++
The annual incidence of acute myeloid leukemia (AML) in children
remains constant, with the exception of a slight peak in infants
and during adolescence. After age 20 years, the incidence of AML
slowly increases with age. Infants with congenital leukemia are
more likely to have AML than acute lymphoblastic leukemia (ALL). Although
the incidence of AML in children in the United States is approximately
7 cases per million children per year or approximately 600 new cases
per year, there is a slightly higher incidence in Hispanic children
of 9 per million per year. The incidence also appears slightly higher in
Japan, Australia, and Zimbabwe. Of note, the incidence of AML has
been increasing slightly although steadily.
++
The cause of AML is unknown, and most children have no known
predisposing factors. Known risk factors include exposure to high-dose
ionizing radiation, previous chemotherapy (especially with alkylating
agents and epipodophyllotoxins), Down syndrome, congenital bone
marrow failure syndromes (Diamond-Blackfan anemia and Kostmann agranulocytosis;
see Chapter 430), chromosome fragility and
impaired DNA repair mechanisms (such as Fanconi anemia), and inherited
disorders, such as neurofibromatosis type I (NF1), which is due
to mutations in neurofibromin, a RAS-directed GTPase (see Chapter 182). Children with NF1 are at increased
risk of malignant disease, including myelodysplastic and myeloproliferative
syndromes. The increased concordance of leukemia in identical twins
(approximately 15%) appears to result from transplacental
transfer of a single leukemic clone rather than from a genetic predisposition
and approaches 100% for infant leukemia.
++
Children with Down syndrome have a greater than 15-fold increased
risk of leukemia compared to infants without Down syndrome. During
the first three years of life, acute myeloid leukemia (AML), especially
the megakaryoblastic subtype, predominates, but thereafter the ratio of
acute lymphoblastic leukemia (ALL) to AML follows the usual childhood
distribution. Besides being at risk for acute leukemia, children
with Down syndrome or trisomy 21 mosaicism are at risk of transient
myeloproliferative disorder (TMD). This syndrome
is usually diagnosed during the first several days to weeks after
birth and cannot be reliably differentiated from congenital AML.
Infants with TMD often have elevated leukocyte counts (> 50,000/μL)
with circulating blasts, hepatosplenomegaly, effusions, and may
have hydrops. Bone marrow aspirations from these children usually
have a lower blast percentage compared to peripheral blood. Unlike congenital
AML, TMD usually resolves spontaneously within several weeks to
months in about 80% of cases without cytotoxic therapy.
However, 5% to 10% of neonates with TMD die from
hepatic failure or multiorgan failure. In some of these patients,
hepatic fibrosis has been associated with megakaryoblast infiltration
of the liver. The blasts from infants with TMD have been shown to
be clonal, have cell surface antigens characteristic of megakaryoblasts,
and have mutations in the GATA-1 gene, an erythroid/megakaryocytic
restricted transcription factor. Recent data indicate that up to
30% of neonates who have spontaneous regression of TMD
will develop AML before age 3 years. It is usually of the megakaryoblastic
subtype and the blasts have been shown to harbor the same GATA-1 mutation
as found in the transient blast population of TMD. Interestingly,
these children respond well to chemotherapy and have about an 80% likelihood
of overall survival. At present, the only neonates with TMD who
are recommended to be treated include those with hepatic manifestations
or very high white blood cell counts at diagnosis (> 50,000/μl).
Treatment for these neonates usually includes low doses of cytosine
arabinoside.
++
The risk of secondary AML among children and adults previously
treated with alkylating agents and topoisomerase-II inhibitors,
especially epipodophyllotoxins, is well established. Leukemia associated
with use of an alkylating agent occurs within 4 to 10 years after
initial therapy, is usually associated with abnormalities of chromosomes
5 and 7, and carries a grave prognosis. Leukemia associated with
use of an epipodophyllotoxin (etoposide and teniposide) has a shorter
latency (2–4 years) and usually is of the myelomonocytic
or monocytic subtype; characteristically, translocations involving
chromosome 11q23 with rearrangement of the MLL gene
are noted. Children with the latter forms of leukemia often achieve
complete remission with chemotherapy but invariably relapse and
die unless they are treated by means of bone marrow transplant.
