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Year: 2013

Randomized trial comparing liposomal daunorubicin with idarubicin as

induction for pediatric acute myeloid leukemia: results from Study
AML-BFM 2004

Creutzig, Ursula ; Zimmermann, Martin ; Bourquin, Jean-Pierre ; et al

Abstract: Outcomes of patients with acute myeloid leukemia (AML) improve significantly by intensi-
fication of induction. To further intensify anthracycline dosage without increasing cardiotoxicity, we
compared potentially less cardiotoxic liposomal daunorubicin (L-DNR) to idarubicin at a higher-than-
equivalent dose (80 vs 12 mg/m(2) per day for 3 days) during induction. In the multicenter therapy-
optimization trial AML-BFM 2004, 521 of 611 pediatric patients (85%) were randomly assigned to L-DNR
or idarubicin induction. Five-year results in both treatment arms were similar (overall survival 76% ±
3% [L-DNR] vs 75% ± 3% [idarubicin], Plogrank = .65; event-free survival [EFS] 59% ± 3% vs 53% ±
3%, Plogrank = .25; cumulative incidence of relapse 29% ± 3% vs 31% ± 3%, P(Gray) = .75), as were
EFS results for standard (72% ± 5% vs 68% ± 5%, Plogrank = .47) and high-risk (51% ± 4% vs 46% ±
4%, Plogrank = .45) patients. L-DNR resulted in significantly better probability of EFS in patients with
t(8;21). Overall, treatment-related mortality was lower with L-DNR than idarubicin (2/257 vs 10/264
patients, P = .04). Grade 3/4 cardiotoxicity was rare after induction (4 L-DNR vs 5 idarubicin). Only 1
L-DNR and 3 idarubicin patients presented with subclinical or mild cardiomyopathy during follow-up. In
conclusion, at the given dose, L-DNR has overall antileukemic activity comparable to idarubicin, promises
to be more active in subgroups, and causes less treatment-related mortality. This trial was registered at
www.clinicaltrials.gov as NCT00111345.

DOI: https://doi.org/10.1182/blood-2013-02-484097

Posted at the Zurich Open Repository and Archive, University of Zurich

ZORA URL: https://doi.org/10.5167/uzh-84481
Journal Article
Published Version

Originally published at:

Creutzig, Ursula; Zimmermann, Martin; Bourquin, Jean-Pierre; et al (2013). Randomized trial comparing
liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from
Study AML-BFM 2004. Blood, 122(1):37-43.
DOI: https://doi.org/10.1182/blood-2013-02-484097
From bloodjournal.hematologylibrary.org at Universitaet Zurich on November 7, 2013. For personal use only.

2013 122: 37-43

Prepublished online May 23, 2013;
doi:10.1182/blood-2013-02-484097

Randomized trial comparing liposomal daunorubicin with idarubicin as

induction for pediatric acute myeloid leukemia: results from Study
AML-BFM 2004
Ursula Creutzig, Martin Zimmermann, Jean-Pierre Bourquin, Michael N. Dworzak, Gudrun
Fleischhack, Norbert Graf, Thomas Klingebiel, Bernhard Kremens, Thomas Lehrnbecher, Christine
von Neuhoff, Jörg Ritter, Annette Sander, André Schrauder, Arend von Stackelberg, Jan Starý and
Dirk Reinhardt

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Copyright 2011 by The American Society of Hematology; all rights reserved.
Regular Article

CLINICAL TRIALS AND OBSERVATIONS

Randomized trial comparing liposomal daunorubicin with idarubicin

as induction for pediatric acute myeloid leukemia: results from Study
AML-BFM 2004
Ursula Creutzig,1 Martin Zimmermann,1 Jean-Pierre Bourquin,2 Michael N. Dworzak,3 Gudrun Fleischhack,4 Norbert Graf,5
Thomas Klingebiel,6 Bernhard Kremens,4 Thomas Lehrnbecher,6 Christine von Neuhoff,1 Jörg Ritter,7 Annette Sander,1
André Schrauder,8 Arend von Stackelberg,9 Jan Starý,10 and Dirk Reinhardt1
1
Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany; 2Pediatric Hematology/Oncology, University of Zurich, Zurich,
Switzerland; 3Department of Pediatrics, St. Anna Children’s Hospital and Children’s Cancer Research Institute, Medical University of Vienna, Vienna,
Austria; 4Department of Pediatric Hematology, Oncology, University of Essen, Essen, Germany; 5Department of Pediatric Oncology and Hematology,
Medical School, Saarland University, Homburg, Germany; 6Pediatric Hematology, Oncology, and Hemostaseology, Children’s Hospital of the University of
Frankfurt, Frankfurt/Main, Germany; 7Department of Pediatric Hematology and Oncology, University Children’s Hospital, Münster, Germany; 8Department
of Pediatric Hematology/Oncology, University Children’s Hospital, Kiel, Germany; 9Department of Pediatric Oncology/Hematology, Charité Universitäts-
medizin Berlin, Berlin, Germany; and 10Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University
Hospital Motol, Czech Pediatric Hematology Working Group, Prague, Czech Republic

