Acute Leukemia in Children

Maureen M. O’Brien, MD, and

Normal J. Lacayo, MD
Acute leukemias represent approximately 30% of all malignancies diag-
nosed in children younger than 15 years and 25% of malignancies in
children and adolescents younger than 20 years. Approximately 3250 new
cases of leukemia are diagnosed annually in the United States. Acute
lymphoblastic leukemia (ALL) accounts for approximately 80% of cases
(2500 cases per year). About 20% of cases (800-900 cases per year) are
acute myeloid leukemia (AML) and a small fraction (1%) is chronic
myeloid leukemia (CML). There is a sharp peak in ALL incidence among
2 and 3 year olds (⬎80 per million), which decreases by ages 8 to 10
years (20 per million). The incidence of ALL among 2 and 3 year olds is
approximately 4-fold greater than that for infants and is nearly 10-fold
greater than that for 19 year olds. In contrast, AML rates are highest in the
first 2 years of life, decrease with a nadir at approximately 9 years of age,
and slowly increase again during adolescence.
Leukemias are believed to arise from hematopoietic progenitor cells
that acquire genetic alterations leading to unchecked proliferation and
self-renewal. Over the past 50 years, our understanding of the
molecular pathogenesis of acute leukemias has markedly increased.
This knowledge, coupled with clinical risk stratification and clinical
investigation, has led to substantial improvements in survival for
children with acute leukemias. Currently, approximately 75% to 80%
of children with ALL and 50% to 60% of children with AML achieve
long-term survival.
Ongoing challenges in the care of children with acute leukemias include
novel strategies for the treatment of relapsed disease, which has a dismal
prognosis, and treatment reduction strategies in children with low-risk
disease in whom long-term complications of treatment are becoming
more evident. In addition, advances in the supportive care of children

This article was published in: Rakel RE, Bope ET. Conn’s Current Therapy 2008. Section 6. Acute
Leukemia in Children, p. 446-453. © 2008 Elsevier Inc.
Dis Mon 2008;54:202-225
0011-5029/2008 $34.00 ⫹ 0
doi:10.1016/j.disamonth.2007.12.003

202 DM, April 2008

during treatment as well as stem cell transplantation have contributed to
the improved survival of children with leukemia.

Diagnosis
Classically, children with acute leukemia present with symptoms of
pancytopenia, including pallor and fatigue from anemia and epistaxis,
ecchymoses, and petechiae due to thrombocytopenia (75% of children
have platelet count ⬍100,000/␮L at diagnosis). White blood cell
(WBC) count may be elevated (⬎50,000/␮L in 20% of children) or
low (⬍10,000/␮L in 50% of children). If they are neutropenic,
children can present with significant infection or overwhelming sepsis.
Children have lymphadenopathy in 50% of cases. Approximately 25%
of children present with bone pain due to bone marrow expansion by
malignant blasts and stretching of periosteal nerves. Rarely, extremity
pain is also due to malignant joint effusion. Children with mediastinal
masses (usually associated with T-cell ALL) can present with cough or
other respiratory symptoms, which can be mistaken for pneumonia or
asthma. Leukemia within the central nervous system (CNS) can
manifest with headache or cranial nerve abnormalities. Uncommonly,
ALL manifests as an isolated testicular mass and AML as a soft-tissue
mass (chloroma).
However, the presenting signs and symptoms of acute leukemia can
be subtle and develop over weeks to months, often beginning with
fatigue and decreased energy. Children can develop persistent or
intermittent fevers and can present to their pediatrician with these
nonspecific complaints, which can be easily attributed to a viral
illness. These children require a careful physical examination includ-
ing evaluation for lymphadenopathy or hepatosplenomegaly. Physical
examination abnormalities or persistent nonspecific symptoms that do
not resolve within 2 to 3 weeks merit further evaluation with a
complete blood count (CBC). Abnormalities of the CBC, such as
cytopenias of more than one lineage or the presence of peripheral
blasts in blood should result in urgent referral to a pediatric oncology
center. These centers provide specialized diagnostic testing, including
flow cytometry and cytogenetic analysis that is standard in the
evaluation of children with leukemia, as well as multidisciplinary
treatment and coordination of patient participation in multi-institu-
tional clinical trials.
Evaluation of any child presenting with concerning symptoms or an
abnormal CBC should include a chemistry panel, to evaluate for
hepatic or renal dysfunction, and elevated uric acid, potassium, and
DM, April 2008 203
phosphate suggesting tumor lysis syndrome. Determination of pro-
thrombin time (PT), activated partial thromboplastin time (aPTT), and
fibrinogen is necessary to evaluate for coagulopathy, which can
increase bleeding risk and is common in acute promyelocytic leukemia
(APML). Patients should be examined for signs of infection, and
appropriate cultures (blood, urine, stool) should be drawn in children
with fever or concerning symptoms. Chest radiography should be
performed to evaluate for the presence of a mediastinal mass, which
can complicate management of the patient due to respiratory distress
and the inability to sedate the child for invasive procedures (see the
Current Diagnosis section at the end of this article).
Ultimately, however, diagnosis depends on the results of bone
marrow aspirate and biopsy, which typically reveal replacement of
normal hematopoeitic precursors with leukemic blasts. Morphologi-
cally, these blasts have high nuclear-to-cytoplasmic ratios and can
have prominent nucleoli, vacuoles (Burkitt’s leukemia), and intracy-
toplasmic inclusions (Auer rod, M2 AML). The presence of more than
25% blasts in the bone marrow is diagnostic of acute leukemia, and
samples are then submitted for morphologic evaluation, flow cytom-
etry, cytogenetic analysis, and further investigational studies. When
the diagnosis of acute leukemia is confirmed, further evaluation will
also include lumbar puncture and morphologic examination of the
cerebrospinal fluid (CSF) for leukemic blasts. In boys, examination for
testicular swelling and masses is necessary to determine whether
leukemic involvement is present; this should be documented by
ultrasound evaluation and testicular biopsy if the diagnosis is in
question because treatment varies depending on involvement of these
sanctuary sites (CNS or testes).