+++
Clonality and Pathogenesis
++
Acute myeloid leukemia (AML) is a clonal disorder that is the
consequence of acquired molecular alterations in hematopoietic progenitor
cells that cause differentiation arrest and confer proliferative
growth advantage to the affected clone. Early studies using X-linked
polymorphism and more recent molecular techniques have demonstrated
clonal origin of AML, showing that leukemic cells share common genetic
composition and are believed to have been derived from a common
ancestral cell. Further clonal evolution leads to acquisition of
new abnormalities, leading to molecular divergence from the original
clone and providing additional complexity to the original clone.1 Initiating
events in the evolution of the leukemic clone and subsequent expansion
and clonal dominance may occur due to different events at different
stages of hematopoietic development, where the initiating event
may lead to maturation arrest followed by a secondary event leading
to clonal dominance of the immature population and development of
the AML. This idea is supported by the fact that no single event has
been demonstrated to cause AML, and it is widely accepted that multiple
molecular events cooperate to lead to leukemic phenotype.2 One
major contributor to AML pathogenesis is acquisition of cytogenetic
abnormalities, including balanced or unbalanced chromosomal translocation,
deletion or duplication of a region, or the entire gene. In childhood
AML, approximately 80% of the patients have one of more
than 300 identified cytogenetic abnormalities ranging in prevalence
from less than 1% to greater than 15%. In addition,
somatically acquired mutations in genes involved in AML pathogenesis
have been identified that cooperate with specific cytogenetic alterations
to cause AML phenotype.
++
During a morphologic remission, the clone is no longer detectable
except with molecular methods. During hematologic relapse, the original
clone reappears. The transforming event in acute myeloid leukemia
(AML) could occur at any point in hematopoiesis from the pluripotent stem
cell to a committed precursor, such as the myeloblast or erythroblast.
Both animal and human data, however, provide evidence that the leukemic
stem cell in AML is a primitive hematopoietic stem cell in most
instances.
++
High-resolution banding, fluorescent in situ hybridization (FISH),
and molecular genotyping methods have helped identify genetic abnormalities
in majority of children with acute myeloid leukemia (AML). Cytogenetic
abnormalities are identified in nearly 80% of childhood
AML, many of which are unique to AML. Nearly 300 recurrent cytogenetic
abnormalities including translocations, deletions, or duplications have
been identified. The most common chromosomal abnormalities in children
and young adults with AML include inv16, t(15;17), (8;21), and chromosome
11q23 abnormalities (Fig. 450-1), which
account for nearly half of the AML cases, and occur at a higher
rate in pediatric populations compared to adults. Other cytogenetic
abnormalities, including monosomy 5 or deletion 5q, monosomy 7,
and trisomy 8, are less common in children and have a higher prevalence
in adults. The molecular events associated with many of the structural
chromosomal changes have now been elucidated. Many of the genes cloned
at the breakpoints of the chromosomal translocations or inversions
are transcription factors. Polymerase chain reaction (PCR)–based
assays are utilized both for diagnostic purposes as well as to evaluate response
to therapy, where one leukemic cell in a background of one million
normal cells in a blood or bone marrow sample can be detected. In
the case of acute promyelocytic leukemia (APL), PCR-based assays
have been utilized to assess disease response and to guide therapy,
where treatment of disease at the molecular level has been shown
to prevent overt leukemic relapse and improve outcome.3,4 Such
approaches in utilizing cytogenetic abnormalities as tools to detect
the presence of residual disease not amenable for identification
by conventional means is being expanded to other cytogenetic abnormalities
(Fig. 450-1).
++
++
Precise diagnosis and classification is essential to successful
management and biologic investigation of childhood leukemia. In
1976, the French-American-British (FAB) Cooperative Group proposed
a classification system based primarily on morphology and cytochemical
features of the blasts and required at least 30% bone marrow blasts
for the diagnosis of acute myeloid leukemia (AML). Although FAB
classification provided a valuable tool for general classification
of AML, it lacked the ability to predict accurately cytogenetic
subclasses, and, in general, did not provide reliable prognostic
information.
