Abstract:

Acute leukemia is the most common

pediatric malignancy and is gener-
ally associated with a favorable
outcome. Nevertheless, the time of
initial presentation is an especially
Diagnosis and
vulnerable period for these patients,
making the role of the frontline
provider critical to prompt diagnosis
and initiation of care. The diagnosis
Initial
of acute leukemia can be challen-
ging due to its nonspecific and
heterogeneous clinical presentation
Management of
and its tendency to mimic other
more common and self-limited ill-
nesses. There are, however, certain
Pediatric Acute
clinical, laboratory, and radiographic
features which can collectively raise
or lower suspicion for acute leuke-
Leukemia in the
mia in the emergency department.
Initial care must also involve
screening for and managing asso-
Emergency
Department
ciated acute complications such as
tumor lysis syndrome, hyperleuko-
cytosis, the presence of an anterior
mediastinal mass, or fever, further
emphasizing the essential respon-
sibility of emergency care providers
Setting
in this setting.

Keywords:
acute lymphoblastic leukemia; acute
myeloid leukemia; tumor lysis syn-
Aroop Kar, MD, Nobuko Hijiya, MD
drome; hyperleukocytosis; mediast-

inal mass
Division of Pediatric Hematology, Oncology,
and Stem Cell Transplantation, Ann &
Robert H. Lurie Children’s Hospital of
Chicago, Chicago, IL.
Reprint requests and correspondence:
Aroop Kar, MD, Division of Pediatric
Hematology, Oncology, and Stem Cell
Transplantation, Ann & Robert H. Lurie
Children’s Hospital of Chicago, 225 E.
Chicago Avenue, Box 30, Chicago, IL 60611.
akkar@luriechildrens.org
1522-8401
© 2018 Elsevier Inc. All rights reserved.
A
cute leukemia is the most common type of malignancy
affecting the pediatric population, accounting for about
30% of cancers below the age of 15 years and 15% of
cancers between the ages of 15 and 19 years. 1 Although
the outcomes for pediatric patients with acute leukemia are
generally favorable with modern therapies, the time of initial
presentation is a particularly vulnerable period for these
patients. 2 It is therefore critical that frontline providers, such
as those in the primary care and emergency department (ED)
settings, are adequately prepared to recognize the presenting
clinical features of acute leukemia, to initiate an appropriate
diagnostic work-up, and to screen for and manage potential acute
complications prior to transferring care to a Pediatric Hematol-
ogy/Oncology (PHO) specialist. Here, we provide a practical
guide for the diagnosis and initial management of children and
adolescents with confirmed or suspected acute leukemia in the
ED setting.

DIAGNOSIS AND INITIAL MANAGEMENT OF PEDIATRIC ACUTE LEUKEMIA... / KAR AND HIJIYA • VOL. 19, NO. 2 135
136 VOL. 19, NO. 2 • DIAGNOSIS AND INITIAL MANAGEMENT OF PEDIATRIC ACUTE LEUKEMIA... / KAR AND HIJIYA
BACKGROUND
Acute leukemia is, by definition, a malignant and
rapidly progressive disease involving the overpro-
duction of immature white blood cell (WBC)
precursors in the bone marrow, called “leukemic
blasts.” Not only do these cells function abnormally,
but they also interfere with the bone marrow's
production of normal WBCs, red blood cells (RBCs),
and platelets. 3 Acute leukemias can be broadly
classified into two main categories depending on
their cell of origin: acute lymphoblastic leukemia
(ALL) and acute myeloid leukemia (AML). ALL is
the most common pediatric cancer overall, has a
peak incidence between the ages of 2 and 5 years, is
far more common than pediatric AML, and generally
has a more favorable prognosis than AML. 2 ALL can
be further divided into B-cell acute lymphoblastic
leukemia (B-ALL) and T-cell acute lymphoblastic
leukemia (T-ALL), with B-ALL accounting for over
80% of these cases. 4 Although certain microscopic,
epidemiological, and clinical features may suggest a
diagnosis of one type of leukemia over another, a
definitive diagnosis cannot be made based on these
factors alone. Accurate diagnosis and classification
requires more specialized testing in the form of
immunohistochemistry, immunophenotyping by
flow cytometry, and genetic testing, which are
performed by experienced hematopathologists and
usually after the patient's care has already been
transferred to a PHO specialist. 5 Therefore, beyond
understanding that acute leukemia presents as a
widely heterogeneous condition with particular
pathological and clinical features associated with
different subtypes, it is neither practical nor
relevant to determine a patient's specific type of
leukemia in the ED setting.
CLINICAL PRESENTATION
The primary care clinic or ED typically serves
as the first point of contact for patients presenting
with newly diagnosed acute leukemia. Therefore,
arguably the most important role of the frontline
provider is to recognize the most common present-
ing features of acute leukemia, in order to
appropriately raise sufficient suspicion to pursue
further work-up and seek guidance from a PHO
specialist.