Classification
Acute leukemia is separated into two major subgroups: ALL and
AML. Historically, the FAB (French–American–British) classification
has been used in which ALL consists of three subtypes, L1 through L3,
and AML consists of eight subtypes, M0 through M7. However, the
1999 WHO classification conference has suggested that, for ALL,
these FAB terms are not relevant because they do not predict
immunophenotype, cytogenetics, or clinical outcome. The exception is
L3 lymphoblasts, which are undifferentiated and contain large nucleoli
and have deep blue vacuolated cytoplasm. This morphology is
synonymous with Burkitt’s (mature B-cell) leukemia.
204 DM, April 2008
 In contrast, the FAB classification for AML remains standard and
characterizes blasts by differentiation pathways. In general, M0 and
M1 blasts are undifferentiated and lack granules. M2 blasts are more
mature, contain cytoplasmic granules, and can have Auer rods
(coalesced granules). M3 blasts are found in APML and have
prominent granules. M4 blasts occur in acute myelomonocytic leuke-
mia and are a mixture of myeloblasts and monoblasts. One specific
subtype, M4eo, shows markedly increased marrow eosinophils and
blasts with large, coarse granules. M4eo morphology is strongly
associated with the cytogenetic abnormality inversion 16 [inv(16)].
M5 AML (acute monoblastic leukemia) blasts have indented nuclei consis-
tent with monoblastic differentiation. M6 AML (acute erythroid leukemia)
blasts show evidence of erythroid lineage, and M7 AML (acute megakaryo-
cytic leukemia) blasts appear undifferentiated. M7 AML is often associated
with extensive bone marrow fibrosis, and the diagnosis may be hampered by
difficulty aspirating an adequate sample. The biopsy is critical to the correct
diagnosis in this case. Children with trisomy 21 (Down syndrome) who
develop AML almost exclusively have M7 AML.

Immunophenotyping
The accuracy of morphologic diagnosis is significantly increased
with the incorporation of immunophenotyping of cell surface cluster
of differentiation (CD) markers by flow cytometry and cytogenetic
analysis for translocations associated with specific subtypes of leuke-
mia. This testing is particularly important for risk stratification in
pediatric ALL. In general, ALL is divided into three major subtypes
based on immunophenotype: B-precursor (70% to 80% of patients),
mature B cell (2% to 5% of patients), and T cell (15% of patients)
blasts. B-precursor blasts express CD10, CD19, and CD20, whereas
mature B-cell blasts express these markers in addition to CD22, CD25,
and surface immunoglobulin (sIg). In contrast, T cell lineage lympho-
blasts express CD2, CD3, CD4, CD5, CD7, and CD8, whereas
myeloid blasts express CD11, CD13, CD15, CD33, CD34, and CD65.
Usually, lymphoblasts of different lineages can be readily distin-
guished from each other and from myeloid leukemias, although in
some cases the leukemic blasts can aberrantly express a variety of cell
surface proteins. Diagnosis in these cases is determined by the
predominance of lymphoid versus myeloid markers, and the blasts
may ultimately be described as biphenotypic.
DM, April 2008 205
TABLE 1. Prognostic features in childhood ALL
Favorable

● Age 1-9.99 years

● WBC at presentation ⬍50,000/␮L
● Immunophenotype (B-precursor)
● Genetic abnormalities
● Hyperdiploidy
● t(12;21) translocation with TEL-AML1 fusion gene
● Triple trisomies of chromosomes 4, 10, 17
● Clinical response: MRD negative (⬍0.01%) at day 8 and end of induction

Unfavorable

● Age ⬍1year or ⬎10 years

● WBC at presentation ⬎50,000/␮L
● Immunophenotype (T-cell)
● Genetic abnormalities
● Hypodiploidy
● t(4;11) translocation with MLL-AF4 fusion gene
● t(9;22) translocation with BCR-ABL fusion gene
● Clinical response
● Induction failure (M3 marrow, ⬎25% blasts)
● MRD positive at end of induction
Abbreviations: MRD, minimal residual disease; MLL, mixed lineage leukemia; WBC, white
blood cell.

