From www.bloodjournal.org by guest on March 24, 2019. For personal use only.

Review article

A review on allogeneic stem cell transplantation for newly diagnosed pediatric

acute myeloid leukemia
Denise Niewerth,1 Ursula Creutzig,2 Marc B. Bierings,3 and Gertjan J. L. Kaspers1
1Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands; 2Department of Pediatric Hematology/Oncology,
University of Muenster, Muenster, Germany; and 3Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands

Survival of pediatric acute myeloid leuke-
mia (AML) has improved considerably
over the past decades. Since 1985, alloge-
neic stem cell transplantation (allo-SCT)
is widely recommended for patients who
have a matched sibling donor. However, it
remains controversial whether allo-SCT
is superior to chemotherapy for children
with newly diagnosed AML. This review
summarizes phase 3 clinical trials that
compared allo-SCT with chemotherapy
(including autologous SCT) in pediatric
AML, excluding studies that did not use
the intention-to-treat analysis or correct
for time-to-transplantation. Although allo-
SCT might prevent more relapses than
chemotherapy, the number needed for
transplantation (with allo-SCT) to prevent
one relapse is in the order of 10 patients.
Moreover, overall survival is similar with
both methods in most recent studies,
apparently because of increased salvaga-
bility of a relapse when initial therapy
concerned chemotherapy only, and be-
cause of a higher treatment-related mor-
tality with allo-SCT. Because allo-SCT also
gives more severe side effects and re-
sults more often in secondary malignan-
cies than chemotherapy, we do not recom-
mend allo-SCT in first remission for
pediatric AML in general. Further re-
search should focus on the possibility
that subgroups might benefit from allo-
SCT, aiming at further improvements in
the prognosis of pediatric AML. (Blood.
2010;116(13):2205-2214)

Introduction
The treatment of children with acute myeloid leukemia (AML) has
improved considerably. This was mainly achieved by more inten-
sive chemotherapy and better supportive care. Currently, up to 90%
of all patients achieve remission, and 60% to 65% will be long-term
survivors.1
The treatment of AML consists of an induction period with
diverse intensive chemotherapy regimens that is based on cytara-
bine and an anthracycline followed by consolidation. Possibilities
for consolidation are allogeneic stem cell transplantation (allo-
SCT), autologous stem cell transplantation (auto-SCT), and chemo-
therapy. For reasons of simplicity, we entitle all transplantations
using different sources of hematopoietic stem cells, cord blood,
bone marrow, and peripheral blood as SCT in this review.
Allo-SCT is a procedure in which a person receives stem cells
from a donor. Currently, patients and donors are typed by molecular
techniques for human leukocyte antigen (HLA) class I and II
antigens. A well-matched donor matches for at least 9 of 10 alleles
at HLA-A, -B, -C, -DRB1, and -DQB1. The donor can be a
matched related donor (MRD), most often a matched sibling donor
(MSD). If no MRD is available, a matched unrelated donor (MUD)
may be available. MUD is sometimes used in high-risk (HR)
patients in first complete remission (CR) or after relapse, and more
studies suggest that MUD–allo-SCT provides similar outcome as
MSD–allo-SCT. For children who lack both a MSD and a MUD, a
haploidentical related donor or an unrelated cord blood donor can
be used.2
In auto-SCT, the patients’ own stem cells are used for rescue
after myeloablative therapy. Graft-versus-host disease (GVHD)
does not occur, so usually, treatment-related mortality (TRM) is
low. However, the relapse rate is higher compared with allo-SCT
because a potential graft-versus-leukemia effect is lacking. It is
generally accepted that auto-SCT in first remission is not different
from chemotherapy in terms of survival.3-7
Since 1985, allo-SCT has been widely recommended for
patients with newly diagnosed AML with a MSD after induction
chemotherapy. The question addressed in this review is whether
results of allo-SCT are better than contemporary chemotherapy for
these patients. In the absence of randomized studies that compared
allo-SCT with other types of postremission therapy, Mendelian/
genetic randomization with intention-to-treat analysis is the least
biased method to compare outcomes.8 In an intention-to-treat
analysis, the patients are analyzed in the arm to which they are
allocated, irrespective of treatment actually received. Other studies
use the as-treated analysis, in which the patients are analyzed
according to the treatment they actually received. However, this
approach has many methodologic pitfalls, as mentioned later in the
discussion. The as-treated analysis should at least be corrected for
time-to-transplantation to adjust for any events that may occur
during the waiting time to transplantation.
It would be helpful to stratify patients into risk groups on the
basis of clinical and biologic characteristics and to evaluate
response to different treatments within these risk groups to identify
the appropriate treatment, including SCT, for each individual
patient.1,3 There is heterogeneity in risk group stratification be-
tween study groups. However, most groups agree that patients with
t(8;21), inv(16), t(16;16), and t(15;17) belong to the low-risk (LR)
group, and patients with monosomy 5, monosomy 7, deletions of
5q, or greater than 15% blasts in the marrow after the first course of
chemotherapy belong to the HR group.9,10 Most groups agree that
children who have acute promyelocytic leukemia (APL), myeloid
leukemia of Down syndrome (ML-DS), t(8,21) or inv(16)/t(16,16)
should not receive allo-SCT during first remission. However,

Submitted December 28, 2009; accepted June 1, 2010. Prepublished online as © 2010 by The American Society of Hematology
Blood First Edition paper, June 10, 2010; DOI 10.1182/blood-2010-01-261800.

