Pediatrics International (2016) 58, 7180

doi: 10.1111/ped.12865

Review Article

Acute myeloid leukemia in children: Current status and future directions

Takashi Taga,1 Daisuke Tomizawa,2 Hiroyuki Takahashi3 and Souichi Adachi4
1
Department of Pediatrics, Shiga University of Medical Science, Otsu, 2Division of Leukemia and Lymphoma, Childrens Cancer
Center, National Center for Child Health and Development, Tokyo, 3Department of Pediatrics, Toho University, Tokyo and
4
Human Health Sciences, Kyoto University, Kyoto, Japan
Abstract

Acute myeloid leukemia (AML) accounts for 25% of pediatric leukemia and affects approximately 180 patients annually in
Japan. The treatment outcome for pediatric AML has improved through advances in chemotherapy, hematopoietic stem cell
transplantation (HSCT), supportive care, and optimal risk stratication. Currently, clinical pediatric AML studies are conducted separately according to the AML subtypes: de novo AML, acute promyelocytic leukemia (APL), and myeloid
leukemia with Down syndrome (ML-DS). Children with de novo AML are treated mainly with anthracyclines and
cytarabine, in some cases with HSCT, and the overall survival (OS) rate now approaches 70%. Children with APL are treated
with an all-trans retinoic acid (ATRA)-combined regimen with an 8090% OS. Children with ML-DS are treated with a less
intensive regimen compared with non-DS patients, and the OS is approximately 80%. HSCT in rst remission is restricted to
children with high-risk de novo AML only. To further improve outcomes, it will be necessary to combine more accurate risk
stratication strategies using molecular genetic analysis with assessment of minimum residual disease, and the introduction
of new drugs in international collaborative clinical trials.

Key words acute myeloid leukemia, acute promyelocytic leukemia, clinical trial, Down syndrome.
Acute myeloid leukemia (AML) accounts for approximately 25%
of pediatric leukemia, and affects approximately 180 patients annually in Japan.1 The prognosis for pediatric AML has improved, and
with recent advances in chemotherapy, hematopoietic stem cell
transplantation (HSCT), and supportive care, the long-term survival rate now approaches 70%. Considering that overall survival
(OS) rates for pediatric cancer patients are now approaching
80%, however, there is considerable room for further improvement.
Currently, for patients with newly diagnosed AML, clinical studies
are conducted separately according to the thre5e disease subtypes:
de novo AML; acute promyelocytic leukemia (APL); and myeloid
leukemia with Down syndrome (ML-DS).
In this review, the current status of pediatric AML (de novo
AML, APL and ML-DS) in Japan, including the history of clinical
trials and comparisons with other developed countries, are presented. Future directions for the diagnosis and treatment of pediatric AML are also discussed.

De novo AML
History of Japanese clinical trials for pediatric AML
ANLL91 study

This trial was the rst multicenter prospective study for pediatric de
novo AML in Japan, supported by a grant from the Ministry of
Correspondence: Takashi Taga, MD, PhD, Department of Pediatrics,
Shiga University of Medical Science, Seta-tsukinowa, Otsu, Shiga
520-2192, Japan. Email: ttaga@belle.shiga-med.ac.jp
Received 23 August 2015; revised 5 October 2015; accepted 22
October 2015.
2015 Japan Pediatric Society

Health and Welfare.2 All patients received etoposide 150 mg/m2

for 5 days followed by cytarabine 200 mg/m2 (12 h infusion) for
7 days and mitoxantrone 5 mg/m2 for 5 days (ECM induction
therapy). The patients with an HLA-matched family donor received
allogeneic HSCT in rst complete remission (CR). The other
patients received eight additional courses of intensication therapy
including continuous or high-dose cytarabine (HDCA) or autologous HSCT. In total, 157 patients were enrolled, and CR, 7 year
event-free survival (EFS), and OS rates were 91%, 55%, and
62%, respectively. In the successor study conducted by the Tokyo
Childrens Cancer Study Group (TCCSG M96-14), similar EFS
(51% in 5 years) and OS rates (58% in 5 years) were observed,
despite the reduction of total chemotherapy courses to seven
courses compared with nine courses in the ANLL91 study.2
AML99 study

The AML99 study was conducted based on the ANLL91 study by

the Japanese Childhood AML Cooperative Study Group (consisting
of the TCCSG, Japan Association of Childhood Leukemia Study
[JACLS], and Kyushu Yamaguchi Childrens Cancer Study
Group [KYCCSG]).3 This study consisted of a risk-oriented
regimen by treatment response to induction therapy, and chromosomal abnormalities of leukemic cells. The regimen consisted of
six chemotherapy courses including continuous or HDCA. The
patients with intermediate-risk (IR) and an HLA-matched family
donor, and all the high-risk (HR) patients received allogeneic
HSCT in rst CR. From 1999 to 2003, 240 patients were enrolled
in total. CR, 5 year EFS and OS rates were 94%, 61%, and 75%,
respectively, which was one of the best reported outcomes among
developed countries.3