ALL Cytogenetics and Risk Stratification

Leukemic blasts are further classified based on their chromosomal
number and cytogenetic profile using standard karyotype analysis as
well as molecular techniques to detect specific translocations that have
both diagnostic and prognostic significance (Table 1). In B-precursor
ALL, modal chromosome number is important in prognosis. Hyper-
diploidy (50-60 chromosomes) occurs in 30% of cases and is associ-
ated with good prognosis, particularly if combined with trisomies of
chromosomes 4, 10, and 17, but hypodiploidy (fewer than 45 chro-
mosomes) is associated with poor outcome.
Specific translocations in ALL lymphoblasts include t(9;22) bcr/abl
translocation (Philadelphia chromosome [Ph], typically the 185-kDa
fusion protein), which occurs in about 5% of ALL patients, mainly
adolescents, and is associated with poor outcome. The t(4;11) transloca-
tion fuses the MLL (mixed lineage leukemia) gene on chromosome 11
band q23 to the AF4 gene on chromosome 4 band q21, forming an
MLL/AF4 fusion gene. This translocation is prevalent in infant ALL
(60% of infants) and is associated with poor outcome, as are other MLL
fusion partner leukemias.
206 DM, April 2008
 In contrast to these translocations associated with poor outcome,
t(12;21)(p12;q22) (TEL/AML-1) is the most common genetic lesion in
childhood ALL, occurring in 15% to 25% of children with B-precursor
ALL and is associated with a good prognosis. The translocation is
cryptic and requires specific molecular techniques (reverse-tran-
scriptase polymerase chain reaction [RT-PCR] or fluorescence in situ
hybridization [FISH] analysis) for detection. This translocation is
generally considered to have good prognosis, with high blast sensi-
tivity to intensive asparaginase therapy, although an association with
late relapse has been reported.
Other translocations include t(1;19) E2A/PBX1 translocation in 5% of
B-precursor ALL patients, which is not currently used for risk stratifica-
tion.
Mature B-cell ALL is characterized by the t(8;14) translocation,
which places the MYC gene under the control of the immunoglobulin
heavy chain promoter. In T-cell ALL, approximately 60% of patients
have an abnormal karyotype, often involving chromosomes 14 or 7 at
the locations of the T-cell receptor (TCR) genes, which become fused
to a transcription factor (LMO2, LYL, TAL1). In addition, T-cell ALL
lymphoblasts have a high frequency (⬎50% of cases) of gain-of-
function Notch-1 mutations, which may be associated with improved
prognosis.
Treatment of the child with ALL is based on risk-adapted therapy. As
cure rates for childhood ALL have improved overall, great interest has
developed in risk stratification of patients based on clinical characteris-
tics, immunophenotype, and cytogenetics in order to identify groups of
low-risk patients for whom toxic therapy can be minimized and high-risk
patients for whom aggressive treatment, including consideration of bone
marrow transplant (BMT), is indicated. For example, T-cell ALL patients
tend to be male and to have elevated WBC count and extramedullary
disease (mediastinal mass, CNS involvement). These patients had histor-
ically poor outcome compared with B-precursor ALL patients. However,
with current intensive treatment protocols, long-term survival for these
patients now approaches 70% to 80%, similar to survival of children with
B-precursor ALL.
Important clinical characteristics for risk stratification include WBC
count and age at the time of diagnosis, which are independent
predictors of prognosis and have been established by the National
Cancer Institute (NCI) as the standard criteria for risk assignment at
diagnosis in precursor B-cell ALL. Other prognostic factors used for
risk assignment during induction therapy include presence of CNS
DM, April 2008 207
disease and specific cytogenetic abnormalities. European investigators
have traditionally used clinical response to a 1-week treatment
prophase with prednisone and intrathecal methotrexate to stratify
those with poor prednisone response to intensive therapy, because this
is an independent predictor of poor clinical outcome.
Response to induction therapy based on bone marrow evaluation is
another cornerstone of risk stratification. Rapid responders with an M1
remission marrow (⬍5% blasts by morphology) by day 8 of induction
have excellent outcomes, and slower responders fare worse. In
extreme cases, patients who fail induction or have continued presence
of overt morphologic leukemia after 4 to 6 weeks of intensive
chemotherapy (which occurs in 1% of patients) have extremely poor
outcomes and should proceed to BMT if remission is eventually
achieved.
New molecular techniques continue to refine risk stratification for
children with ALL. Minimal residual disease (MRD) monitoring by
multiparameter flow cytometry can detect leukemic blasts at a level of
0.1% to 0.01% even in a morphologically M1 bone marrow aspirate
sample. Studies have demonstrated that children with negative blood
MRD by day 8 of induction have an excellent prognosis, and those
with positive bone marrow MRD by day 29 (end of induction) have
high rates of relapse. Current clinical trials for children with leukemia
now incorporate MRD monitoring at the end of induction into risk
stratification for additional therapy and are evaluating the sensitivity
and specificity of MRD in predicting later relapse.
Based on these considerations, at the time of diagnosis, children with
ALL are stratified as standard risk (age 1-9.99 years and WBC
⬍50,000/␮L) or high risk (age ⬍1 year or ⬎10 years, WBC
⬎50,000/␮L, overt CNS leukemia). Once cytogenetic and induction-
response data are available, patients are further stratified into lower
risk (trisomies of chromosomes 4, 10, and 17 or TEL/AML1 and
translocation), standard risk (unremarkable cytogenetics), high risk
(adolescents, infants), or very high risk [induction failure, t(9;22),
t(4;11)], and subsequent treatment intensity is based on this classifi-
cation.

AML Cytogenetics and Risk Stratification

Factors with favorable prognostic significance in AML include
Down syndrome, the karyotypic abnormalities inv(16) and t(8;21)
seen in the core binding factor leukemias, and (15;17) (Table 2). Poor
208 DM, April 2008
TABLE 2. Prognostic features in childhood AML
Low Risk

● inv(16) or t(16;16)
● t(8;21)
● t(15;17)
● Down syndrome

Standard Risk

● Absence of low-risk features

● Absence of high-risk features

High Risk

● FLT3-internal tandem duplication

● M6 and M7
● t(6;9)
● Monosomy 7
● del5q
● Treatment-related AML
● MDS/AML
● RAEB-T
● Primary induction failures
Abbreviations: AML, acute myeloid leukemia; MDS, myelodysplastic syndrome; RAEB-T,
refractory anemia with excess blasts in transformation.

