ZH 804212003187

Review article
Diagnosis and management of acute myeloid leukemia in children and

adolescents: recommendations from an international expert panel
*Ursula Creutzig,1 *Marry M. van den Heuvel-Eibrink,2 Brenda Gibson,3 Michael N. Dworzak,4 Souichi Adachi,5
Eveline de Bont,6 Jochen Harbott,7 Henrik Hasle,8 Donna Johnston,9 Akitoshi Kinoshita,10 Thomas Lehrnbecher,11
Guy Leverger,12 Ester Mejstrikova,13 Soheil Meshinchi,14 Andrea Pession,15 Susana C. Raimondi,16 Lillian Sung,17
Jan Stary,18 Christian M. Zwaan,2 †Gertjan J. L. Kaspers,19 and †Dirk Reinhardt,1 on behalf of the AML Committee of the
International BFM Study Group
1Department of Pediatric Hematology/Oncology, Medical School Hannover, Hannover, Germany; 2Department of Pediatric Oncology/Hematology, Erasmus
MC-Sophia Children’s Hospital, Rotterdam, The Netherlands; 3Department of Haematology, Royal Hospital for Sick Children, Glasgow, United Kingdom; 4St
Anna Children’s Hospital and Children’s Cancer Research Institute, Department of Pediatrics, Medical University of Vienna, Vienna, Austria; 5Department of
Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan; 6Department of Pediatrics, Division of Pediatric Oncology/Hematology,
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University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; 7Oncogenetic Laboratory, Department of Pediatric Hematology and
Oncology, Justus-Liebig-University, Giessen, Germany; 8Department of Pediatrics, Aarhus University Hospital Skejby, Aarhus, Denmark; 9Division of
Hematology/Oncology, Children’s Hospital of Eastern Ontario, Ottawa, ON; 10Department of Pediatrics, St Marianna University School of Medicine, Kawasaki,
Japan; 11Pediatric Hematology and Oncology, University of Frankfurt, Frankfurt, Germany; 12Department of Haemato-Immuno-Oncology, Trousseau Hospital,
Assistance Publique–Hôpitaux de Paris, University Paris VII, France; 13Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and
Oncology, Charles University Prague, 2nd Medical School, Prague, Czech Republic; 14Division of Pediatric Hematology/Oncology, University of Washington
School of Medicine, Seattle, WA and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 15Pediatric Oncology and Hematology
Lalla Seràgnoli Unit, University of Bologna, Bologna, Italy; 16Department of Pathology, St Jude Children’s Research Hospital, Memphis, TN; 17Division of
Haematology/Oncology, Hospital for Sick Children, Toronto, ON; 18Department of Pediatric Hematology and Oncology, Charles University Prague, and Czech
Pediatric Hematology Working Group (CPH), Prague, Czech Republic; and 19Department of Pediatric Oncology/Hematology, VU University Medical Center,
Amsterdam, The Netherlands
Despite major improvements in outcome tional BFM Study Group AML Committee lar markers in pediatric AML is presented.
over the past decades, acute myeloid was to set standards for the manage- The general management of pediatric
leukemia (AML) remains a life-threatening ment, diagnosis, response assessment, AML, the management of specific pediat-
malignancy in children, with current sur- and treatment in childhood AML. This ric AML cohorts (such as infants) or sub-
vival rates of ⬃ 70%. State-of-the-art rec- paper aims to discuss differences be- types of the disease occurring in children
ommendations in adult AML have re- tween childhood and adult AML, and to (such as Down syndrome related AML),
cently been published in this journal by highlight recommendations that are spe- as well as new therapeutic approaches,
Döhner et al. The primary goal of an cific to children. The particular relevance and the role of supportive care are dis-
international expert panel of the Interna- of new diagnostic and prognostic molecu- cussed. (Blood. 2012;120(16):3187-3205)
Introduction
Childhood acute myeloid leukemia (AML) is a rare and heteroge- Despite broad overlap in the diagnostic and treatment recommen-
neous disease, with an incidence of 7 cases per million children dations for AML for children and adults, there are important differences
younger than 15 years. In high-income countries, intensive therapy in both the diagnostic criteria and disease management, which merit
in conjunction with effective supportive care has increased survival age-specific recommendations. The absence of published recommenda-
rates to ⬃ 70%. In 1990 and 2003, expert working groups made tions specific for pediatric AML motivated an international group of
recommendations for diagnosis, outcomes, standardization of re- pediatric hematologists and oncologists (panel and participating
sponse criteria, and reporting standards for AML.1,2 Recent improve- groups see “Appendix”) to develop evidence- and expert opinion-
ments in identifying the molecular genetics and pathogenesis of based consensus recommendations for the diagnosis and manage-
AML have been implemented in the new World Health Organiza- ment of AML in children, incorporating emerging information on
tion (WHO) classification of AML.3 These changes, and the the biology of the disease. The scope of the review is presented in
definition of new diagnostic and prognostic markers and their the “Appendix.” Recommendations for specific subgroups are also
associated targeted therapies, have prompted the update of earlier included. This article discusses diagnostic procedures and initial workup,
recommendations by an international group, on behalf of the prognostic factors, response criteria, and management, and in particular
European LeukemiaNet for AML in adults in 2010.4 focuses on differences between adults and children with AML.
Submitted March 7, 2012; accepted July 26, 2012. Prepublished online as Blood The online version of this article contains a data supplement.
First Edition paper, August 9, 2012; DOI 10.1182/blood-2012-03-362608.
*U.C. and M.M.v.d.H.-E. contributed equally to this study.
†G.J.L.K. and D.R. contributed equally to this study. © 2012 by The American Society of Hematology
BLOOD, 18 OCTOBER 2012 䡠 VOLUME 120, NUMBER 16 3187

3188 CREUTZIG et al BLOOD, 18 OCTOBER 2012 䡠 VOLUME 120, NUMBER 16
ence of ambiguous morphology and cytochemistry, immunopheno-

WHO classification and pediatric AML typing may further support the lineage definition. Acute
megakaryoblastic leukemia (AMKL, FAB M7) and minimally
The recent WHO 2008 classification is applicable to both adult and
differentiated AML (FAB M0) have to be confirmed by immunophe-
pediatric AML3,5 and has been summarized by Döhner et al.4 The
notyping, although the former may show typical morphologic
classification contains most, but not all, cytogenetic subgroups
features.7 The presence of myelofibrosis frequently associated with
specific to children. Differences in genetic background between
acute megakaryoblastic leukemia, and consequent sampling prob-
children and adults are given in Table 1 and discussed further in
“Cytogenetics.” lems may lead to an underestimation of blasts by both morphology
Compared with previous classifications (European Group of and immunophenotyping. In case of a low blast count (⬍ 20%),
Immunologic Characterization of Leukemias [EGIL], WHO 2001),6 repeated bone marrow sampling, including biopsy, needs to be done.
the new WHO classification introduced a stringently defined Differentiation between AML and MDS. Differentiating be-
subclass of acute leukemias of ambiguous lineage (mixed pheno- tween AML and advanced MDS may be difficult in children with a
type acute leukemias [MPALs]), mainly on the basis of detailed low percentage of blasts. In these patients, a trephine biopsy is
immunophenotypic criteria (Table 2) or presence of t(9;22)(q34; necessary. Differentiating between AML and MDS is important for