72 T Taga et al.
CCLSG AML9805 study

In parallel to the AML99 study, the Japanese Childhood Cancer and

Leukemia Study Group (CCLSG) performed another prospective
childhood AML study, termed AML9805, from 1998 to 2003.4
The aim of this study was to improve the outcome of children with
AML by morphological response-based risk stratied therapy. Remission induction therapy consisted of two courses of pirarubicin,
vincristine, and continuous-dose cytarabine (AVC1). The patients
who achieved CR were treated with either of the two consolidation
therapies according to the French-American- British (FAB) classication system. The patients who did not respond to the initial
courses of AVC1 underwent salvage therapy. Of the 101 patients
registered, 74 achieved CR with the rst AVC1 course. The EFS
and OS rates at 5 years were 53.4% and 74.2%, respectively.4
Japanese Pediatric Leukemia/Lymphoma Study Group AML-05
study

Following the excellent outcomes of the AML99 study, a nationwide

multicenter study (termed the AML-05 study, UMIN000000511)
was conducted by a new national collaboration established in
2003, the Japanese Pediatric Leukemia/Lymphoma Study Group
(JPLSG), to further optimize risk-stratied therapies for childhood
AML; in which the four existing pediatric leukemia study groups
(TCCSG, JACLS, KYCCSG, and CCLSG) were merged.5
In the JPLSG AML-05 study, patients were stratied into three
risk groups according to specic cytogenetic characteristics and
morphological treatment responses after two courses of common
induction therapy. Low-risk (LR) children were dened as those
with t(8;21) or inv16 (core binding factor, CBF), and a good bone
marrow response to the rst induction course. HR children were
those with abnormalities of monosomy 7, 5q-, t(16;21)(p11;q22),
t(9;22), fms-related tyrosine kinase 3 internal tandem duplication
(FLT3-ITD), and/or poor response to the rst induction course.
IR children were those who were neither LR nor HR. Only patients
designated HR were candidates for HSCT in rst CR in AML-05.
Patients in CR after two courses of induction therapy received a further three courses of consolidation chemotherapy, which were intensied using HDCA, whereas four courses of consolidation
therapy were given in AML99. In particular, the cumulative doses
of anthracyclines and etoposide were reduced, aiming to decrease
the risk of late complications, such as anthracycline-induced
cardiotoxicity for the LR group.
Between November 2006 and December 2010, 443 eligible patients were registered in the AML-05 study. The 3 year EFS and OS
rates were 54.2% and 73.1%, respectively, which was similar to the
outcomes of the AML99 study. The key ndings of the AML-05
study were as follows: (i) the EFS for CBF leukemia was worse
than in the AML99 study due to excessive treatment reduction, especially with anthracyclines;5 (ii) the outcome for non-CBF AML
was similar to that in the AML99 study, even with the reduction
of treatment courses and restriction of HSCT indication at rst remission; (iii) serious pulmonary complications in infants frequently
occurred during induction therapy and dose reduction would be
needed for this group;6 (iv) the outcome for AML with
myelodysplastic syndrome (MDS)-related changes was poor;7 and
2015 Japan Pediatric Society

(v) the outcome for FLT3-ITD-positive AML could not be improved even with escalation to HR because of poor treatment response to induction therapy before HSCT.
Therapy according to risk stratification

It is important to provide appropriate risk stratication for AML patients in order to design optimal treatment strategies, including
HSCT, because treatment-related mortalities and late complications would be increased by uniform therapeutic intensication.
Like the JPLSG AML-05 study described in the previous section,
chemotherapy for AML consists of one or two courses of induction
therapy, followed by post-remission therapy including HSCT with
risk stratication based on chromosomal abnormalities of leukemic
cells, and response to initial induction therapy.
The outcomes of recent clinical trials, risk stratication and indication for HSCT, cumulative doses of anthracyclines and
cytarabine for de novo AML in children are summarized in
Tables 13, respectively.3,5,813
Induction therapy

The treatment of pediatric AML consists of multi-agent chemotherapy, especially with cytarabine and anthracyclines. In addition, a
third class of chemotherapeutics, such as etoposide, is often used,
although it is unclear if this provides additional benets. The regimen for induction therapy is based on a 3 plus 7 system,
consisting of continuous infusion of cytarabine 100200 mg/m2
for 7 days and daunorubicin (DNR) 4560 mg/m2 for 3 days, which
was established in the 1970s.14 The ADE regimen (cytarabine
200 mg/m2 [i.v., q12 h] for 10 days combined with DNR and
etoposide), became the standard for children with AML in the
UK and USA due to its effectiveness in the MRC AML10 study.15
In Japan, the ECM regimen has been used in the ANLL91,
AML99 and JPLSG AML-05 studies and is established as the standard for pediatric AML.2,3,5
Post-remission induction therapy (Intensification therapy)