prognostic factors include failure to achieve remission, FLT3 (a

member of the receptor tyrosine kinase family) internal tandem
duplication (FLT3-ITD), therapy-related AML, AML arising from
myelodysplastic syndrome (MDS), FAB subtypes M6 and M7, mono-
somy 7, del5q (less common), and refractory anemia with excess
blasts in transformation (RAEB-T).
Patients without favorable or poor prognostic factors are considered to
have an intermediate risk status. Remission induction and long-term
survival vary substantially between these subgroups; therefore, accurate
risk stratification is critical to identify patients who will benefit from
aggressive therapies such as hematopoietic stem-cell transplantation or
novel therapies, as well as patients who have good outcome with current
regimens.
The use of MRD in pilot studies shows that it can identify a subset of
patients at higher risk of relapse. This group of patients can benefit from
new therapeutic approaches. As the MRD technology improves, its
sensitivity and specificity and positive predictive value for relapse will
also improve.
DM, April 2008 209
Treatment
Acute Lymphoblastic Leukemia
The vast majority of children with ALL are treated in a clinical trial. In the
United States and Canada, although a small number of centers treat children
on institutional protocols, most pediatric oncology centers are members of the
Children’s Oncology Group (COG) and enroll children in multicenter
national trials. These clinical trials allow adequate patient numbers to
determine efficacy of regimens, coordination of biological and molecular
studies, and access of any child to the current state-of-the-art standard of care.
Informed consent must be obtained for treatment according to the trial
protocol as well as the submission of bone marrow or peripheral blood
samples for biological studies.
At the time of diagnosis, typically in conjunction with another
diagnostic procedure (bone marrow aspirate/biopsy or lumbar punc-
ture), the child should have placement of a central venous catheter
(CVC) that can be used for delivering medications and for blood
sampling. The type of CVC will depend on the individual institutional
practices. In general, implanted catheters (portacaths) are associated
with lower infection rates, but external multilumen catheters (Broviac
or Hickman) should be placed in small infants and in patients likely to
need BMT. In a child with a large mediastinal mass in whom sedation
for procedures is not possible, bone marrow aspirate and lumbar
puncture might need to be performed with local anesthesia only, and
a peripherally inserted central catheter (PICC) may be placed in lieu of
a CVC until the mediastinal mass has responded to chemotherapy.
Treatment Phases. The treatment of ALL is divided into three general
phases: remission induction (4-6 weeks), consolidation and delayed
intensification (6 months), and maintenance. The total treatment lasts
between 24 and 36 months.
Induction. The induction regimen for standard-risk patients (age
1-10 years, WBC ⬍50,000/␮L) includes three chemotherapeutic
agents, daily oral corticosteroid (prednisone or dexamethasone) for 28
days, four doses of weekly intravenous vincristine (Vincasar), and one
dose of intramuscular pegylated asparaginase (Elspar). This is com-
bined with CNS prophylaxis and treatment with intrathecal metho-
trexate. For high-risk patients, an anthracycline (daunorubicin [Ceru-
bidine] or doxorubicin [Adriamycin]) is added to improve the rate of
remission induction in this group. Overall, 98% of patients achieve
first morphologic remission (M1 marrow defined as ⬍5% bone
marrow blasts with recovery of trilineage hematopoeisis and periph-
210 DM, April 2008
eral blood counts) at day 29 of induction with this regimen. Patients
with M2 marrow (5% to 25% blasts) after 29 days of induction receive
2 additional weeks of therapy, and those who remain M3 (⬎25% bone
marrow blasts) have failed induction. Children who fail to achieve first
remission after 6 weeks of induction have a very poor prognosis and
should be considered for myeloablative allogeneic BMT if they
achieve remission with an alternative regimen.
A number of complications can develop during induction. The
majority of these are secondary to chemotherapeutic agents and can be
managed with aggressive supportive care. Prolonged use of high-dose
steroids can result in hypertension, hyperglycemia, weight gain, mood
changes, and gastritis. Perturbation of clotting factors by asparaginase
therapy, which interferes with hepatic protein production, can lead to
bleeding or thrombosis depending on the balance of procoagulant and
anticoagulant factors. Asparaginase therapy can also result in acute
anaphylaxis as well as severe pancreatitis, both of which are indica-
tions for omission of future asparaginase therapy (except in the case of
allergy, when Erwinia asparaginase can be substituted). Use of
anthracyclines requires monitoring of cardiac function, and vincristine
can cause peripheral neuropathy, constipation, and ileus. Finally, the
risks of infection and tumor lysis syndrome are highest during
induction. Management of these problems is detailed in the section on
supportive care.
Consolidation, Interim Maintenance, and Delayed Intensification.
Following achievement of first remission, the intensity of the consol-
idation, interim maintenance, and delayed intensification phases de-
pends on risk stratification including clinical features, cytogenetics,
and response to therapy or MRD. In general, consolidation is charac-
terized by intensive therapy including cyclophosphamide (Cytoxan),
cytarabine (Cytosar), 6-thioguanine (Tabloid)1 or 6-mercaptopurine
(Purinethol), asparaginase (Elspar), and vincristine (Vincasar). For
lower-risk patients, consolidation may include only vincristine and
antimetabolite therapy. Depending on risk stratification, consolidation
lasts between 4 and 8 weeks.
Consolidation is followed by interim maintenance, which lasts 8 weeks
and includes antimetabolite therapy with daily oral 6-mercaptopurine,
weekly oral methotrexate (Trexall), intermittent vincristine, and glucocor-
ticoid pulses as well as continued CNS prophylaxis with intrathecal
methotrexate. For higher-risk patients, interim maintenance is augmented