BLOOD, 30 SEPTEMBER 2010 䡠 VOLUME 116, NUMBER 13 2205

 From www.bloodjournal.org by guest on March 24, 2019. For personal use only.
2206 NIEWERTH et al
indications for allo-SCT differ significantly between study groups
for the remaining patients. In Europe the tendency is to avoid SCT
in CR1, whereas the Children’s Oncology Group (COG) recom-
mends allo-SCT in a larger proportion of patients. An overview of
the selected clinical trials is given first, followed by a discussion on
the usefulness of allo-SCT in perspective of its effectiveness, side
effects, and costs compared with chemotherapy only (including
auto-SCT) in children and adolescents with newly diagnosed AML.
Methods
PubMed was searched in December 2008 using the search terms “acute
myeloid leukemia,” “pediatric,” and “allogeneic stem cell transplantation”
and was limited to human trials not started before 1985, reporting patients
with AML younger than 21 years and written in English. The point at which
the intention-to-treat analysis started, if used, differs per study group. This
information was not consistently provided by the investigators of the
reviewed studies. To summarize risk group classification for the different
study groups was beyond the purpose of this review and has been reviewed
previously.10 APL, myelodysplastic syndrome (MDS), secondary AML,
and ML-DS were preferred to be excluded from analysis. Event-free
survival (EFS) had been calculated from the date of diagnosis to last
follow-up or first event (failure to achieve remission, resistant leukemia,
relapse, second malignancy, or death from any cause). Overall survival
(OS) had been calculated from the date of diagnosis to death of any
cause or last follow-up and disease-free survival (DFS) from the date of
remission to last date of follow-up or event (relapse, second malignancy, or
death of any cause). To calculate the amount of patients who need to receive
a transplant to prevent one relapse, the number needed for transplantation
(NNT) was used. The NNT was calculated with the following formula:
NNT ⫽ 1/(EFSallo-SCT ⫺ EFSchemotherapy).
Pediatric cooperative group trials that compared allo-SCT with chemo-
therapy according to the intention-to-treat analysis are summarized in Table
1. Pediatric cooperative group trials that did not use the intention-to-
treat analysis but did correct for time-to-transplantation are summarized in
Table 2. Trials that did not use one of these analyses are not presented in the
tables, because these study results are too flawed.
Results
Associazione Italiana di Ematologia e Oncologia Pediatrica
The Associazione Italiana di Ematologia e Oncologia Pediatrica
(AIEOP) group has conducted 4 consecutive studies since 1982.11
AIEOP LAM92 included patients with newly diagnosed AML, in
the age range from birth to 15 years. All patients received induction
and consolidation chemotherapy. This was followed by auto-SCT
or allo-SCT if there was a HLA-matched family donor available or
consolidation chemotherapy, irrespective of risk group. The pa-
tients were stratified into LR and HR groups, which showed
different outcomes in OS, 67% ⫾ 6% versus 47% ⫾ 5% respec-
tively (P ⫽ .04). When the studies AIEOP LAM87, LAM87M, and
LAM92 were taken together, an advantage in 5-year DFS was
found for allo-SCT (64% ⫾ 6%) over chemotherapy (28% ⫾ 5%)
and auto-SCT (55% ⫾ 5%) after correction for time-to-transplanta-
tion (Table 2). We note that all the data should be interpreted with
caution because of the retrospective and uncontrolled nature of this
analysis. In the most recent AIEOP 2002 study, LR patients are
only eligible for SCT after they relapse. HR patients are eligible for
allo-SCT if a family donor is available; otherwise, they will
undergo auto-SCT after induction chemotherapy (Table 3). For
patients in CR2 or patients with M7 AML, unrelated donors for
allo-SCT are used.11
BLOOD, 30 SEPTEMBER 2010 䡠 VOLUME 116, NUMBER 13
Berlin-Frankfurt-Munster
The Berlin-Frankfurt-Munster (BFM) group has completed
5 consecutive AML trials since 1978; AML-BFM 78, 83, 87, 93,
and 98. Only HR patients were eligible for allo-MSD-SCT. In trial
AML-BFM 93, all HR patients received induction and consolida-
tion chemotherapy, followed by allo-SCT if a sibling donor was
available. Morphologic French-American-British type and day
15 marrow were used to determine a standard-risk (SR) and a HR
group, which had a 5-year survival of 71% ⫾ 4% and 50% ⫾ 3%,
respectively. The as-treated results were corrected for time-to-
transplantation according the Mantel-Byar analysis.12 For AML-
BFM 87 and 93 taken together, the OS of the HR patients who
underwent allo-SCT was similar to the OS of HR patients who did
not receive a SC transplant (62% ⫾ 3% vs 64% ⫾ 8%; P ⫽ .4). In
trial AML-BFM 98, patients were again stratified into SR and HR
groups, and only HR patients received allo-SC transplants, if they
had a matched family donor. Mantel-Byar analysis was used to test
the effect of SCT on survival. Five-year OS for HR patients was
54% ⫾ 3%, and it was for SR patients 75% ⫾ 4%. Five-year OS
for HR patients with or without SCT in CR1 was similar (as treated,
69% ⫾ 14% vs 64% ⫾ 4%; P ⫽ .25).12,13
One aim of trial AML-BFM 98 was to evaluate prospectively
the effect of MSD-SCT in HR patients of this study and the
following interim phase in 2003. The intention-to-treat analysis
showed no advantage of allo-MSD-SCT in children and adoles-
cents with HR-AML (47% ⫾ 7% for 5-year DFS donor vs
43% ⫾ 4% no donor, P ⫽ .52; and 58% ⫾ 9% for 5-year OS donor
vs 56% ⫾ 4% for no donor, P ⫽ .16)14 (Table 1).
The ongoing AML-BFM 2004 trial aims to optimize therapy for
children and adolescents with AML. Patients are again stratified
into HR and SR subgroups. Chemotherapy is intensified, and the
quality of supportive therapy is optimized. During the first 2 years
of the trial HR patients received allo-SC transplant in CR1. Since
2006, when the data of the intention-to-treat analysis from trial
AML-BFM 98 became available, allo-SCT became restricted to
patients in second CR and refractory AML (Table 3).15
Children’s Cancer Group (United States)
The Children’s Cancer Group (CCG) has completed 5 trials for
children younger than 21 years with newly diagnosed AML
(CCG-251, -213, -2861, -2891, and -2941). All comparisons were
analyzed as intention-to-treat. Overall, children with a donor had a
significantly better OS and DFS than did children without donor
(54% vs 45%, P ⫽ .026 for OS; 47% vs 37%, P ⫽ .005 for DFS;
Table 1). The relapse risk at 8 years was significantly lower for
children with a donor than for children without a donor (36% vs
56%; P ⬍ .001).16
In trial CCG-2891, children with a MSD were allocated to
allo-SCT, the others were randomly assigned between auto-SCT or
consolidation chemotherapy. No risk group stratification was done.
Allo-SCT had a significantly better 8-year DFS and OS than did
chemotherapy (60% ⫾ 9% vs 53 ⫾ 8%, P ⫽ .05 for OS; 55% ⫾ 9%
vs 47% ⫾ 8%, P ⫽ .01 for DFS; Table 1).6,7
In trial CCG-2961, patients were stratified into 2 risk groups on
the basis of cytogenetics. The 5-year OS for LR patients (72%)
differed from the OS of HR patients (39%). For consolidation
treatment, patients were assigned to allo-SCT or to intensive
chemotherapy. Five-year DFS for those with donor was 60% ⫾ 8%,
better than the 50% ⫾ 5% of those without donor (P ⫽ .021), but
OS at 5 years was not significantly different (67% ⫾ 8% vs
62% ⫾ 5%; P ⫽ .425; Table 1). In a subsequent subgroup analysis,
Table 1. Studies on allo-SCT versus chemotherapy in pediatric newly diagnosed AML with analysis according to the intention-to-treat principle
Indication for Percentage of With Underwent
Group/study/patients Period allo-SCT in CR1 Age, y EFS/% of DFS OS, % donor, % allo-SCT, % TRM, %