Outcomes of patients with acute myeloid leukemia (AML) improve significantly

Key Points
by intensification of induction. To further intensify anthracycline dosage without
• AML induction with liposomal increasing cardiotoxicity, we compared potentially less cardiotoxic liposomal daunorubicin
daunorubicin (80 mg/m2 (L-DNR) to idarubicin at a higher-than-equivalent dose (80 vs 12 mg/m2 per day for 3
per day for 3 days) shows days) during induction. In the multicenter therapy-optimization trial AML-BFM 2004,
antileukemic activity 521 of 611 pediatric patients (85%) were randomly assigned to L-DNR or idarubicin
induction. Five-year results in both treatment arms were similar (overall survival 76% 6 3%
comparable to idarubicin
[L-DNR] vs 75% 6 3% [idarubicin], Plogrank 5 .65; event-free survival [EFS] 59% 6 3%
(12 mg/m2 per day for 3 days).
vs 53% 6 3%, Plogrank 5 .25; cumulative incidence of relapse 29% 6 3% vs 31% 6 3%,
• Liposomal daunorubicin P(Gray) 5 .75), as were EFS results for standard (72% 6 5% vs 68% 6 5%, Plogrank 5 .47)
promises to be more active and high-risk (51% 6 4% vs 46% 6 4%, Plogrank 5 .45) patients. L-DNR resulted in
in the t(8;21) subgroup and significantly better probability of EFS in patients with t(8;21). Overall, treatment-related
causes less treatment-related mortality was lower with L-DNR than idarubicin (2/257 vs 10/264 patients, P 5 .04).
toxicity. Grade 3/4 cardiotoxicity was rare after induction (4 L-DNR vs 5 idarubicin). Only 1 L-DNR
and 3 idarubicin patients presented with subclinical or mild cardiomyopathy during
follow-up. In conclusion, at the given dose, L-DNR has overall antileukemic activity comparable to idarubicin, promises to be more
active in subgroups, and causes less treatment-related mortality. This trial was registered at www.clinicaltrials.gov as #NCT00111345.
(Blood. 2013;122(1):37-43)

Introduction
Intensification of induction treatment has had the greatest impact In children, the risk of anthracycline cardiotoxicity is higher than
on improving the rate of first remission and overall survival (OS) in in adults, owing to the developing heart muscle, and there are limits
adult and pediatric acute myeloid leukemia (AML).1,2 Recently, to increasing pediatric anthracycline doses during induction or total
Löwenberg et al3 reported the effect of increasing anthracycline doses cumulative doses.6 According to animal testing and experiences in
during induction in adults. However, dose-related anthracycline first human clinical studies, a liposomal formulation of daunorubicin
toxicity, especially acute and late cardiotoxicity, might limit further (L-DNR) offers the possibility to increase single and cumulative
treatment intensification, particularly in children.4-6 dosages of anthracyclines without increasing cardiotoxicity.8-12
Standard AML induction therapy in children and adults comprises Here we report on the randomized introduction of L-DNR
3 days of anthracycline administration [eg, daunorubicin >60 mg/m2, during induction in the Multicenter Therapy-Optimization Trial
idarubicin 10-12 mg/m2, or the anthracenedione mitoxantrone AML-BFM 2004 for the Treatment of Acute Myeloid Leukemias
10-12 mg/m2] and 7210 days of cytarabine (100-200 mg/m2). in Children and Adolescents at a dose of 80 mg/m2 per day for
With these regimens, 80%-90% of children and adolescents 3 days, which is higher than the dose of idarubicin that is pro-
achieve complete remission (CR).7 vided in the control arm (standard 12 mg/m2 per day for 3 days,

Submitted February 12, 2013; accepted April 17, 2013. Prepublished online as The publication costs of this article were defrayed in part by page charge
Blood First Edition paper, May 23, 2013; DOI 10.1182/blood-2013-02-484097. payment. Therefore, and solely to indicate this fact, this article is hereby
marked “advertisement” in accordance with 18 USC section 1734.
The online version of this article contains a data supplement. © 2013 by The American Society of Hematology