Post-remission induction therapy, including allogeneic HSCT, is

stratied by risk group according to specic cytogenetic characteristics and response to induction therapy.
For patients with CBF leukemia, who are considered to have a
good prognosis, only chemotherapy is performed. For patients with
poor response to induction therapy, or with HR cytogenetics such
as monosomy 7, and 5q- among others, who are thought to have
poor prognosis, allogeneic HSCT in rst remission is indicated.
For non-CBF-AML patients without HR features, allogeneic
HSCT is still controversial, but there is a trend towards omitting
HSCT in line with recent improvements in chemotherapy and the
potential acute and late complications of HSCT. In addition to the
conventional cytogenetic abnormalities, recent progress in molecular genetics has identied various novel genetic abnormalities such
as mutations of CEBPA or NPM1, which are reported to be good
prognostic factors.16,17 The prognostic signicance of many of
the other newly identied mutations, however, is still controversial.
For example, cKIT mutation was reported to be a poor prognostic
indicator for relapse in Japanese studies (AML 99 and AML-05),18
but not in the Childrens Oncology Group (COG) or European

AML in children 73
Table 1 Outcome of recent clinical trials for pediatric de novo AML
Study

Period

Age (years)

HSCT (%)

3 year EFS (%)

3 year OS (%)

RR (%)

TRM (%)

AML993

20002002

240

018

Allo 17, Auto 2

20062010

443

018

12

30

SJCRH-AML028
NOPHO-AML 20049
MRC-AML1210

20022008
20042009
19952002

216
151
564

021
015
015

25
15
11

21
30
32

8
1
10

BFM 200411

20042010

521

018

NA

29

AIEOP AML2002/0112

20022011

482

018

Allo 29, Auto 21

24

10

COG AAML0531
(GO arm)13

20062010

1022

029

NA

75 (SR 86, 72, HR

57) (5 years)
73 (SR 93, IR 73,
HR 69)
71
69
63 (LR 83, IR 70,
HR 39)
74 (SR 89, HR 65)
(5 years)
67 (SR 83, HR 64)
(8 years)
69 (LR 85, IR 69,
HR 48)

32

AML-055

61 (SR 71, IR 60,

HR 57) (5 years)
54 (LR 69, IR 57,
HR 53)
63
57
54 (10 years)

32

55 (SR71, HR 46)
(5 years)
55 (SR 63, HR 53)
(8 years)
53 (LR 71, IR 51,
HR 31)

AML, acute myeloid leukemia; CR, complete remission; EFS, event-free survival; GO, gemtuzumab ozogamicin; HR, high-risk group; HSCT,
hematopoietic stem cell transplantation; IR, intermediate-risk group; LR, low-risk group; NA, not evaluated; OS, overall survival; SR, standard-risk
group; RR, relapse rate; TRM, treatment-related mortality.
Table 2 Risk stratication and indication for HSCT in recent clinical trials for de novo AML
Study
AML993

AML-055
SJCRH-AML028
NOPHO-AML 20049
MRC-AML1210
BFM 200411

AIEOP AML2002/0112
COG AAML0531
(GO arm)13

Low (standard) risk

t(8; 21) and WBC
<50 000/L, inv(16) and
CR after Ind-1 or,
age <2 years without HR
features
All t(8; 21), inv(16) and,
CR after Ind-1, and,
absence of FLT3-ITD
t(8; 21), inv(16), t(9; 11)
No HR features, t(8; 21)
and inv(16) with CR after
Ind-2
t(8; 21), inv(16) and CR
after Ind-1
FAB M1/M2 with Auer
rods,M4eo or t(8; 21) and
inv(16) and <5% BM
blasts on day 15 and
absence of FLT3-ITD
t(8; 21), inv(16) and, CR
after Ind-2
All t(8; 21), inv(16) and,
CR after Ind- 1 and absence
of FLT3-ITD-HAR

High risk

Indication HSCT in 1st CR

No LR or HR
features

Intermediate risk

7, 5q-, t(16;21)(p11;q22),
Ph1, or, non-CR after Ind-1

All HR and IR with MFD

No LR or HR
features

7, 5q-, t(16;21)(p11;q22),
Ph1, or FLT3-ITD or,
non-CR after Ind-1
7, FLT3-ITD, t(6; 9),
AMKL, t-AML, AML
from MDS
15% blasts after Ind-1or
non-CR after Ind-2, or MLL
rearrangement
>15% blasts after Ind-1
or 7, 5, 5q-, abn(3q),
complex ( abnormalities)
No SR features