q11.2)/BCR-ABL1 or t(v;11q23)/MLL rearrangement.3,5,6 The new treatment allocation, as MDS can only be cured by hematopoietic
classification aims to create uniform subgroups defined by unifying stem cell transplantation (HSCT). In adults, a blast threshold of
molecular targets, which allow selection of specific treatment. 20% is used to differentiate between these diseases, but in children
blast percentages between 20% and 30% may be seen in MDS
(refractory anemia with excess of blasts in transformation).8
AML-specific genetics, hyperleukocytosis, extramedullary disease,
Diagnostic procedures and initial workup and progression within a short time frame (2-4 weeks) are
supportive of AML rather than MDS. Children with Down
The minimal diagnostic requirements in childhood AML are
syndrome (DS) should be diagnosed with AML in case of evidence
morphology with cytochemistry, immunophenotyping, karyotyp-
ing, FISH, and specific molecular genetics in the bone marrow, for leukemic blasts in the bone marrow, even if the blast threshold
which is comparable with common practice in adults. The initial of 20% is not reached. This is not considered MDS but myeloid
diagnostic tests may be done on peripheral blood if the patient’s leukemia of Down syndrome (ML-DS). The same exception is
condition contraindicates a bone marrow aspirate. valid for AML with low blast counts and recurrent genetic
However, investigation of CNS involvement at diagnosis is not abnormalities t(15;17), t(8;21), inv(16), or t(16;16).3
practiced routinely in adults but is considered necessary in children
because specific treatment is required in case of CNS involvement Recommendation
(see “CNS-directed therapy”). However, in patients with a bleeding
tendency, such as those with severe thrombocytopenia and/or To differentiate between AML with a low blast count and MDS,
coagulopathy and patients with acute promyelocytic leukemia serial bone marrow aspirates and trephine biopsies are required, as
(APL), lumbar puncture should be postponed until the risk of well as detailed cytogenetic analyses.
hemorrhage has passed. CNS positivity is generally defined
by ⬎ 5 ⫻ 106/L white blood cells (WBCs) in the cerebrospinal Immunophenotyping
fluid, with blasts present in a nonbloody tap.
Table 3 lists the recommended procedures and diagnostic tests Immunophenotyping is a rapid method to determine lineage and
in the initial workup of pediatric patients with AML. In the distinguish between AML and acute lymphoblastic leukemia
presence of high-risk conditions or premorbid conditions, addi- (ALL). It is required to classify the AML FAB subtypes M0
tional tests may be required. (negative MPO activity by cytochemistry, but positive by immuno-
phenotyping for myeloid markers, such as MPO [proenzyme]
Recommendations and/or CD13, CD33, CD117) and FAB M7 (positive for platelet
markers, such as CD41 and/or CD61). However, immunophenotyp-
At diagnosis, morphology, cytochemistry, immunophenotyping,
ing does not usually substitute for morphologic classification
and molecular and cytogenetics of the bone marrow aspirate are
according to FAB criteria and blast cell enumeration. According to
required. In the event of a dry tap or of a suspected underlying
the currently used WHO 2008 classification, only the markers
myelodysplastic syndrome (MDS), a bone marrow trephine biopsy
MPO, lysozyme, CD11c, CD14, CD64, i(intracellular)CD3, CD19,
has to be performed as well. All patients should have a cerebrospi-
iCD22, iCD79a, and CD10 are essential to assign lineage affilia-
nal fluid examination for evidence of CNS involvement.
tions and to define otherwise not specified MPAL. The latter
includes biphenotypic leukemia, bilineage leukemia with distinctly
Morphology
differentiated blast populations, and undifferentiated leukemia
The morphologic classification of AML is based on the lineage- without any lineage commitment.
associated phenotype (undifferentiated, myeloid, monoblastic, eryth- At present, there is no standardization of antibody panels used
roblastic, or megakaryoblastic) and defined according to the for immunophenotyping among the large trial groups. However,
French-American-British (FAB) classification.7 Morphologic stud- upcoming standards suggest the use of multicolor monoclonal
ies reveal the percentages of undifferentiated, granulated or atypi- antibody combinations that include CD45 to enable optimal gating
cal blasts, intracellular structures, such as Auer rods, and presence and analysis of the blast population within the complex context of
of myelodysplasia. Cytochemistry confirms lineage affiliation and residual hematopoiesis.9 In addition, these procedures might im-
classifies myeloid (myeloperoxidase [MPO]-positive) and mono- prove flow cytometry techniques for assessing minimal residual
blastic differentiation (nonspecific esterase-positive). In the pres- disease (MRD) in pediatric AML.10
BLOOD, 18 OCTOBER 2012 䡠 VOLUME 120, NUMBER 16 DIAGNOSIS AND MANAGEMENT OF AML IN CHILDREN 3189
Table 1. Comparison of biologic properties and genetic abnormalities in pediatric (children and adolescents < 18 years of age) and adult
(age < 60 years) AML
Adult AML Pediatric AML
Frequency/special Prognosis 5-y survival Frequency/special Prognosis 5-y survival
features (age 18-60 y) features/occurrences (age < 18 y)
Epidemiology 12 (20-39 y) to — 2 (⬍ 1 y) —
Incidence rate (age-adjusted/100 person-years)206 30 (40-59 y) 0.7 (5-19 y)
Biology
De novo AML 83% 30%-40% ⬎ 95% 60%-75%
Secondary (MDS-related) AML207,208 17% Adverse 1% Adverse
Abnormal karyotypes 55% Depends on subgroups 70%-80% Depends on subgroups
WHO classification
AML with recurrent genetic abnormalities14,15,209-211

t(8;21)(q22;q22)/RUNX1-RUNX1T1 8% Favorable 12%-14% Favorable

inv(16)(p13.1q22)/CBFB-MYH11 5% Favorable 8% Favorable
t(15;17)(q22;q21)/PML-RARA 5%-10% Favorable 6%-10% Favorable
t(9;11)(p22;q23)/MLLT3-MLL 2% 50% 7% Intermediate or favorable
(63%-77%)
t(10;11)(p12;q23)/MLLT10-MLL 1% Unclear 3%, mainly infants Adverse
AML with t(6;9)(p23;q34)/DEK-NUP214 1% Adverse ⬍ 2% Adverse
AML with inv(3)(q21q26.2) or 1% Adverse ⬍ 1% Adverse
t(3;3)(q21;q26.2)/RPN1-EVI1
AML (megakaryoblastic) with ⬍ 1% Unclear AMKL only; infants Intermediate
t(1;22)(p13;q13)/RBM15-MKL1
Provisional entity: AML with mutated NPM133,212,213 35% (53% in CN) Favorable in case of FLT3- 5%-10% (14%-22% in Favorable
ITD negative CN), type A mutation
dominant, increasing by
age
Provisional entity: AML with mutated CEBPA212 10% in CN Favorable 5% (14% in CN) Favorable
FLT3-ITD27,30,213-215 20%-40% (⬃ 50% in CN) Adverse 10% (18% in CN) Context dependent*
Not included in WHO 2008
Adverse karyotypes/mutations 32% 5%-6%

t(7;12)(q36;p13)/t(7;12)(q32;p13) Not in adults — Infants Adverse
t(5;11)(q35;p15.5)/NUP98/NSD122 Not in adults — Mostly in CN Adverse
New mutations
N-RAS35,40,216 10% No prognostic significance 20% (3% in CN) No prognostic significance
MLL-PTD45 3%-5% Adverse 3% Not yet defined
c-KIT 40,43,87,217 17% in CBF leukemia Adverse in t(8;21) 25% in t(8;21) Unclear
WT131,36,214 10% in CN Adverse combined with 13% in CN Adverse combined with
FLT3-ITD FLT3-ITD
PTPN1142 Not in adults — 5%-21%, infants only Unclear
IDH1/251 16% Context-dependent mutation Rare, 2%-3% No prognostic significance
TET2218 8%-17% Unclear Very rare Unclear
DNMT3A219 20% Unclear Rare Unclear
WHO classification continued
AML with myelodysplasia-related changes220,221 48% Unfavorable Low No prognostic significance

Therapy-related myeloid neoplasms213 6% Adverse 3.5% Adverse
Acute myeloid leukemia, not otherwise specified ⬃ 17% Intermediate ⬃ 15% Intermediate
(NOS)213,222;27
Myeloid sarcoma (syn.: extramedullary myeloid 1% — 2%-4%, leukemia cutis Favorable in case of favorable
tumor; granulocytic sarcoma; chloroma) (infants), chloroma karyotypes
Myeloid proliferations related to DS
Transient abnormal myelopoiesis (syn.: transient Not in adults — In 5% of the newborns Favorable
myeloproliferative disorder)223 with DS
Myeloid leukemia associated with Down syndrome Not in adults — 400-fold increased risk 90%
(ML-DS) for AMKL
Blastic plasmacytic dendritic cell neoplasia Rare Adverse Not seen —
Acute leukemias of ambiguous lineage —
MPAL134 Rare Adverse 4.5% 65%
Therapy
Percentage in clinical trials ⬍ 40% — 50%-96% —
HSCT in first CR ⬃ 60% — 13%-30% —
CNS Not analyzed — Intrathecal prophylaxis —
Favorable, intermediate, and adverse were defined according to the definitions given14,15,224: favorable indicates 5-year survival ⬎ 60% in adults and ⬎ 70% in children;
intermediate, 23%-60% in adults and 50%-70% in children; and adverse, ⬍ 23% and ⬍ 50%, respectively, in children and adults.
— indicates not applicable; and AMKL, acute megakaryoblastic leukemia.
*Different prognosis in combination with different other mutations.
Table 2. Immunophenotyping panel for diagnosis of AML and mixed phenotype AML in children
Diagnosis of AML*
Precursor stage CD34, CD117, CD133, HLA-DR
Myelomonocytic markers CD4, CD11b, CD11c, CD13, CD14, CD15, CD33, CD36, CD64, CD65, CD184 (CXCR4), intracellular† myeloperoxidase
(iMPO), i-lysozyme
Megakaryocytic markers CD41, CD42, CD61
Erythroid marker CD235a
Leukemia specific antigen NG2 homolog‡
Lineage aberrant antigens CD2, CD7, CD19, CD56
Pan-leukocyte markers CD11a, CD45
Diagnosis of MPAL§
Myeloid lineage iMPO or evidence of monocytic differentiation by at least two of i-lysozyme, CD11c, CD14, CD64
B-lineage CD19 (strong) with at least 1 of iCD79a, iCD22, CD10; or CD19 (weak) with at least 2 of iCD79a, iCD22, CD10
T-lineage iCD3 or surface CD3
*The table provides a list of selected markers (bold type represents the mandatory minimal panel required to fulfill WHO and EGIL criteria3,6), differing from the adult panel

reported by Döhner et al4,214 in only a few markers (italics), which may have diagnostic or therapeutic implications.
†Intracellular expression is represented by prefix “i.”
‡Most cases with rearranged MLL gene express the NG2 homolog reacting with the monoclonal antibody 7.1.
§The requirements for assigning MPAL are based on the WHO 2008 criteria.3 Note that MPAL can also be diagnosed if there are 2 or more blast populations from different
lineages.
Another methodologic transition concerns the interpretation of immunophenotypic analysis during diagnosis of children with
immunophenotypic expression data. Rigid cut-off points for deter- AML, which has been modified from that recommended for adults
mining marker positivity (eg, 10% or 20%) are being replaced by with AML.
biologically more meaningful semiquantitative estimates of blast
population appearances compared with those of normal popula- Recommendation
tions.11 Table 2 summarizes the suggested antigen panel for
The mandatory minimal panel required to fulfill WHO and EGIL
criteria for AML includes CD34, CD117, CD11b, CD11c, CD13,
Table 3. Recommended tests and procedures in the initial workup
of pediatric patients with AML CD14, CD15, CD33, CD64, CD65, iMPO, i-lysozyme, CD41, and
CD61; and for MPAL: CD19, iCD79a, iCD22, CD10, and iCD3.
Test/procedure Rationale
Tests to establish the diagnosis