BLOOD, 4 JULY 2013 x VOLUME 122, NUMBER 1 37

38 CREUTZIG et al BLOOD, 4 JULY 2013 x VOLUME 122, NUMBER 1

Figure 1. CONSORT diagram of AML-BFM 2004

showing the flow of participants from enrollment
to randomization, therapy, follow-up, and analysis.

corresponding to 60 mg/m 2 per day for 3 days L-DNR, included in the protocol, because the chemotherapy regimen was similar to
equivalent dose conversion of 1:5),13,14 both in combination that of standard-risk (SR) AML patients (except for additional all-trans-
with cytarabine and etoposide. A dose equivalent of 1:1 was assumed retinoic acid courses). Outcome results with and without APL patients were
for daunorubicin vs L-DNR, because the active substances are calculated. Patients with Down syndrome, to whom a reduced anthracycline
dosage is given a priori, were intentionally excluded from this analysis.
chemically identical, and only the pharmacokinetics are differ-
The AML-BFM 2004 study was performed in Germany, Austria,
ent. The aim was (1) to improve outcome by increasing anthracycline
Switzerland, and the Czech Republic. The study was approved by the
dosage during induction; and (2) to evaluate treatment-related national ethics committees and institutional review boards in each country.
mortality (TRM) and toxicity, including acute and long-term Written informed consent from patients, parents, or guardians was obtained
cardiotoxicity. at study entry in accordance with the Declaration of Helsinki. Central review
of bone marrow morphology and cytogenetics was performed. Compre-
hensive cytogenetic data from 485 of the 521 patients (93%) were available.
Cytogenetic analysis was performed as previously described.15 Further,
Patients and methods routine testing for internal tandem duplications of FLT3 (FLT3-ITD) was
done at initial diagnosis, as stratification to the high-risk (HR) group was
Patients based on positivity for FLT3-ITD, among other criteria.
Between March 2004 and April 2010, 611 AML patients ,18 years of age Treatment plan
were enrolled in the population-based study AML-BFM 2004. Of these,
521 were randomized (257 L-DNR induction vs 264 idarubicin induction) The main study objective of AML-BFM 2004 was the improvement of
and 90 (15%) were not randomized (for details, see Figure 1 CONSORT prognosis by intensification of chemotherapy without increasing toxicity by
[Consolidated Standards of Reporting Trials] diagram). Patient outcome (1) randomized introduction of L-DNR (80 mg/m2 per day for 3 days) in a
was analyzed as randomized on an intent-to-treat basis, and toxicities were dose higher than the assumed equivalent dose of idarubicin (12 mg/m2 per
analyzed as treated. Patients with acute promyelocytic leukemia (APL) were day for 3 days) during induction, each combined with cytarabine and
BLOOD, 4 JULY 2013 x VOLUME 122, NUMBER 1 LIPOSOMAL DAUNORUBICIN IN PEDIATRIC AML 39

Figure 2. Treatment schedule of AML-BFM 2004

induction. First induction, AIE (cytarabine/idarubicin/
etoposide) or randomized (R1) with ADxE (cytarabine/
L-DNR/etoposide); second induction, (high-dose cytarabine
[3g/m 2 ]/mitoxantrone) (HAM); consolidation, HAM or
randomized (R2) AI/2-CDA (cytarabine [0.5 g/m2 ]/
idarubicin/2-chloro-2-deoxyadenosine) vs AI (cytar-
abine [0.5 g/m2]/idarubicin); intensification: HAE (high-
dose cytarabine [3 g/m2 ]/etoposide), CNS-RT (central
nervous system [cranial] irradiation randomized [R3] to
12 or 18 Gy). APL patients received additional all-trans-
retinoic acid during all therapy courses. The cumula-
tive anthracycline dosages in SR and HR patients were,
with AIE induction, 350 and 450 mg/m2, respectively;
with ADxE, 410 and 510 mg/m2. IT, intrathecal.