++
In 2002, the World Health Organization (WHO) proposed a new classification
system that incorporated diagnostic cytogenetic information, which
more reliably correlated with outcome into AML classification. In
this classification, patients with t(8;21), Inv(16), t(15;17) and
those with MLL translocations, which collectively
constituted nearly half of the cases of childhood AML were classified
as “AML with recurrent cytogenetic abnormalities.” This
classification system also decreased the marrow blast percentage
requirement for the diagnosis of AML from 30% to 20%,
with additional clarification that those with the recurrent cytogenetic
abnormalities did not need to meet the minimum blast requirement. More
recently, WHO expanded the number of cytogenetic abnormalities linked
to AML classification, and for the first time included specific
gene mutations (FLT3, CEBPA, and NPM mutations)
in its classification system (Table 450-1).
Such a genetically based classification system links AML class with
outcome and provides significant biologic and prognostic information.
With new emerging technologies aimed at genetic, epigenetic, proteomic,
and immunophenotypic classification, AML classification will continue
to evolve and provide informative, prognostic, and biologic guidelines
to clinicians and researchers.
++
+++
Clinical and Laboratory
Features
++
The initial signs and symptoms for most children with acute myeloid
leukemia (AML) include anemia, thrombocytopenia, and neutropenia caused
by bone marrow infiltration with leukemic blasts and decreased production
of normal cells. Patients commonly present with pallor, fatigue,
epistaxis, gum bleeding, petechiae, or purpura, as well as fever
or infection that has not responded to antibiotic therapy. Children with
AML may have bone or joint pain, but these symptoms occur more often
in children with acute lymphoblastic leukemia (ALL). Bulky peripheral lymphadenopathy
is not a common finding, and massive hepatosplenomegaly is rare
with AML except among infants. Extramedullary leukemia can present
as gingival hyperplasia, central nervous system (CNS) leukemia (headache,
cranial nerve palsy), and skin nodules. Neonates and infants with
AML frequently have leukemia cutis characterized by a papular or
nodular rash that is salmon or bluish to slate gray in color. Clinical
findings of CNS leukemia at diagnosis are rare. They include signs
of increased intracranial pressure or cranial nerve palsy, seventh nerve
palsy being the most common. Fewer than 5% of patients
with AML have myeloblastomas (also known as granulocytic
sarcoma or chloroma) at diagnosis or during
the course of the illness. These are solid tumors of blasts and
immature myeloid cells that typically occur in the bones and soft
tissues of the head and neck (often involving the orbits), intracranial
or epidural sites.
++
Peripheral blood counts at diagnosis in children with AML can
be quite varied. The leukocyte count ranges from less than 1000/μL
to more than 500,000/μL. Approximately
15% to 20% of children have an initial leukocyte
count greater than 100,000/μL. Higher
leukocyte counts are associated with the FAB, M4, and M5 subtypes,
whereas lower leukocyte counts (< 5000/μL)
are commonly seen in acute promyelogonous or M3 leukemia (acute
promyelocytic leukemia [APL]). Most patients have
a normocytic anemia (median hemoglobin concentration of 7 g/dL
in one series), and approximately 50% of patients have
platelet counts less than 50,000/μL. Disseminated
intravascular coagulation is extremely common among almost all patients
with APL and some infants with monocytic leukemia.
++
The characteristic bone marrow findings include hypercellularity
with more than 20% blasts (usually 70–90% blasts).
A bone marrow biopsy infrequently shows myelofibrosis (except for
megakaryoblastic) and occasional multilineage dysplasia.
++
In most cases of AML, the diagnosis is straightforward after
examination of the peripheral blood sample and a bone marrow aspirate.
Other conditions that can cause diagnostic difficulty include the
myeloproliferative disorders such as juvenile myelomonoctic leukemia,
myelodysplastic syndromes, sepsis that causes a leukemoid reaction,
or neutropenia caused by maturation arrest in granulocytic-monocytic precursors.
In the presence of sepsis, the bone marrow findings may suggest
acute promyelocytic leukemia because of a promyelocyte arrest with
toxic granulation. However, normal granulocytic maturation ensues
within a few days with resolution of the infection. As previously
discussed, acute myeloid leukemia among neonates with Down syndrome
is difficult, if not impossible, to differentiate from transient myeloproliferative
disorder (TMD).