AML BFM 98 ⴙ Interim9850 July 1998 to March 2004 HR patients ⬍ 18 5-y DFS (P ⫽ .52) 5-y OS (P ⫽ .16) 23 13
n ⫽ 275 (CR)
Total, n ⫽ 494
Donor, n ⫽ 63 47 ⫾ 7 58 ⫾ 9 3
No donor, n ⫽ 188 43 ⫾ 4 56 ⫾ 4 4
POG88217,26 1988-1993 All patients ⱕ 21 3-y EFS 3-y OS 16* 14† P ⫽ .005
Total, n ⫽ 321
Allo-SCT, n ⫽ 89 52 ⫾ 8 Not given Not given
Auto-SCT, n ⫽ 115 38 ⫾ 6 (P ⫽ .01) Lower than allo-SCT (P ⫽ .007) 15
Chemo, n ⫽ 117 36 ⫾ 6 (P ⫽ .06) Similar to allo-SCT (P ⫽ .15) 2.7
BLOOD, 30 SEPTEMBER 2010 䡠 VOLUME 116, NUMBER 13

CCG 28916,7 October 1989 to April 1995 All patients ⬍ 21 8-y DFS (chemo vs allo, 8-y OS (chemo vs allo, P ⫽ .05) 28* 19†
P ⫽ .01)
Total, n ⫽ 537
Allo-SCT, n ⫽ 181 55 ⫾ 9 60 ⫾ 9 14
Auto-SCT, n ⫽ 177 42 ⫾ 8 48 ⫾ 8 5
Chemo, n ⫽ 179 47 ⫾ 8 53 ⫾ 8 4
CCG-251, -213, -2861, -2891, and -294116 1979-1996 All patients ⬍ 21 8-y DFS (P ⫽ .005) 8-y OS (P ⫽ .026) 25* Not given P ⬍ .001
Total, n ⫽ 1464
Allo-SCT, n ⫽ 373 47 ⫾ 6 54 ⫾ 6 17 ⫾ 4
No donor, n ⫽ 1091 37 ⫾ 4 45 ⫾ 4 7⫾2
CCG 296117 August 1996 to March 2002 All patients ⬍ 21 5-y DFS (P ⫽ .021) 5-y OS (P ⫽ .425) 27* Not given P ⫽ .007
Total, n ⫽ 633
Donor, n ⫽ 170 60 ⫾ 8 67 ⫾ 8 8
No donor, n ⫽ 463 50 ⫾ 5 62 ⫾ 5 3
EORTC-CLG 5892120 June 1993 to December 2000 All patients ⬍ 18 5-y DFS 5-y OS 22† 19†
Total, n ⫽ 145
Donor, n ⫽ 39 63 ⫾ 8 78 ⫾ 7 8
No donor, n ⫽ 106 57 ⫾ 5 65 ⫾ 5 5
UK-MRC AML 104,32 May 1988 to March 1995 All patients ⬍ 14 Not given 10-y OS (P ⫽ .3) 28† 20† P ⫽ .001
Total, n ⫽ 315
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Donor, n ⫽ 85 68 9
No donor, n ⫽ 230 59 1‡

CLG indicates Children Leukemia Group; and UK-MRC, United Kingdom Medical Research Council.
*Percentage calculated from patients who achieved CR and are eligible for random assignment.
†Percentage calculated from total group of patients.
‡Three deaths, 1 after auto-SCT and 2 after MUD
REVIEW OF ALLOGENEIC SCT FOR PEDIATRIC AML
2207
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2208 NIEWERTH et al BLOOD, 30 SEPTEMBER 2010 䡠 VOLUME 116, NUMBER 13