Unfortunately, there is no single clinical feature
that, in isolation, is considered to be highly
specific for a diagnosis of acute leukemia. This
is in part because any of the presenting features of
acute leukemia can mimic those of many other
more common and self-limiting illnesses seen in
TABLE 1. Common presenting clinical features
of pediatric acute leukemia.
Constitutional Hemorrhagic
Fever Bruising
Fatigue Bleeding
Weight loss Petechiae
Infiltrative Gastrointestinal
Hepatomegaly Abdominal pain
Splenomegaly Abdominal distension
Lymphadenopathy Anorexia
Musculoskeletal Dermatologic
Bone pain Pallor
Limping Rash
the pediatric population, such as viral infections,
further complicating the diagnostic challenge
faced by frontline providers. There are, however,
certain clinical features that are considered to
be more concerning for leukemia than others.
Moreover, patients who present with a combination
of these features without a convincing alternative
explanation should raise additional concern. 6
A recently published meta-analysis of over 3000
cases of pediatric leukemia, described in 33 studies
from 21 countries, retrospectively quantified the
most common signs and symptoms in children and
adolescents presenting with leukemia. 6 Over 90
different presenting clinical features were identified
overall, the most frequent of which are summarized
in Table 1. Over 50% of patients with leukemia
presented with hepatomegaly, splenomegaly, pallor,
fever, and/or bruising. In addition, over one third of
patients presented with a history of recurrent
infections, fatigue, limb pain, lymphadenopathy,
bleeding tendency, petechiae, and/or rash. Other
features included limping, weight loss, anorexia,
abdominal pain, and abdominal distension. 6 Bone
pain that awakens a patient from sleep is particu-
larly concerning. It is also important to note that in
infants and very young children who cannot
articulate or localize their complaints, generalized
illness or pain commonly manifests as fussiness or
irritability. 7
Although relatively uncommon, clinically overt
central nervous system (CNS) leukemia (i.e. pres-
ence of leukemic cells in the cerebrospinal fluid)
can present with headache, nausea/vomiting, leth-
argy, irritability, nuchal rigidity, papilledema, cra-
nial nerve palsies, and other manifestations of
increased intracranial pressure. 4 In addition, tes-
ticular involvement usually presents with painless
 DIAGNOSIS AND INITIAL MANAGEMENT OF PEDIATRIC ACUTE LEUKEMIA... / KAR AND HIJIYA • VOL. 19, NO. 2 137
testicular enlargement, although this is only clini-
cally apparent in 1–2% of males with newly
diagnosed ALL. 8 In our experience, some patients
with acute leukemia may present without any
abnormal physical examination findings; therefore,
a normal physical examination does not rule out the
possibility of leukemia. In fact, 6% of patients in the
previously described meta-analysis were reported to
be asymptomatic at diagnosis. 6
The first step of evaluation is to obtain a thorough
history of presenting symptoms and perform a
comprehensive review of systems, with particular
attention to those features that would be more
concerning for a diagnosis of acute leukemia. It is
also important to inquire about whether the patient
has been previously evaluated by another provider
for the current illness, what the results of any prior
physical examinations or bloodwork revealed, and
whether any corticosteroids have been adminis-
tered, as the use of corticosteroids may mask the
manifestations and diagnosis of acute leukemia.
After completion of a detailed history, the clinician
should carefully review the vital signs and perform a
thorough physical examination, once again paying
attention to those characteristics which are more
specific to a diagnosis of acute leukemia. This
should include palpation for hepatosplenomegaly
and lymphadenopathy of the head/neck, axillae, and
inguinal regions, as well as a detailed neurological
examination in all patients and a testicular exam-
ination in males to screen for signs of extramedul-
lary disease.
We suggest that a patient presenting with a
constellation of these signs or symptoms, especially
with an otherwise unexplained illness, should be
strongly considered for further oncologic work-up
under the guidance of a PHO specialist. Conversely,
we consider a relative lack of any of these features to
be more reassuring against a diagnosis of leukemia,
especially in the presence of a likely alternative
diagnosis. However, if there is ambiguity as to
whether a patient's clinical presentation is concern-
ing for acute leukemia, there should be a low
threshold for at least requesting the guidance of a
PHO specialist and pursuing further work-up if
indicated.