1
Not FDA approved for this indication.

DM, April 2008 211

with escalating-dose IV methotrexate and asparaginase. This less-inten-
sive phase is then followed by delayed intensification, which includes
reinduction and reconsolidation. High- risk patients may then receive
second interim maintenance and delayed intensification courses before
proceeding to maintenance therapy.
For all patients, an additional goal of this phase of treatment is to target
involved sanctuary sites (see the later discussion of CNS prophylaxis). In
male patients, the testis is a sanctuary site and requires close monitoring
at the time of each physical examination. For patients with testicular mass
or swelling at the time of diagnosis, enlargement should be confirmed by
ultrasound and then leukemic involvement proved by testicular biopsy.
For patients with biopsy-proved testicular disease, treatment includes
bilateral testicular irradiation at 2400 cGy in 12 once-daily fractions (200
cGy per fraction).
Maintenance. Maintenance therapy consists of daily oral 6-mercapto-
purine, weekly oral methotrexate, monthly intravenous vincristine, and
5-day pulses of oral dexamethasone. Maintenance continues until total
duration of therapy is 2 years from the start of interim maintenance for
female patients and 3 years from the start of interim maintenance for male
patients. Length of treatment differs because male patients have a poorer
prognosis than female patients, which can be improved by prolonged
maintenance therapy.
Therapy for High-Risk Groups. The current very-high-risk ALL
COG protocol includes a subset of patients with poor outcomes and an
expected 5-year event-free survival (EFS) rate of ⬍45%. This group
includes patients with Ph⫹ ALL [t(9;22)], hypodiploidy, MLL rear-
rangement with a slow early response to induction chemotherapy, and
induction failures (an M3 [⬎25% blasts] bone marrow at the end of
induction therapy or MRD ⬎1%). In this group of patients, allogeneic
BMT is recommended in first remission for those with matched sibling
donors. In addition, protocols for patients with t(9;22) now include the
BCR-ABL tyrosine kinase inhibitor imatinib (Gleevec) in combination
with intensive multiagent chemotherapy in an effort to improve
outcomes for this subgroup. For infants with MLL rearrangement with
rapid induction response, treatment currently consists of intensive
chemotherapy on high-risk protocols due to excessive treatment-
related mortality in this subgroup during BMT.
Central Nervous System Prophylaxis. The CNS is a sanctuary site for
leukemic blasts due to poor penetrance of the CNS by many chemo-
therapeutic agents. Historically, it was found that without CNS
prophylaxis in patients without overt CNS leukemia at diagnosis, these
212 DM, April 2008
patients would relapse in the CNS at a high rate even while
maintaining bone marrow remission. CNS status is determined by a
diagnostic lumbar puncture at the time of diagnosis (CNS 1, ⬍5
WBCs, no blasts on cytospin; CNS 2, ⬍5 WBCs, blasts seen on
cytospin; CNS 3, ⱖ5 WBCs with blasts on cytospin or overt signs of
CNS leukemia such as facial nerve palsy).
In the past, CNS leukemia prophylaxis was achieved with cranial
radiation, which provides effective prophylaxis but with excessive
long-term toxicity, including neurocognitive impairment and in-
creased risk of secondary malignancy. As a result, CNS prophylaxis is
currently achieved with repeated doses of intrathecal methotrexate
throughout all phases of therapy. Research is ongoing to determine the
effect of this treatment on long-term neurocognitive function. Patients
with CNS 2 status receive additional doses of intrathecal methotrexate
during induction and are subsequently treated with the same regimen
as CNS 1 patients. Currently, cranial radiation (1800 cGy) combined
with intrathecal methotrexate is reserved for patients with documented
CNS 3 disease or patients without CNS disease who have high risk of
relapse in the CNS (1200-1800 cGy), such as T-cell ALL patients.
Relapse Treatment. Although the overall outcomes for children with
ALL have markedly improved over the past 40 years, the treatment of
children who experience relapse remains a significant challenge. The
number of children with relapsed acute leukemia equals or exceeds the
incidence of most other pediatric tumors. Despite intensive and risk-
stratified treatment regimens, 15% to 20% of patients relapse, and the vast
majority of these children ultimately die of disease.
The majority of relapses (75%) occur within 3 years from diagnosis,
and treatment and prognosis depend on site of relapse (bone marrow
or extramedullary), timing of relapse (months from diagnosis), and
immunophenotype. For children enrolled in the Children’s Cancer
Group (CCG) 1900 series trials between 1997 and 2002, 12% of
patients experienced bone marrow relapse, 4% experienced CNS
relapse, and 1.3% experienced testes relapse. The 3-year survival rates
were 28%, 60%, and 60%, respectively. Second remission rates range
from 70% to 90% in different series depending on timing and site of
relapse, but the 3-year survival rate for patients with marrow relapse
within 3 years of diagnosis is less than 10%.
Factors associated with extremely poor outcome include T-cell ALL
relapse and early bone marrow relapse (duration of first remission ⬍36
months). Outcomes are somewhat better for isolated CNS or testicular
relapse and late bone marrow relapse with B-precursor ALL.
DM, April 2008 213
 Treatment of early marrow relapse involves intensive reinduction
chemotherapy in an attempt to achieve second remission, followed by
myeloablative allogeneic BMT for patients with an acceptable donor.
For patients without an unrelated donor, intensive chemotherapy with
consideration of phase I/II studies of novel agents is indicated given
the extremely poor prognosis for this group, many of whom will
relapse again before BMT even when a donor is available. For patients
with late bone marrow relapse (⬎36 months from diagnosis), research
is currently ongoing to determine the role of BMT versus intensive
chemotherapy, although for patients with a matched sibling donor,
most oncologists would proceed with BMT if the patient achieves
second remission.
Isolated CNS relapse has a more favorable outcome than bone
marrow relapse. In terms of risk stratification, early CNS relapse (⬍18
months from diagnosis) is considered similar in prognosis to late
marrow relapse, and patients with late CNS relapse (⬎18 months from
diagnosis) have the most favorable outcome. Patients are treated with
weekly intrathecal triple chemotherapy (methotrexate, cytarabine,
hydrocortisone) until the CSF is negative for blasts. Craniospinal
radiation therapy is also indicated, with a dose of 2400 (cranial)/1500
(spinal) cGy for early CNS relapse and cranial radiation to 1800 cGy
for late CNS relapse. In addition, all CNS relapse patients receive
intensive systemic reinduction, consolidation, and maintenance che-
motherapy because CNS relapse is a harbinger of eventual relapse in
the bone marrow. Current studies are ongoing to determine if the
cranial radiation dose in children with late CNS relapse can be
decreased further to 1200 cGy following 12 months of intensive
chemotherapy incorporating agents known to cross the blood-brain
barrier (dexamethasone, high-dose methotrexate, asparaginase, and
high-dose cytarabine).
Testicular relapse is suspected when testicular swelling or mass is
noted on physical examination. Relapse should be confirmed with
testicular biopsy and evaluation for concurrent bone marrow, and CNS
relapse should be undertaken and treated as described earlier. Treat-
ment of isolated testicular relapse (ITR) has historically involved
bilateral testicular radiation to 2400 cGy combined with intensive
systemic chemotherapy. However, as with isolated CNS relapse, the
most significant factor influencing survival following ITR is the length
of the first remission. Patients with ITR ⬍18 months from diagnosis
have 5-year EFS rates of 45% compared with 60% EFS rate for
patients with ITR ⱖ18 months from diagnosis.
214 DM, April 2008
 Testicular radiation is effective at eradicating leukemia, but risk of
sterility and endocrine late effects following testicular radiation are
significant, with a majority of boys requiring hormonal replacement at
some stage for induction of puberty, continuing pubertal maturation,
or both. Primary germ cell dysfunction is associated with doses of
1200 cGy, and testicular doses of 2400 cGy result in Leydig cell
failure, particularly in prepubertal boys.
Current research protocols for patients with late ITR involve the use of
intensive systemic chemotherapy including high-dose methotrexate
(shown to penetrate the blood-testes barrier) with inclusion of testicular
radiation to 2400 cGy only in boys who have persistent biopsy-proven
testicular relapse after intensive systemic induction chemotherapy. As in
isolated CNS relapse, therapy is combined with intensive systemic
chemotherapy for 2 years due to the risk of subsequent bone marrow
relapse following ITR.
Acute Myeloid Leukemia
Acute myeloid leukemia (AML) accounts for 20% of new cases of
pediatric leukemia each year. AML represents a biologically hetero-
geneous group of diseases that arises from abnormal myeloid cell
progenitors. Despite aggressive therapy, overall cure rates remain at
about 50%. The key to improvement in this group of diseases has been
identifying different subgroups of patients based on karyotypic and
molecular characteristics. The current approach is to further refine
risk-stratification and to develop risk-based or molecularly targeted
therapies. The therapy outline is modeled after the St. Jude AML 2002
Consortium Study.
Induction. On completion of a diagnostic work-up and evaluation of
eligibility for a clinical trial, the next step is to proceed with informed
consent. We advocate enrollment in open clinical trials from the Chil-
dren’s Oncology Group or multi-institutional consortia for all eligible
patients with consent from the parents or guardians.
Induction chemotherapy is started as we await molecular and karyotype
testing for risk stratification. Due to the intensity of the induction phase
of therapy and the need for supportive care, we advocate the early
placement of an indwelling central venous catheter if this can be achieved
safely. Therapy consists of anthracyclines (usually daunorubicin or
idarubicin [Idamycin]) for 3 days, cytosine arabinosine for 7 to 10 days,
and etoposide (Toposar)1 or thioguanine for 5 days.