All HR

No SR features

All HR

7, 5, 5q- or >15%
blasts after Ind-1 or
FLT3-ITD-HAR

HR with donor

No LR or HR
features

No LR or HR
features

IR: no LR
or HR features

SR and HR with MSD

HR with donor
IR and HR with MSD
HR with MSD

Patients with no MFD, eligible for auto-HSCT. AML, acute myeloid leukemia; CR, complete remission; GO, gemtuzumab ozogamicin;
HAR, high allelic ratio; HSCT, hematopoietic stem cell transplantation; HR, high risk; Ind, induction therapy; IR, intermediate risk; LR,
low risk; MDS, myelodysplastic syndrome; MFD, matched family donor; MSD, matched sibling donor; SR, standard risk.

studies.19 Thus, the prognostic impact of novel genetic abnormalities

should be carefully evaluated before inclusion in risk stratication
systems.
Similar to induction therapy, intensication therapy for pediatric AML consists of multi-agent chemotherapy with cytarabine
and anthracyclines, usually consisting of four to six courses including induction therapy.

Since the 1990s, the use of HDCA in intensication courses has

been a standard for AML treatment. It is proven that HDCA has
contributed to an improved survival rate for CBF leukemia, especially in children and young adults.2022 HDCA was used in three
of ve post-remission courses in the IR group and in four of ve
courses in the LR group for intensication therapy in the AML99
study. Intensive use of HDCA in the AML99 study seems to have
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74 T Taga et al.
Table 3 Cumulative dose of anthracyclines and cytarabine in recent clinical trials for pediatric de novo AML
Study

Anthracyclines
Type

AML99 LR3
AML99 IR/HR3
AML05 LR5
AML05 IR/HR5
SJCRH AML028
NOPHO-AML 20049
MRC AML1210
BFM 2004 SR11
BFM 2004 HR11
AIEOP AML2002/0112
COG AAML0531 (GO arm)13

MIT, IDA
MIT, IDA
DNR, MIT
MIT, IDA
DNR, MIT
IDA, L-DNR, MIT
IDA,MIT
DNR, MIT

Cytarabine

Cumulative dose (mg/m2)

Cumulative dose (g/m2)

295300
370375
225
375
450550
480
300610
350410
450510
460
540

78.480.0
59.461.0
77.4
77.4
41.566.8
49.3
10.634.6
41
47
41.659.6
45.6

Calculated relative to the amount of daunorubicin using a conversion rate of 5:1 for daunorubicin to mitoxantrone/idarubicin.
AML, acute myeloid leukemia; DNR, daunorubicin; GO, gemtuzumab ozogamicin; IDA, idarubicin; L-DNR, liposomal daunorubicin; MIT, mitoxantrone.

contributed to the superior outcome, although the indication of

HSCT at rst remission was relatively low.3
Indication for HSCT

Since the 1980s, HSCT from an HLA-matched related family donor has been widely performed for pediatric AML at rst remission, but there are no randomized clinical studies comparing
chemotherapy and allogeneic HSCT. To date, the only studies
available have compared chemotherapy and allogeneic HSCT by
familial donor availability and a mendelian/genetic randomization
with intent-to treat analysis.
A few reports showed superior outcomes for HSCT from an
HLA-matched family donor over chemotherapy, but most of
the recently conducted studies in the USA and Europe found
no advantage of HSCT.2327 Thus, considering recent improvements in chemotherapy, and the potential risk of acute and late
toxicities of HSCT, there is a trend towards restricting HSCT at
rst remission to HR patients only. Currently, a clinical study
evaluating the role of reduced-intensity conditioning in HSCT
for de novo AML (FLAMEL-15) is planned by the JPLSG
SCT committee.
Relapsed AML

The outcomes for children with newly diagnosed AML are improving, but once they relapse, their prognosis remains poor, with
reported OS rates of 2436%.2834 In Japan, 71 patients who relapsed following rst-line treatment under the AML99 protocol
were analyzed retrospectively.35 Sixty-six patients received
reinduction chemotherapy and 33 (50%) achieved CR. Twentynine CR2 patients and 35 non-CR2 patients underwent allogeneic
HSCT. The 5 year OS rate after relapse was 37%. The 5 year OS
rate was signicantly higher in patients who underwent HSCT in
CR2 compared with those in non-CR2. On multivariate analysis
early relapse and FLT3-ITD positivity were adverse prognostic factors for survival.35 Given that outcome for relapsed AML patients
treated with conventional chemotherapy with or without allogeneic
HSCT is poor, the introduction of novel and more effective chemotherapeutics is urgently required.
2015 Japan Pediatric Society