etoposide; and (2) randomized introduction of 2-chloro-2-deoxyadenosine version 9.1; SAS Institute, Cary, NC). Date of evaluation was March 15,
(6 mg/m2 per day for 2 days) as intensification during the cytarabine/ 2012, and median follow-up time was 5.0 (range 0.5-8.5) years.
idarubicin consolidation for HR patients (Figure 2). Apart from that, the The study was designed to have a power of 80% to detect a 13% dif-
treatment schedule of AML-BFM 2004 was for the most part similar to the ference in 5-year EFS probability (pEFS, baseline 50%) by including 245
AML-BFM 98 protocol.16,17 An exception was the second induction with patients per group. Two interim analyses were planned after 3 and 5
HAM, which was administered generally to all patients in the AML-BFM years. Sample size calculation was done according to Freedman22 and
98 trial, but in AML-BFM 2004 to HR patients only. Two additional short corrected for interim analysis using the R procedure gsDesign.
cycles with 0.5 g/m2 cytarabine and HDAC (1 g/m2) plus anthracyclines were
given after first induction (SR patients) or second induction (HR patients),
followed by intensification with HDAC/etoposide and maintenance. The
indication for allogeneic hematopoietic stem cell transplantation (HSCT) from
sibling donors in CR1 was restricted to HR patients17 and, since 2006, Results
recommended only for HR patients with bone marrow blasts .5% after
Patient characteristics
second induction.18 Intrathecal cytarabine was given 11-12 times according
to age-dependent dosage regimens. Randomized cranial irradiation (12 vs Table 1 shows characteristics of the cohorts randomized in the
18 Gy), which was performed over 2 study periods, was stopped in May
L-DNR or idarubicin arm. Patient characteristics were comparable
2009.17
in the randomized groups and also in the corresponding groups as
Definitions and statistics
treated (data not shown).

Patients were stratified into either a SR or HR group. SR was defined as Overall results
FAB (French-American-British) M1/M2 with Auer rods; FAB M4eo or
favorable cytogenetics [t(8;21)/AML1-ETO or inv(16) or t(16;16) and/or Five-year pOS and pEFS values in all patients (n 5 611) were
CBFB/MYH1)]; bone marrow blasts ,5% on day 15; or FAB M3 (all patients). 74% 6 2% and 55% 6 2%, respectively (Figure 3). Survival rates
HR was defined as all others. SR patients were reclassified to the HR group if were improved compared with the previous study, AML-BFM 98
FLT3-ITD positive. (n 5 473, 65% 6 2%, Plogrank 5 .001), whereas pEFS results were
Early death (ED) was defined as death before or within the first 6 weeks in the same range (51% 6 2%, Plogrank 5 .24, results updated).16
(42 days) of treatment and further subdivided into (1) ED before or within Results for the 217 SR patients were favorable: pOS 89% 6 2%,
the first 15 days of therapy, which mainly reflects lethal events due to
pEFS 71% 6 3%, and results for the 394 HR patients were
hyperleukocytosis/leukostasis and bleeding; and (2) ED within days 16-42
suitable, pOS 65% 6 3%, pEFS 46% 6 3%. In comparing patients
of treatment, which mainly reflects deaths due to infectious complications
during aplasia after induction.19 CR was defined according to the CALGB who were randomized (n 5 516) and nonrandomized (n 5 90)
(Cancer and Leukemia Group B) criteria20 achieved at the end of intensification (patients with ED before day 15 excluded), pEFS results were
treatment. OS was calculated from date of diagnosis to death of any cause, similar (56% 6 2% vs 54% 6 6%, Plogrank 5 .88).
and event-free survival (EFS) from diagnosis until first event (failure to
achieve remission [calculated as an event at t 5 0], relapse, secondary Randomization of L-DNR vs idarubicin
malignancy, or death by any cause) or last follow-up. Probabilities of
survival were estimated using the Kaplan–Meier method with standard Results for L-DNR (n 5 257) vs idarubicin (n 5 264) patients were
errors according to Greenwood21 and compared with the log-rank test. similar: 5-year pOS 76% 6 3% vs 75% 6 3%, Plogrank 5 .65, pEFS
Cumulative incidence functions of relapse, secondary malignancy, and 59% 6 3% vs 53% 6 3%, Plogrank 5 .25 (Figure 4) and cumulative
incidence of cardiac toxicity were constructed by the method of Kalbfleisch incidence of relapse at 5 years 29% 6 3% vs 31% 6 3%, PGray 5 .79
and Prentice.21 Competing events for cardiac toxicity were HSCT in CR1, (Table 2). Results in SR or HR patients were also similar (5-year
relapse, and death. Functions were compared by Gray test. Toxicity was pEFS SR 72% 6 5% vs 68% 6 5%, Plogrank 5 .47; HR 51% 6 4%
assessed according to the National Cancer Institute common toxicity vs 46% 6 4%, Plogrank 5 .45). TRM was lower in the L-DNR group
criteria (CTC) version 2.0 (http://ctep.cancer.gov/protocolDevelopment/
than the idarubicin group; for details see “Acute toxicity” below, and
electronic_applications/docs/ctcv20_4-30-992.pdf). Cardiotoxicity of grade
1/2 was called subclinical, and grade 3/4, clinical. During follow-up, patients Table 2. Results according to treatment as randomized were similar
had to be evaluated once a year for symptoms and echocardiographic to those as given (data not shown). When APL patients were
changes suggestive of cardiac toxicity. excluded, results were similar to those of the total group (5-year
Univariate analysis was conducted by Wilcoxon test for quantitative pOS 74% 6 3% vs 74% 6 3%, Plogrank 5 .75, pEFS 56% 6 3% vs
variables and Fisher exact test or x2 statistics for qualitative variables. 51% 6 3%, Plogrank 5 .33). There was 1 ED from intracerebral
Computations were performed using SAS (Statistical Analysis System, bleeding in an APL patient.
40 CREUTZIG et al BLOOD, 4 JULY 2013 x VOLUME 122, NUMBER 1

