Indian J Pediatr (February 2013) 80(2):144–148
DOI 10.1007/s12098-012-0917-3
SYMPOSIUM ON PGIMER MANAGEMENT PROTOCOLS ON ONCOLOGICAL EMERGENCIES
Hyperleukocytosis: Emergency Management
Richa Jain & Deepak Bansal & R. K. Marwaha
Received: 9 March 2012 / Accepted: 26 October 2012 / Published online: 24 November 2012
# Dr. K C Chaudhuri Foundation 2012
Abstract Hyperleukocytosis is defined as peripheral blood
leukocyte count exceeding 100,000/mm3. Acute leukemia is
the most common etiology in pediatric practice. Hyperleu-
kocytosis is a medical emergency. The increased blood
viscosity, secondary to high white cell count and leukocyte
aggregates, results in stasis in the smaller blood vessels.
This predisposes to neurological, pulmonary or gastrointes-
tinal complications. In addition, patients are at risk for tumor
lysis syndrome due to the increased tumor burden. Initial
management includes aggressive hydration, prevention of
tumor lysis syndrome, and correction of metabolic abnor-
malities. A red cell transfusion is not indicated in a hemo-
dynamically stable child, as it adversely affects the blood
viscosity. Leukapheresis is the treatment of choice for a very
high count, or in patients with symptomatic hyperleukocy-
tosis. The technical expertise required, a relative difficult
venous access in younger children, risk of anticoagulation
and possible non-availability of the procedure in emergency
hours are limitations of leukapheresis. However, it is a
rewarding procedure and performed with relative ease in
centers that perform the procedure frequently. An exchange
transfusion is often a practical option when hyperleukocy-
tosis is complicated with severe anemia. The partial ex-
change aids in correcting both, without the risk of volume
overload or hyperviscosity, which are the limitations of
hydration and blood transfusion, respectively. Etiology and
management of hyperleukocytosis in relevance to the pedi-
atric emergency room is outlined.
R. Jain : D. Bansal (*) : R. K. Marwaha
Hematology/Oncology Unit, Department of Pediatrics,
Advanced Pediatrics Center,
Post Graduate Institute of Medical Education and Research,
Chandigarh 160012, India
e-mail: deepakritu@yahoo.com
Keywords Acute lymphoblastic leukemia . ALL . CML .
Hydration . India . Leukostasis . Priapism
Introduction
Hyperleukocytosis is defined as peripheral blood leukocyte
count exceeding 100,000/mm3 [1]. It typically occurs in
hematological malignancies, including acute lymphoblastic
leukemia(ALL), particularly T-cell ALL, infant ALL or
hypodiploid ALL, and acute myeloid leukemia (AML).
Chronic myeloid leukemia, especially in blast crisis may
present with hyperleukocytosis [2]. Hyperleukocytosis com-
plicates the course of leukemia in 5–22 % children [3, 4].
Differential Diagnosis
Hyperleukocytosis should be differentiated from leukemoid
reaction, when a high total leukocyte count (TLC) (typically
>50,000/mm3) occurs in the presence of non-malignant dis-
orders. It is observed in certain infections, including pertus-
sis, staphylococcus aureus, Pneumococcus, tuberculosis and
varied inflammatory conditions [5, 6]. Generally, the counts
do not exceed 100,000/mm3. The predominant cells are
mature lymphocytes and granulocytes. Differentiation can
be done through history, examination and peripheral smear
examination. A high number of nucleated RBCs (nRBC) in
blood can also raise the TLC erroneously, especially when a
counter is used. This is commonly observed in patients with
thalassemia major and in neonates. The counter generates a
raised value of TLC, as the nRBC’s are spuriously counted
as leucocytes. The TLC generally is less than 100,000/mm3.
Here again, the examination of peripheral smear will con-
firm the presence of nRBC’s, and a corrected TLC can be
calculated.
Indian J Pediatr (February 2013) 80(2):144–148
Complications of Hyperleukocytosis
Hyperleukocytosis is an emergency as it may cause several
complications, resulting in morbidity or mortality. Vascular
obstruction can occur, leading to organ damage from tissue
hypoxia, thrombosis or hemorrhage. Metabolic derange-
ments are common due to high blast count. The most com-
monly affected organs are central nervous system (CNS)
and the lungs [2, 7, 8]. A CNS bleed, leukostasis or throm-
bosis, either independently or in combination, can cause
CNS symptoms. Manifestations include irritability, altered
sensorium, seizures, focal neurological deficits and raised
intracranial pressure. Pulmonary leukostasis may result in