DIAGNOSTIC WORK-UP
At a minimum, initial work-up should include
ordering a complete blood count with differential
(CBC/diff) from the peripheral blood, as well as
microscopic review of the peripheral blood smear by
an experienced laboratory technologist or ideally a
hematopathologist if available. Under normal cir-
cumstances, the immature WBC precursors called
“blasts” are limited to fewer than 5% of the
nucleated cells of the bone marrow. These cells
should never be observed in the peripheral blood
except in the setting of profound WBC overproduc-
tion in response to infection or from bone marrow
invasion by granulomas, fibrosis, or tumor cells such
as in the case of leukemia. Therefore, although
immunophenotyping by flow cytometry is the most
definitive test for identifying leukemic blasts, the
detection of blasts in the peripheral blood by
microscopy is considered to be highly suspicious
for leukemia, especially in the presence of other
concerning clinical features. 8 However, it is worth
remembering that because leukemia originates in
the bone marrow, the gold standard for ruling out
leukemia is sampling of the bone marrow rather
than the peripheral blood, and in many cases acute
leukemia can present without detectable blasts in
the peripheral blood. Therefore, in our experience,
the absence of blasts in the peripheral blood
certainly does not rule out an underlying diagnosis
of leukemia. (See Table 2)
To complicate matters further, in our anecdotal
experience, sometimes “abnormal,” “atypical,” “im-
mature,” or “suspicious” WBCs have been reported
in the peripheral blood without being explicitly
identified as blasts. Although such findings may be
related to common infections, these situations
should be approached with caution and considered
in the context of other clinical and laboratory
findings, as sometimes such patients have been
diagnosed with leukemia upon either repeated
testing, repeated analysis by an expert hemato-
pathologist, or bone marrow evaluation. We strongly
recommend that such cases of ambiguity be
discussed with a PHO specialist, as they may need
further evaluation. In addition, if blasts or otherwise
unusual WBCs are reported in the peripheral blood,
it is worth discussing with the PHO specialist
whether to proceed with sending peripheral blood
for immunophenotyping by flow cytometry for more
definitive diagnosis and classification of leukemia.
As mentioned previously, several of the key
manifestations of acute leukemia are related to
bone marrow suppression due to infiltration of
leukemic cells, so most cases of acute leukemia
present with an abnormal CBC. Up to 90% of
patients with newly diagnosed acute leukemia
present with anemia and/or thrombocytopenia of
varying degrees. 3 In contrast, acute leukemia may
present with either a high, low, or normal total WBC
count, although the absolute neutrophil count
(ANC) is often decreased. The anemia is typically
normocytic (having a normal mean corpuscular
138 VOL. 19, NO. 2 • DIAGNOSIS AND INITIAL MANAGEMENT OF PEDIATRIC ACUTE LEUKEMIA... / KAR AND HIJIYA
volume, or MCV), and the reticulocyte count is
typically normal or low as a reflection of impaired
RBC production. 3 Due to the potential for severe
anemia either at diagnosis or shortly thereafter, a
type and screen should also be ordered in prepara-
tion for possible RBC transfusion.
In contrast to leukemia, acute idiopathic, or
immune, thrombocytopenic purpura (ITP), which is
usually a benign and self-limited condition, classically
presents with isolated and severe thrombocytopenia
in patients who are otherwise healthy and asymp-
tomatic. In addition, patients with acute ITP often
have a more abrupt onset of bleeding or bruising
symptoms than those with acute leukemia. 9 In our
experience, however, this distinction may be chal-
lenging when there are also abnormalities in WBC
count or ANC which may be related to viral illness,
and/or when there is concurrent anemia which may
be attributed to viral suppression or bleeding.
Isolated leukopenia is common with many viral
infections and benign WBC disorders, and without
other concerning clinical features is unlikely to
represent leukemia. 3 However, concurrent cytope-
nias may occur as a result of infectious suppression
as well, further complicating the picture. 10 In
general, it is reasonable to consider acute leukemia
as a possible etiology when two or especially three
cell lines are affected, understanding that the
differential diagnosis in such cases is very broad.
This includes transient infectious or drug/toxin-
related marrow suppression, nutritional deficiencies
in vitamin B12 or folate, severe iron deficiency,
acquired or inherited bone marrow failure, hypers-
plenism, hemophagocytic lymphohistiocytosis
(HLH), bone marrow infiltration by lymphomas or
solid tumors, juvenile idiopathic arthritis (JIA), or
systemic lupus erythematosus (SLE). 3
For the most accurate CBC results, we recom-
mend sampling of blood by venipuncture as opposed
to the capillary bed (“finger prick”). In addition,
certain laboratory errors can be misleading, for
example in the case of platelet clumping (causing a
falsely low platelet count) or hemodilution (causing
a false relative decrease in all three cell lines).
Therefore, it is worth considering confirmation of
any significant and unexpected laboratory abnor-
malities with repeated testing. Laboratory results
should also be interpreted in the context of a
patient's overall fluid status, as dehydration or
excess IV hydration can contribute to hemoconcen-
tration or hemodilution, respectively.
A chemistry or basic metabolic panel, with the
addition of a phosphorus level (typically not
included with a routine chemistry or basic meta-
bolic panel), should be ordered to screen for several
potential complications. As described in more detail
later, levels of potassium, phosphorus, and calcium
help assess for evidence of tumor lysis syndrome
(TLS), which may involve hyperkalemia, hyperpho-
sphatemia, and/or hypocalcemia. Of note, occasionally
leukemia may instead present with hypercalcemia, the
interpretation and management of which is outside of
the scope of this article. 4 In addition, elevated levels of
BUN and creatinine may signify impaired renal
function as a consequence of TLS, leukemic kidney
infiltration, and/or illness-related dehydration or
shock. Levels of uric acid and lactate dehydrogenase
(LDH), both markers of increased cell turnover, should
also be ordered, as these values can be elevated in the
setting of tumor lysis. 11 A liver panel should also be
ordered and may reveal transaminitis or hyperbilir-
ubinemia related to hepatic infiltration. 12 The results
of the metabolic and liver panels are also important for
appropriately and safely dosing chemotherapeutic
agents which may require metabolism or excretion
by the kidney or liver, and/or cause nephrotoxicity or
hepatotoxicity.