Table 1. Baseline data for patients randomized to L-DNR vs idarubicin

L-DNR Idarubicin P*
n 257 264
Age, y, median (Q1-Q3) 9.8 (2.4-14.5) 8.3 (2.2-14.1) .28
Leukocytes, 3103/mL, 15 050 (4785-61 700) 16 300 (4550-56 350) .88
median (range)
Gender .66
Male 135 (52) 133 (50)
Female 122 (48) 131 (50)
CNS involvement, n/total 22/252 (9) 39/259 (15) .03†
n (%)
Extramedullary organ 67 (26) 56 (21) .19
involvement
Cytogenetic data available, 239/257 (93) 247/264 (94)
n/total n (%)
Cytogenetic data .11
t(8;21) 29 (12) 29 (12) Figure 4. Estimated 5-year pEFS in patients randomized to L-DNR (ADxE) vs
t(15;17) 24 (10) 14 (6) idarubicin (AIE). SE, standard error.
inv(16) 24 (10) 20 (8)
Normal 41 (17) 63 (26)
Other 121 (51) 121 (49) patients with .5% blasts in the L-DNR arm (59/239 5 25% vs
Risk groups .68 35/235 5 15%, P 5 .008); however, the difference was not evident
SR 94 (37) 92 (35) in day 28 blast counts (Table 2).
HR 163 (63) 172 (65)

Data are n (%) unless stated otherwise. Q, quartile; CNS, central nervous system.
*By x2 test. Acute toxicity
†No differences were found in OS, EFS, or cumulative incidence of relapse in
CNS-positive or -negative patients. Time to recovery of neutrophils to 500/mL after induction was
similar in both arms (L-DNR median 20.0 days, quartile 1 [Q1]-Q3
14-26 days, vs idarubicin median 21.0 days, Q1-Q3 12-27 days;
Cytogenetic subgroups P 5 .73), as was time to recovery of platelets to 20 000/mL
(L-DNR median 9.0 days, Q1-Q3 2-17 days, vs idarubicin median
Results in 29 patients with t(8;21) and treated with L-DNR were
12.0 days, Q1-Q3 3-17 days; P 5 .16).
significantly better than in those who received idarubicin (n 5 29):
The rate of severe infections was slightly, but not significantly,
pEFS 76% 6 8% vs 54% 6 9%, Plogrank 5 .04. This difference for
lower with L-DNR (PFisher 5 .21) (Table 3). After induction, trans-
pEFS was not seen for the whole group of core-binding-factor
aminases were more often elevated in L-DNR patients than in those
leukemias (Plogrank 5 .28), and there were no significant differ-
treated with idarubicin; however, this was transient and not of clinical
ences after administration of either L-DNR or idarubicin in patients
importance. Skin toxicity was low in both groups. Four L-DNR
with inv(16). No further differences were seen in the cohort analysis
patients suffered from either arrhythmia (n 5 1) or reduced cardiac
of patients with t(15;17), normal karyotype, or MLL rearrangements
function grade 3/4 (n 5 3), which occurred during sepsis in 2 patients.
(data not shown).
In 5 idarubicin patients, cardiac function was reduced, and 3 of
those also had arrhythmia. Because 3 of these patients suffered
Bone marrow blast count on days 15 and 28 from additional severe infections, these cases cannot be considered
as cardiotoxicity caused solely by anthracyclines. One of these
Data of early response to induction treatment evaluated by analysis
patients died on d 3 of induction with life-threatening bleeding and
of d 15 bone marrow showed a significantly higher number of
acute respiratory distress syndrome (ARDS); another 2 patients died
on days 17 and 22, respectively, from severe infections. The other
2 patients presented with grade 3 cardiotoxicity after induction,
one of them with concurrent pneumonia. There was no grade 1-4
cardiotoxicity in the patients of the L-DNR and idarubicin groups
after the HAM course.
ED and TRM in patients treated with L-DNR and idarubicin
are illustrated in Table 2. ED before day 15 was mostly due to
cerebral bleeding, related to initial hyperleukocytosis and co-
agulation disturbance or to ARDS. TRM following induction
treatment occurred in 2 patients due to fungal and bacterial
infections after L-DNR induction and in 5 patients of the idarubicin
group (severe infections/septicemia/ARDS). Another 5 patients of
the idarubicin group died after HAM or the subsequent 3 in-
tensive courses due to bacterial and fungal septicemia, abscess, or
thromboembolism. Considering also TRM during intensifica-
tion, the TRM rate of the L-DNR group was significantly
Figure 3. Estimated probability of 5-year OS and EFS in all patients from AML- lower compared with the idarubicin group: 2 of 257 vs 10 of
BFM 2004. SE, standard error. 264, P 5 .04.
BLOOD, 4 JULY 2013 x VOLUME 122, NUMBER 1 LIPOSOMAL DAUNORUBICIN IN PEDIATRIC AML 41