1
Not FDA approved for this indication.

DM, April 2008 215

 Some pilot and front-line studies are using chemotherapy with or
without gemtuzumab ozogomycin (Mylotarg). This drug is an anti-CD33
monoclonal antibody conjugated with ozogomycin. It is not known at this
time whether its use during induction will result in an increased
relapse-free survival.
Most induction regimens result in remission rates of 85% to 90% when
repeated twice. The use of time-intense induction (timing a second
induction during early count recovery after the first induction) usually
results in prolonged hospital stay for nearly all patients during the
induction phase. This allows timely and intense supportive care in the
inpatient setting. Family members and the patient undergo HLA typing
because a matched sibling hematopoietic stem cell transplant may be
indicated for very high-risk factors (monosomy 7, 7q-, primary induction
failures) or high-risk factors (FLT3-ITD, MDS-AML, M6 and M7
subtypes, and RAEB-T). A matched unrelated donor may also be
considered for very-high-risk patients.
The FAB-defined APML subtype is the only subtype of AML with
molecularly targeted therapy. The induction regimen for this subtype of
AML includes all-trans-retinoic acid (ATRA) in combination with an-
thracyclines, cytosine arabinoside, and arsenic.
Consolidation. With the induction of a remission, the next phase of
therapy includes typically three courses of consolidation. Common
combination therapies include mitoxantrone (Novantrone) and cytosine
arabinoside, high-dose cytosine arabinoside with L-asparaginase,1 cyto-
sine arabinoside and etoposide,1 and 2-CdA (2-chlorodeoxyadenosine,
Leustatin)1 with cytosine arabinoside. In this setting, patients with
very-high-risk or high-risk factors may proceed with a hematopoietic
stem-cell transplant if a matched sibling donor is available. In addition,
for very-high-risk patients, a matched unrelated donor transplant may be
considered because the outcome on chemotherapy alone is very poor.
Maintenance. Maintenance therapy fails to demonstrate any benefit
following intense induction and consolidation therapy, except in the molec-
ularly targeted APML subtype. ATRA is continued during maintenance.
Central Nervous System Therapy. Central nervous system prophylaxis is
achieved using intrathecal cytosine arabinoside at diagnosis, followed by
triple intrathecal therapy (cytosine arabinoside, hydrocortisone, and metho-
trexate) during each subsequent course of therapy. Intrathecal therapy is used
in most protocols because of the historical observation that many patients
develop CNS relapse in the absence of CNS prophylaxis.
Hematopoietic Stem Cell Transplantation. Hematopoietic stem cell
transplantation results in a statistically significant survival advantage
216 DM, April 2008
compared with chemotherapy alone, specifically for patients with high or
very high risk factors. Due to the morbidity and mortality associated with
transplantation, it is not recommended for patients with good risk factors,
such as inv(16) t(8;21) or t(15;17), even those who have a matched sibling
donor. For patients with favorable risk factors, transplantation is reserved
for the relapse setting or second remission. In contrast, patients with high-
or very-high-risk factors may be candidates for a matched sibling donor
transplant in first remission. For patients with very-high-risk factors, a
matched unrelated donor in first remission may be indicated due to the
inferior outcome using chemotherapy alone. In the relapsed patients,
matched and unmatched donor transplantations are less controversial
because the outcome with chemotherapy is very poor. The preparative
regimens for transplant usually include high-dose chemotherapy (busul-
fan,1 cyclophosphamide, cytarabine arabinoside) or total body irradiation
with high-dose chemotherapy.
Relapse Treatment. Most relapses occur in the bone marrow. The
prognosis is very poor for those who relapse less than 1 year from remission
(⬃10% survival). Those who relapse longer than 1 year from remission fare
better but still with dismal outcomes (⬃20% to 30% survival). The treatment
approach is to use chemotherapy to achieve remission and to follow
chemotherapy with hematopoietic stem-cell transplantation. Reinduction
therapy usually consists of mitoxantrone and etoposide1 or L-asparaginase1
with high-dose cytarabine arabinoside. Once a remission is achieved with
chemotherapy, the use of any available matched or mismatched donor is
recommended, including cord blood stem cells. Other active agents include
2-CdA1 or gemtuzumab ozogomycin. Two new drugs that will be available
for children with refractory and relapsed AML through the Children’s
Oncology Group include the combination of clofarabine (Clolar)1 (a novel
nucleoside analogue) with cytosine arabinoside and the combination of
lestaurtinib2 (an FLT3 inhibitor) with idarubicin and cytosine arabinoside.
Relapse in extramedullary sites is less common. CNS relapses will
require administration of intrathecal therapy and craniospinal irradiation.
It is unclear whether systemic therapy and hematopoietic stem cell
transplantation result in increased relapse-free survival. For soft-tissue
relapses (granulocytic sarcoma), local and systemic therapy followed by
a stem cell transplant, similar to the approach for bone marrow relapse,
are indicated.
A cornerstone for the success of AML therapy has been the

