CME

Pediatric Acute Lymphoblastic

Leukemia: From Diagnosis
to Prognosis
Warren Alperstein, MD; Mary Boren, MD; and Jennifer L. McNeer, MD, MS

Abstract
Warren Alperstein, MD, is a Resident in
Pediatric acute lymphoblastic leukemia is the most common childhood cancer. Although
Pediatrics, Comer Children’s Hospital, Pritz-
the appearance of the disease is often quite dramatic, there are many patients who pres- ker School of Medicine, University of Chi-
ent much more indolently, creating a diagnostic dilemma for the primary care pediatrician. cago. Mary Boren, MD, is a Resident in Pe-
The appropriate diagnostic work-up assesses the initial extent of disease and stability of a diatrics, Comer Children’s Hospital, Pritzker
patient, and provides information that is important for risk stratification. Such information School of Medicine, University of Chicago.
includes patient age and white blood cell count at diagnosis, leukemia immunophenotype, Jennifer L. McNeer, MD, MS, is an Attending
presence or absence of extramedullary disease, and blast cytogenetic abnormalities. After Physician, Section of Pediatric Hematol-
therapy is initiated, the response of the disease to treatment is key for predicting outcomes. ogy/Oncology/Stem Cell Transplant, Comer
Altogether, this information is used to guide overall treatment intensity. Chemotherapy is Children’s Hospital; and an Assistant Profes-
administered in sequential blocks or phases, and lasts for several years. In general, outcomes sor of Pediatrics, Pritzker School of Medi-
cine, University of Chicago.
are excellent and the majority of patients survive, but there are still subsets of patients who
Address correspondence to Jennifer
do not fare as well, either due to resistant or recurrent disease, or due to long-term and late
L. McNeer, MD, MS, 5841 S. Maryland Av-
effects of therapy. [Pediatr Ann. 2015;44(7):e168-e174.]
enue, MC 4060, Chicago, IL 60637; e-mail:
jmcneer@peds.bsd.uchicago.edu.
Disclosure: Jennifer L. McNeer discloses
consulting fees from Jazz Pharmaceuticals.
The remaining authors have no relevant fi-
nancial relationships to disclose.
10.3928/00904481-20150710-10
© Shutterstock

e168 Copyright © SLACK Incorporated


A
previously healthy 3-year-old
toddler presented to an outside
emergency room with fever and
abdominal pain. Physical examination
and computed tomography scan of the
abdomen suggested appendicitis, and
the patient underwent an uncomplicated
appendectomy. However, on pathologic
evaluation there was no appendicitis.
The boy was diagnosed with mesenteric
adenitis and discharged home. The fevers
and abdominal pain continued, and bilat-
eral leg pain developed. Upon evaluation
by his primary pediatrician, otitis media
was diagnosed and he was prescribed an-
tibiotics. The fevers continued, and labo-
ratory work was significant for elevated
inflammatory markers. Echocardiogram
and bone scan were obtained, and due to
enhancement of several vertebrae as well
as the left ankle on bone scan, a referral
to pediatric rheumatology was made.
In addition to the above history, the
review of systems at the time of the
rheumatology visit was significant for
decreased oral intake over several weeks,
resulting in a 4-lb weight loss. During
physical examination, the patient ap-
peared generally uncomfortable and was
lying in bed in a flexed position, but there
were no focal findings.
The patient was admitted for further
evaluation. A complete blood count
(CBC) revealed a white blood cell
(WBC) count of 5.2 × 103/mcL, hemo-
globin of 9.2 g/dL, and a platelet count
of 102 × 103/mcL. The differential was
48% neutrophils, 45% lymphocytes, and
7% monocytes. A comprehensive meta-
bolic panel (CMP) was unremarkable.
C-reactive protein was elevated at 162
mg/L (normal <5 mg/L) and erythrocyte
sedimentation rate was 162 mm/h (refer-
ence range 0-15 mm/h). Lactate dehy-
drogenase (LDH) was elevated at 511
U/L (normal 116-245 U/L), as was the
ferritin, which was 465 ng/mL (normal,
20-300 ng/mL).
Because of the anemia and throm-
bocytopenia, an oncology consult was
PEDIATRIC ANNALS • Vol. 44, No. 7, 2015
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requested. Bone marrow aspirate and
biopsy were performed, which revealed
B-cell acute lymphoblastic leukemia
(B-ALL).