hypoxia, respiratory distress and can require respiratory
support. Chest radiograph may show presence of diffuse
infiltrates. Other organ systems can also be involved. Gas-
trointestinal hemorrhage may occur, resulting in bleed, hem-
atemesis or pain abdomen. Priapism, clitoral engorgement
and dactylitis are the rarer manifestations of leukostasis.
An important complication relating to the high tumor
burden in patients with hyperleukocytosis is the tumor lysis
syndrome (TLS). TLS may present with isolated lab de-
rangement, including hyperuricemia, hyperkalemia, hyper-
phosphatemia, hypocalcemia or with associated clinical
symptoms, including oliguria or anuria, seizures, altered
sensorium ranging from irritability and confusion to frank
coma [9]. The most common time for TLS to occur is within
2–3 d following the initiation of chemotherapy, however
spontaneous TLS may occur in the absence of any therapy.
Pathophysiology
Two potential mechanisms have been suggested to explain
the complications caused by hyperleukocytosis. According
to the traditional explanation, there is an increase in blood
viscosity, secondary to high TLC and leukocyte aggregates,
resulting in stasis in the smaller blood vessels. The second
proposed mechanism is of adhesive interactions between the
damaged endothelium of the vessel and leukemic blasts,
precipitating leukostasis. The toxins and cytokines released
by the vascular endothelium exacerbate the situation [1, 2].
Clinically significant hyperleukocytosis usually occurs in
the presence of a TLC exceeding 300,000/mm3 in ALL, and
more than 200,000/mm3 in AML. However, several factors
may result in symptoms at a lower TLC. These include
severe anemia, thrombocytopenia, renal dysfunction, super-
imposed infection, dehydration and acidosis. The CNS
events and pulmonary leukostasis are more common in
children with AML, while TLS is observed with a higher
frequency in ALL [9–11]. In an analysis of 234 children
with hyperleukocytosis from St Jude hospital, 19 % of
children with AML had hemorrhagic complications,
145
including intracranial or pulmonary bleeds, vs. 2.5 % with
ALL [10]. Metabolic complications occurred more frequently
in patients with ALL than AML. The early mortality was
significantly higher in children with AML than ALL [10].
This difference is likely due to the larger size of blasts in
AML, along with increased adhesiveness. Larger myeloblasts
do not circulate freely in capillaries and small blood vessels,
leading to sequestration and vascular damage. The symptoms
may be more pronounced, and occur at lower TLC in children
with monocytic leukemia, where the blasts have a higher
propensity for adhesiveness and tissue invasion [12].
Investigations
Complete blood count with examination of peripheral smear
is the initial investigation in a patient with suspected leuke-
mia, and this would reveal the diagnosis of hyperleukocy-
tosis as well. It is a good practice to communicate directly
with the pathologist to ensure a timely and reliable report. It
is often possible for the pathologist to comment on the likely
possibility of AML vs. ALL from examination of the pe-
ripheral smear, including cytochemical stains.
All children, once diagnosed with hyperleukocytosis,
should be evaluated for the attendant complications. Most
importantly, they should be screened for TLS. Serum elec-
trolytes (including sodium, potassium, calcium, phosphate)
along with renal functions and uric acid should be requested
immediately. A coagulogram should be performed as dis-
seminated intravascular coagulation may be observed in
AML; association increases the chances of hemorrhage. A
blood gas analysis should be done to look for acidosis. A
chest radiograph may reveal a mediastinal mass suggesting
possibility of T cell-ALL, and pulmonary infiltrates in case
of leukostasis or infection. Blood samples for uric acid and
blood gas should be transported on ice, and analyzed early,
as the high TLC may result in false lowering of uric acid and
hypoxemia.
Management
Initial management is directed towards aggressive hydration,
use of allopurinol for prevention of TLS, and prevention or
correction of metabolic abnormalities. The definitive manage-
ment involves reduction of the tumor load by chemotherapy.
An outline of management is illustrated in Fig. 1.
Fluids
All patients should be initiated on continuous intravenous
hydration with potassium and calcium free fluids (N/2 or N/
4 5 % Dextrose is appropriate), 2–4 times of normal
146 Indian J Pediatr (February 2013) 80(2):144–148