1
Not FDA approved for this indication.
2
Orphan drug in the United States.

DM, April 2008 217

participation of the majority of de novo childhood AML patients in
clinical trials. As we better understand the biology of this disease and
the number of available targeted agents increase, it will be very
important to offer phase I and phase II studies to as many patients as
possible so we can further improve the outcomes of all childhood
AML patients who relapse.
Atypical Manifestations. Rarely, AML manifests as congenital leuke-
mia or extramedullary leukemia (skin, gingival, chloromas, or CNS).
Congenital leukemia occurs in the first few weeks of life and can manifest
as leukemia cutis. The skin lesions might spontaneously disappear, but
they usually reappear with bone marrow involvement. Skin and CNS
leukemia are more common in infants than in older children. At
diagnosis, only 5% to 15% of patients present with CNS disease. They
commonly are asymptomatic; however, some present with headache,
vomiting, papilledema, or cranial nerve palsy. For patients who present
with chloromas (myeloblastomas or granulocytic sarcomas), these are
commonly found in the head or neck region. These lesions can result in
later bone marrow involvement. All patients with atypical manifestation
need systemic therapy as outlined previously. These atypical manifesta-
tions can also occur in relapse.
Acute Complications. Tumor lysis syndrome, hyperleukocytosis, and
transfusion support are discussed in the supportive care section.
Infections. Due to severe and prolonged neutropenia, patients are at risk
for bacterial infections (viridans streptococcal infection after high-dose
cytarabine arabinoside) and fungal infections (candidemia and aspergil-
losis). Dental examination and oral hygiene during and after chemother-
apy are routinely recommended to prevent ␤-hemolytic streptococcal
infection. Fungal prophylaxis is recommended; agents available include
fluconazole (Diflucan) and voriconazole (Vfend). These antifungal drugs
should be used with caution due to drug interactions. Routinely, patients
are started on trimethoprim-sulfamethoxazole (TMP-SMX; Septra) for
Pneumocystis jiroveci pneumonia (PCP; formerly Pneumocystis carinii
pneumonia) prophylaxis. The dose is 150 mg/m2/day in two divided doses
3 days per week.
Febrile Neutropenia. The definitions of fever can vary slightly; we use
any fever higher than 38.3°C or higher than 38°C that persists for 1 hour
with an absolute neutrophil count less than 500. We treat empirically with
ceftazidime (Fortaz) and vancomycin (Vancocin) at the commonly
recommended doses to treat gram-positive and gram-negative organisms.
Extended coverage is strongly recommended if viridans streptococcal
sepsis or typhilitis is suspected.
218 DM, April 2008
Supportive Care
Although improved chemotherapy combinations and risk stratification
have contributed greatly to better outcomes in childhood leukemias,
excellent supportive care and treatment of complications of both the
underlying disease and therapy have also played critical roles in the
survival of these patients. Important aspects of supportive care include
management of hyperleukocytosis, tumor lysis syndrome and metabolic
derangements, and infection.
Hyperleukocytosis
Hyperleukocytosis (WBC ⬎100,000/␮L) can lead to clinical symptoms
due to leukostasis, a clinicopathologic syndrome caused by the sludging
of circulating leukemic blasts in tissue microvasculature due to altered
rheology as well as interactions with blood vessel endothelial surfaces.
Symptoms are typically neurologic (ranging from confusion and somno-
lence to stupor and coma) or pulmonary with dyspnea, infiltrates on chest
x-ray, and respiratory distress. This syndrome is most common in AML
and is rarely seen in ALL, even with markedly elevated WBCs. In
general, in an ALL patient, a WBC count greater than 200,000/␮L or a
WBC count greater than 100,000/␮L with clinical symptoms of leuko-
stasis is an indication for intervention. Intervention can include aggressive
hydration, cytoreduction with hydroxyurea (Hydrea),1 or leukopheresis
for aggressive removal of circulating blasts until definitive therapy can be
initiated. In the AML patient, clinically relevant leukostasis can occur
with a WBC of 100,000/␮L.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) results from the rapid turnover of malignant
lymphoblasts. Cell death leads to release of intracellular contents, leading to
hyperkalemia, hyperuricemia with secondary uric acid nephropathy and
oliguric renal failure, and hyperphosphatemia with secondary hypocalcemia.
In the presence of a high blast burden (WBC ⬎100,000/␮L) or extremely
rapid cell turnover (Burkitt’s leukemia), the ensuing metabolic derangements
and uric acid nephropathy can be life threatening, although TLS can occur in
any child with acute leukemia.
Therefore, at the time of diagnosis (or suspected diagnosis) of ALL, TLS
prophylaxis should be initiated with intravenous hydration at 2400 to 3000
mL/mm2/day to maintain urine output at greater than 100 mL/m2/hour until
peripheral blasts and extramedullary disease are reduced. This fluid should be
1
Not FDA approved for this indication.

DM, April 2008 219

alkalinized to a target urinary pH of 6.5 to 7.5 to facilitate uric acid excretion.
Patients at lower risk of significant TLS (low WBC) should receive
allopurinol (Zyloprim) 300 mg/m2/day orally in three divided doses through-
out the first 4 to 7 days of induction therapy because rapid blast lysis with the
initiation of treatment can result in TLS. In fact, prior to the use of
allopurinol, acute uric acid nephropathy developed in as many as 10% of
ALL patients. In patients at high risk for TLS and subsequent uric acid
nephropathy and renal failure, urate oxidase (rasburicase [Elitek]) may be
administered intravenously. Urate oxidase rapidly converts uric acid to
soluble allantoin; in this case, urinary alkalinization is not necessary. This
medication is well tolerated except for infrequent allergic reaction and has
markedly reduced the frequency with which Burkitt’s leukemia or lymphoma
patients require dialysis due to TLS.
In addition to management of hyperuricemia, patients must be closely
monitored for hyperkalemia and hyperphosphatemia and treated appro-
priately with binding agents or dialysis (or both) in severe cases.

Infection
Infection is a major source of morbidity and mortality throughout
treatment for leukemia, although it is most prominent during the intensive
portions of ALL treatment such as induction and delayed intensification
blocks as well as all portions of ALL therapy. In addition to risk of
bacterial infection, depression of T cell-mediated immunity can predis-
pose to viral, fungal, and opportunistic infections.
Bacterial. The rate of invasive bacterial infection and sepsis increases
as WBC, in particular absolute neutrophil count (ANC), falls. Specifi-
cally, the risk of serious bacterial infection either with gram-negative rods
from the patient’s own gastrointestinal tract or gram-positive organisms
through damaged oral mucosal surfaces or via central venous catheters,
markedly increases when the ANC falls below 500/␮L. Because of lack
of white blood cells, patients are predisposed to severe infection and
might lack the usual clinical signs and symptoms of inflammation (pain,
erythema, purulent drainage).
Therefore, the clinician must be vigilant for subtle signs of infection,
and broad-spectrum antibiotics should be initiated immediately in neu-
tropenic patients who develop fever (⬎38.0°C). Various combinations of
antibiotics can be used but most commonly includes an antipseudomonal
cephalosporin such as ceftazidime or cefipime. For patients with clinical
signs of sepsis such as hypotension or specific symptoms (severe
mucositis or abdominal pain), antibiotic coverage should be broadened to
include additional gram-negative coverage with an aminoglycoside,
220 DM, April 2008
gram-positive coverage with vancomycin, and anaerobic coverage with
metronidazole or clindamycin. Carbapenems (ie, meropenem) are indi-
cated in children with penicillin or cephalosporin allergy.
Children receiving high-dose cytarabine therapy (AML and relapsed
ALL patients) have a high incidence of life-threatening streptococcus
viridans bacteremia. Any child who has received this therapy and presents
with fever and neutropenia should receive intravenous vancomycin as
well as ceftazidime regardless of presence of specific symptoms.
All patients should receive P. jiroveci prophylaxis with TMP-SMX at a
dose of 5 mg/kg/day divided into three doses on three sequential days per
week throughout therapy and continue for 6 months from the completion
of treatment. For patients with sulfa allergy or who cannot tolerate
TMP-SMX, second-line options include inhaled pentamidine (Pentam),
oral dapsone (Aczone),1 or oral atovaquone (Mepron).
Viral. Leukemia patients presenting with a rash suggesting primary
varicella or shingles reactivation should be admitted to the hospital for
intravenous acyclovir (Zovirax) treatment until the lesions are crusted,
due to risk of dissemination. Asymptomatic children exposed to a sick
contact with primary varicella should receive prophylactic intravenous
immunoglobulin (IVIg) or, if available, VZIg (varicella zoster immune
globulin). Other viral infections do not require hospitalization or specific
therapy unless complications occur (eg, respiratory distress with RSV
infection). Patients should receive annual influenza vaccination, but in
general, children with leukemia can tolerate routine viral respiratory and
gastrointestinal illnesses and do not require specific isolation precautions
outside of the hospital.
Fungal. Fungal infections represent an area of additional concern for
patients being treated for leukemia, mainly during periods of prolonged
neutropenia such as ALL induction or any intensive block of AML therapy.
The most common pathogens include Candida and Aspergillus species. In
neutropenic patients, fever longer than 5 to 7 days despite adequate antibiotic
therapy is an indication for the empiric initiation of broad antifungal therapy,
usually with liposomal amphotericin B (Ambisome), as well as imaging for
occult fungal infection in the sinuses, lungs, liver, or spleen.
Treatment of a probable or confirmed invasive fungal infection often
requires long-term multiagent antifungal therapy. Current AML protocols
include fungal prophylaxis with either fluconazole or voriconazole due to
the high risk of infection in this population and the high rate of morbidity