+++
Management of
Newly Diagnosed Acute Myeloid Leukemia
++
Substantial improvement in survival rate from less than 10% to
approximately 50% of children with acute myeloid leukemia
(AML) has occurred during the past 30 years. The improvement is
the result of a higher percentage of children entering complete
remission, a decrease in relapse rate because of more effective
postremission strategies, including allogeneic hematpoietic stem
cell transplantation (HSCT), and improvements in supportive care.
All children with AML should be referred to pediatric oncology centers
and treated on clinical trials.
+++
Induction of
Remission
++
The most widely used remission-induction regimen includes treatment
with an anthracycline (usually daunorubicin) and cytarabine arabinoside
with or without thioguanine or etoposide. With these regimens, 85% to
95% of children with acute myeloid leukemia (AML) enter complete
remission after receiving 1 to 2 cycles of induction chemotherapy.
Because the remission-induction phase of therapy is associated with prolonged
cytopenias (3–5 weeks), 2% to 5% of patients
may die of infectious or hemorrhagic complications before completing
the induction phase. Deaths during the first several days after diagnosis
are rare and often are caused by leukostasis or disseminated intravascular
coagulation. Leukostasis, or plugging of blasts in vessels, is associated
with elevated peripheral blast counts (more than 100,000/μL)
and can cause hemorrhagic infarction of the brain or other organs.
A greatly elevated leukocyte count is a medical emergency, and measures
should immediately be taken to decrease the leukocyte count with chemotherapy
(eg, hydroxyurea), exchange transfusion, or leukopheresis if the
patient has symptoms, such as hypoxemia or mental status changes.
Intensifying the doses or timing of chemotherapy during the remission-induction
phase of treatment has not increased the percentage of children
achieving complete remission but has resulted in a decrease in relapse
rates and improvement in overall survival rates.
++
All-trans-retinoic acid (ATRA) has been shown to
be a very effective drug for inducing remissions in patients with
acute promyelocytic leukemia. All-trans-retinoic
acid used alone is not curative but when ATRA is combined with induction
chemotherapy, usually with an anthracycline, the combination is
effective at achieving greater than 90% remission rates and
with continued chemotherapy and ATRA, a 75% to 85% survival.
++
Supportive care measures during all phases of therapy for AML
are critical. They include providing indwelling central venous access,
antiemetic agents, psychosocial support for the child and family,
monitoring for the metabolic consequences of leukemic cell lysis
(tumor lysis syndrome), empiric therapy for fever and neutropenia
with broad-spectrum antibiotics, prophylactic platelet transfusion,
administration of allopurinol or rasburicase in situations of very
high leukemic counts, and prophylaxis of Pneumocystis jiroveci pneumonia
and fungal infections. Use of hematopoietic growth factors has not
increased remission rates or overall survival rates among children
with AML. In some studies, use of these factors has been associated
with slightly less infectious morbidity during periods of neutropenia.
All blood products should be irradiated to prevent transfusion-associated
graft-versus-host disease (GVHD).
+++
Central Nervous
System Therapy
++
Unlike for acute lymphoblastic leukemia (ALL), management of
occult central nervous system (CNS) leukemia with intrathecal chemotherapy alone
or combined with cranial irradiation has not been shown to improve
overall survival among children with acute myeloid leukemia (AML).
Most AML protocols, however, include intrathecal chemotherapy because
isolated CNS disease has been found in approximately 20% of children
who receive no CNS-directed therapy. Between 3% and 20% of
children with newly diagnosed AML have been reported to have leukemic
blasts in the cerebrospinal fluid; they are treated with weekly
intrathecal chemotherapy until the cerebrospinal fluid is cleared
of leukemic blasts. Cranial radiation is not required. The presence
of leukemic blasts in the spinal fluid at diagnosis does not appear
to have an adverse impact on prognosis.
+++
Treatment in
Remission
++
Unlike therapy for acute lymphoblastic leukemia (ALL), the use
of modestly myelosuppressive combination chemotherapy after remission
has had little effect on reducing the relapse rate among patients
with acute myeloid leukemia (AML). With intensification or consolidation chemotherapy
that has included high doses of cytarabine, the 5-year leukemia-free
survival rates have increased from 10% to 50% overall, but
up to 75% in some groups with good risk AML. The optimal
intensity and duration of postremission chemotherapy remain under
active investigation. The use of novel treatment approaches, including
combining immunotoxins with chemotherapy, or adding targeted therapies,
such as inhibitors of activated tyrosine kinases (FLT3 or c-KIT)
or proteasome inhibitors to treatment regimens, are experimental strategies
that are being pursued.