Table 2. Results of randomized patients presenting with reduced shortening fraction (SF) CTC grade 1. Later
L-DNR Idarubicin P* controls were without pathological findings. Another case with sub-
n 257 264 clinical cardiotoxicity remained unclear, as follow-ups were refused
ED (before d 42) 5 (2) 7 (3) .59 (see Table 4). Two girls showed mild therapeutically compensated
ED (before d 15) related to initial 3 2 clinical cardiomyopathy in CR1. One developed cardiac functional
complications impairment (CTC grade 3) during consolidation, suffered from
ED/TRM (d 15 or later) after induction 2 5 hypotension 1.5 years after diagnosis, and 6 months later from
Death in CCR (TRM) 1 (0.4) 6 (3) .02 arrhythmia with a reduced SF CTC grade 1. She recovered during
TRM during intensification courses 0 5
follow-up and remained without signs of cardiotoxicity 4.5 years
TRM after HSCT in first CR 1 1
after diagnosis. The second girl showed reduced SF CTC grade 2
Total ED/TRM following induction 2 10 .04
after induction and received no further idarubicin, but mitoxan-
treatment
Blasts .5% at d 15, n/total n (%) 59/239 (25) 35/235 (15) .01
trone. After 4 years of follow-up, she had mildly reduced SF CTC
Blasts .5% at d 28, n/total n (%) 46/202 (23) 37/206 (18) .27 at 2 occasions, and ACE inhibitor treatment was indicated. In all
Nonresponders 24 (9) 25 (10) .97 patients of both treatment groups with controls, SF improved during
CR achieved 228 (89) 232 (88) .79 times of follow-up.
Relapse, cumulative incidence, 74 (29 6 3) 79 (31 6 3) .79
n (% 6 SE)
Multivariate analysis
Secondary malignancies, cumulative 1 (1 6 1) 3 (1 6 1) .29
incidence, n (% 6 SE) Cox regression analysis was performed including the following
5-y pOS, % 6 SE 76 (3) 75 (3) .65 variables: treatment arm, cytogenetic risk group [SR: t(8;21),
5-y pEFS, % 6 SE 59 (3) 53 (3) .25
inv(16), t(15;17) vs other], MLL rearrangements, age (, vs >10
Data are n or n (%) unless stated otherwise. CCR, continuous complete remission. years), leukocytes (, vs >20 000 3 103/mL), and an interaction
*By Gray test (except for 5-year pOS and pEFS, which are by log rank test). term between therapy (randomized treatment with L-DNR) and
t(8;21). Only unfavorable cytogenetics was an independent risk
factor (hazard risk ratio 5 2.64, 95% confidence interval 1.72-4.04,
Late toxicity Px2 5 .000; the interaction between treatment and t(8;21) was not
significant (Px2 5 .97).
Secondary malignancies. One patient in the L-DNR arm devel-
oped a secondary malignancy (acute lymphoblastic leukemia), as
did 3 patients in the idarubicin arm (1 acute lymphoblastic leukemia
and 2 myelodysplastic syndrome).
Late cardiotoxicity. Five-year cumulative incidence of late Discussion
and persistent (subclinical and clinical) cardiotoxicity in CR1 was
assessed in median after 5 (0.9–8.5) years, excluding those with Dose intensity during induction, along with the cumulative dose of
transient cardiac dysfunction (ie, CTC grade 1 recorded at only anthracyclines, plays a major role in the treatment of AML.2,3,13