A full coagulation panel, including prothrombin
time (PT)/international normalized ratio (INR),
partial thromboplastin time (PTT), fibrinogen
level, and D-dimer, should be ordered to rule out
disseminated intravascular coagulation (DIC). Al-
though rare overall, DIC can be seen in cases of
acute leukemia and classically manifests with
elevated PT/INR, PTT, and D-dimer, decreased
fibrinogen, thrombocytopenia, and signs of bleeding
and/or thrombosis if clinically overt. It is worth
mentioning here that a specific subtype of AML
called acute promyelocytic leukemia (APL), al-
though representing only 4–10% of pediatric AML
cases, has historically been associated with high
mortality in the acute phase due to its high risk of
DIC and life-threatening hemorrhage at diagnosis. 5
Fortunately, APL is now considered to be highly
curable due to the use of all-trans-retinoic acid
(ATRA) and arsenic trioxide, but these patients
are still particularly vulnerable during the period of
initial diagnosis. 13 Although “Auer rods,” or needle-pt?
>shaped structures in the cytoplasm of myeloid
precursor cells, may be present in various subtypes
of AML, the presence of numerous Auer rods within
each cell is more suspicious for APL. 5 Therefore, when
such cells are found on a peripheral blood smear, and
especially with concurrent evidence of DIC, we
strongly recommend enlisting the guidance of a PHO
specialist in considering empiric treatment with ATRA
while awaiting more confirmatory testing for APL.
Due to the immunocompromised status of a
patient with newly diagnosed leukemia, blood
cultures should be ordered, and a urinalysis with
 DIAGNOSIS AND INITIAL MANAGEMENT OF PEDIATRIC ACUTE LEUKEMIA... / KAR AND HIJIYA • VOL. 19, NO. 2 139
TABLE 2. Initial diagnostic work-up of pediatric acute leukemia and potential complications.
Laboratory Testing
CBC with differential
WBC, hemoglobin, platelet count
Reticulocyte count
Review of peripheral smear
Type & screen
Chemistry panel/basic metabolic panel
Sodium, potassium, * chloride, bicarbonate/CO2, BUN,
creatinine, calcium *
Phosphorus *
Uric acid *
Lactate dehydrogenase (LDH)
Liver panel
Total protein, albumin, alkaline phosphatase, bilirubin, AST, ALT
*
Screen for tumor lysis syndrome.
**
As clinically indicated.
urine culture may be considered, for any patient
presenting with fever and/or other signs of sepsis,
discussed in more detail later. It is also reasonable to
order more specific infectious testing as clinically
indicated. For example, a patient with signs or
symptoms of an upper respiratory tract infection may
benefit from ordering a nasopharyngeal respiratory viral
panel to look for a source. In addition, in our experience,
some patients present with features of infectious
mononucleosis which can mimic those of acute
leukemia (fever, fatigue, weight loss, lymphadenopathy,
hepatosplenomegaly, and/or cytopenias). Such patients
may present a diagnostic dilemma in the absence of
more definitive bone marrow evaluation and may
benefit from ordering laboratory testing for Epstein–
Barr virus (EBV) or cytomegalovirus (CMV). As with
routine care, a blood gas with lactic acid level should
also be considered when septic shock is suspected.
We recommend that a chest x-ray (PA/lateral films)
be routinely ordered for any patient with confirmed or
highly suspected leukemia based on clinical presenta-
tion and/or bloodwork, with the primary purpose of
assessing for an associated anterior mediastinal mass,
the management of which is described later. 5 Other
findings on chest x-ray may include cardiomegaly and
pulmonary vascular plethora (due to anemia), pulmo-
nary air space opacification (due to pneumonia,
hemorrhage, or leukostasis), or pleural effusions (due
to leukemic infiltration or infection). Chest x-ray may
also incidentally report splenomegaly or skeletal
abnormalities consistent with leukemia. 14 Computed
tomography (CT) of the chest may be considered if the
chest x-ray reveals a mediastinal mass, discussed later.
Laboratory Testing (continued)
Coagulation panel
PT, PTT, fibrinogen, D-dimer
Blood cultures ** (if febrile)
Urinalysis/urine culture ** (if febrile)
Viral testing **
Blood gas with lactic acid **
Imaging
Chest x-ray (PA/lateral)
Additional skeletal imaging **
Chest CT **
Echocardiogram **
Renal/bladder ultrasound **
It would also be reasonable to consider additional
radiographic imaging of areas of suspected skeletal
involvement. Children presenting with acute leuke-
mia commonly have radiographic skeletal abnor-
malities at diagnosis, including a spectrum of
findings such as transverse lucent metaphyseal
bands, diffuse demineralization, subperiosteal cor-
tical bone erosion, periosteal reaction, lytic bone
lesions, osteosclerosis, and pathologic fractures. 14
Although the presence of bone lesions does not
typically affect management of the leukemia itself,
patients with identified fractures (or who are at high
risk of fracture) generally benefit from supportive/
preventive care. We therefore recommend involve-
ment of the orthopedic team in these cases as well as
physical/occupational therapists as indicated, upon
transfer of care to a PHO specialist.