Complete blood counts and differential count Diagnosis, initial risk
Conventional cytogenetics and FISH
Bone marrow aspirate Diagnosis
Conventional cytogenetics can detect structural and numerical
Bone marrow trephine biopsy* Diagnosis
cytogenetic abnormalities in 70%-80% of children with AML.
Lumbar puncture† Diagnosis, treatment,
prognosis
Certain fusion genes, products from cryptic translocations, or loss
Immunophenotyping Diagnosis of chromosome material can only be reliably detected using FISH.
Cytogenetics Diagnosis, treatment, The diagnostic cytogenetic workup in children and adults is
prognosis similar.4 The most frequent chromosomal abnormalities in children
Molecular genetics/translocations/mutations (see Diagnosis, treatment, with AML include t(8;21)(q22;q22), inv(16)(p13.1q22) (together
Table 4) prognosis referred as core binding factor [CBF]-AML), t(15;17)(q22;q21)/
Additional tests/procedures at diagnosis PML-RARA, and 11q23/MLL-rearranged abnormalities (up to 25%),
Demographics and medical history‡ Initial risk
which together account for ⬃ 50% of pediatric AML, a much
Performance status (WHO score) Initial risk
higher frequency than in adults.12-15 Additional abnormalities that
Physical examination Diagnosis, side effects
are more predominant in pediatric AML are, for example, t(1;
Syndromes, comorbidities Treatment, prognosis
Biochemistry, coagulation tests§ Initial risk
22)(p13;q13)/RBM15(OTT)-MKL1(MAL).16,17 Further types are
Serum pregnancy test储 Treatment the cryptic abnormalities t(7;12)(q36;p13)/ETV6(TEL)-
Hepatitis A, B, C; CMV, EBV, VZV, blood group Rh¶ Diagnosis, side effects HLXB9(MNX1), which are strongly associated with a ⫹19 and
Chest x-ray, 12-lead, electrocardiography (ECG); Diagnosis, side effects t(5;11)(q35;p15.5)/NUP98-NDS1, predominantly found in cytoge-
echocardiography netically normal AML (CN-AML).18-22 However, both transloca-
tions have not yet been included in the WHO 2008 classification
Table 3 is analogous to the table of Döhner et al.4
*Mandatory in patients with a dry tap (punctio sicca) and in case of dysplasia in (Table 1).
the peripheral blood or bone marrow, or in the differentiation from MDS. Importantly, the 2008 WHO classification categorizes t(9;
†Required in all patients. Patients with clinical symptoms of suspected CNS 11)(p22;q23)/MLL-MLLT3(AF9) as an entity and recommends that
involvement should be evaluated by imaging study for intracranial bleeding, leptomen-
ingeal disease, and mass lesion; lumbar puncture should be postponed or is partners in the variant MLL translocations should be identified.
considered optional in other settings (eg, high WBC count or APL). Frequently, 11q23/MLL rearrangements are complex and/or cryp-
‡Includes race or ethnicity, family history, prior exposure to toxic agents, prior tic. For example, the t(10;11)(p12;q23)/MLL-MLLT10(AF10) or
malignancy, therapy for prior malignancy, and information on smoking.
§Biochemistry: sodium, potassium, calcium, phosphate, creatinine, aspartate
t(6;11)(q27;q23)/MLL-MLLT4(AF6) can generate the fusion via
aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase, inversions, insertions, or translocations involving other chromosomes.
bilirubin, and uric acid; on indication, add other tests. Coagulation tests: prothrombin The best method to evaluate these cases is the sequential G-banding to
time (PTT), international normalized ratio (INR) where indicated, and activated partial
FISH with a MLL probe or RT-PCR, using specific primers.
thromboplastin time (aPTT).
储In adolescents (female) of child-bearing potential. Monosomy 7, monosomy 5/5q deletions, and aberrations of
¶Additional tests may be considered (eg, HIV-1, Parvo B19, and HLA typing). 12p are rare events (seen in 3%-5% of patients) that occur in nearly
Table 4. Genetically defined prognostic groups in pediatric AML kinases, and type II mutations, inducing maturation arrest, compris-
Prognosis14,15,22,27 Genetics ing most of the translocations. The frequency and nonrandom
Favorable t(8;21)(q22;q22)/RUNX1-RUNX1T1 associations of type I and type II mutations in pediatric AML
inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB-MYH11 (Figure 1; Table 1) differ from adults, highlighting the difference in
t(15;17)(q22;q21)/PML-RARA* AML biology over age groups.27 In CN-AML, several mutations,
Molecular (in CN-AML) such as NPM1, FLT3, WT1, and biallelic CEPBA mutations, are
NPM1-mutated AML clinically relevant and should be included in standard diagnostics.27-31
CEBPA double mutation Interestingly, the frequency and distribution of the subtypes of NPM1
t(1;11)(q21;q23)/MLL-MLLT11(AF1Q)
mutations differ between children and adults.29,32-34 Mutations in the
GATA1s†
WT1 gene are found mainly in CN-AML and are often associated with
Intermediate‡ Cytogenetic abnormalities not classified as favorable
FLT3-ITD mutations.35-37 The frequency of activating mutations of
or adverse§
Adverse ⫺7,储 ⫺5 or del(5q)
tyrosine kinase receptor genes, such as FLT3 (predominantly in CN-
inv(3)(q21q26.2) or AML, t(15;17)(q22;q21)/PML-RARA and t(5;11)(q35;p15.5)/NUP98-
t(3;3)(q21;q26.2)/RPN1-MECOM(EVI1-MDS1-EAP) NSD1), increases with age.22,30,31,35 Point mutations in the activating

t(6;9)(p23;q34)/DEK-NUP214 loop domain of the FLT3 receptor (frequency 2%-8% in children) are
t(7;12)(q36;p13)/ETV6(TEL)-HLXB9(MNX1) mutually exclusive of FLT3-ITD mutations.27,30,38
t(4;11)(q21;q23)/MLL-MLLT2(AF4) Mutations in genes involved in the RAS-RAF-ERK signal transduc-
t(6;11)(q27;q23)/MLL-MLLT4(AF6) tion pathway (PTPN11, NF-1, N-RAS, K-RAS) occur in 5%-21% of
t(5;11)(q35;p15.5)/NUP98-NSD1
children with AML, more frequently in those with CBF-AML, and in
t(10;11)(p12;q23)/MLL-MLLT10(AF10)¶
young children with MLL-rearranged AML (Figure 1).27,39-42
complex karyotype#
C-KIT mutations occur in ⬃ 25% of children with CBF-AML,
WT1mut/FLT3-ITD**
t(9;22)(q34;q11.2)††
but in only 5%-8% of those with other leukemia types.30,35,43,44
MLL-PTDs are rare in childhood AML.45
Frequencies, response rates, and outcome measures should be reported by In addition to mutations, aberrant expression levels of genes
genetic group, and, if sufficient numbers are available, by specific subsets indicated.
*t(15;17)/PML-RARA is treated separately from other AMLs.
have recently been reported in both adults and children; however,
†In particular in DS patients and infants with acute megakaryoblastic leukemia, the biologic and clinical relevance might differ. Whereas BAALC
analysis of GATA1s mutations should be included. Identification of GATA1s- and ERG overexpression is associated with CN-AML, EVI1
associated leukemia in trisomy 21 mosaicism can prevent overtreatment.
expression, which in adults is associated with monosomy 7 and
‡Includes all AMLs with normal karyotype, except for those included in the
favorable subgroup; most of these cases are associated with poor prognosis, but they inv(3), rarely occurs in children but is mainly found in association
should be reported separately as they may respond differently to treatment. with t(6;11)(q27;q23)/MLL-MLLT4(AF6) and FAB types M6/7.46,47
§For most abnormalities, adequate numbers have not been studied to draw firm Recent whole-genome sequencing studies have identified that
conclusions on their prognostic significance.
储Excluding recurrent genetic aberrations, as defined in the WHO 2008 novel somatic mutations in TET2, IDH1, IDH2, and DNMT3A are
classification. highly prevalent in adult AML but not in childhood AML.27,48-52
¶Results in t(10;11)(p12;q23) are heterogeneous; therefore, intermediate progno- The detection of the different, prognostically relevant MLL
sis may also be adequate.
#Three or more chromosome abnormalities in the absence of one of the
fusions genes is also important; for further details concerning the
WHO-designated recurring translocations or inversions. impact of molecular aberrations on outcome in pediatric AML, see
**There are differences in the risk allocation of FLT3-ITD considering the allelic ratio. “Prognostic factors, Molecular genetics.”
††t(9;22) is rare, but it is included because its poor prognostic impact is known.
Recommendation
all subtypes of childhood AML.14,15,23
Monosomal karyotypes, Routine evaluation should include the evaluation of a prognosti-
which are associated with poor prognosis in adults, are extremely cally relevant and potentially targetably selected set of molecular
rare in children.24 Trisomies 8 und 21 are often associated with genetic markers FLT3-ITD, WT1, C-KIT, CEBPA (double muta-
additional aberrations.14,15 Cytogenetic abnormalities correlate tion), NPM1, and further specific MLL-abnormalities with favor-
strongly with age: ⬃ 50% of infants have MLL-rearranged AML, able or very poor prognosis (eg, MLL-AF1Q, AF6, AF10).
whereas CBF-AML occur typically in older children.25
Genome-wide studies
Recommendation
Several gene expression profiling studies have been conducted in
Routine evaluation should include the evaluation of prognostically
recent years in pediatric AML to study their diagnostic potential
relevant genetic aberrations by cytogenetics/FISH, including at
and to determine whether they can replace current labor-intensive
least the following fusion genes at diagnosis: RUNX1-RUNX1T1,
diagnostic procedures that involve many different techniques.
CBFB-MYH11, PML-RARA, and MLL rearrangements. Other rare
However, the value of gene expression profiling for routine
fusion genes mentioned in Table 4 should be traced to determine
diagnostics is currently limited.53
adverse risk patients.
Molecular genetics Biobanking
Several gene mutations and aberrantly expressed genes have been Biobanking of primary AML blasts, DNA, and RNA is relevant for
recognized in pediatric AML, further contributing to the disease’s patient care as it allows confirmation of initial findings or adding
heterogeneity. AML is thought to result from at least 2 classes of new data if required (ie, in case of relapse). It is a prerequisite for
cooperating mutations as hypothesized by Gilliland and supported translational research. Stored material can be used to identify and
by animal models.26 These classes can be categorized as type I characterize new prognostic markers, validate methods such as
mutations inducing proliferation, such as abnormalities in tyrosine MRD, and enable experimental research of biologic mechanism,
Figure 1. Pie chart illustrating the molecular and genetic aberrations as well as their nonrandom associations in pediatric AML. (A) Total group: Integrative analysis of
recurrent cytogenetic aberrations (MLL-rearrangements, t(8;21), inv(16), t(15;17), t(7;12), and t(6;9), CN and other nonspecific cytogenetic subgroups and type I molecular
aberrations (in FLT3-ITD, WT1, N-RAS, K-RAS, PTPN11, and c-KIT) based on 237 unselected de novo pediatric AML patients. Each sector indicates the percentage of patients
harboring 1 or more of the aforementioned mutations. (B) CN group: Pie chart based on 40 cytogenetically normal de novo pediatric AML patients analyzed for the presence of
type II molecular aberrations (in NUP98-NSD1, CEBPA dm, NPM1, MLL-PTD, and other molecular aberrations) and type I molecular aberrations (in FLT3-ITD, WT1, N-RAS,
K-RAS, PTPN11, and c-KIT). Each sector indicates the percentage of patients harboring 1 or more of the aforementioned mutations. None indicates patients with only wild-type
alleles of genes tested. Adapted from Hollink et al22 and Balgobind et al27 with permission.
subgroups, and leukemogenesis. To discriminate between germline ample, cryptic translocations of t(5;11)(q35;p15.5)/NUP98-NDS1 or
and somatic genetic aberrations in pediatric AML, the panel mutations such as WT1 or NPM1, can modify the prognostic relevance
suggests storing additional material, such as buccal swabs. of the FLT3-ITD.22,37,58 The prognostic impact of other mutations
mentioned in “Diagnostic procedures and initial workup, Molecular
Recommendation genetics” remains unclear.
Table 4 proposes genetically defined prognostic groups based
Biobanking of leukemic blasts, DNA, and RNA as well as germline on similar data obtained from large studies in Europe and the
material is advised for potentially required diagnostic procedures United States on the prognostic impact of mutations.14,15,22,27 These
and translational research. studies also represent the currently recommended standardized
reporting for correlation of cytogenetic and molecular genetic data
in pediatric AML.
Prognostic factors
Response and prognosis
Collaborative research in childhood and adult AML has identified
Response to the first course of treatment and cytogenetics and