+++
Bone Marrow
Transplantation
++
The use of marrow ablative doses of chemotherapy with or without
total body irradiation, followed by hematopoietic stem cell transplantation (HSCT)
from a histocompatible family donor, in the care of children with
acute myeloid leukemia (AML) in initial remission, was first attempted
in the mid-1970s (see Chapter 133). Although
there is a statistically significant disease-free survival advantage
for allogeneic HSCT compared with chemotherapy, this has not translated
into increased overall survival, in part because of HSCT-related
mortality. Currently, patients in the United States will be offered
allogeneic HSCT during their first remission if they have standard
or high-risk AML, but only after relapse and achieving a second remission
for patients with favorable-risk AML. In several large, prospectively
randomized pediatric trials, it has been shown that autologous bone
marrow transplant (BMT) is comparable to intensive chemotherapy
in the first remission of AML.
++
Prognostic factors include host factors and response to therapy,
as well as disease characteristics. These factors are generally
interdependent, the sum of which ultimately determine disease response
and patient outcome. In addition, prognostic factors may change
as treatment changes, thus necessitating the evaluation of all established
and putative prognostic markers within the framework of a defined
therapy. Efforts to identify risk factors in acute myeloid leukemia
(AML) are directed to define populations who may benefit from alternative
therapies. Patients at lower risk of relapse may benefit from treatment
de-escalation, sparing them adverse side effects. Management of
high-risk patients may prove more difficult, as the nearly myeloablative
nature of AML therapy leaves little room for therapy escalation
short of stem cell transplantation. Host factors, such as gender,
age, race, and constitutional abnormalities, have been studied for
their correlation with outcome in children with AML. Although some
host factors including race5 and nutritional status6 have
been linked to clinical outcome, currently their correlation has
not been strong enough to justify alteration of therapy.
++
Disease characteristics inherent to AML include factors such
as diagnostic white blood cell (WBC) count, morphologic classification (French-American-British—FAB
subtype), and biological characteristics, such as cytogenetics or
gene mutations. Although WBC count has been demonstrated to be a
prognostic factor in AML, where those with high WBC count have a worse
outcome,7 it has been determined that WBC count reflects
the underlying biology of the disease and in the context of cytogenetics
and other molecular alteration, it is not an independent predictor
of relapse.8
++
Diagnostic cytogenetics is widely recognized as one of the most
significant prognostic factors in AML, distinguishing favorable
risk patients from those at high risk of relapse. Two of the most
commonly identified translocations in pediatric AML, t(8;21) and
inv(16) leukemias, collectively account to 15% to 20% of
childhood AML. Together, these leukemias are often referred to as
core-binding-factor (CBF) leukemias because the AML1-ETO fusion produced
by the t(8;21) and the CBFa-MYH11 fusion produced by the inv(16)
both disrupt CBF.9,10 Numerous adult and pediatric studies
have demonstrated that patients with t(8;21) or inv(16) have superior
outcome compared to other AML patients.11,12 Acute promyelocytic
leukemia (APL) is currently the most curable form of AML with cure
rates of 70% to 90% in children and adults.13 The
underlying t(15;17) translocation in APL, which leads to formation
of the PML-RARalpha fusion protein, leads to maturational arrest
in the promyelocyte stage. This maturation arrest can be overcome with
pharmacologic doses of all-trans retinoic acid (ATRA). Due to its
sensitivity to prodifferentiation therapy, (ATRA) APL is treated
differently than other AML subtypes with excellent outcomes.14-16 More
recently, addition of arsenic acid to ATRA and chemotherapy has
provided further improvement in outcome.17
++
Karyotypes associated with poor outcome have been identified
in a smaller proportion of pediatric patients with AML. Monosomy
7 (–7), monosomy 5 (–5) and deletion of q arm
of chromosome 5 (del5q), which collectively account for approximately
5% of the cases of childhood AML, are strongly associated
with poor remission induction and high relapse risk.11,18,19 Complex
cytogenetics, where multiple cytogenetic abnormalities are present
in the leukemic blasts have been associated with higher relapse