Table 2 summarizes the recommended diagnostic
testing for confirmed or suspected new diagnoses of
acute leukemia, as well as screening for its potential
complications as described in the following section.
It is important to maintain close communication
with a PHO specialist as laboratory and radiographic
findings result.
INITIAL MANAGEMENT
AND ACUTE COMPLICATIONS
We recommend routinely admitting patients with
newly diagnosed or highly suspected acute leukemia
for inpatient monitoring, diagnostic work-up, and
initial treatment, either to the PHO service or to the
140 VOL. 19, NO. 2 • DIAGNOSIS AND INITIAL MANAGEMENT OF PEDIATRIC ACUTE LEUKEMIA... / KAR AND HIJIYA

TABLE 3. Management of acute complications of pediatric acute leukemia.

Tumor lysis syndrome (TLS)
Close monitoring of renal function and urine output
Aggressive IV hydration (with or without TLS)
Consider dextrose with half-normal or normal saline at 1.5 x maintenance rate
Do NOT supplement with potassium, phosphorus, calcium, or sodium bicarbonate
Allopurinol (with or without TLS); adjust dose if renal insufficiency
Correction of metabolic derangements
Severe hyperuricemia: Rasburicase, especially with acute kidney injury (AKI) and/or high WBC count; screen males for G6PD deficiency
and monitor for hemolysis
Hyperkalemia: electrocardiogram/cardiorespiratory monitoring; calcium gluconate, sodium polystyrene sulfonate, albuterol,
insulin, sodium bicarbonate
Hyperphosphatemia: aluminum hydroxide, sevelamer hydrochloride
Hypocalcemia: calcium gluconate (if symptomatic)
Consider renal/bladder ultrasound
Consultation with Nephrology team if significant AKI and/or metabolic derangements

Hyperleukocytosis
Close monitoring of neurologic and respiratory systems
Aggressive IV hydration
Consider hydroxyurea, emergent chemotherapy, and/or rarely leukapheresis (with PHO specialist)
Consider platelet transfusion to maintain level N 20 000/mL to prevent intracranial hemorrhage
Generally avoid RBC transfusion if hemodynamically stable; if necessary, transfuse slowly

Anterior mediastinal mass

Close monitoring of respiratory, cardiovascular, and neurologic systems for signs of superior vena cava syndrome/superior
mediastinal syndrome
Elevate head of bed, consider upright/prone positioning or oxygen, consider PICU for monitoring
Consider echocardiogram if cardiovascular compromise
Consider chest CT if safe and indicated per PHO specialist
Avoid sedation/anesthesia whenever possible
Consult Pediatric Surgery team to discuss least invasive method of biopsy if necessary
Consult Anesthesiology team prior to imaging or procedures which may require sedation/anesthesia

Fever/infection
Close monitoring for signs of septic shock
Blood cultures; consider urinalysis/urine culture, viral testing, blood gas if indicated
Empiric broad-spectrum antibiotic therapy with antipseudomonal coverage (e.g. cefepime, ceftazidime,
piperacillin-tazobactam, meropenem)
Consider additional gram-positive, gram-negative, and/or anaerobic coverage if indicated
Follow routine algorithm for management of septic shock
In case of severe anemia, use caution with giving crystalloid for fluid resuscitation due to risk of hemodilution; favor use
of RBC transfusions for hemodynamic support

pediatric intensive care unit (PICU) depending on
the severity of illness. Indications for PICU admis-
sion may include severe anemia, respiratory or
neurological compromise, cardiovascular instabili-
ty, or severe metabolic derangements with renal
insufficiency which may require hemodialysis.
Unless emergently necessary for the critically ill
patient, treatment in the form of chemotherapy
typically does not begin until a definitive diagnosis is
made based on the results of immunophenotyping
by flow cytometry, as the choice of therapy depends
on the specific subtype of leukemia, and pre-
treatment may limit diagnostic interpretation.
Rather than treatment of the leukemia itself, the
essential role of the frontline provider is to maintain
stability of the patient by screening for, managing,
and preventing acute complications of the leukemia.