several prognostic factors. These factors have been variably used
for risk stratification. The most relevant factors are genetic molecular genetics are the 2 most important indicators of outcome.
abnormalities and treatment response, with substantial differences Both are independent prognostic factors and are usually essential
between adult and childhood AML. In the AML-Berlin/Frankfurt/ elements of the risk group classification.59-61
Muenster (BFM) studies, age could not be used as an independent Most study groups evaluate treatment response morphologi-
prognostic factor in infants and adolescents, but this may not be the cally in the bone marrow after the first (eg, on day 15 or day 28) and
case for other study groups, which reflects treatment depen- second induction courses. This may be challenging in hypoplastic
dency.25,54 Very high blast counts at diagnosis are associated with bone marrows. Blast cell reduction until day 15 and treatment
an increased risk of early death and nonresponse, but not necessar- response after the first and second induction are strongly predictive
ily with disease-free survival.55 of outcome.59-61
Cytogenetics Recommendation
As in adult AML, CBF-AML and t(15;17)(q22;q21) in children are Determination of treatment response after first and second induc-
highly predictive of a favorable outcome. Translocation t(1;11)(q21; tion courses is recommended for risk group stratification.
q23)/MLL-MLLT11(AF1Q) is a newly described translocation Monitoring of residual disease. Residual disease can be moni-
associated with favorable outcome in childhood AML.56 However, tored by morphology, immunophenotyping, and quantification of
prognosis of different MLL fusions is heterogeneous.56,57 molecular aberrations and gene expression levels. Although some
Cytogenetics indicating an adverse outcome include ⫺7 (excluding study groups have used MRD diagnostics for treatment stratifica-
recurrent genetic aberrations, as defined in the WHO 2008 classification, its definitive clinical benefit is still under investigation and
tion3), t(6;11)(q27;q23)/MLL-MLLT4(AF6), t(10;11)(p12;q23)/MLL- also probably treatment dependent.10,62 Depending on the method
MLLT10(AF10), t(7;12)(q36;p13)/ETV6(TEL)-HLXB9(MNX1), t(6;9) and the informative marker used, MRD monitoring can be applied
(p23;q34)/DEK-NUP214, and t(5;11)(q35;p15.5)/NUP98-NSD1 and in variable subsets of pediatric AML; however, a single approach
other rare abnormalities, such as 12p (Table 4).14,15,22 Further, adverse may not meet the specific features of all patients.
cytogenetics described in adult AML, such as 5q⫺, inv(3)(q21q26.2) Immunophenotyping. MRD assessment by immunophenotyp-
or t(3;3)(q21;q26.2)/RPN1-EVI1, are very rare in children. ing can be done in up to 96% of children with AML. However, the
Results of studies on complex karyotypes (⬎ 3 chromosomal heterogeneity of leukemia-associated immunophenotypes and fre-
abnormalities, excluding recurrent changes) have been inconsis- quent antigen shifts over time can limit the sensitivity and
tent, in part because of differences in definition.14,15 Intermediate- specificity of immunophenotypic detection of MRD. Whereas
risk factors include normal and other karyotypes. However, some groups failed to show an independent prognostic impact,
CN-AML has been shown to be a heterogeneous disease and the other groups have used the technique for treatment intensifica-
clinical outcome highly dependent on the presence of additional tion.10,62,63 Current technologic advances, such as ⱖ 6-color flow
molecular aberrations and cryptic translocations (see “Molecular cytometry, may overcome any limitations. However, method
genetics”). The prognostic value of rare recurrent chromosomal standardization and quality control are essential.
aberrations remains to be elucidated and can be a future risk- Fusion genes. The high specificity and sensitivity (up to 10⫺5)
stratification tool for pediatric AML. of real-time quantitative PCR of AML fusion genes of
RUNX1(AML1)-RUNX1T1(ETO), CBFB-MYH11, PML-RARA, and
Molecular genetics MLLT3(AF9)-MLL lend themselves to MRD monitoring but are
applicable in only ⬃ 35% of pediatric patients. The assessment of
The recognition of novel molecular subgroups in pediatric AML early response requires strict definition of time points because the
(see “Diagnostic procedures and initial workup, Molecular genet- MRD level may vary several logs in a short time frame.64
ics”; Figure 1) has led to stratified treatment by using the identified Low-level PCR positivity (⬍ 10⫺4) of RUNX1(AML1)-
mutated genes as treatment targets or by identifying patients RUNX1T1(ETO) or CBFB-MYH11 can be detected in patients in
eligible for myeloablative therapy.35 long-term remission; therefore, the evaluation of molecular relapse
In CN-AML, single-gene mutations are of specific interest, must consider the dynamics of increasing levels of fusion genes by
especially the NPM1 and biallelic CEPBA mutations, as they are quantitative PCR.65 Importantly, the kinetics of relapse differs
associated with favorable outcome.27-31 In contrast, a FLT3-ITD mutant between genetic subtypes with a median time from molecular to
to wild-type ratio (ITD allelic ratio) of ⬎ 0.4 has been associated with clinical relapse between 2 and 8 months.65 If confirmed to be of
adverse outcome.30 Coincidentally occurring translocations, for ex- prognostic significance, increasing levels of MRD measured by
fusion genes may indicate the need for early HSCT or restart of Table 5. Response criteria in AML
chemotherapy. Category Definition
Mutation-specific MRD. Although methods for MRD monitor- Complete remission (CR)* Bone marrow blasts ⬍ 5%; absence of blasts with
ing using specific mutations, such as NPM1, FLT3-ITD, or Auer rods; absence of extramedullary disease;
GATA1s, have been established in childhood AML, the clinical absolute neutrophil count ⬎ 1.0 ⫻ 109/L
significance requires to be clarified.33,63,66 Additional candidate (1000/␮L); platelet count ⬎ 80 ⫻ 109/L
mutations may be WT1, C-KIT, N-/K-RAS, PTPN11, or FLT3-point (80 000/␮L); independence of red cell
mutations. transfusions
CR with incomplete recovery (CRi)† All CR criteria except for residual neutropenia
(⬍ 1.0 ⫻ 109/L 关1000/␮L兴) or thrombocytopenia
Recommendation
(⬍ 80 ⫻ 109/L 关80 000/␮L兴)
MRD measurement should be incorporated in the context of Treatment failure