risk and worse outcome. Some studies define complex karyotype as
the presence of 5 or more abnormalities,18,20 whereas others
use greater than or equal to 3 abnormalities.12,21-23
++
Molecular alterations including mutations, deletions, insertions,
or duplications in the genes involved in hematopoiesis have been
associated with AML pathogenesis. Whether it is the constitutive
activation of a receptor by intrinsic receptor gene mutations (FLT3,c-KIT, and c-Fms mutations),24-26 the
autocrine/paracrine stimulation of the receptor by a ligand
secreting tumor (vascular endothelial growth factor—VEGF
receptor),27,28 or the activation of the downstream effectors
(eg, RAS genes),29-31 such activating
events directly contribute to disease pathogenesis, progression,
and resistance to chemotherapy. The presence of mutations in several
genes has been associated with disease outcome and has been used
to identify patients at high risk of relapse, as well as those expected
to do well. Internal tandem duplication of the FLT3 gene
(FLT3/ITD), a gene involved in regulation
of stem cell differentiation, has been associated with high risk
of relapse in children with AML.8,32 This mutation occurs
in approximately 12% of childhood AML patients and is prevalent
in patients with normal cytogenetics and those with high diagnostic
WBC. Recent studies have linked allelic variation of FLT3/ITD to
disease outcome, where those with high allelic ratio (~80% of
those with FLT3/ITD) have exceedingly
high risk of relapse with conventional chemotherapy, whereas FLT3/ITD-positive
patients with low allelic ratio have an outcome similar to those
without FLT3/ITD (Fig.
450-2A).8 Mutations of other
genes have been associated with favorable outcome. CEBPα is
a transcription factor that regulates granulocytic differentiation.
Mutations in CEBPα gene, which leads to neutrophilic
maturation arrest, have been identified in approximately 5% of
childhood AML. This mutation is mainly observed in patients with
normal karyotype and is associated with extremely low relapse risk
and favorable outcome (Fig. 450-2B)33 Nucleophosmin
(NPM), a nucleocytoplasmic shuttling protein with prominent nucleolar
localization, regulates the ARF-p53 tumor-suppressor pathway. Mutations
in the NPM gene have been reported in AML that lead to the abnormal
cytoplasmic localization of the affected protein.34 NPM
mutations have been reported in 30% to 50% of
adult AML,35 with a prevalence of approximately 10% in
children.36
++
++
Evaluation of the prognostic significance of NPM mutations suggests
that presence of NPM mutations correlate with favorable outcome
in adult AML patients with normal karyotype without FLT3/ITD.35,37,38 Studies
in pediatric AML have demonstrated the prevalence of NPM mutations
in 7% to 10% of patients with the prevalence of
nearly 20% in those with normal karyotype. Early data suggests
that presence of NPM mutations children with normal cytogenetic
and no FLT3/ITD is predictive of improved
outcome similar to those with core binding factor AML.39,40 Larger,
more definitive studies are needed to confirm NPM mutation as a
prognostic factor in childhood AML (Fig. 450-2).
+++
Management of
Refractory Acute Myeloid Leukemia
++
The prognosis is poor for children who do not enter remission
with an anthracycline-cytarabine regimen or who have a relapse.
Allogeneic hematopoietic stem cell transplantation (HSCT) offers
these patients the best chance for long-term survival.
++
De novo or acquired drug resistance is the main cause of treatment
failure among patients with acute myeloid leukemia (AML), and several
mechanisms of drug resistance have been elucidated. Increased expression
of the multidrug resistance gene (MDR1) and its
product, P-glycoprotein, has been detected in blasts from approximately
40% to 60% of children and adults with relapsed
AML. Increased expression of P-glycoprotein promotes the cellular
efflux of many natural-product drugs, including anthracyclines and
etoposide, and is associated with in vitro resistance. Several P-glycoprotein
inhibitors, including cyclosporine, are capable of reversing the
multidrug resistant phenotype in vitro through
direct interaction with P-glycoprotein, but clinical trials have
failed to show a benefit of adding mdr reversal agents to chemotherapy.
Alternative approaches to circumvent resistant disease using targeted
immunotherapies and vaccine therapies, as well as small molecule
inhibitors of signal transduction and protein degradation pathways
are all being actively tested in patients with relapsed and/or
refractory AML.