Table 2. Studies on allo-SCT versus chemotherapy in pediatric newly diagnosed AML without intention-to-treat analysis but with correction
for time-to-transplantation
Indication Percentage
for allo-SCT Age, of EFS/% Have a Underwent
Group/study/patients Period in CR1 y of DFS OS, % donor, % allo-SCT, % TRM, %

AIEOP LAM 87-92 trials11 March 1982 to September 2001 All patients ⬍ 15 5-y DFS Not given Not given 29* (LAM92) Not given
Total, n ⫽ 388
Allo-SCT, n ⫽ 78 64 ⫾ 6
Auto-SCT, n ⫽ 110 55 ⫾ 5
Chemo, n ⫽ 89 28 ⫾ 5
P Not given
TCCSG AML M91-13 and AML M96-1430 August 1991 to September 1998 All patients 5-y DFS Not given Not given 20†‡ Not given
Total, n ⫽ 170
Allo-SCT, n ⫽ 34 81 ⫾ 19
Auto-SCT, n ⫽ 32
Chemo, n ⫽ 104 66 ⫾ 10
P .22
AML BFM87 and -9313 December 1986 to June 1998 HR patients ⬍ 15 Not given 5-y OS Not given 11
Total, n ⫽ 356
Allo-SCT, n ⫽ 39 62 ⫾ 3 10
No allo-SCT, n ⫽ 317 64 ⫾ 8 Not given
P .40
LAME 89/9121 December 1988 to December 1998 All patients ⬍ 20 5-y DFS 5-y OS 26* (LAME91) 26%* (LAME91) Not given
Total, n ⫽ 244
Allo-SCT, n ⫽ 74 57 ⫾ 7 71 ⫾ 7
Chemo, n ⫽ 170 52 ⫾ 4 55 ⫾ 4
P .18 .006

TCCSG indicates Tokyo Children’s Cancer Study Group.

*Percentage calculated from total group of patients.
†Percentage calculated from patients who achieved CR and are eligible for random assignment.
‡Twenty-four related donors, 8 unrelated donors, and 2 unrelated cord blood donors.

no significant differences in either DFS or OS among LR patients
with and without a donor were seen. Of the HR patients, only
14 patients were left for consolidation treatment. Of these, 57%
with donor and 14% without donor survived. In CCG AML trials
since 1987, patients with a MRD have had significantly better DFS
and OS than patients receiving chemotherapy.17
The CCG and the Pediatric Oncology Group (POG) are now
merged into the COG. Because allo-SCT did not result in a
significantly better DFS or OS than chemotherapy in LR patients,
the COG is no longer recommending MRD-SCT in CR1 for this
group of patients (Table 3).18
The COG compared POG 8821, CCG-2891, CCG-2961, and
MRC AML10 in a meta-analysis and found significant differences
in outcome for SR patients who were eligible for allo-SCT in CR1
compared with consolidation chemotherapy. The 8-year DFS for
patients undergoing allo-SCT compared with chemotherapy was
58% ⫾ 7% and 39% ⫾ 5% (P ⬍ .01), and the OS was 62% ⫾ 7%
and 51% ⫾ 5% (P ⬍ .01), respectively. For LR and HR patients no
significant differences were found. Without risk stratification,
allo-SCT was significantly superior to chemotherapy for OS, DFS,
and relapse.9
Dutch Childhood Oncology Group
The Dutch Childhood Oncology Group AML92/94 study included
patients younger than 18 years with newly diagnosed AML,
ML-DS, myelosarcoma, or AML after MDS.19 As consolidation
therapy, patients were eligible for allo-SCT if a MSD was
available; the other patients were randomly assigned between
auto-SCT and chemotherapy. No significant difference was ob-
served in relapse risk between patients treated with chemotherapy
alone and patients who received a transplant. This study was not
designed to compare results of chemotherapy with SCT as optimal
consolidation, and compliance with the protocols for transplanta-
tion was often violated, resulting in strong selection bias.19 In 1998,
the Dutch Childhood Oncology Group joined the MRC AML-12
and -15 studies (Table 3).
European Organization for Research and Treatment of Cancer
Children Leukemia Group
The Children Leukemia Group of the European Organization for
Research and Treatment of Cancer (EORTC) conducted 2 trials, of
which the prospective randomized trial 58921 studied the value of
early allo-SCT with an HLA-identical sibling versus chemo-
therapy. Maintenance chemotherapy was given to patients who did
not receive a transplant. Included were children younger than 18
years with newly diagnosed AML or HR myelodysplasias. The
5-year DFSs for the donor versus no-donor groups are 63% ⫾ 8%
and 57% ⫾ 5% respectively, and the 5-year OSs from CR for donor
versus no donor are 78% ⫾ 7% and 65% ⫾ 5%, respectively
(Table 1). Relapse occurred in 29% of the donor group and in 38%
of the no donor group. No P values have been given because of the
insufficient number of events.20
Leucémie Aiguë Myéloblastique Enfant
Trial LAME91 of the Leucémie Aiguë Myéloblastique Enfant
(LAME) cooperative group included patients from birth to 20 years
of age. After induction and 1 or 2 courses of consolidation
chemotherapy, patients with a HLA-identical family donor were
allocated to allo-SCT. Although auto-SCT was not scheduled, some
Table 3. Recent and ongoing studies in pediatric AML without information on treatment outcome but with guidelines on risk-group stratified allo-SCT or not
Standard
Group/study Period Risk groups, % Low risk risk High risk Who underwent allo-SCT