Resistant disease (RD) Failure to achieve CR or CRi (general practice;
clinical trials and used, if appropriate, for treatment stratification.
phase 2/3 trials), or failure to achieve CR, CRi,
or PR (phase 1 trials); only includes patients

surviving ⱖ 7 days after completion of initial
Response and survival criteria treatment, with evidence of persistent leukemia
by blood and/or bone marrow examination (this
Response assessment should be stated by bone marrow
examination ⬍ day 42 and at the end of
The response criteria for adult AML are widely used in pediatric intensification courses)
AML, with some minor modifications (Table 5).4 Early death
Death in aplasia Death occurring ⱖ 7 days after completion of initial
Treatment failure treatment while cytopenic; with an aplastic or
hypoplastic bone marrow obtained within 7 days
Early death can be defined more precisely using the time point of
of death, without evidence of persistent
42 days because response status is normally evaluated within leukemia (⬍ day 42)
42 days. At later time points, death from nonresponse (relapse) or Death from indeterminate cause
treatment-related mortality in remission should be distinguished as Early bleeding/leukostasis Deaths occurring before completion of therapy,
competing events. or ⬍ 7 days after its completion; or deaths
occurring ⱖ 7 days after completion of
initial therapy with no blasts in the blood, but
no bone marrow examination available
Management (⬍ day 42)
Relapse‡ Bone marrow blasts ⱖ 5%; or reappearance of
General aspects of treatment
blasts in the blood; or development of
All children with AML should preferably be treated within the extramedullary disease
context of well-designed clinical trials to ensure highest quality and Definitions of response criteria are based primarily on those given by Cheson et
safety of diagnostics and management. AML treatment in child- al2 and amended by Creutzig and Kaspers.225 Table 5 is analogous to the table of
hood should be risk-adapted, based on biologic factors to avoid Döhner et al.4
*All criteria need to be fulfilled; marrow evaluation should be based on a count of
overtreatment in patients with favorable prognosis and to improve 200 nucleated cells in an aspirate with spicules; if ambiguous, consider repeating
outcome in those with unfavorable prognosis (see “Prognostic examination after 5-7 days; flow cytometric evaluation may help to distinguish
factors”). The aim of therapy is to cure the child by eradicating the between persistent leukemia and regenerating normal marrow; a marrow biopsy
should be performed in cases of dry tap, or if no spicules are obtained; no minimum
leukemic clone while avoiding side effects and late effects as much duration of response required. The categories morphologic leukemia-free state,
as possible. Intensive polychemotherapy based mainly on anthracy- partial remission (PR), cytogenetic CR (CRc), and molecular CR (CRm) may be
clines and purine analogues should be started as soon as AML is useful in the clinical development of novel agents in phase 1 or 2 clinical trials. For
diagnosed. Hyperleukocytosis and APL should be regarded as definitions, see Döhner et al.4
†The criterion of CRi is of value in protocols that use intensified induction or
medical emergencies because of their early hemorrhagic risk (see double-induction strategies, in which hematologic recovery is not awaited but
“APL” and “Hyperleukocytosis”). intensive therapy will be continued. In such protocols, CR may even not be achieved
After induction therapy, postremission treatment is necessary to in the course of the entire treatment plan. In these instances, the overall remission
rate should include CR and CRi patients. Some patients may not achieve complete
maintain remission. Additional CNS-directed intrathecal therapy is hematologic recovery, even with longer observation times. As treatment courses
routine. In general, maintenance therapy has not been proven should be very condensed (with minimal delay) in pediatric patients, treatment is
effective in children and adults, except in patients with APL continued, even without complete platelet recovery. Therefore, the recommended
cut-off value for platelets indicating CR is 80 ⫻ 109/L.
(see “APL”).4,67,68
‡In patients with low blast percentages (5%-10%), a repeat marrow should be
Several clinical trials suggest that increased intensity is associ- performed to confirm relapse. Appearance of new dysplastic changes should be
ated with improved outcome in most AML subtypes, except APL, closely monitored for emerging relapse. In a patient who has been recently treated,
ML-DS, and inv(16). However, treatment-related toxicity, particu- dysplasia or a transient increase in blasts may reflect a chemotherapy effect and
recovery of hematopoiesis. Cytogenetics should be tested to distinguish true relapse
larly cardiotoxicity, must be balanced against antileukemic efficacy from therapy-related MDS/AML.
to result in long-term cure (see “Induction”).
Improvements in supportive care have had a major impact on
increased survival rates in childhood AML. Treatment intensity can Pediatric Hematology and Oncology (NOPHO) Group, the Japa-
be achieved either by high cumulative dosages of anthracyclines or nese Childhood AML Cooperative Study Group (JPLSG), and the
purine analogues or intensively timed chemotherapy.69-71 The St Jude AML Study Group have focused more on high-dose
Medical Research Council (MRC) Study Group delivered rela- cytarabine (or other antimetabolites, such as cladribine). The
tively high doses of anthracyclines, whereas the Nordic Society of AML-BFM study group has used both drugs in relatively high
doses. Despite these different approaches, survival rates have been Dosage of cytarabine. The use of high-dose cytarabine (Hi-
roughly similar. The number of treatment courses used by different DAC) in first induction did not improve the CR rate or survival in
groups has varied between 4 and 8, again with similar outcomes. adults or children.4,10,86 HiDAC may benefit CBF-AML patients
Supplemental Table 1 (available on the Blood Web site; see the when given in consolidation. The results of the AML-BFM 98 and
Supplemental Materials link at the top of the online article) gives 2004 trials in patients with t(8;21) AML demonstrated a significant
an overview of the results of recent pediatric AML trials. favorable impact of HiDAC plus mitoxantrone in second induction.87
Additional agents. Other drugs that have been used during
Recommendation
induction include aclarubicin, amsacrine (adults), mitoxantrone
Children with AML should be treated within controlled clinical (children and adults), and 2-chlorodeoxyadenosine (children).4,88-90
trials. Treatment of childhood AML requires an intensive It is not clear whether these agents improve early treatment
anthracycline- and cytarabine-based therapy using at least 4 or response, event-free survival, or overall survival compared with
5 courses. daunorubicin plus cytarabine at equivalent doses. Similarly, the
benefit of gemtuzumab ozogamicin (GO), a calicheamicin conju-
Induction gated to a CD33 antibody, has not been defined in children with de

novo AML (see “Antibody-targeted drugs”).
One or 2 courses of induction therapy are routinely used in children
and adults. Standard induction therapy comprises 3 days of an anthracy-
cline (eg, daunorubicin at least 60 mg/m2, idarubicin 10-12 mg/m2, or Recommendation
the anthracenedione mitoxantrone 10-12 mg/m2) and 7-10 days of
cytarabine (100-200 mg/m2 continuously or twice daily intravenously; One or 2 courses of induction therapy comprising 3 days of an
ie, “3 ⫹ 7” or “3 ⫹ 10”). With these regimens, ⬎ 85% of children and anthracycline and 7-10 days of cytarabine should be applied.
adolescents achieve complete remission (CR). Although a third drug,
such as etoposide or 6-thioguanine, is commonly included in induction, Postremission strategies
their benefit has not been proven.72
Anthracyclines. Various anthracyclines have been evaluated in Consolidation/intensification. In most pediatric studies, 2 to
prospective randomized pediatric clinical trials. There is evidence 5 courses of chemotherapy with non–cross-resistant drug combina-
that higher doses of anthracyclines improve outcome in children tions similar to those given during induction are used to consolidate
and adults.73,74 However, toxicity, especially acute and late cardio- and maintain remission. There is no clear evidence that more than
toxicity, is dose related and limits the cumulative dose.75,76 3 consolidation courses (after 2 induction courses) are beneficial.72,83
Cumulative dosages ⬎ 300 mg/m2 have been associated with sig- High-dose cytarabine. The Cancer and Leukemia Group B
nificant later cardiac toxicity.77 There is no safe dose, but the (CALGB) study in adults showed that 4 courses of HiDAC (3 g/m2
antileukemic benefit of anthracyclines is such that most groups use per every 12 hours on days 1, 3, and 5) were superior to 4 courses of
a relatively high dose. The cumulative dose should consider host lower-dose (100 mg/m2 continuous intravenously on days 1-5)
factors, such as age and sex.78 To avoid high peak serum cytarabine.91 This benefit of cytarabine dose intensification, how-
concentrations of anthracyclines, splitting the daily dose or using ever, was restricted to patients with CBF-AML and, to a lesser
prolonged drug infusions has been proposed; however, results extent, to patients with CN-AML.92
concerning the benefit of dose scheduling are conflicting; hence, Results of several pediatric trials (NOPHO AML 93, MRC
there is no consensus on the best regimen.75,79-81 Anthracyclines AML 10, AML-BFM 2004, and AML99 of the JPLSG) and those
with a low cardiac exposure, such as liposomal anthracyclines, may of the adult CALGB study show that relapse rates can be reduced
be of benefit.79,81 by introducing intensive chemotherapy courses that include
Given an arbitrary conversion rate of 5:1 (daunorubicin HiDAC.92-97
60 mg/m2 ⫻ 3 days: idarubicin 12 mg/m2 ⫻ 3 days), a better HSCT. HSCT is used as postremission consolidation therapy,
blast cell reduction at day 15 with comparable acute toxicity and both autologous and allogeneic HSCT have been studied.
was achieved in the AML-BFM 93 trial by idarubicin (however, Autologous HSCT. Several trials and a meta-analysis of pediat-
without an overall survival benefit).82 The randomized comparison ric AML trials have found no benefit for auto-HSCT compared with
between mitoxantrone (first induction 12 mg/m2, second induction nonmyeloablative chemotherapy in first CR.95,98-101 In the absence
8 mg/m2, each ⫻ 3 days) and daunorubicin (50 mg/m2 ⫻ 3 days) of benefit, the toxicity associated with the conditioning regimen in
in the MRC12 trial revealed similar results.83 The AML-BFM auto-HSCT further negates against auto-HSCT. However, there is a
2004 trial has shown that a liposomal formulation of daunorubicin role for auto-HSCT in relapsed APL without detectable MRD.102
allows the daunorubicin dose to be increased (80 mg/m2 ⫻ 3 days) Allogeneic HSCT. The benefit of allo-HSCT as postremission
without increasing acute and long-term cardiotoxicity thus far. consolidation treatment in first CR AML in children remains
Cardioprotection with dexrazozane was another option to controversial. The significantly lower relapse risk associated with
reduce cardiotoxicity during anthracycline exposure.84 However, allo-HSCT compared with postremission chemotherapy has not
the approved indications for this drug have been revised because of consistently translated into an improvement in survival.103-105
a possible higher rate of secondary malignancies in pediatric cancer Moreover, it has been calculated that at least 10 children must be
patients (http://www.fda.gov/Drugs/DrugSafety/ucm263729).85 transplanted to avoid 1 relapse.105 The risk-benefit for patients
relies on intensity of prior chemotherapy, risk group allocation, CR
Recommendation status, donor type, predicted transplant-related mortality, and
long-term toxicity. There is consensus that favorable-risk patients
In childhood AML, the cumulative dose and application modus of should not be transplanted in first CR, but for intermediate- and
anthracyclines must be considered because the risk of acute and high-risk patients results are controversial, showing either no
long-term cardiotoxicity depends on both dosage and patient benefit in first CR or some benefit in intermediate- and high-risk
conditions. patients.103,105,106
A meta-analysis of the comparative outcomes by risk group for irradiation. Results including the nonrandomized patients showed
HSCT and chemotherapy for 1373 children enrolled in 4 coopera- an increased risk of CNS and/or bone marrow relapses in nonirradi-
tive group clinical trials (Pediatric Oncology Group [POG] 8821, ated patients.117 However, other studies with comparable overall
CCG 2891, CCG 2961, and MRC AML10) showed a benefit for outcomes do not support a benefit from CNS irradiation. Pui and
allo-HSCT in intermediate-risk patients only.103 The analysis was Howard recently reported that changing the intrathecal regimen
weakened because a large number of patients could not be stratified from triple intrathecal therapy to cytarabine alone increased the
by risk group, and this resulted in a possible selection bias. In CNS relapse rate.118 Finally, the optimal number of intrathecal
addition, in some of the studies, the results of the chemotherapy treatments (range 4-12) remains unknown.
only groups were inferior to those achieved in other pediatric trials.
In pediatric AML, conditioning regimens with myeloablative Recommendation
chemotherapy are preferred to total body irradiation as the latter is
associated with more late effects and an increased risk of secondary CNS treatment needs to consist of intrathecal treatments with
malignancies.107-109 However, the optimal conditioning regimen cytarabine or methotrexate or in combination with steroids, al-
remains to be identified and standardized.110,111 though the optimal number of administrations is unknown.
Additional CNS-directed therapy in patients with CNS involve-