1
Not FDA approved for this indication.

DM, April 2008 221

from these infections. Similar prophylaxis should be considered for any
child undergoing intensive therapy for relapsed ALL.
Hemorrhage
Prior to the introduction of ATRA, APML induction therapy was
associated with significant treatment related mortality due to hemorrhagic
complications. Today the use of ATRA3 with chemotherapy is usually not
complicated by a bleeding diathesis. However, the use of ATRA is
associated with the retinoic acid syndrome. This is a syndrome charac-
terized by severe respiratory distress, capillary leak syndrome, and
pseudotumor cerebri. This complication is successfully managed with
temporary cessation of ATRA and administration of decadron. ATRA is
usually restarted at a lower dose once the side effects have resolved.
Transfusion
Other important aspects of supportive care for children with leukemia
include the judicious use of blood component transfusions.
In general, packed red blood cell transfusions are recommended for hemoglo-
bin levels less than 8 g/dL or at higher hemoglobin levels if the child is
symptomatic (fatigue, headache, shortness of breath, tachycardia). At the time of
diagnosis, children are often severely anemic but minimally symptomatic
because the anemia has evolved slowly over time. In this setting, blood
transfusion should be administered slowly over hours to avoid volume overload.
All transfusions should be irradiated to prevent transfusion-related graft-versus-
host disease (GVHD) and to prevent cytomegalovirus (CMV) exposure.
Platelet transfusions are indicated for platelet counts less than
10,000/␮L or for bleeding. Platelets should be administered to a platelet
count greater than 50,000/␮L before diagnostic lumbar puncture to
prevent a traumatic tap, which can be difficult to interpret and can
introduce peripheral blasts into the spinal fluid.
In general, growth factors such as G-CSF (granulocyte colony-stimu-
lating factor, Neupogen) and erythropoietin (Epogen, Procrit) are rarely
administered to children being treated for leukemia due to the theoretical
risk of stimulating a malignant clone, although G-CSF is becoming an
integral part of some highly intensive relapsed ALL protocols.
Late Effects of Therapy
The success of leukemia therapy comes at a price. Although
treatment-related mortality continues to decrease as we implement

3
FDA approved for APL but not ALL, AML, or CML.

222 DM, April 2008

better supportive care strategies, an increasing number of survivors
suffer from late effects of therapy. The Children’s Oncology Group
has recently published detailed long-term follow-up guidelines for
pediatric oncologists and other physicians (http://www.survivor-
shipguidelines.org/). These guidelines do not supplant disease-specific
follow-up care, but they seek to complement and standardize the care
of childhood, adolescent, and young adult cancer survivors. All
pediatric oncology centers should establish late effects clinics to
provide care for the increasing population of survivors. As the number
of long-term effects investigators grows, their experience and exper-
tise are integral parts of clinical trial development. The ultimate
objective is to modulate the intensity of therapy to maximize its
efficacy and to minimize the short-term and long-term sequelae.
It is necessary for all cancer survivors to have a record of a summary
of their cancer therapy. Most leukemia cancer survivors graduate to
long-term follow-up within 4 or 5 years after completing therapy.
After this, they need follow-up visits once a year. The most concerning
toxicity occurs in the CNS from high-dose methotrexate or cytarabine
arabinoside and from intrathecal methotrexate with or without cranio-
spinal irradiation. These patients can experience a lower educational
attainment due to diminished cognitive functioning and usually
experience a greater need for special education services.
Many studies document increased weight and body mass index in
survivors of childhood leukemia. There is also now increased awareness
of adverse cardiovascular and diabetes risk profiles (the metabolic
syndrome) due to leukemia therapy. Patients who receive high cumulative
doses of anthracyclines also need yearly follow-up of cardiac function.
Fertility is another issue of concern; this is now more commonly
addressed with adolescents and young adults at diagnosis if the planned
therapy could result in sterility.
Psychosocial evaluation continues to be an important part of long-term
follow-up because many patients deal with issues of assistance to procure
educational resources, job placement, and health insurance.

Current Diagnosis
● History (including family history of blood disorders or cancer) and
physical examination.
● Complete blood count with a manual white blood cell differential and
review of the peripheral smear.
● Chest x-ray (PA and lateral views).
DM, April 2008 223
● Serum electrolytes, bun, creatinine, uric acid, calcium, phosphorus,
LDH, ALT, bilirubin.
● Coagulation studies: PT, PTT, fibrinogen.
● Varicella titer (IGG).
● Bone marrow aspirate and biopsy for morphology, blast cell immuno-
phenotype, cytogenetics, and minimal residual disease studies.
● Lumbar puncture with csf cell count, morphology on a spun prepara-
tion, protein, and glucose.

Abbreviations: ALT, alanine aminotransferase; BUN, blood urea nitro-

gen; CSF, cerebrospinal fluid; IgG, immunoglobulin G; LDH, lactate
dehydrogenase; PA, posteroanterior; PT, prothrombin time; PTT, partial
thromboplastin time.
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