PRESENTATION OF ALL
Demographics
Acute lymphoblastic leukemia
(ALL) is the most common childhood
cancer. There are about 2,500 to 3,000
new cases of pediatric ALL diagnosed
in the United States each year, with a
peak incidence in children between
ages 2 and 5 years.1 The exact patho-
genic events leading to the develop-
ment of ALL are unknown. However,
Some may present with
symptoms of anemia,
namely fatigue and
lethargy.
about 5% of cases are associated with
inherited genetic syndromes. Those
with Down syndrome have a 10- to
30-times greater risk of developing
any type of leukemia, most commonly
ALL. Children with certain autosomal
recessive genetic diseases associated
with chromosomal fragility such as
ataxia-telangiectasia, Nijmegen break-
age syndrome, and Bloom syndrome
have an increased risk of ALL. There is
no clear link between infectious expo-
sure and the development of ALL. On
the other hand, exposure to high-dose
radiation and benzene are recognized
risk factors for developing ALL, but
these associations are rarely found in
children.2
Symptoms
The symptoms of ALL can be very
nonspecific, may gradually become
evident over a period of months, or
they may appear acutely.3 Approxi-
mately half of patients present with fe-
ver, which is thought to be induced by
pyrogenic cytokines released from leu-
kemic cells. Half of patients have firm,
nontender lymphadenopathy. Young
children may present with a limp, bone
pain, or unwillingness to walk because
of leukemic infiltration of the perios-
teum, bone, or a joint. Some may pres-
ent with symptoms of anemia, namely
fatigue and lethargy. Rarely, ALL may
present with bleeding secondary to
thrombocytopenia or a serious infec-
tion secondary to neutropenia. How-
ever, peripheral blood counts can be
relatively normal, and there are not al-
ways circulating blasts. Therefore ALL
cannot be ruled out when the blood
counts are not overtly abnormal, as in
the illustrative case.
Laboratory Evaluation and
Diagnosis
The initial evaluation includes a
CBC with differential and review of
the peripheral blood smear, examining
carefully for the presence of leukemic
blasts, which are present at diagnosis
in about 90% of patients.2 Hyperleu-
kocytosis (>100 × 103 WBC/mcL)
occurs at diagnosis in about 12% of
white children and in about 23% of
African-American children,2 who are
more likely to be diagnosed with the
T-lymphoblastic immunophenotype
of ALL (T-ALL). It is important in all
patients, but in particular those with
hyperleukocytosis to assess for tumor
lysis syndrome (TLS) by obtaining a
CMP and uric acid level. Tumor lysis
syndrome can occur spontaneously or
with the initiation of chemotherapy,
and is characterized by hyperphospha-
temia, hyperkalemia, hypocalcemia,
and hyperuricemia that occur when
leukemic cells rupture and release their
contents into the circulation. This most
commonly occurs in tumors with a
high proliferation rate, and the risk of
TLS can be gauged both by the WBC
e169

count and the initial LDH. All patients
should have a chest radiograph to as-
sess for a mediastinal mass, which is
more commonly observed in patients
with T-ALL than B-ALL.
A bone marrow aspirate and biopsy is
obtained at initial presentation to docu-
ment the extent of marrow involvement
and to determine immunophenotype
(ie, B-cell versus T-cell disease). Lym-
phoblasts contain fine chromatin, small
nucleoli, and scant agranular cytoplasm
(Figure 1). Acute lymphoblastic leuke-
mia is defined as involvement of 25%
of marrow cellularity by lymphoblasts,
but can be diagnosed in cases with fewer
blasts if a known recurring cytogenetic
abnormality is identified.4 The particu-
lar immunophenotype is identified using
flow cytometry, a process by which cells
are stained with a panel of antibodies to
determine which markers are expressed
on the surface of the malignant cells. In
B-ALL, the tumors cells are positive for
terminal deoxynucleotidyl transferase
(TdT), an enzyme that is expressed only
in immature B and T cells and certain B-
Figure 1. Bone marrow aspirate demonstrating acute lymphoblastic leukemia. Sheets of lymphoblasts
with characteristic smooth chromatin and scant cytoplasm are present.
e170
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lineage proteins such as CD19, CD22,
CD20, and CD79a, and negative for
surface immunoglobulin, which appears
only on mature B cells. Cases of T-ALL
express TdT and variable combinations
of T-lineage antigens such as CD1a,
CD3, CD4, CD5, CD7, and CD8.3 Be-
sides determining the immunophenotype
of the leukemia, the marrow sample is
also processed for cytogenetic analysis
to aid with risk stratification.