Following are the descriptions of some of the most
common acute complications which may arise in
the setting of newly diagnosed acute leukemia, as
 DIAGNOSIS AND INITIAL MANAGEMENT OF PEDIATRIC ACUTE LEUKEMIA... / KAR AND HIJIYA • VOL. 19, NO. 2 141
well as guidelines for initial management/preven-
tion, summarized in Table 3. We strongly recom-
mend that the management of such complications
take place under the close supervision of a PHO
specialist.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) refers to the metabolic
abnormalities that occur due to the release of
intracellular components into the circulation as a
result of tumor cell death. It usually occurs within the
first 12 to 72 hours after initiation of chemotherapy,
but it may also occur spontaneously at the time of
diagnosis prior to any treatment. 15 TLS occurs more
often in malignancies with rapid growth and/or high
tumor burden. These include non-Hodgkin lympho-
mas, especially Burkitt lymphoma, and acute leuke-
mias presenting with a high WBC count. 16 Although
there is no widely accepted definition for TLS, for our
purposes here, it is sufficient to be aware of the
characteristic triad of hyperuricemia, hyperkalemia,
and/or hyperphosphatemia, with or without resultant
hypocalcemia. Hyperuricemia results from the break-
down of nucleic acids released from the leukemic cells
and is the most common finding in TLS. When uric
acid is present in high concentrations in acidic urine, it
can crystallize in the renal parenchyma and tubules
with subsequent intraluminal obstruction and oliguria
with acute kidney injury (AKI). Hyperkalemia carries
the highest risk of mortality due to its potential for
causing severe arrhythmia, and may be amplified by
renal dysfunction such as that caused by hyperurice-
mia. Hyperphosphatemia can cause acute nephrocal-
cinosis and renal failure due to precipitation of calcium
phosphate crystals. Hypocalcemia occurs due to the
precipitation of phosphorus with calcium and can be
either asymptomatic or symptomatic, causing nausea,
anorexia, muscle cramps, tetany, and/or altered
consciousness. 11
Prevention of TLS is critical in all cases of
suspected acute leukemia even without laboratory
evidence of TLS at diagnosis, and aggressive
hydration is considered to be the most important
factor in preventing TLS. 16 There is no universally
agreed upon manner in which to administer
hydration, but at our institution we commonly
initiate IV fluids with dextrose and half-normal (or
normal) saline at 1.5 × maintenance rate for cases
without TLS. It is common practice to withhold any
potassium, phosphorus, or calcium from fluids. In
addition, the alkalinization of fluids is no longer
routinely recommended as it had been in the past,
as the benefit of alkalinization has not been clearly
demonstrated, and it may in fact promote precipi-
tation of xanthine and hypoxanthine stones in the
renal tubules, or calcium phosphate crystals in the
setting of hyperphosphatemia. 4 We also recom-
mend initiating allopurinol for patients with newly
diagnosed leukemia to prevent the overproduction
of uric acid, although the dose may need to be
adjusted in the setting of renal insufficiency. Renal
function and urine output should be closely moni-
tored, and if there are concerns, then it is
reasonable to obtain imaging such as a renal/bladder
ultrasound.
When TLS is present at diagnosis, interventions
should be directed at the specific metabolic derange-
ments identified, with aggressive IV hydration being
an essential component of treatment. In our experi-
ence, mild/borderline hyperuricemia may be man-
aged with aggressive hydration and allopurinol alone,
whereas more significant hyperuricemia, especially
in the setting of AKI and/or high tumor burden (high
WBC count), typically calls for the use of rasburicase
(recombinant urate oxidase) to break down existing
uric acid. It is important to note that rasburicase may
cause life-threatening hemolysis and methemoglobi-
nemia, especially in patients with G6PD deficiency,
so is therefore contraindicated in these patients. 16
Patients and family members (particularly males as
this is an X-linked disorder) should be adequately
screened for this condition prior to administration of
rasburicase and monitored closely for evidence of
subsequent hemolysis. Hyperkalemia should prompt
evaluation with an electrocardiogram and cardiore-
spiratory monitoring looking for abnormalities/ar-
rhythmias, and consideration of calcium gluconate
(for cardioprotection), sodium polystyrene sulfonate,
albuterol, insulin, and/or sodium bicarbonate de-
pending on severity of the hyperkalemia and pres-
ence of other concurrent metabolic derangements. 15
Hyperphosphatemia should prompt consideration of
a phosphate binder; while aluminum hydroxide has
been used for this purpose, we typically choose
sevelamer hydrochloride given its lack of calcium and
associated aluminum toxicity. Hypocalcemia noted
on a chemistry or basic metabolic panel should be
followed by more accurate measurement of serum
calcium, using either an ionized calcium level or a
calculated level based on correction for serum
albumin level. The treatment for hypocalcemia is
calcium gluconate; however, we generally recom-
mend only treating hypocalcemia in symptomatic
patients, and caution must be exercised when
treating hypocalcemia in the setting of concurrent
hyperphosphatemia. 16 We recommend consultation
with the nephrology team in cases of significant AKI
and/or metabolic derangements, especially when not
responding to hydration and medical management, as
142 VOL. 19, NO. 2 • DIAGNOSIS AND INITIAL MANAGEMENT OF PEDIATRIC ACUTE LEUKEMIA... / KAR AND HIJIYA
some patients with TLS may require hemodialysis.