Pursuing a strategy of recommending sibling donors for standard-
risk AML and reserving alternative donors for high-risk disease is ment. CNS positivity (ie, CNS3 status) at the time of AML
in conflict with smaller family size and fewer children with diagnosis necessitates intensified, CNS-directed therapy. Appar-
matched siblings, and recently improved outcome with HSCT ently, unlike in pediatric ALL, a low number of (sporadic)
using unrelated matched donors.112 Whether HSCT from an cerebrospinal fluid blasts (CNS2 status) does not influence the CNS
alternative donor is superior to intensive chemotherapy alone as relapse risk in pediatric AML.119 In contrast to ALL, CNS positivity
consolidation therapy in first CR remains to be determined. It has to is not a crucial factor within the AML risk group stratification
be mentioned that high levels of MRD before HSCT have been because it does not affect overall survival.120 However, those with
associated with poorer outcome.113 CNS involvement (as defined in “Diagnostic procedures and initial
In summary, the role of HSCT in children with AML in first CR workup”) relapse more frequently in the CNS.119 Therefore,
should be reassessed as the field evolves, particularly within patients with CNS involvement require intensified intrathecal
specific risk groups. There is consensus, however, that HSCT therapy to clear blasts from the CNS fluid. Although most study
should be offered to all children with relapsed AML in second CR. groups have added CNS irradiation to the regimen of these patients,
In addition, many groups offer HSCT to children with high-risk or recent observations suggest that frequent intrathecal chemotherapy
refractory disease and exploit the graft-versus-leukemia effect.114 combined with intensive systemic chemotherapy may yield similar
There is agreement that favorable-risk patients should not be results.119,121
offered HSCT.105 The role of allo-HSCT in intermediate- and In infants, cranial irradiation should be avoided or delayed by
high-risk patients may be redefined by improving risk stratification, bridging or substituting with intrathecal chemotherapy. In patients
including the identification of new prognostic markers and improve- with CNS involvement undergoing HSCT, post-transplantation
ments in MRD monitoring. CNS therapy should be considered.122 There is no proven superior
approach for patients with CNS relapse.123
Recommendation
Hematopoietic growth factors as priming agents
Auto-HSCT is not recommended for children with AML in first
CR. Allo-HSCT in first CR is not beneficial in childhood AML with Sensitization of leukemic cells with hematopoietic growth factors
favorable risk factors. In other risk groups, the benefit of allo- (priming), such as G-CSF and GM-CSF, has been studied predomi-
HSCT must be balanced against toxicity. Allo-HSCT in second CR nantly in adults with the aim of increasing cytotoxicity of chemo-
is generally considered. therapy.4 However, it cannot be recommended as routine practice in
either adults and children, as the data are conflicting, and recent
CNS-directed therapy studies raise doubt about the beneficial role of G-CSF.124-126
CNS involvement at diagnosis and at relapse is seen in 5%-10% of

pediatric patients with AML. Factors associated with CNS leuke-
mia include hyperleukocytosis, monocytic leukemia [FAB M4 or Management of special patient groups
M5, including M4eo with inv(16)], MLL gene rearrangement, and Children under 2 years of age
younger age.115
CNS treatment is given to all pediatric patients, including those The biology of AML in children younger than 2 years is different
who do not have detectable CNS involvement, assuming that from that of older children. Morphologic, cytogenetic, molecular
systemic therapy has limited efficacy to eradicate hidden AML genetics, and initial response show that these patients generally
blasts in the CNS compartment. CNS treatment has varied from have features of high-risk AML.54 MLL rearrangements are fre-
intrathecal chemotherapy (single-agent cytarabine or methotrexate, quent (⬃ 50%), and some rare aberrations t(7;12)(q36;p13)/t(7;
or triple cytarabine, methotrexate, and hydrocortisone) alone or 12)(q32;p13), t(7;12)(q36;p12), and t(1;22)(p13;q13)/RBM15(OTT)-
given in combination with cranial radiotherapy. Cranial irradiation MKL1(MAL) are nearly exclusive to this age group. In contrast,
seems to be effective in preventing CNS leukemia; however, the CBF-AML and t(15;17) are rarely seen.
risk of late toxicities and secondary malignancies, as well as the In principle, management of young children is not different
increasing use of HiDAC, which crosses the blood-brain barrier, from that of older children. However, immaturity of organs (lung,
and the lack of evidence of superiority for cranial irradiation, led to liver, brain) in infants younger than 1 year and differences in
it being abandoned by all major study groups.116 The AML-BFM pharmacokinetic and pharmacodynamic profiles of certain drugs
87 trial was the only prospective study testing the benefit of cranial (eg, cytarabine) increase their susceptibility to toxicities. Drug
dosage in infants is generally calculated according to body weight Recommendation

(mg/kg) rather than body surface. Pharmacokinetic analysis has
MPAL should be treated according to the dominant lineage defined
shown that children younger than 2 years have a reduced cytarabine
by genetics, morphology, cytochemistry, and immunophenotyping.
clearance, which prompted the AML-BFM study group to adjust
the dose of HiDAC by age.127 AML in Down Syndrome and other genetic disorders
Compared with older children, acute toxicities in infants during
induction chemotherapy are both more common and more severe, Children with specific inborn diseases are at increased risk of
particularly sepsis, gut toxicity, and pulmonary toxicities.54 Acute developing AML, with DS being the most frequent genetic disorder
and chronic cardiotoxicity is higher in infants than older children.78 associated with increased likelihood of AML.136
Cranial irradiation should be avoided or postponed to avoid Children with DS or DS mosaicism are at a 14- to 20-fold risk of
neurologic late effects (see “AML in Down syndrome and other developing acute leukemia. Approximately 5% of newborns with
genetic disorders”). DS have transient leukemia (also referred to as transient abnormal
Congenital AML is rare and is curable when it occurs.54 A myelopoiesis or transient myeloproliferative disorder), which usu-
GATA1 mutation-associated leukemia based on an underlying ally disappears spontaneously.137 Within the first 4 years of life