AIEOP LAM 2002 December 2002 to December 2009 LR, 18; HR, 82 Isolated t(8;21), inv(16)/t(16;16), and CR — All others HR patients; SR patients after
after course 1 relapse only
AML-BFM 200415 March 2004 to December 2009 LR, 30; HR, 70 FAB M1/M2 with Auer rods, FAB — All patients who are not low risk HR patients (until 2006); afterward
M4Eo⫹, t(8;21), inv(16), and blasts on no patients in CR1
day 15 ⬍ 5% and absence of
FLT3/ITD
St Jude AML0830 March 2008-2013 LR, 31; SR, 32; HR, 37 t(8;21) or inv(16) or t(16;16) and good All others t(6;9), t(8;16), t(16;21), ⫺7, ⫺5, or 5q⫺, HR patients; also eligible for
BLOOD, 30 SEPTEMBER 2010 䡠 VOLUME 116, NUMBER 13

response to therapy FLT3-ITD unless MRD negative after natural killer cell therapy, like
induction course I, FAB M0 or M6, FAB M7 SR patients
without t(1;22), treatment related-AML,
RAEB-2 or secondary AML after MDS,
patients with poor response to therapy
(MRD ⬎ 5% at day 22, and/or MRD
⬎ 0.1% after induction course II)
NOPHO-AML 200425 January 2004- 2014 LR, 80; HR, 20 Less than 15% blasts after the first and — 11q23 abnormalities other than t(9;11), HR patients
CR after the second course, or ⬎ 15% blasts at day 15, or lack of
t(8;21), inv(16), t(16;16), t(9;11) and remission after 2 courses of chemotherapy
CR after the second course
COG AAML053118 August 2006-2010 LR, 25; SR, 57; HR, 18 t(8;21), inv(16), t(16;16) All others ⫺7, ⫺5, ⫺5q; bone marrow M3 (⬎ 15% SR and HR patients
blasts) after course 1, except for those with
low risk cytogenetics
ELAM0223 March 2005-2012 LR, 14; SR, 81; HR, 5 t(8;21) All others ⫺7, ⫺5q, t(9;22), t(6;9) SR and HR patients
JPLSG AML-05 November 2006-2013 LR, 40; SR, 40; HR, 20 t(8;21), inv(16), t(16;16) All others ⫺7, ⫺5q, t(9;22), t(16;21), FLT3/ITD, no CR HR patients
after course 1
MRC/DCOG AML 15 March 2005 to February 2010 LR, 30; SR, 55; HR, 15 t(8;21) and inv(16)/t(16;16), irrespective All others More than 15% blasts after the first course, or HR patients
of marrow status after first course or adverse cytogenetics 关⫺5, ⫺7, del(5q),
the presence of other genetic abn(3q), t(9;22), complex karyotype兴
From www.bloodjournal.org by guest on March 24, 2019. For personal use only.