Future for pediatric de novo AML

As mentioned here, EFS and OS rates for childhood AML are

approaching 60% and 70%, respectively. This has been achieved
with intensied multi-drug chemotherapy with cytarabine and
anthracyclines, optimal indication for HSCT by risk stratication,
and advances in supportive care. For further improvement, the
development of a more denitive risk stratication system, the
intensication of current AML chemotherapy, and the introduction
of new treatment options, including molecular targeted drugs are
necessary.
New genetic abnormalities have been discovered as a result of
recent progress in molecular genetics. Presently, the prognostic impact of these newly found abnormalities is controversial. Once their
signicance is more clearly established, however, it is likely that
they will have a major inuence on future risk stratication of
pediatric AML.
Recently, much attention has been focused on minimal residual
disease (MRD) as a prognostic factor for children with AML. The
detection of MRD involves searching for chimeric transcripts, or
specic gene abnormalities on polymerase chain reaction (PCR)
and/or specic surface antigens on ow cytometry of residual leukemic cells at morphological remission. For AML patients the assessment of MRD on PCR is problematic because only 4570%
of the MRD of candidate patients can be detected and the residual
chimeric transcripts, such as RUNX1-RUNX1T1 and CBFBMYH11, do not always correlate with risk of relapse. In contrast, recent studies from St Jude Childrens Research Hospital (St Jude),
the UK, and COG showed the prognostic impact of ow-based
MRD detection,3638 and it is already used for risk stratication
in the current St Jude and COG studies. But, given that the prognostic impact of MRD clearly correlates with prior treatment, the
role of ow cytometry-based MRD detection is under evaluation
in the current ongoing JPLSG AML-12 study, which commenced
in 2014.
Intensication of current AML chemotherapy, especially increased use of cytarabine and anthracyclines, would be another
key strategy to improve the outcome of pediatric AML. Intensication of anthracyclines in the induction phase clearly improved outcome in adult studies.39,40 Anthracycline intensication, however,

AML in children 75
may lead to an increase in late cardiotoxicity, which would not be
acceptable for children with AML because they have a higher
susceptibility to anthracyclines, and may experience signicant
life-long sequelae.
Intensication of cytarabine, especially the use of HDCA, is
another consideration. As mentioned here, the use of HDCA during
intensication has contributed to improved outcome, especially in
CBF leukemia, but the effectiveness of its use in the induction
phase is still controversial.4146 Currently, the JPLSG AML-12
study (UMIN000013288), a randomized controlled study of
ECM versus HDCA-based induction therapy, is underway in
Japan.
Finally, the general consensus in the eld is that only limited
improvement in outcome will be achieved with intensication of
conventional chemotherapy with or without HSCT, highlighting
the necessity for the introduction of new drugs based on AML
biology. Several candidate drugs are currently in development for
adult and pediatric AML: including clofarabine, a new purine nucleoside analog;47 FLT3 inhibitors;48 KIT inhibitors;49 Polo-like
kinase inhibitors;50 proteasome inhibitors;51 epigenetic modiers,
such as demethylating agents and histone deacetylase inhibitors;52
and novel immunotherapies targeting AML antigens such as bispecic T-cell engager (BiTE) antibodies for CD33 and chimeric
antigen receptor (CAR), and T-cell therapy targeting CD33,
CD123, and others.53,54 The development of novel drugs to treat
childhood malignancy, however, remains a major challenge in
Japan because under the Japanese universal health-care system,
use of off-label drugs is prohibited; thus, it is crucial to develop
promising agents with the aim of obtaining approval for marketing
authorization. Unfortunately, company-initiated trials are rarely undertaken due to the small number of children with cancer, and lack
of incentives encouraging pharmaceutical companies to develop
drugs for childhood malignancy. Meanwhile, investigator-initiated
drug development, as well as fund raising for pediatric trials, are urgently required.

Acute promyelocytic leukemia

Overview

Acute promyelocytic leukemia is a subtype of AML, characterized

by a differentiation disorder at the promyelocyte stage. It is classied as M3 or M3v in the FAB system and APL with t(15;17)
(q22;q12); and PML-RARA according to the World Health Organization 2008 classication.5558 APL in children accounts for
1015% of AML cases, and it is estimated that approximately 10
patients per year develop pediatric APL in Japan. The clinical features and biology of childhood APL are considered to be the same
as those in adults. APL blasts have a translocation of chromosome
15 and 17, and the product of this translocation, the PML-RARA
fusion protein, inhibits transcription by competitively inhibiting
the binding of the normal RARA transcriptional activator protein
to DNA, resulting in defective myeloid differentiation. It is known
that patients with APL often have complex presentations, with disseminated intravascular coagulation (DIC), which is often fatal at
the onset or during initial induction therapy of APL.