At diagnosis, the presence or absence
of extramedullary disease must be docu-
mented. Central nervous system (CNS)
involvement is defined as the presence of
cranial nerve palsies by history or physi-
cal examination, or the finding of leuke-
mic blasts in the cerebrospinal fluid ob-
tained via lumbar puncture. In all boys,
a testicular examination, and for some a
biopsy, is required to determine whether
there is testicular involvement. Patients
with extramedullary disease require
modification of their therapy to intensify
therapy to these immune-privileged sites.
Although making a diagnosis is usu-
ally straightforward once a bone mar-
row biopsy is obtained, occasionally
diagnostic difficulties arise in children
with severe viral infections. At times,
the immune response may increase the
production of normal precursor B cells
in the bone marrow, leading to suppres-
sion of other hematopoiesis and resulting
in modest granulocytopenia. It is usually
not difficult to distinguish such processes
from B-ALL because reactive popula-
tions of lymphoblasts include cells from
all stages of early B-cell development
and never replace the marrow. In con-
trast, neoplastic lymphoblasts tend to
have a uniform immunophenotype repre-
senting one or another stage of early B-
cell development, the hallmark of acute
leukemia.3
RISK STRATIFICATION
Risk stratification for children with
ALL is of utmost importance as we are
increasingly tailoring therapy for each
patient. By using risk-based treatment
we can provide less toxic treatment to
patients with more favorable progno-
ses, and for those with higher-risk dis-
ease, we can intensify therapy early on
to improve outcomes.
Immunophenotype and National
Cancer Institute Risk Groups
The initial distinction to be made
is between B-cell and T-cell leukemia.
This initial distinction is critical as T-
ALL is more aggressive and requires
higher-intensity treatment. Histori-
cally, patients with T-ALL did not fare
as well as those with B-ALL, but with
modern therapeutic approaches the
outcomes for patients with T-ALL are
approaching those of patients with B-
ALL.5-8
Patients with B-ALL are initially
divided into standard- and high-risk
subsets at the time of diagnosis, based
on age and WBC count. These criteria
were established as prognostically im-
portant by the National Cancer Institute
(NCI) in 1996 and retain significance
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Summary of B-Cell Acute Lymphoblastic Leukemia Risk Classification
Risk Factor
NCI risk group
Cytogenetics
Other characteristics
Minimal residual disease
Abbreviations: BM, bone marrow; CNS, central nervous system; iAMP, intrachromosomal amplification of chromosome 21; NCI, National Cancer Institute; WBC, white blood cell.
a
Hyperdiploidy: >50 chromosomes or DNA index of ≥1.16.
b
Hypodiploidy: <44 chromosomes or DNA index <0.81.
to this day.9 Patients who are between
ages 1 and 10 years at the time of diag-
nosis and have a WBC <50 × 103/mcL
are considered to have standard-risk
disease. As a group, these patients
have a 4-year event-free survival (EFS)
rate of >80%.10 Patients who are ei-
ther younger than age 1 year or age
10 years or older age at diagnosis, or
have a WBC ≥50 × 103/mcL are con-
sidered high risk, and require more in-
tense treatment regimens. In particular,
infants younger than age 1 year with
ALL have very aggressive disease, and
treatment regimens exist specifically
for patients in this age group.
Cytogenetics
Cytogenetic abnormalities within
the leukemic blasts are an important
component of risk stratification for
patients with B-ALL, and individual
abnormalities are considered to be
favorable, unfavorable, or intermedi-
ate. Favorable factors include a trans-
location between chromosomes 12
and 21 [t(12;21)], which results in the
ETV6-RUNX1 fusion protein, or hy-
perdiploidy (>50 chromosomes per
leukemic cell), specifically with triso-
mies of chromosomes 4 and 10. Ap-
proximately 50% of patients younger
PEDIATRIC ANNALS • Vol. 44, No. 7, 2015
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TABLE 1.