1 time point) and those with either HSCT in CR1 or relapse. The Based on several randomized trials comparing anthracyclines in AML
incidence values were 0.7% (n 5 1) in the L-DNR group and 1.8% therapy, idarubicin appeared to be very efficacious.13,14 However,
(n 5 3) in the idarubicin group (Table 4). In detail, the sole patient children are more susceptible to anthracycline cardiotoxicity than
in the L-DNR cohort was a 3-year-old girl who suffered from mild adults because of ongoing heart muscle growth. It is thus of high
therapeutically compensated clinical cardiomyopathy (grade 3). importance to minimize cardiotoxicity in anthracycline-based
Treatment with angiotensin-converting enzyme (ACE) inhibitors regimens.
was stopped 7.6 years after diagnosis. L-DNR is a liposomally entrapped daunorubicin with a more
In patients treated with idarubicin, 1 patient suffered from favorable pharmacology than free daunorubicin.23 Low accumu-
subclinical cardiomyopathy after 2.3 and 4.0 years from diagnosis, lation of L-DNR in the heart has been proven in animals, and
minimal cardiotoxicity despite significant antileukemic activity
was found in a mouse model.8,9 In 277 AIDS patients with Kaposi
Table 3. Toxicity (CTC score III/IV) after induction in patients treated sarcoma, no cardiotoxicity of L-DNR was seen, after cumulative
with L-DNR and idarubicin doses of up to 1700 mg/m2.10 Hence, liposomal anthracyclines are
L-DNR Idarubicin P believed to cause less cardiotoxicity at higher cumulative doses
General condition 86/223 (39) 116/260 (45) .18 than conventional anthracyclines.10,11,24-26
SGOT, SGPT 32/225 (14) 20/258 (8) .02 Based on these data, we assumed that higher doses of this
Arrhythmia 1/215 (0.5) 3/252 (1.2) .40 liposomal anthracycline could be administered safely. Notably,
Cardiac function (congestive heart failure) 3/183 (1.6) 5/221 (2.3)* .65 we found previously that idarubicin was somewhat superior to
Echocardiography 0/186 (0) 0/214 (0) — conventional DNR in induction at a conversion factor of 1:5,14 but
Cardiac total 4/183 (2.1)* 5/214 (2.3)† 1.0
observations of the Children’s Cancer Group27 made us doubt that
Central neurotoxicity 4/226 (1.8) 7/261 (2.7) .50
the idarubicin dose could be further increased. Thus, in AML-BFM
Infection 70/226 (31.0) 95/261 (36.4) .21
Pulmonary toxicity 33/204 (16) 35/248 (14) .54
2004, we randomized L-DNR at a dose of 80 mg/m2 per day for
Mucositis 58/225 (26) 64/259 (25) .79
3 days vs standard induction with idarubicin at 12 mg/m2 per day for
Skin toxicity 8/223 (3.6) 7/256 (2.7) .58 3 days (corresponding to L-DNR 60 mg/m2/ per day for 3 days).
Overall, we found similar response rates after induction and com-
Data are n/total n (%). SGOT, serum glutamic oxaloacetic transaminase; SGPT,
parable long-term outcome. Hence, this surmised mild dose increase
serum glutamic pyruvic transaminase.
*One patient died associated with sepsis. did not translate into largely different efficacy. Notably, our study
†Three patients died associated with ARDS and sepsis (see “Acute toxicity”). was underpowered to discriminate small differences: to show a
42 CREUTZIG et al BLOOD, 4 JULY 2013 x VOLUME 122, NUMBER 1