We also recommend discussing with the PHO
specialist the optimal frequency of monitoring for
tumor lysis (chemistry or basic metabolic panel,
phosphorus, uric acid, ionized calcium if applicable)
based on the severity of abnormalities present at
diagnosis and the timing of initial therapy.
Hyperleukocytosis
Hyperleukocytosis is generally defined as a WBC
count over 100,000/mL. 11,16 However, clinically
significant hyperleukocytosis typically occurs
with WBC counts over 200,000/mL in AML and
300,000/mL to 500,000/mL in ALL. This difference
in thresholds is hypothetically related to the larger
and more adherent blasts of AML compared with
those of ALL. 11,16 Hyperleukocytosis occurs more
commonly in patients with AML, T-ALL, and infant
ALL, as well as other more specific subtypes such as
Burkitt leukemia. 16 Hyperleukocytosis may either
be asymptomatic or cause symptomatic leukostasis,
in which there is intravascular clumping of leukemic
blasts leading to sluggish blood flow and subsequent
hypoxia/infarction or hemorrhage of tissue. 17 This
occurs more frequently in AML than in ALL and
most often affects the lungs and the brain, but has
also been reported to cause renal failure, papille-
dema, dactylitis, priapism or clitorism, acute myo-
cardial infarction, and cardiac failure. 11 Patients
with pulmonary leukostasis present with hypoxia
and respiratory distress which can rapidly progress
to respiratory failure, showing diffuse interstitial
infiltrates on chest x-ray. 16,17 CNS leukostasis can
present with headache, confusion, somnolence,
stroke, and/or seizure. 17
Although many patients with hyperleukocytosis
are asymptomatic, those presenting with WBC
count over 100,000/mL should prompt a thorough
evaluation with particular attention to the neuro-
logical, ophthalmologic, and respiratory examina-
tions. As previously mentioned, patients with high
WBC counts are also more likely to present with TLS
due to their high tumor burden, so this should be
assessed for and monitored closely both before and
even more so after initiation of chemotherapy.
Initial management of hyperleukocytosis (especially
with evidence of concurrent leukostasis) often
includes aggressive hydration and initiation of
tumor-directed therapy in the form of chemother-
apy and/or hydroxyurea, and in some rare cases
leukapheresis, all under the care of a PHO specialist.
Platelets should be transfused for bleeding symp-
toms or to maintain levels above a threshold of at
least 20,000/mL to prevent intracranial hemor-
rhage. However, if the patient is hemodynamically
stable, RBC transfusions should be avoided until
after reduction of the WBC count due to their high
viscosity and potential to worsen leukostasis. If
absolutely necessary, RBC transfusions should be
administered slowly. 16
Anterior Mediastinal Mass
As mentioned previously, a chest x-ray (PA/lateral
films) should be performed in all cases of confirmed
or highly suspected leukemia given the potential for
an associated anterior mediastinal mass, even in
those without respiratory signs or symptoms. In the
pediatric population, the most common causes of an
anterior mediastinal mass include Hodgkin and non-
Hodgkin lymphomas and T-ALL. 16 Approximately
half of T-ALL cases present with an anterior
mediastinal mass. 5 Other etiologies include neuro-
blastoma, germ cell tumors, and sarcomas. 11 “Su-
perior vena cava syndrome” (SVCS) refers to the
signs and symptoms resulting from compression or
thrombosis of the superior vena cava, whereas
“superior mediastinal syndrome” (SMS) also in-
cludes tracheal compression. However, because
SVCS frequently coexists with respiratory compro-
mise in children with mediastinal masses, the terms
SVCS and SMS are often used interchangeably. 16
From a respiratory standpoint, the most common
symptoms of SVCS/SMS in children are dyspnea,
cough, wheeze, and orthopnea, which are typically
exacerbated in the supine position due to decreased
thoracic volume. Less commonly, patients can
present with anxiety, confusion, lethargy, headache,
visual disturbance, and syncope, which may be
indicative of carbon dioxide retention and central
venous stasis and require more immediate inter-
vention. Cardiovascular obstruction can lead to
head and neck edema, plethora, and cyanosis of the
face, neck, and upper extremities; cervical and
thoracic venous distension; and conjunctival suffu-
sion and edema. 16 Therefore, careful examination
and close cardiorespiratory monitoring are essential
components of initial evaluation.
Patients with an anterior mediastinal mass should
generally be placed in the position in which they can
breathe most comfortably. Supine positioning may
lead to further airway compression, impaired
venous return, and rapid cardiorespiratory collapse
in patients with significant airway compromise. 18
Therefore, elevating the head of the bed is indicated
for those patients with orthopnea or cardiovascular
compromise, as this position can lessen airway
compression and assist with venous drainage and
decreasing edema. 19 However, we often recommend
 DIAGNOSIS AND INITIAL MANAGEMENT OF PEDIATRIC ACUTE LEUKEMIA... / KAR AND HIJIYA • VOL. 19, NO. 2 143
this position even in asymptomatic patients as a
precaution, especially while asleep. Symptoms may
also improve in the upright or prone position, and
patients may benefit from oxygen therapy. 11 In our
experience, patients with significant cardiovascular
or respiratory compromise (or at risk thereof) due to
a mediastinal mass typically require admission to
the PICU for support and observation, so it is worth
consulting the PICU in these situations. We also
recommend considering an echocardiogram in
cases of cardiovascular instability.