In 1988, the effectiveness of ATRA for the treatment of APL

was reported from China, and the effect was subsequently demonstrated to be the result of induced differentiation of APL cells.
Introduction of ATRA enabled patients with APL to achieve CR
without developing organ bleeding due to DIC. The duration of
remission on ATRA alone, however, was short, and recently combination chemotherapy with ATRA and other anti-leukemic agents
has been used nationwide in developed countries.
The treatment strategy for childhood APL is similar to adults.
Approximately 95% of children with APL achieved CR and the
EFS and OS rates were 8090% and approximately 90%, respectively. HSCT for children and adults is not indicated for patients
at rst remission, but especially autologous HSCT is indicated for
patients after recurrence. Treatment using new agents such as arsenic trioxide (ATO) and/or gemtuzumab ozogamicin (GO) have
been used for patients with ATRA resistance.
Treatment strategies based on ATRA induction therapy and anticancer drugs, intensication therapy mainly by anthracyclines,
maintenance therapy with ATRA alone, or ATRA with other
anticancer drugs have been established in several developed countries.59,60 Recent clinical trials for children with APL are summarized in Table 4.6165 The International consortium for childhood
APL (ICC-APL) was organized by the International BFM group;
and the ICC-APL01 study, as an arm in the AIEOP study
including MRD intervention, is ongoing. PETHEMA (Spain) is
carrying out the ongoing LPA2005 study with adults,66 and COG
has been performing the AAML1331 study, following the original
AAML0631 study.
History of Japanese clinical trials for pediatric APL
AML99-M3 study

A multi-institutional prospective study, AML99-M3, undertaken

by the Japanese AML cooperative study group, enrolled 58 patients
from 1999 to 2004.61 The treatment regimen included ATRA and
anthracyclines combined with cytarabine in both the induction
and consolidation phases, and intermittent ATRA alone for 1 year
for maintenance. Although two patients died of hemorrhage by
DIC in induction, the remainder (n = 56) achieved CR. Two patients who achieved CR relapsed in the bone marrow after 15 and
19 months, respectively. The 7 year EFS and OS rates were
91.4% and 93.1%, respectively, similar to recent clinical trials in
the USA and Europe.
JPLSG AML-P05 study

The result of the AML99-M3 study was excellent, but severe hemorrhage due to DIC during the induction phase, and prolonged neutropenia with a relatively high incidence of sepsis because of more
intensive consolidation chemotherapy compared with other studies,
were problematic issues. On the basis of these results, a nationwide
prospective study in Japan for childhood APL by JPLSG was performed from 2006 (UMIN000000645). All patients received at
least 3 day ATRA monotherapy, followed by cytarabine and daunorubicin as the rst induction therapy. The second induction therapy and the subsequent three courses of consolidation therapy
consisted of ATRA, either high- or intermediate-dose cytarabine,
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76 T Taga et al.
Table 4 Outcome of recent clinical trials for pediatric APL
Group
Japan
European
AIEOP
PETHEMA
BFM
COG

Study
61

AML99-M3
AML-P05
APL9362
AIDA049363
LPA96/9964
AML93/98/200465
C9710

Period

Cumulative dose of
anthracyclines (mg/m2)

CR rate (%)

19972004
20062011
199398
19932000
19962004
19932007
19992005

58
43
31
107
66
81
56

352
280
495
650
650-750
300-410
400

96.6
85.7
97
96
92
95
91

5 year EFS (%)

5 year OS (%)

TRM (%)

91.4 (7 years)
83.6 (3 years)
71
76
77
65 (10 years)
53 (3 years)

93.1 (7 years)
90.7 (3 years)
90
89
87
82 (10 years)
87 (3 years)

3
2
3
4
8
7
5

Calculated relative to the amount of daunorubicin: conversion rate of 5:1 for daunorubicin to mitoxantrone/idarubicin, 0.5:1 for daunorubicin to
pirarubicin, 0.4:1 for daunorubicin to aclarubicin. APL, acute promyelocytic leukemia; CR, complete remission; EFS, event-free survival; OS,
overall survival; TRM, treatment-related mortality.

triple intrathecal injection, and a single dose of anthracyclines.