constitutional (mosaicism) of trisomy 21 should be excluded 10%-20% of these infants will develop myeloid leukemia with
because treatment is not required (see “AML in Down syndrome megakaryoblastic features (ML-DS). Transient leukemia and
and other genetic disorders”). There are also rare reports of durable ML-DS are characterized by mutations in exon 2 of the hemato-
spontaneous remissions in newborns. Therefore, in clinically logic transcription factor GATA1, which result in loss of the
asymptomatic and stable newborns, intensive chemotherapy should activation domain and leads to a truncated protein GATA1s.138,139
be deferred until the hematologic course evolves or clinical The leukemic blasts originate from fetal liver hematopoiesis.140
Although most newborns with DS experience spontaneous remis-
symptoms requiring treatment develop.128
sion within 4-10 weeks, some have severe and life-threatening
Recommendation clinical symptoms associated with pancytopenia or organ
infiltration. Hydrops fetalis is the most severe complication, and
Infants tolerate intensive therapy, including HSCT, but their pleural effusions and ascites can be life-threatening in the unborn
increased susceptibility to toxicities requires complex, sophisti- infant. Within the first weeks of life, some children develop fatal
cated therapy concepts comprising age-adapted drug dosages and liver cirrhosis with hyperbilirubinemia (conjugated biliru-
high treatment expertise. bin ⬎ 250␮mol/L).141 In patients with life-threatening symptoms
resulting from hyperleukocytosis or organomegaly/organ dysfunc-
Myeloid sarcoma tion, intervention with exchange transfusion and/or low-dose
cytarabine chemotherapy (1-1.5 mg/kg ⫻ 5-7 days) is usually
Myeloid sarcoma (MS; also termed extramedullary AML, extramed- applied.137,141
ullary myeloid tumor, and granulocytic sarcoma) is a rare manifes- ML-DS can be successfully treated with intensity-reduced
tation of AML characterized by the occurrence of 1 or more chemotherapy and without HSCT, resulting in event-free survival
myeloid tumor masses (or infiltrations) at an extramedullary site.129 and survival rates of ⬎ 85%.142-144 As children with DS are
MS mainly occurs concurrently with AML but sometimes presents especially susceptible to chemotherapy and have a compromised
before bone marrow involvement as the first manifestation. Usu- immune system, side effects and infections are frequent and
ally, the skin is affected (leukemia cutis), but other organs treatment-related deaths are as frequent as relapse.142,145,146
[chloroma, eg, in orbits (associated with t(8;21)), lymph nodes,
Recommendation
bone, soft tissue, kidneys, testes] may also be involved. The
presence of ⬍ 20% malignant bone marrow blasts distinguishes Newborns with DS who have transient leukemia with severe
MS from frank de novo AML.130 clinical symptoms secondary to leukemic infiltrates should receive
Isolated primary MS and MS with a low blast count composes supportive care, and consideration should be given to the use of
2%-4% of all cases of childhood AML.131 MS is most frequent in low-dose cytarabine.
young children (median age, 5 years), and its incidence decreases ML-DS should receive reduced-intensive chemotherapy and
with age. MS can be misdiagnosed, primarily as non-Hodgkin particular attention given to the high risk of severe infections.
lymphoma. Intensive AML-specific chemotherapy stratified accord- HSCT is not indicated in first CR in ML-DS.
ing to general AML risk factors is recommended for all patients
Patients with congenital syndromes, associated with increased
with MS.131 Local irradiation may be considered, but prospective
chromosome fragility because of disturbed DNA-repair mecha-
studies are lacking because of the rarity of these manifestations.132
nisms (eg, Fanconi anemia and Bloom syndrome), as well as those
Recommendation with congenital diseases of the myelopoiesis (eg, Kostmann
syndrome and Diamond-Blackfan anemia) are at a considerably
MS requires systemic treatment similar to that given for increased risk of developing AML.147,148 Optimal therapy, includ-
de novo AML. ing scheduling and intensity, has not yet been defined for these rare
subgroups. In congenital neutropenia and Fanconi-anemia associ-
Mixed phenotype acute leukemia ated AML, less intensive therapy aimed at blast reduction followed
by allo-HSCT may be successful. In Fanconi-anemia associated
The survival of children with MPAL is superior to that of adults.133 AML, cross-linking chemotherapy, high anthracycline dosages,
Several retrospective analyses show that ALL-directed therapy is and irradiation should be avoided.149
very effective in patients with a dominant lymphoblastic Little is known about AML in familial cancer syndromes, such
phenotype.134,135 as those involving germline CEBPA mutations. The few reported
cases of pediatric AML have been successfully treated with chemotherapy, including alkylating agents and topoisomerase II
conventional chemotherapy and allo-HSCT in first CR.150 inhibitors, and/or radiotherapy.163
The etiology and strong association with specific translocations
Acute promyelocytic leukemia
involving 11q23 (MLL) and less often with 5q⫺/⫺5 and 7q⫺/⫺7
APL is characterized by chromosomal rearrangements of 17q21 in children are similar to that seen in adults.164 As in adults, the
involving RARA, which is most commonly fused to the PML prognosis of t-AML in children is generally poor, which is because
(promyelocytic leukemia) gene as a result of the t(15;17)(q22;q21) of resistance and cumulative toxicities of previous chemo-
translocation. In ⬍ 5% of cases, RARA is fused to an alternative therapy.4,165 Results from small studies suggest that these patients
partner, causing a variable sensitivity to all-trans retinoic acid benefit from AML-type induction courses (double induction),
(ATRA). APL is considered a medical emergency because of the followed by allogeneic HSCT, if remission can be achieved.165
risk of life-threatening hemorrhage; therefore, treatment with
ATRA should be initiated immediately. Recommendations
In patients with high WBC counts (arbitrarily defined
Children with t-AML should participate in prospective AML trials
as ⬎ 10 ⫻ 109/L in children), the combined use of ATRA with
that take into account prior chemotherapy. Allo-HSCT is recom-

chemotherapy decreases the incidence of the APL differentiation
mended in first CR.
syndrome,102 which is characterized by fever, weight gain, respira-
tory distress, and pleural and pericardial effusions and occurs
in ⬃ 10% of children with APL treated with ATRA or arsenic
trioxide. Pseudotumor cerebri during initial ATRA administration Relapsed and primary refractory AML
is common in children (11%) and can be treated with steroids.151,152
In children, a dose of 25 mg/m2 per day ATRA appears to Approximately 5% of children with AML have refractory disease
produce outcomes equal to the higher dose of 45 mg/m2 per day and 30% experience relapse.166 Bone marrow is the most common
commonly used in adults with a better safety profile.152-155 site of relapse, with the CNS being involved in up to 10% of cases
The use of ATRA in maintenance is generally recommended.102 (including combined relapses). Approximately 50% of patients
Limited data obtained in children also support the use of ATRA in have an early relapse, arbitrarily defined as within 1 year of initial
maintenance.155 Recent trials in adults suggest that subgroups of diagnosis. In general, the prognosis in these children is poor.167,168
AML patients may not require (prolonged) maintenance treat-
ment.156 This is also an important area for future clinical research in Prognostic factors in relapsed AML
pediatric APL. The international study Relapsed AML 2001/01 confirmed early
High cumulative dosages of anthracyclines combined with treatment response (bone marrow evaluation shortly before the
ATRA are very effective in treating APL.157 However, high doses of second reinduction course) as the most important prognostic
anthracyclines carry a risk of cardiotoxicity in children, and it factor.169 Duration of first CR and CBF-leukemia are also important
would appear that a reduced cumulative dose of anthracyclines prognostic factors in relapse.167,168,170,171
combined with HiDAC may be an equally successful approach.158
An intergroup protocol for children with APL (International
Current treatment in relapsed AML
Consortium for childhood APL; ICC APL; www.clinicaltrials.gov;
#NCT01226303) has recently been opened. Quantitative monitor- Different protocols and schedules have been used to induce a
ing of MRD will direct treatment of molecular relapse to prevent second remission, but currently antimetabolite (cytarabine, fludara-
frank relapse. Such treatment has been shown to be beneficial, bine) and anthracycline-based approaches are mainly used.171,172
although only in sequential clinical trials in adults.102,159,160 With a realistic option for cure, reinduction should be offered to all
Several studies in adults and children have demonstrated the children and adolescents with relapsed AML who can tolerate
effectiveness of ATRA combined with arsenic trioxid without intensive treatment.167 Patients enrolled on the recently completed
conventional chemotherapy in refractory, relapsed, or newly diag- randomized international relapsed AML 2001/01 study comparing
nosed APL.161,162 However, more safety and efficacy data need to fludarabine/cytarabine/G-CSF with the addition of liposomal dauno-
be generated before routinely introducing arsenic in newly diag- rubicin showed a second CR rate of 59% and 69%, respectively,
nosed APL protocols in children.102 translating to a survival rate of 38% for all patients.169
As in first-line treatment, CNS-directed therapy with several
Recommendations
administrations of intrathecal triple chemotherapy is usual. Allo-
In children, ATRA at 25 mg/m2 per day should already be started if HSCT is recommended for all children who achieve CR, using
APL is suspected, as it reduces the risk of fatal hemorrhage. It either related or unrelated HLA-matched donors, although formal
should be used throughout treatment. The intensive, risk-adapted evidence is lacking. If necessary, time to transplantation may be
chemotherapy regimen in APL should be based on anthracyclines, bridged with consolidation chemotherapy. The use of haploidenti-
cytarabine, and ATRA to avoid excessive anthracycline exposure. cal or very high-risk allo-HSCT must be balanced against the
Monitoring to detect molecular relapse allows earlier treatment, potential treatment related mortality and the possibility of survival
which might improve outcome. in late relapse after treatment with chemotherapy only.173
Patients who respond poorly to the first course of reinduction
chemotherapy, who do not achieve a second CR and who relapse
for the second time, can be offered more experimental therapy or
Therapy-related AML palliation alone. Data on allo-HSCT in AML with blast persistence
are scarce; however, survival rates are generally poor.167
Therapy-related secondary AML (t-AML) is one of the most Other options include GO (see “Antibody-targeted drugs”)
frequent secondary malignancies and generally follows the use of alone or in combination with other agents.174,175 More intensive
approaches include clofarabine monotherapy or combined with improved outcome in children with AML over the last 10 years is
cytarabine and/or liposomal daunorubicin/cyclophosphamide and probably associated with better supportive care strategies.
have shown moderate survival rates (26% and 38%, respectively)
in these heavily pretreated patients.176,177 Hyperleukocytosis
Initial hyperleukocytosis (arbitrarily defined as WBC ⱖ 100 ⫻ 109/L)

