. Nessler, Sta¨dtische Kinderklinik, Karlsruhe; Th. Wehinger, Sta¨dtische Kinderklinik, Kassel; M. Rister,
Kinderklinik Kemperhof, Koblenz; F. Berthold, Universita¨ts-Kinderklinik, Cologne; W. Sternschulte, Sta¨dtisches Kinderkrankenhaus, Cologne; M.
Suttorp, Universita¨ts-Kinderklinik, Kiel; D. Ko¨rholz, K. Rieske, Universita¨ts-Kinderklinik, Leipzig; P. Bucsky, Universita¨ts-Kinderklinik, Lu¨beck;
H.Ch. Dominick, Kinderklinik St. Annastift, Ludwigshafen; U. Kluba, Universita¨ts-Kinderklinik, Magdeburg; W. Scheurlen, Sta¨dtische
Kinderklinik, Mannheim; P. Gutjahr, Universita¨ts-Kinderklinik, Mainz; H. Christiansen, Universita¨ts-Kinderklinik, Marburg; R.J. Haas, von
Haunersches Kinderspital, Munich; St. Mu¨ller-Weihrich, L. Stengel-Rutkowski, Kinderklinik d. Technischen Universita¨t, Mu¨nchen-Schwabing; Ch.
Bender-Go¨tze, M. Fu¨hrer, Universita¨ts-Kinderpoliklinik, Munich; H. Ju¨rgens, Universita¨ts-Kinderklinik, Mu¨nster; A. Jobke, Cnopfsche Kinderklinik, Nuremberg; U. Schwarzer, Sta¨dtische Kinderklinik, Nuremberg; G. Eggers, M. Hagen, Universita¨ts-Kinderklinik, Rostock; R. Schumacher,
Kinderklinik, Schwerin; R. Dickerhoff, Johanniter Kinderklinik, St. Augustin; J. Treuner, Olgahospital, Stuttgart; D. Niethammer, T. Klingebiel,
Universita¨ts-Kinderklinik, Tu¨bingen; W. Behnisch, Universita¨ts-Kinderklinik, Ulm; J. Ku¨hl, Universita¨ts-Kinderklinik, Wu¨rzburg.
Principal investigators in Austria: C. Urban, Universita¨ts-Kinderklinik d. Landeskrankenhauses, Graz; F.M. Fink, Universita¨ts-Kinderklinik d.
A.o¨. Landeskrankenhauses, Innsbruck; K. Schmitt, G. Ebetsberger Landes-Kinderkrankenhaus, Linz; I. Slavc, AKH-Universita¨ts-Kinderklinik,
Vienna; H. Gadner, St. Anna-Kinderspital, Vienna.
Principal investigators in Switzerland: P. Imbach, Kinderklinik d. Kantonsspital, Aarau; P.A. Avoledo, Universita¨ts-Kinderspital, Basel; A.
Feldges, Ostschweizerisches Kinderspital, St. Gallen; M. Nenadov-Beck, C. Desseng, CHUV-Kinderklinik, Lausanne; U. Caflisch, Kinderspital,
Lucerne; L. Nobile Buetti, Kinderklinik Hospital La Carita`, Locarno; F. Niggli, Universita¨ts-Kinderklinik, Zurich.
Study coordinators: J. Ritter, U. Creutzig, Universita¨ts-Kinderklinik, Mu¨nster, Germany; J. Hermann, Universita¨ts-Kinderklinik, Jena, Germany;
and H. Gadner, St. Anna-Kinderspital, Vienna, Austria.
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