Finally, patients received maintenance therapy with ATRA for
15 days every 3 months for 1 year. Between April 2006 and March
2011, 46 children with newly diagnosed APL were enrolled in the
study. Of the 46 patients, three were excluded because of PML/
RARA negativity, and the remaining 43 patients, including two with
molecular variants, were evaluated. The median age at diagnosis
was 9 years (range, 11 months15 years). The median follow-up
period was 4.47 years (range, 07.45 years). FLT3-ITD was positive
in six out of 40 patients examined. Two patients died during induction therapy: one of coagulopathy in the rst course, and the other
of infection in the second course. Two patients developed differentiation syndrome that resolved with temporary cessation of ATRA
and supportive therapies. Three patients did not achieve CR after
two courses of induction therapy, and the overall CR rate was
85.7%. Neither cardiac adverse events nor treatment-related death
were observed during consolidation and maintenance therapies.
Three patients relapsed during or after maintenance therapy, and
another developed secondary acute myeloid leukemia. Consequently, the 3 year EFS and OS rates were 83.6% and 90.7%,
respectively. Age <5 years at diagnosis, and non-M1 marrow after
rst induction therapy were associated with lower EFS. High white
blood cell (WBC) count (>10 000/L), low platelet count
(<40 000/L), FLT3-ITD positivity, and additional chromosomal
abnormalities did not inuence the risk. According to the JPLSG
criteria for anthracycline equivalents, the cumulative anthracycline
dose in this study was converted to 280 mg/m2 of doxorubicin. The
dose was much lower than that in recent US or European protocols,
especially in those designed primarily for adult APL patients for
whom >600 mg/m2 of anthracyclines was used. Compared with
these studies, we achieved equivalent good results with minimum
doses of anthracyclines. Therefore, single treatment with anthracyclines in each consolidation phase appears sufcient for the
treatment of childhood APL.

of the PML-RARA fusion gene is one of the most effective tools for
measuring remission status and prediction of relapse.6871 As a result of recent progress described here and previous Japanese trials,
a new prospective trial, named the JPLSG AML-P13 study
(UMIN000015348), is currently being carried out. In this study, induction therapy is the same as in the previous AML-P05 study, but
all three courses of intensication consist of ATO only. The patients who could not achieve CR will be treated with ATO and/or
GO. Moreover, MRD is measured routinely, and for the patients
with positive MRD after intensication, reinduction therapy including GO will be initiated.

Future for pediatric APL

AML99 Down study

Recently, it was reported that ATRA with ATO was superior to

ATRA with anthracyclines for newly diagnosed APL in adults.67
The efcacy and safety of these strategies, however, are not clearly
understood in children. Ultimately, if the dose of anthracyclines
could be reduced by ATO, it will be useful for childhood APL
because of the potential for less cardiotoxicity. Moreover, detection

A multi-institutional prospective study, designated the AML99

Down study, enrolled 72 patients from 2000 to 2004 and was conducted by the Japanese AML Cooperative Study Group. The study
evaluated a slightly modied regimen from a previous trial using
pirarubicin instead of daunorubicin, and a reduced total number
of treatment courses from six to ve.74 The 3 year EFS and OS rates

2015 Japan Pediatric Society

Myeloid leukemia with Down syndrome

Overview

Although exact numbers are not available, it is estimated that 2030

patients per year develop ML-DS in Japan. ML-DS has unique
characteristics: a predominance of acute megakaryoblastic leukemia; tendency to occur during the rst 4 years of life; and higher
sensitivity to chemotherapeutic agents. The latter translates into
a good treatment response, with the drawback of increased
treatment-related toxicities compared with non-DS children with
AML. As a result, in recent clinical studies in several countries,
ML-DS children were treated separately and less intensively than
non-DS AML children.
Recent clinical trials for ML-DS are summarized in Table 5.6876
In Europe, the ML-DS 2006 study by the International BFM
group, which is based on the BFM98 protocol for de novo
AML, is ongoing. This protocol consists of four courses with an
HDCA-containing regimen. The US AAML0431 study, conducted from 2007 to 2011 by the COG, which also included an
HDCA regimen, showed excellent outcomes (n = 204; 3 year
EFS and OS rates were 90%, and 92.7%, respectively).73
History of Japanese clinical trials for ML-DS

AML in children 77
Table 5 Outcome of recent clinical trials for myeloid leukemia with Down syndrome
Study

Period

Daunorubicin
(Pirarubicin)
2

BFM98 for DS72

NOPHO AML9373
MRC AML10/1274
CCG 2861/289175
COG A297176
LD-cytarabine77
AML99 DS78
JCCLSG 9805DS79
JPLSGAML D0580

19982003
19882002
19882002
19891999
19992003
19902003
20002004
19982006
20082010

67
41
46
160
132
34
72
24
72

Cytarabine

Etoposide

TRM

EFS

OS

(mg/m )

(mg/m )

(mg/m )

(%)

(%)

(%)

220240
300
670
320
320
0
(250)
(190)
(250) (SR)
(170) (HR)

2329 000
48 600
10 600
15 800
27 200
7400
3500
12 600
3500 (SR)
12 800 (HR)

950
1600
0
1600
0
0
2250
200
1350 (SR)
1050 (HR)

5
5
15
4
3
0
1
12.5
(1)

89 (3 years)
85 (8 years)
74 (5 years)
77 (6 years)
79 (5 years)
67 (5 years)
83 (4 years)
83 (5 years)
83 (2 years)

91
NA
74
79
84
77
84
88
88

DS, Down syndrome; EFS, event-free survival; HR, high-risk group; OS, overall survival; SR, standard-risk group; TRM, treatment-related mortality.