Table 4. Late cardiotoxicity in patients treated with L-DNR and and subclinical cardiotoxicity, and the 11-year cumulative incidence
idarubicin of late clinical cardiotoxicity was 2.5%.35 However, our current
L-DNR Idarubicin data on acute and long-term cardiotoxicity, although preliminary,
n 170 185 clearly reveal that an induction dose of 3 3 (80 mg/m2 per day)
CTC score I 9 10 L-DNR does not increase cardiotoxicity. Cardioprotection with
After relapse/HSCT* 4 3 dexrazoxane might be another option to reduce anthracycline
No relapse/no HSCT and CTC score I only 5 6† cardiotoxicity.36 However, the application of that drug in those
once*
,18 years old is discouraged owing to the risk of secondary
No relapse/no HSCT and CTC score I present 0 1
malignancies.37
.6 mo
CTC score III/IV 2 3
In summary, L-DNR proves to be an effective drug within a
After relapse/HSCT* 1‡ 1
multiagent approach for treating de novo AML in children and
No relapse/no SCT and CTC score III/IV present 1 2 adolescents in general, and has specific activity in patients with
.6 mo t(8:21). This specific effectiveness of L-DNR was also found in
Total: No relapse/no HSCT and CTC score I-IV 1 3 Relapsed AML 2001/01,38 suggesting that core-binding-factor AML
present .6 mo is much more sensitive to anthracyclines in general (or more specific
There were no CTC II cardiotoxicities.
to L-DNR) than other subtypes of AML. L-DNR shows a favorable
*Excluded for the calculation of induction-related cardiotoxicity. overall profile, as well as a favorable cardiac toxicity profile, and
†One patient refused follow-up. eventually allows an increased anthracycline dose without increasing
‡Patient died 7 days after HSCT with sepsis and cardiac failure. cardiotoxicity. The AML-BFM study group will therefore continue
to use L-DNR in their forthcoming de novo AML trial.
pEFS improvement from 53% to 59% with 80% power, a 5 5%
2-sided, 1050 patients per group would have been needed. However,
our results in subgroups of patients and TRM show that L-DNR still
proved to be more effective and favorable.
For example, results by randomization were better for patients Acknowledgments
with t(8;21) treated with L-DNR vs idarubicin. We suggest that this
The authors thank the colleagues, data managers, and techni-
might be due to the prolonged active plasma level of the liposomal
cians of the participating hospitals for their valuable cooperation
drug. We found it interesting to note that at day 15, a typical
and Jans-Enno Müller (Hannover) and Nora Mühlegger (Vienna)
response assessment time point,28,29 the idarubicin cohort showed
for competent data management. The authors acknowledge gratefully
lower blast counts, whereas the 2 cohorts were no longer different
the help of Ursula Bernsmann (Hannover) and Gesche Tallen
at d 28 before the second treatment course. Again, this could be
(Berlin) in preparing the manuscript.
indicative of a prolonged effect of L-DNR compared with idarubicin,
This work was supported by the Deutsche Krebshilfe e.V. and
and could be important for t(8;21) leukemias, which have a rel-
partly by the project (Ministry of Health, Czech Republic) for
atively slow blast-cell clearance over time compared with other
conceptual development of research organization 00064203 (Uni-
cytogenetic subtypes. Notably, AML-BFM 2004 was designed with-
versity Hospital Motol, Prague, Czech Republic).
out HAM treatment in all SR patients, including those with t(8;21),
unlike AML-BFM 98. We have shown30 that second induction
with HAM is beneficial for these patients. Nevertheless, we consider
now that the more favorable activity of L-DNR over idarubicin in
first induction could compensate at least partly for the lack of HAM. Authorship
Overall, our 2004 results even improved over those of 1998. This
can mainly be seen by the high 5-year survival rates (74% 6 2% vs Contribution: U.C., M.Z., J.-P.B., M.N.D., and D.R. designed and
65% 6 2%, Plogrank 5 .001). performed research and wrote and edited the paper; M.Z., U.C.,
Improved survival rates in pediatric AML, similar to those in and D.R. analyzed the data; C.v.N., A. Sander, and J.S. performed
our study, have recently been reported by different treatment diagnostic studies and edited the paper; G.F., N.G., T.K., B.K.,
groups from Japan, Europe, and the United States.31-34 In view T.L., J.R., A. Schrauder, A.v.S., and J.S. provided study materials
of these good results, which have been achieved with different but or patients and edited the manuscript; and all authors reviewed
always intensive strategies, it is even more important to reduce the final version of the manuscript.
acute and long-term toxicities to ensure the highest possible quality Conflict-of-interest disclosure: D.R. is a member of the advisory
of life. In our study, most acute toxicities, including hematological board from Galen. The remaining authors declare no competing
and infectious complications, were in the expected range or tended financial interests.
to be lower after treatment with L-DNR compared with idarubicin. A complete listing of the participating AML-BFM institutions
This is explicitly underpinned by a lower TRM rate in patients of and investigators appears in the supplemental Appendix (available
the L-DNR arm. Cardiotoxicity was low after induction in both on the Blood Web site; see the Supplemental Materials link at the
arms, and during follow-up, only 1 L-DNR patient and 2 idarubicin top of the online article).
patients required treatment with ACE inhibitors. However, the Correspondence: Ursula Creutzig, AML-BFM Trial Centre,
assessment of long-term anthracycline cardiotoxicity requires longer Department of Pediatric Hematology and Oncology, Hannover
follow-up.6 Results from the prior AML-BFM trials (mainly with Medical School, Children’s Hospital, Carl-Neuberg-Strasse 1,
idarubicin treatment) showed a relatively low rate of early clinical D-30625 Hannover, Germany; e-mail: [email protected].
BLOOD, 4 JULY 2013 x VOLUME 122, NUMBER 1 LIPOSOMAL DAUNORUBICIN IN PEDIATRIC AML 43

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