abnormalities

FAB indicates French-American, British; RAEB, refractory anemia with excess blasts; NOPHO, Nordic Society of Pediatric Hematology and Oncology; MRC, Medical Research Council; and DCOG, Dutch Childhood Oncology Group.
REVIEW OF ALLOGENEIC SCT FOR PEDIATRIC AML
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2210 NIEWERTH et al
children did receive this treatment. Maintenance chemotherapy
was only given to patients who did not receive a transplant. The
comparison of chemotherapy and allo-SCT was corrected for
time-to-transplantation. No formal intention-to-treat analysis was
performed, but all patients in CR1 with a HLA-identical family
donor actually received the scheduled allograft.21 Allo-SCT re-
sulted in a lower relapse risk (28% ⫾ 14% for allo-SCT vs
47% ⫾ 9% for chemotherapy; P ⫽ .02)22 and a nonsignificantly
higher 5-year DFS (57% ⫾ 7% for allo-SCT vs no 52% ⫾ 4% for
allo-SCT; P ⫽ .18).21 The OS for patients who received an allograft
was significantly better compared with patients who did not receive
an allograft (71% ⫾ 7% vs 55% ⫾ 4%; P ⫽ .006; Table 2).
Allo-SCT did not significantly improve the outcome of patients
with t(8;21)- or inv(16)-positive AML.21 In their subsequent
ELAM02 clinical trial they do not offer allo-SCT to patients with
t(8;21)23 (Table 3).
Nordic Society of Pediatric Hematology and Oncology
The Nordic Society of Pediatric Hematology and Oncology
AML93 trial included patients younger than 17 years.24 Allo-SCT
was recommended to all patients in CR1 with a HLA-matched
family donor, the other patients mainly received chemotherapy.
Auto-SCT was optional in the first part of the trial, on a
nonrandomized basis, and MUD was performed in a few patients.
Patients who received an auto-SC transplant have been included in
the chemotherapy group. Intention-to-treat analysis was not per-
formed, and no correction for time-to-transplantation was done;
therefore, results should be interpreted with great caution, and we
only refer to overall survival. The OS of patients who underwent
allo-SCT or chemotherapy was similar (68%; P ⫽ .9). This was
due to a significantly better prognosis for the children who relapsed
after chemotherapy in CR1 and received a SC transplant in CR2
(EFS ⫽ 64% ⫾ 8%) than for children who relapsed after SCT in
CR1 (EFS ⫽ 18% ⫾ 15%) and children who received chemo-
therapy only in CR1 and CR2 (EFS ⫽ 6% ⫾ 4%).24
In the ongoing Nordic Society of Pediatric Hematology and
Oncology AML 2004 trial, SCT is reserved for HR patients. The
outcome of SCT with the use of MSD or MUD will be compared
(Table 3).25
Pediatric Oncology Group (United States)
The POG 8821 trial included patients with previously untreated
AML. Patients with an isolated myelosarcoma or secondary AML
were eligible if the previous treatment was for another type of
malignancy. After induction therapy, patients with a MRD were
eligible for allo-SCT, others for auto-SCT or consolidation chemo-
therapy.5 With the use of an intention-to-treat analysis, the 3-year
EFS after randomization was better for children who underwent
allo-SCT (52% ⫾ 8%) than for those given chemotherapy
(36% ⫾ 6%; P ⫽ .06) and significantly better than for children
who underwent auto-SCT (38% ⫾ 6%; P ⫽ .01). OS after allo-
SCT was not significantly different to that after chemotherapy
(P ⫽ .15) but superior to that after auto-SCT (P ⫽ .007). No OS
rates were given (Table 1).26
In the next POG 9421 study, children younger than 21 years
were eligible for allo-SCT if they had a HLA-identical sibling
donor; otherwise, they were allocated to consolidation chemo-
therapy. The 3-year OS for patients who underwent consolidation
chemotherapy or allo-SCT were 37% and 67%, respectively
(P ⬍ .001). These are as-treated data without correction for
time-to-transplantation and thus are probably biased.27
BLOOD, 30 SEPTEMBER 2010 䡠 VOLUME 116, NUMBER 13
St Jude Children’s Hospital
Trial AML91 at the St Jude Children’s Research Hospital applied
allo-SCT if patients had a HLA-matched sibling donor and
auto-SCT or chemotherapy in the other patients. After adjustment
for time-to-transplantation, patients receiving chemotherapy alone
did not have a significantly greater risk of an event than patients
receiving allo-SCT or auto-SCT. The use of SCT during first
remission did not improve survival, although no percentages were
given.28
St Jude trial AML-97 excluded ML-DS in the analysis. Only
patients with HR AML were candidates for allo-SCT. Others were
eligible for auto-SCT, but in 1998 auto-SCT was substituted with
2 courses of chemotherapy. The final results have not yet been
reported.28 Their most recent trial AML-02 also stratified the
patients into risk groups (Table 3).29
Japan
The Tokyo Children’s Cancer Study Group conducted 2 trials,
AML M91-13 and AML M96-14.30 Allo-SCT was allocated in
CR1, if a HLA-matched donor, either related or unrelated, was
available. Children that did not have a donor were allocated to
chemotherapy or auto-SCT (selected by physician’s choice). To
adjust for time-to-transplantation, the landmark analysis was used.
The 5-year DFS of the chemotherapy group was not significantly
lower compared with the allo-SCT group (66% ⫾ 10% vs
81% ⫾ 19%, respectively; P ⫽ .22; Table 2).30
After these 2 trials, the Japanese Childhood AML Cooperative
Study Group conducted trial AML99. In this trial, allo-SCT (related
and unrelated) was given in CR1 to all HR patients and was
recommended to SR patients with a MRD. The remaining SR
patients were randomly assigned between chemotherapy plus
auto-SCT or chemotherapy only. However, auto-SCT was elimi-
nated in June 2002. All LR patients received chemotherapy only.
For the SR patients, the 5-year DFS of the matched donor group
was significantly higher than that of the no donor group (as-treated:
82% [67%-100%] vs 53% [42%-67%]; P ⫽ .029), respectively.
Five-year OS was not statistically different for matched donor
versus no donor (as-treated: 82% [67%-100%] vs 69% [58%-82%];
P ⫽ .38). The 5-year OS of 16 HR patients who underwent
allo-SCT (6 related SCT, 6 unrelated SCT, and 4 cord blood SCT)
was 69%.31
United Kingdom Medical Research Council
The United Kingdom Medical Research Council trials AML10 and
AML12 only included patients with de novo AML in their analysis.
In MRC AML10 the pediatric part concerned patients younger than
14 years and allocated patients to allo-SCT if they had a matched
sibling donor. Patients without a MSD were randomly assigned to
receive auto-SCT after 4 courses of consolidation chemotherapy or
no further treatment. Comparisons were based on an intention-to-
treat analysis.4 Patients with a donor had a significantly reduced
relapse risk than did the patients without a donor (26% vs 42%;
P ⫽ .02), although fewer relapses were counterbalanced by more
procedure-related deaths (P ⫽ .001). No statistically significant
difference was observed in survival between children with or
without a donor at 10 years (68% vs 59%; P ⫽ .34; Table 1). The
investigators concluded that allo-SCT or auto-SCT after 4 courses
of intensive chemotherapy showed no survival advantage.32
Risk group stratification on the basis of cytogenetics and
response to the first course of chemotherapy was done in MRC
AML12, for the pediatric part in children younger than 16 years. In
 From www.bloodjournal.org by guest on March 24, 2019. For personal use only.

BLOOD, 30 SEPTEMBER 2010 䡠 VOLUME 116, NUMBER 13 REVIEW OF ALLOGENEIC SCT FOR PEDIATRIC AML 2211

Figure 1. Survival of studies on allo-SCT versus chemotherapy in pediatric newly diagnosed AML. (A) EFS/DFS for studies analyzed according to the intention-to-treat
principle, (B) OS for studies analyzed according to the intention-to-treat principle, and (C) DFS and (D) OS for studies analyzed according to the as-treated principle corrected
for time-to-transplantation; n.g. indicates not given. For the BFM98 ⫹ Interim98 study, only HR patients were included. The studies are ordered from lowest to highest survival
with chemotherapy only.