were 83% and 84%, respectively, and treatment-related mortality

was only 1.4%. In this study, failure to achieve M1 marrow after
initial induction was a poor prognostic factor.
CCLSG AML9805 Down study

The CCLSG performed a prospective study using continuous or

high-dose cytarabine combined chemotherapy for patients with
ML-DS.79 Of the 24 patients enrolled from 1998 to 2006, 21
achieved CR, and three died during remission induction therapy
due to serious infection. All but one patient maintained CR without
serious complications. The 5 year EFS and OS rates were 83.1%
and 87.5%, respectively.
JPLSG AML-D05 study

As shown in these previous studies, the majority of ML-DS patients could be cured with relatively mild chemotherapy compared
with AML in non-DS children,7281 but patients are rarely salvageable once they relapse.82 On the basis of these results, a nationwide
prospective study in Japan for ML-DS was conducted by JPLSG
(UMIN000000989).80 Between January 2008 and December
2010, patients with ML-DS were enrolled. The patients received
one course of induction therapy with pirarubicin, intermediate-dose
cytarabine, and etoposide (CET), which was the same as the induction in the AML99 Down study, and they were then stratied into
two risk groups, standard risk (SR) or HR, according to the
morphological response. Patients with a good response (SR: M1
marrow achieved after initial CET) received less intensive chemotherapy, in which the total dose of etoposide was reduced compared
with the AML99 Down protocol (omitted at the 2nd and 4th
courses). For those with a poor response (HR: M1 marrow not
achieved after initial CET), a salvage regimen with more intensive
use of cytarabine was given either by 24 h continuous infusion or
high dose, which was used in the CCLSG AML 9805 Down study.
No intrathecal chemotherapy was given.
A total of 74 patients were registered, and 72 were eligible in
AML-D05. Overall, 69 (95.8%) of 72 patients achieved CR after
initial CET and were stratied to the SR group. Two patients
who did not achieve CR after induction therapy with CET were
stratied to the HR group, and both patients achieved CR by

salvage induction therapy. One SR patient died of sepsis after initial

CET. One patient was removed from the study, at the physicians
request, with pathological cells in the bone marrow (<5%) during
intensication therapy. No therapy-related deaths were observed
during intensication therapy. Ten patients relapsed in the bone
marrow. Nine were in the SR group (two during intensication
therapy); and one was in the HR group and relapsed during intensication. No extramedullary relapse, including central nervous
system, was observed. The 3 year EFS and OS rates were 83.3
4.4% and 87.5 3.9%, respectively. No patients with secondary
cancer or severe cardiotoxicity were observed, and therapy-related
mortality for this study was only 1.4%. Age at diagnosis <2 years
old was a signicant favorable prognostic factor on both univariate
and multivariate analysis. Other factors, including sex, high WBC
count (>20 000/L), FAB morphologies (non M7), chromosomal
abnormalities (sole trisomy 21 or monosomy 7), and no GATA1
mutation did not adversely affect the risk of relapse.
Future for ML-DS

The Japanese trials described here investigated less intensive chemotherapy for ML-DS compared with those conducted in Western
countries. Treatment outcomes were similar despite the dose reduction of chemotherapeutic agents compared with previous studies,
and the overall outcomes were good. Combined with the results
from the Toronto group with an ultra-low-dose cytarabine-based
regimen,77 further dose reduction might be possible for specic
subgroups. In contrast, most relapses occurred in the SR group dened by morphological treatment response, and relapsed patients
are rarely salvageable, even in those receiving stem cell transplantation.82 In terms of treatment outcome, ML-DS is a heterogeneous
disease, so risk-oriented therapy is a reasonable strategy. Unexpectedly, risk stratication by morphological treatment response in the
AML-D05 study did not work well, because there were few HR patients. To nd a more accurate method for the identication of the
subgroup with poor prognosis, we are currently analyzing the role
of MRD with various methods (ow cytometry, PCR, WT1 expression, and GATA1 mutation) in the ongoing JPLSG AML-D11
study (UMIN 000007237), which has a treatment protocol that is
the same as the AML-D05 study. Moreover, new therapeutic
2015 Japan Pediatric Society

78 T Taga et al.
approaches using new drugs such as Wee 1 inhibitor,83 Aurora
kinase inhibitor84 and histone deacetylase inhibitors85 will be
needed for relapsed/treatment-refractory patients.

Acknowledgments
The authors deeply appreciate the invaluable cooperation of the
members of the JPLSG AML committee and the large number of
physicians working at the institutions, central diagnostic laboratories, and the ofce and data center of JPLSG. The clinical studies
of JPLSG were supported by a Grant for Clinical Cancer Research
and Grant-in-Aid for Cancer Research from the Ministry of Health,
Labour and Welfare of Japan.

Disclosure
The authors declare no conict of interest.

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