Whether symptomatic or not, the presence of a
mediastinal mass presents an additional challenge
when trying to pursue further diagnostic work-up in
the form of CT imaging or a biopsy, given the
associated risks of supine positioning and sedation/
anesthesia. Patients who cannot tolerate supine
positioning may require decubitus or prone posi-
tioning if CT evaluation is necessary, but some
patients with significant compression may not be
able to tolerate any horizontal positioning at all. In
addition, sedation/anesthesia should generally be
avoided whenever possible, as even patients with
stable respiratory status while awake may develop
significant obstruction when sedated, and endotra-
cheal intubation may not reach beyond the point of
obstruction. 11 Therefore, diagnosis should be made
in the least invasive manner possible in order to avoid
unnecessary sedation/anesthesia. Evaluation should
begin with testing peripheral blood if blasts are
present, and then considering the sampling of
palpable lymph nodes, pleural or pericardial fluid,
or bone marrow under local anesthesia, before
considering biopsy of the mass itself (which may
still be feasible in some circumstances under local
anesthesia). 20 In some cases in which cardiorespira-
tory compromise is severe and the risk of either
proceeding with or waiting for diagnostic procedures
is too great, empiric chemotherapy must be initiated
emergently (typically in the form corticosteroids)
before biopsy is feasible, knowing that this may limit
interpretation of the biopsy. 11 We recommend close
involvement of the PHO specialist and consultation
with the anesthesiology, surgical and medical imaging
teams in order to determine the safest method of
obtaining imaging and/or a biopsy.
Fever/Infection
As previously described, over 50% of patients with
newly diagnosed leukemia present with fever. 6
However, recent data suggest that very few of
these patients are diagnosed with an identifiable
blood stream infection. Specifically, in a review of
126 patients with ALL and reported fever at
diagnosis, only two patients were found to have
bacteremia. While false-negative blood cultures
remain a possibility, it has instead been hypothe-
sized that fever may result from the malignancy
itself due to the release of proinflammatory cyto-
kines such as IL-6, TNF-α, and interferons. 21
Nevertheless, we consider patients with newly
diagnosed leukemia to be immunocompromised
because even with a normal or elevated WBC
count or absolute neutrophil count (ANC), these
cells likely do not function normally in the face of an
infection (so-called “functional neutropenia”). As
there are relatively few guidelines or data regarding
the use of empiric antibiotics in this setting, at our
institution we assume that all patients with newly
diagnosed acute leukemia presenting with fever or
other signs of sepsis have infection until proven
otherwise.
For these patients, we recommend ordering
peripheral blood cultures and considering a urinal-
ysis with urine culture prior to initiating empiric
antibiotic therapy. We recommend the use of broad-
spectrum antibiotic therapy with antipseudomonal
coverage, such as cefepime, ceftazidime,
piperacillin-tazobactam, or meropenem depending
on institutional preference and availability. Addi-
tional gram-positive, gram-negative, and/or anaero-
bic coverage can be considered in certain
circumstances depending on identified or suspected
sources of infection (eg, vancomycin or clindamycin
for skin/soft tissue infections) or degree of illness/
hemodynamic instability. Providers should monitor
closely for signs of septic shock and follow the
routine algorithm for fluid resuscitation and pressor
support as needed. However, caution should be
exercised in the case of severe anemia, in which it
may be more beneficial to administer RBC products
than crystalloids, which may worsen the anemia
with excessive hemodilution. Decisions regarding
empiric antibiotics and transfusions should be made
under the guidance of the PHO specialist involved.
SUMMARY
As the first point of contact for these patients, the
frontline provider plays an essential role in the
initial evaluation and management of children and
adolescents presenting with newly diagnosed or
highly suspected acute leukemia. All frontline
providers in the ED should have an awareness of
the presenting features which should raise suspicion
for acute leukemia and accordingly prompt the
involvement of a PHO specialist in guiding further
evaluation and care. For those patients who warrant
144 VOL. 19, NO. 2 • DIAGNOSIS AND INITIAL MANAGEMENT OF PEDIATRIC ACUTE LEUKEMIA... / KAR AND HIJIYA
additional work-up based on clinical suspicion, we
have included some guidelines for the testing which
is most commonly indicated, as well as both a
rationale for each assessment and a guide for
interpreting results. Finally, we have described the
presentation of several potential acute complica-
tions of acute leukemia, as well as some practical
recommendations for their prevention and initial
management. Altogether, we hope to find that this
education will give frontline providers a more
meaningful understanding of this disease process
and its acute complications, some additional exper-
tise and comfort with the initial evaluation and
management of these patients, and an opportunity
for more effective communication with PHO spe-
cialists, ultimately resulting in safer and more
efficient care of patients presenting with new onset
of acute leukemia in the ED.
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