this trial, allo-SCT was limited to SR and HR patients. LR patients
received chemotherapy only, as well as the SR and HR patients
without a donor. No auto-SCT was scheduled. When the results
of AML10 and AML12 were combined, no significant improve-
ment of DFS (2 P ⫽ .06) or OS (2 P ⫽ .1) was seen in any risk
group with allo-SCT, analyzed according to the intention-to-
treat principle.4 In addition, the 4-year survival with chemotherapy
only was 62%.33
In trial MRC AML15, allo-SCT in CR1 was restricted to HR
patients (results not yet published; Table 3; Figure 1).
Number needed to transplant to avoid relapse
To further assess the effectiveness of allo-SCT in comparison with
chemotherapy, the number needed for transplantation was calcu-
lated. The number needed for transplantation to prevent one relapse
varies from 6.3 to 14.3 (6.3, 10, 10, 11.1, 12.5, and 14.3), with a
 From www.bloodjournal.org by guest on March 24, 2019. For personal use only.
2212 NIEWERTH et al
median of 10 patients in the 6 studies, which showed a significant
advantage of allo-SCT.6,16,17,21
Toxicity of SCT
Little is known about the incidence of and the risk factors for the
late effects of treatment of childhood AML because there have been
few real long-term survivors. However, because the number of
survivors is increasing, it is important to evaluate the toxicities of
the different treatment methods. The survival advantage given by
allo-SCT needs to be considered in the context of the risks of the
procedure. These include acute and late toxicities and quality of life
(QOL), but also financial costs.
The advantages of SCT are often counterbalanced by mortality,
related mainly to the complications of infection and GVHD, and
the long-term toxicity of the treatment. The TRM rate after
allo-SCT of our reviewed studies ranged from 7% to 17% and for
chemotherapy from 1% to 8%.7,16,17,20,32,34 Because little informa-
tion is available on the toxicity of SCT exclusively in children, also
information about toxicity in adults is included. Overall, the acute
toxicities of SCT include infectious complications, hepatic veno-
occlusive disease, interstitial pneumonia, and acute GVHD. The
late toxicities of SCT include endocrinologic deficiencies that lead
to growth failure and infertility, cataract, neurocognitive abnormali-
ties, chronic GVHD, and cardiac dysfunction. Secondary malignan-
cies occur after SCT in a higher percentage than after chemo-
therapy only.35,36 Obviously, chemotherapy has side effects as well.
The acute toxicities observed after chemotherapy include severe
myelosuppression with infections in neutropenia, mucositis, and
acute cardiotoxicity. The late toxicities of chemotherapy include
late cardiotoxicity, including cardiac failure and dysrhythmia,
neurocognitive dysfunction, and secondary malignancies.
The effect on QOL of intensive consolidation therapy and SCT
was determined in patients older than 18 years, 1 year after
treatment in the MRC AML10 trial. Patients who received SCT had
significantly more side effects than patients who received chemo-
therapy. The side effects after allo-SCT were also worse than after
auto-SCT, both of which were worse than after chemotherapy.35
Similar outcomes were reported by Zittoun et al36 They studied
98 patients from 15 to 60 years old after inclusion of the
EORTC-GIMEMA AML8A trial and found that QOL, physical
condition, and sexual functioning were significantly worse after
allo-SCT than after auto-SCT or chemotherapy. Leahey et al37
compared the late effects in 26 survivors of AML and MDS
younger than 18 years treated with chemotherapy with or without
cranial irradiation and 26 patients treated with chemotherapy
followed by either auto-SCT, MSD-SCT, or MRD-SCT. Chemo-
therapy and SCT had similar adverse effects on growth, renal, and
cardiac function. Significantly more patients after SCT needed
estrogen supplementation for ovarian failure than did patients who
received chemotherapy. Leung et al38 evaluated the late conse-
quences of treatment in 77 patients who survived pediatric AML for
more than 10 years. Patients treated with chemotherapy plus total
body irradiation as part of allo-SCT had significantly more side
effects than patients who received chemotherapy only. Parsons et
al39 did a quality-adjusted survival analysis on pediatric trial
POG8821, using the quality-adjusted time without symptoms or
toxicity (q-TWiST) method. Patients who received allo-SCT spent
significantly more time in TOX (the period of treatment-related
symptomatic toxicities with grade ⱖ 3), more time in TWiST, the
period representing the best possible quality of life, during which
patients experience no toxicities of treatment or symptoms of
disease, had more relapse-free time (P ⫽ .03) and time alive
BLOOD, 30 SEPTEMBER 2010 䡠 VOLUME 116, NUMBER 13
(P ⫽ .07) than chemotherapy-only patients according to the
intention-to-treat principle. The time after relapse was not signifi-
cantly different, 6.2 months for chemotherapy and 4.5 months for
allo-SCT. Finally, Goemans et al40 reported that significantly more
children with relapsed AML had late effects if treated with
allo-SCT than if treated with chemotherapy only.
Cost-effectiveness of SCT
In the review by Redaelli et al41 it appeared that transplantation is
the most expensive procedure in the treatment of AML and is
mainly because of the costs of hospitalization. The costs of
auto-SCT are 30% to 50% less than the costs of allo-SCT when the
costs of relapse are excluded. With the costs of relapse included,
allo-SCT is significantly less expensive than auto-SCT because of
more relapse after auto-SCT. Three studies have evaluated cost-
effectiveness of chemotherapy compared with allo-SCT.42-44 In
general, those studies have found that SCT was cost-effective
because, despite the higher overall costs of SCT, allo-SCT resulted
in longer quality-adjusted survival.41 However, such comparisons
may change in case of more effective chemotherapy as used now, at
least in pediatric AML.
Uyl-de Groot et al45 performed an analysis of the costs of
patients with AML younger than 65 years in 2 different hospitals in
the Netherlands, applying either the Hemato-Oncologie voor
Volwassenen Nederland 29 protocol (n ⫽ 37) or the EORTC
AML10 protocol (n ⫽ 47). The costs of allo-SCT are the highest in
both studies, followed by auto-SCT. Allo-SCT and auto-SCT with