Favorable
Age: 1-10 years
WBC <50 x 103/mcL
Hyperdiploidya
Trisomy 4 & 10
t(12;21)
<0.01% on Day 29 BM
than age 10 years with B-ALL will
have favorable cytogenetics.11
Unfavorable cytogenetic abnor-
malities include t(9;22), known as the
“Philadelphia chromosome,” which
results in production of the BCR-ABL
fusion protein, a constitutively active
tyrosine kinase that requires incorpo-
ration of a tyrosine kinase inhibitor
(TKI) into therapy. The presence of
t(9;22) increases with patient age, such
that only 2% to 4% of young patients
(younger than age 10 years) harbor this
abnormality in their leukemic blasts,
whereas up to 25% of adults with ALL
do.12 Other unfavorable abnormali-
ties include hypodiploidy (<44 chro-
mosomes per cell), rearrangement of
the MLL gene located at chromosome
11q23, and intrachromosomal ampli-
fication of chromosome 21.11 Any of
these abnormalities would lead to a
patient’s disease being considered high
risk, regardless of initial age and WBC
count.
There are other recurrent chromo-
somal aberrations that do not currently
carry prognostic significance, such as
t(1;19) or trisomies of other various
chromosomes. Although these abnor-
malities may not lead to modification
of treatment regimens, they can be ob-
Unfavorable
Age: <1 year and ≥10 years
WBC ≥50 x 103/mcL
Hypodiploidyb
t(9;22)
MLL rearrangement
iAMP21
CNS or testicular disease
≥0.01% on Day 29 BM
served prospectively at times of disease
reassessments to help gauge a patient’s
disease status (ie, whether remission
has been achieved).
The cytogenetics of T-ALL are not
yet as clearly elucidated, and are not
currently used in risk stratification
schemes. Recurrent abnormalities tend
to be related to genes within the T-cell
receptor, located on chromosomes 7
and 14.11
Disease Response
Ultimately, the most important pre-
dictor of outcome is disease response
to chemotherapy, and whether remis-
sion can be achieved. Classically,
remission was assessed morphologi-
cally, and defined as <5% blasts in the
bone marrow. Now with more precise
techniques (flow cytometry and poly-
merase chain reaction), even minute
levels of residual leukemia can be
detected—referred to as minimal re-
sidual disease (MRD). For patients
with B-ALL, the Children’s Oncology
Group (COG) assesses MRD at two
time points during the initial 4-week
induction therapy: (1) in the periph-
eral blood on day 8 and (2) in the bone
marrow on day 29 (at the end of induc-
tion therapy), with a goal of <0.01%
e171

Figure 2. Schema of the Children’s Oncology Group therapy for acute lymphoblastic leukemia. Duration
of consolidation is dependent on risk group (4 weeks for standard risk, 8 weeks for high risk). Protocols
vary as to whether or not there is a second interim maintenance phase.
leukemic cells in the marrow by day
29 of therapy. The 5-year EFS rate for
patients with <0.01% MRD (“nega-
tive MRD”) at the end of induction is
nearly 90%, and increasing levels of
MRD portend a worse prognosis, with
a 5-year EFS rate of about 30% for the
group of patients with MRD >1% at the
end of induction therapy.13 In a multi-
variate analysis, MRD was found to be
the most important prognostic factor
e172
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for survival, but the NCI criteria of age
and WBC count, as well as favorable
cytogenetics, retained prognostic sig-
nificance.13
In summary, an individual patient’s
treatment is adjusted based on the par-
ticular risk group to which that patient
is ultimately assigned (Table 1). Al-
though the nuances of risk stratifica-
tion schemes vary slightly between dif-
ferent cooperative groups, all take into
account age, WBC, cytogenetics, and
disease response.
Treatment and Prognosis
The treatment for ALL occurs in se-
quential blocks of therapy (Figure 2).
This therapy consists of both initial and
delayed aggressive phases of therapy
(induction/consolidation and delayed
intensification) with an intervening less
intense phase of treatment known as
interim maintenance. After the comple-
tion of these blocks of more aggressive
therapy, which generally takes between
6 and 9 months, there is a prolonged
maintenance therapy that, on COG pro-
tocols, lasts approximately 2 years for
girls and 3 years for boys. During this
time, children feel relatively well, with
most of the therapy being low-dose oral
chemotherapy. Normal school and extra-
curricular activities are often resumed.
For all patients with ALL, both sys-
temic therapy and CNS-directed therapy
are required. Systemic chemotherapy
involves a combination of intravenous
and oral medications, with intramuscu-
lar drugs used in some cases as well.