Recommendation
is associated with a high risk of hemorrhage (mainly in the CNS)
Children with relapsed AML should be treated with reinduction and leukostasis, which are often fatal. Patients with monocytic or
chemotherapy followed by allo-SCT. myelomonocytic leukemia (FAB M4/M5) and hyperleukocytosis
as well as APL patients have an increased risk of early death, and
emergency strategies to reduce these leukemia-related complica-
tions are needed.189,190
New therapy approaches In the case of hyperleukocytosis, emergency care with intensive
monitoring and careful hydration with concurrent administration of
The intensification of conventional chemotherapy along with
rasburicase may be necessary.191 If there are also symptomatic

improvements in supportive care has improved the prognosis in
coagulopathy and/or leukostasis, exchange transfusion or leu-
childhood AML. However, side effects and toxicity still remain a
kapheresis can be life-saving. Initiation of chemotherapy should
major concern. New compounds, such as epigenetically active
not be delayed. A controlled but effective cell reduction (eg,
agents, tyrosine kinase inhibitors, and antibody-mediated treat-
low-dose cytarabine; leukapheresis) together with enforced diure-
ment, might be effective but less toxic approaches in AML.
sis, or even hemodialysis, may prevent the severe tumor lysis
syndrome.189,190
Antibody-targeted drugs
Gemtuzumab ozogamicin. Gemtuzumab ozogamicin (GO), a Recommendation

calicheamicin-conjugated CD33 antibody, has shown promising For patients with initial hyperleukocytosis and symptomatic coagu-
results in children with AML.175,178,179 GO causes considerable lopathy and/or leukostasis, emergency strategies should be initiated
toxicity, especially myelosuppression with an extended thrombocy- to reduce the risk of fatal hemorrhage and leukostasis.
topenia, and veno-occlusive disease, but less frequently in children
than in adults.175 Moreover, such toxicity is dose related and has Prophylactic anti-infectious treatment
been shown to be significantly less pronounced at GO doses
of ⱕ 6 mg/m2 in recent studies.180 Salvage studies demonstrated Antifungal prophylaxis. The incidence of invasive fungal infec-
that the drug was beneficial in children who had poor chances of tions in children with AML is ⬃ 20%, which is similar to that in
survival by conventional therapy.175,181,182 adults, for whom prophylaxis with an antifungal agent is recom-
In adults, study MRC AML15 showed that GO was beneficial in mended. In adults, prophylactic posaconazole is more effective at
those with favorable cytogenetics and in part of patients in the reducing invasive aspergillosis and thus reducing mortality than
intermediate-risk group; however, there was no benefit to those in fluconazole or itraconazole.192 Unfortunately, posaconazole is not
the adverse-risk group.174 In addition, other recent international licensed for use in children younger than 13 years, and its dosage
studies on adult AML (by the French and United Kingdom groups) has not yet been defined for young children in the prophylactic
confirmed a survival benefit for AML subgroups when GO was setting; itraconazole, voriconazole, micafungin, or liposomal am-
added to induction chemotherapy.180,183-185 Recent data from a photericin B may be used instead. However, these compounds have
prospective nonrandomized COG trial showed that GO did not limitations, such as variable absorption or multiple potential
cause increased toxicity, but data on efficacy are pending.186 drug-drug interactions (eg, itraconazole and voriconazole), or can
However, as the approved indications for GO have been revised in only be administered intravenously (eg, echinocandins and ampho-
the United States by the FDA request, it may not be easily available tericin B formulations).193 As in other childhood malignancies,
for use in pediatric AML outside of clinical trials. cotrimoxazole prophylaxis should be used for Pneumocystis
jirovecii.194,195
Tyrosine kinase inhibitors
Recommendations
AML patients with activating FLT3 or KIT mutations are candi-
dates for targeted therapy. Many FLT3-targeting tyrosine kinase Antifungal prophyaxis (including trimethoprim-sulfamethoxazole
inhibitors (sorafenib, CEP701, PKC412, AC220) have been on trial for prophylaxis of P jirovecii) should be administered to all
in children or used on a compassionate-use basis.187 A recent report children.
from the St Jude Children’s Research Hospital demonstrated the
Antibiotic prophylaxis. Up to 70% of children have a microbio-
feasibility of combining sorafenib and conventional chemotherapy
logically documented bacterial infection per course of AML
in childhood AML, with some evidence of efficacy limited to
therapy, and bacterial infections remain a common cause of toxic
patients with FLT3-ITD.188
death.196 Importantly, the cumulative incidence of bacteremia with
viridans group streptococci is ⬎ 40% and is, in particular, associ-
ated with use of HiDAC and mucositis.197 However, there are
Supportive care insufficient data to recommend routine vancomycin prophylaxis in
this setting.198 A recent Cochrane review analyzing pediatric and
Several aspects of supportive care deserve special consideration in adult patients with various underlying malignancies suggested that
children, such as approval and dosing of pharmaceutical agents and antibiotic prophylaxis in afebrile neutropenic patients significantly
proxy-reporting of preferences and quality-of-life status. The reduced all-cause mortality, with the most significant reduction in
mortality observed in trials assessing prophylaxis with quino-

lones.199 Therefore, according to current guidelines, fluoroquino- Appendix
lone prophylaxis might be considered for high-risk patients with Panel
expected prolonged and profound neutropenia (absolute neutrophil
count ⬍ 100/␮L for ⬎ 7 days).199-202 This potential benefit of quino- The panel included 21 representatives from national groups from
lones must be weighed against an increase in antimicrobial resistance to Europe, the United States, and Japan collaborating in the AML
fluoroquinolones, which are not licensed for use in children. committee of the International Berlin/Frankfurt/Muenster (I-BFM)
Study Group who have clinical and research expertise in pediatric
Recommendation AML. Between May 2011 and February 2012, the panel met twice
in person and communicated extensively via electronic discussion
The use of fluoroquinolones may be considered as prophylaxis (mails and telephone conferences).
against Streptococcus viridans and gram-negative sepsis.
Participating groups
Hematopoietic growth factors Participating groups included the following: AIDA, Associazione
Italiana di Ematologia e Oncologia Pediatrica (Italy); BFM,

Although a recent survey demonstrated that there is a wide Berlin/Frankfurt/Münster (Germany, Austria, Switzerland, Czech
variation in the prophylactic use of G-CSF in children with Republic); COG, Children’s Oncology Group (United States);
AML,203 the routine use of hematopoietic growth factors, such as DCOG, Dutch Childhood Oncology Group (The Netherlands);
G-CSF or GM-CSF, is not recommended in this patient population. JPLSG, Japan Pediatric Leukemia and Lymphoma Study Group
Although G-CSF significantly decreases the duration of neutrope- (Japan); LAME, Leucémie Aiguë Myéloblastique Enfant (France);
nia in induction therapy, it does not influence the incidence of NCRI, National Cancer Research Institute (United Kingdom);
febrile neutropenia or microbiologically documented infections or NOPHO, Nordic Society of Pediatric Hematology and Oncology
affect infection-associated mortality.204,205 (Denmark, Finland, Island, Norway, Sweden); and St Jude AML
It has also been recently demonstrated that children who Study Group (United States).
overexpress the differentiation-defective G-CSFR isoform IV and
Scope of the review
receive G-CSF have a high risk of relapse.124 However, in critically
ill patients, shortening neutropenia by G-CSF may be an option. The expert panel has developed diagnostic and treatment recommen-
dations for AML in children and adolescents, motivated by recent
Recommendation recommendations from the adult AML panel.4 All the main
pediatric AML study groups were included, and an extensive
Prophylactic hematopoietic growth factors, such as G-CSF, should PubMed literature search (keywords ⫽ pediatric/childhood acute
not be used routinely. myeloid leukemia/AML, relapsed acute myeloid leukemia, diagno-
Transfusion support is an important issue in childhood AML. sis, risk stratification, therapy management, minimal residual
Information regarding this topic is given in the supplemental disease, mutations AML, cytogenetic/karyotype AML) was per-
Appendix (available on the Blood Web site; see the Supplemental formed. The majority of recommendations is based on well-
Materials link at the top of the online article). planned but nonrandomized therapy optimizing studies often
including randomized questions or on expert opinions with a
consensus of the panel.
Future perspectives
Diagnosis and treatment in pediatric AML has improved consider- Acknowledgments
ably during the past decades, with children currently achieving
5-year overall survival rates of ⬃ 70%. This has resulted from the The authors thank Hartmut Döhner (University Hospital of Ulm,
cooperative studies of national groups, leading to a stepwise Ulm, Germany) for valuable advice, constructive criticism, and
improvement of treatment, including improved supportive care. extensive guidance while preparing the manuscript; Ursula Berns-
The definition of risk groups has led to a more risk-adapted mann (Medical School Hannover, Hannover, Germany) for help in
treatment, avoiding overtreatment in low-risk patients and includ- preparing the manuscript; and Dr Vani Shanker (St Jude Children’s
ing more intensive therapy in others. The current risk definition is Research Hospital, Memphis, TN) for editing the manuscript.
mainly based on cytogenetics, a limited number of molecular
markers, and the response to induction therapy. Future genome-
wide approaches, such as gene expression analysis, methylation
Authorship
array studies, genomic profiling, miRNA profiling, and whole-
genome sequencing, will further expand the potential of diagnos- Contribution: U.C. assembled the sections; U.C., M.M.v.d.H.-E.,
tics and promote the identification of genes and involved pathways, D.R., G.J.L.K., B.G., and C.M.Z. wrote the final version of the
providing better insight into the leukemogenesis of pediatric AML. manuscript; and all authors reviewed the literature, wrote first
Knowledge of the biology may then translate into better treatment drafts of specific sections, and reviewed the final version of the
options and improved cure rates in conjunction with better manuscript.
risk-group adapted therapy and reduced late effects of therapy. Conflict-of-interest disclosure: The authors declare no compet-
International cooperation is extremely important, as not only is ing financial interests.
AML rare but also a very heterogenous disease, and only interna- Correspondence: Ursula Creutzig, Hannover Medical School,
tional collaboration will provide adequate numbers of patients to Children’s Hospital, Department of Paediatric Haematology and
power trial questions within subgroups as new targeted therapies Oncology, Carl-Neuberg-Str 1, D-30625 Hannover, Germany;
become available to children. e-mail: ursula@creutzig.de.
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Review article

Diagnosis and management of acute myeloid leukemia in children and

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BLOOD, 18 OCTOBER 2012 䡠 VOLUME 120, NUMBER 16 3187

ence of ambiguous morphology and cytochemistry, immunopheno-

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AML with recurrent genetic abnormalities14,15,209-211

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Not included in WHO 2008

Adverse karyotypes/mutations 32% 5%-6%

WHO classification continued

AML with myelodysplasia-related changes220,221 48% Unfavorable Low No prognostic significance

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Tests to establish the diagnosis

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Molecular genetics Biobanking

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MRD measurement should be incorporated in the context of Treatment failure

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CNS involvement at diagnosis and at relapse is seen in 5%-10% of

dosage in infants is generally calculated according to body weight Recommendation

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Initial hyperleukocytosis (arbitrarily defined as WBC ⱖ 100 ⫻ 109/L)

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Gemtuzumab ozogamicin. Gemtuzumab ozogamicin (GO), a Recommendation

mortality observed in trials assessing prophylaxis with quino-

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