the use of marrow-derived SCs appear to be a lot more expensive
than for peripheral blood SCT (PBSCT). Therefore, a reduction in
costs could be realized when PBSCT would replace marrow
transplantation.45 However, most studies in adults that compared
PBSCs and SCs from bone marrow as source show increased
chronic GVHD after PBSCT. In children, mortality rates were
higher after using PBSCs from a MSD for transplantation. How-
ever, when using unrelated donors in children, no difference
between PBSCs and SCs from bone marrow was observed.46
Hematopoietic SCs from an unrelated cord blood (UCB)
transplant are possibly a good option for children that lack a MSD.
With an UCB transplant, grafts are readily available, thereby
limiting time pressure on transplantation timing as dictated by
donor availability, especially in the unrelated setting. However, the
antileukemic efficacy of UCB in comparison to other SC sources is
currently not completely clear.2
Discussion
The question addressed in this review is whether allo-SCT is a
better treatment for children with newly diagnosed AML than
chemotherapy alone. A similar analysis was done in 2002. At that
time, allo-SCT in CR1 was recommended in Europe for most
patients excluding LR patients. However, there was already a trend
to reduce the use of SCT in CR1.47
In general, allo-SCT results in a significantly lower relapse risk
than chemotherapy alone as consolidation therapy for AML.4,9,16,21,22
In the 7 studies that showed a significant advantage of allo-SCT, the
median NNT to prevent one relapse was 10 patients (range,
6-14 patients). Therefore, when all studies would be included, this
number will most probably be higher. However, fewer relapses are
often counterbalanced by a higher TRM and more toxicity caused
by allo-SCT. Moreover, the salvage rate from relapse after allo-
SCT in CR1 is often lower than if children had chemotherapy only.
 From www.bloodjournal.org by guest on March 24, 2019. For personal use only.
BLOOD, 30 SEPTEMBER 2010 䡠 VOLUME 116, NUMBER 13
Thus, overall survival with allo-SCT is comparable with intensive
chemotherapy in most recent studies. An exception is seen in the studies
reported by Perel et al21 and Entz-Werle et al,20 who report improved OS
with allo-SCT, with larger differences in favor of allo-SCT between OS
and DFS/EFS, suggesting increased salvage rate for relapse after
allo-SCT in CR1. However, a confounder in both studies was the
maintenance chemotherapy given only to patients who did not receive a
transplant in CR1. This maintenance chemotherapy results in inferior
outcome,21,48 and thus has a negative effect on long-term outcome of the
chemotherapy only group.
Despite lack of convincing evidence in favor of allo-SCT in
newly diagnosed pediatric AML, it cannot be excluded that
subgroups benefit. There is consensus that the LR group has an OS
with chemotherapy only, which is so good that allo-SCT is not
applied in these patients. In SR patients, however, a benefit of
allo-SCT was found in some studies, and the meta-analysis on
CCG, POG, and MRC AML 10 studies by Horan et al9 reported a
significant benefit in DFS and OS for SR patients treated with
allo-SCT. Tsukimoto et al31 found this benefit only for DFS but not
for OS in the Japanese study, whereas in the United Kingdom
Medical Research Council AML trials no benefit was found at all. It
remains an open question whether SR patients benefit from
allo-SCT in this time of effective chemotherapy, and this requires
further clinical research, especially to determine which patients, if
any, within this group will actually benefit from allo-SCT.
The studies that reported subgroup analyses did not show a
benefit of allo-SCT for HR patients.4,9,14 Only study CCG-296117
suggested a benefit, but patient numbers were small, and no
P values were provided. Thus, allo-SCT cannot be considered
standard of care in HR patients, and, if done, it should be performed
in the setting of a clinical study.
Another key question in general is the timing of allo-SCT in the
context of the chemotherapy protocol. Allo-SCT given after only
1 or 2 courses of chemotherapy might have inferior results because
of relatively high minimal residual disease levels in such a
situation. However, allo-SCT given after 5 courses of intensive
chemotherapy may not add much antileukemic activity any more.
This issue was beyond the limits of the present review.
Despite limited information about the cost-effectiveness of allo-SCT
compared with chemotherapy, it is clear that allo-SCT is more expensive
than chemotherapy. Most studies that reported about the cost-
effectiveness (done in adults) conclude that allo-SCT is more cost-
effective than chemotherapy.41-44 However, the survival rates with
chemotherapy only are increasing, so a more recent analysis on this
important subject is warranted, including pediatric studies.
Because chemotherapy has become significantly more intensive
and effective in the past decades, the actual survival benefit of
allo-SCT has become less and statistically nonsignificant for the
total group of patients. Comparison of outcome for patients treated
with chemotherapy alone and patients who also underwent allo-
SCT is difficult for several reasons. (1) There is considerable
heterogeneity of the type and intensity of pretransplantation
chemotherapy and also for the chemotherapy for patients who did
not receive a transplant. The amount and type of preceding
chemotherapy may have an effect on the efficacy of allo-SCT.
(2) Only patients in remission normally undergo SCT (refractory
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Authorship
Contribution: D.N. wrote the paper; and U.C., M.B.B., and
G.J.L.K. discussed the format and content of the article and
contributed to the writing, review, and editing of the final manuscript.
Conflict-of-interest disclosure: The authors declare no compet-
ing financial interests.
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 From www.bloodjournal.org by guest on March 24, 2019. For personal use only.

2010 116: 2205-2214

doi:10.1182/blood-2010-01-261800 originally published
online June 10, 2010

A review on allogeneic stem cell transplantation for newly diagnosed

pediatric acute myeloid leukemia
Denise Niewerth, Ursula Creutzig, Marc B. Bierings and Gertjan J. L. Kaspers

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