Similar classes of drugs are used in in-
duction/consolidation and delayed in-
tensification, but with substitutions of
certain medications for one another—
for example, dexamethasone for pred-
nisone or doxorubicin for daunorubicin,
incorporating noncross-resistant agents
into later phases of therapy to eradicate
any remaining drug-resistant malignant
cells.14 CNS-directed treatment consists
of intrathecal chemotherapy adminis-
tered at the time of lumbar punctures,
and is necessary regardless of CNS sta-
tus at diagnosis to protect against CNS
relapses. Those patients with overt in-
volvement of the CNS often require cra-
nial radiation at some point during their
treatment, in addition to intrathecal che-
motherapy.
Besides classic cytotoxic chemother-
apy, in some cases more targeted therapy
is incorporated into treatment regimens.
Copyright © SLACK Incorporated

The paradigm for this is Philadelphia-
chromosome positive (Ph+) ALL. The
BCR-ABL fusion protein that is pro-
duced by the t(9;22) is a constitutively
active tyrosine kinase and is the target
of the TKI imatinib mesylate. Although
imatinib monotherapy is effective in the
treatment of chronic myeloid leukemia
in chronic phase, it does not lead to du-
rable remissions in Ph+ ALL when given
as a single agent.15 However, when used
in conjunction with an intensive chemo-
therapy backbone, imatinib improves
the outcomes for patients with Ph+ ALL
significantly.16,17 In fact, hematopoietic
stem cell transplant (HSCT) was previ-
ously recommended in first remission
for all patients with Ph+ ALL, but this is
no longer necessary, as use of a TKI in
conjunction with chemotherapy affords
patients equivalent, and perhaps better,
outcomes compared with HSCT.16,17
More recently a group of patients
has been identified using genome-wide
analysis whose leukemic blasts do not
contain the 9;22 translocation, but har-
bor a gene expression profile similar
to that of patients with Ph+ ALL.18,19
These patients are considered to have
BCR-ABL-like or Ph-like ALL, and
generally poor outcomes have been re-
ported. The majority of these patients
have been found to have constitutive
activation of cytokine receptors or tyro-
sine kinase pathways.20 Further investi-
gation has revealed that aberrations in
genes that regulate kinase signaling
are present in the majority of patients
with Ph-like ALL, many of which are
predicted to respond to existing TKIs
or other signaling pathway inhibitors.21
Efforts are in progress to evaluate for
these alterations at the time of diagno-
sis, so that for affected patients, target-
ed therapy can quickly be incorporated
into their chemotherapy regimens.21,22
With modern treatment, over 80%
of children diagnosed with ALL are
cured, and most of these children re-
main quite healthy with careful follow
PEDIATRIC ANNALS • Vol. 44, No. 7, 2015
CME
up and monitoring for late effects of
therapy. However, during therapy, acute
toxicity such as nausea, vomiting, hair
loss, myelosuppression, and neuropa-
thy can significantly impact patients’
daily lives. At times, certain toxicities
such as infection and pancreatitis can
be life-threatening, even with optimal
supportive care. Furthermore, despite
our overall excellent outcomes, 10% to
20% of patients still relapse, many of
whom are considered to have standard-
risk disease at diagnosis.10,13,23,24 Al-
though many children who are cured of
their ALL are quite healthy, late effects
such as neuropathy, avascular necrosis,
cataracts, cardiomyopathy, and neuro-
cognitive deficits remain a significant
concern. Finally, there are certain che-
motherapies used in leukemia regi-
mens, namely alkylators, topoisomer-
ase inhibitors, and anthracyclines that
carry a risk of secondary malignancies
or the development of myelodyspla-
sia. These are rare after ALL therapy;
however, appropriate counseling for
families at the time of diagnosis and
monitoring for these complications af-
ter therapy are required.
CONCLUSION
In summary, ALL is the most com-
mon childhood cancer, but thankfully
is still rare. Initial symptoms can be
nonspecific and indolent, requiring
astute observation and evaluation by
the primary care physician. Once a di-
agnosis is made, oncologists carefully
risk stratify patients so that treatment
can be tailored accordingly. Therapy
is lengthy, with initial intense phases
followed by a prolonged maintenance
phase; as our knowledge of the un-
derlying mechanisms driving leuke-
mogenesis improves, our therapy will
continually become more specific to
individual patients.
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