Hyperleukocytosis

• Send tumor lysis work up, coagulogram, chest X-ray, blood gas
• Obtain EDTA sample for cross match
• Establish IV access; start potassium and calcium free fluids
• Start Allopurinol (250-500 mg/m2/d)

Asymptomatic Symptomatic leukostasis

No pulmonary or CNS stasis, no bleeds or
TLC > 200-300 x 10 3 /µ L

Hb >6-7g% Hb >6-7 g%
Severe anemia with impending
congestive cardiac failure (Hb <5-6g%)

• IVF: Two times maintenance • IVF: 70-100% maintenance • IVF: 3-4 times maintenance
• No red cell transfusion • Urgent leukapheresis or exchange transfusion • No red cell transfusion
• Treat coagulopathy (Platelets, FFP as needed)

• Monitor for TLS q 8-12 hourly; If present, manage as detailed elsewhere

• Vitals/sensorium/urine output monitoring 2-4 hourly
• Start definitive therapy as soon as diagnosis established

Fig. 1 Flow sheet detailing management of hyperleukocytosis

maintenance. Typically, the fluids may be initiated at a rate that
is twice the maintenance, and can be increased in a symptom-
atic patient who persists to have a high TLC. The fluid rate
depends on the tumor burden as well as the hemoglobin (Hb).
If the Hb is ‘reasonable’ (≈7–8 g/dL or more), higher fluid
volumes can be administered, while monitoring for fluid over-
load and urine output. If the Hb is very low (less than ≈6 g/dL),
less fluids should be given, as higher volumes may precipitate
congestive heart failure. There is no role of routine use of
diuretics in hyperleukocytosis, as the goal is hemodilution
and reduction of viscosity. Diuretics are however indicated if
there is co-existing TLS and fluid overload.
Transfusion of Blood Products
Platelets should be transfused at counts below 20,000/mm3
to prevent CNS bleed, or in the presence of any active
mucosal or visceral bleeds [1]. A platelet transfusion does
not increase the blood viscosity significantly. Packed red
blood cell transfusion is not indicated in a hemodynamically
stable child, as it increases the blood viscosity. In case of
severe anemia, with impending congestive cardiac failure,
leukapheresis or exchange transfusion are better options. Coa-
gulopathy may be observed in children with AML (particu-
larly promyelocytic variant). If present, it should be corrected
by transfusion of 10–15 mL/kg of fresh frozen plasma.
Prevention of Tumor Lysis
Aggressive hydration therapy administered for hyperleuko-
cytosis, aids in the prevention of TLS as well. The reader
may wish to read a recent review on TLS [13]. Briefly,
Allopurinol is started in all children, at a dose of 250–
500 mg/m2/d (maximum 800 mg/d) in three divided doses.
Tablet Zyloric is available in 100 and 300 mg strengths. In
case of established TLS with raised uric acid, the preferred
therapy is with recombinant urate oxidase, administered intra-
venously, at a dose of 0.05–0.2 mg/kg, to be repeated if
Indian J Pediatr (February 2013) 80(2):144–148
needed. It is more effective than allopurinol in preventing and
treating TLS, and decreasing the need for dialysis. A small case
series has shown its efficacy in preventing TLS in spite of a
very high TLC [3, 14]. (Inj Rasburicase1.5 mg; ≈ Rs 12,000).
Reduction of TLC is necessary to prevent morbidity and
mortality in symptomatic leukostasis and preventing tumor
lysis prior to initiating chemotherapy. It can be done by
leukapheresis or exchange transfusion.
Leukapheresis is the treatment of choice for a very high
TLC (>2–3 lakh), or in patients with symptomatic hyper-
leukocytosis [15]. It is the removal of circulating leukocytes
from the blood and re-infusion of the leukodepleted blood.
A single leukapheresis decreases the TLC by 20–50 %.
Most patients require a single procedure; rarely more than
two procedures are necessary [8, 16]. The difficult venous
access in younger children, technical difficulty of the pro-
cedure in small children, particularly those less than 15 kg,
risk of anticoagulation, inadequate experience and non-
availability of the procedure in emergency hours are the
limitations.
Exchange transfusion can be done with fresh whole blood or
with a mix of packed red blood cells and plasma (in a ratio of 2–
3:1), with platelet supplementation. Recommended volume
varies from 70 to 150 mL/kg, with an aim to reduce the blasts
by at least 50 % [17, 18]. It is a safe procedure even in neonates
or infants with hyperleukocytosis, and in neonates can be
performed through the umbilical catheterization [19]. It is par-
ticularly beneficial when hyperleukocytosis is accompanied
with severe anemia. The partial exchange aids in correcting
both, without the risk for volume overload or hyperviscosity,
which are the limitations of hydration and blood transfusion,
respectively. In the authors experience, a partial exchange with
~2 bags of whole or reconstituted blood in a child weighing 15–
25 kg, corrects the anemia safely, following which aggressive
hydration can be instituted. There has been no head to head
comparison between exchange transfusion and leukapheresis
on efficacy and safety. However, there is data to suggest that
both the procedures may be equally efficacious in reducing the
TLC, with a mean reduction in TLC of 50–60 % with either.
The choice between the two would depend on the clinical
scenario, with age, weight, ease of procedure and availability
of equipment being some of the deciding factors [18]. In the
authors’ institute, leukapheresis is increasingly preferred, in
parallel with the increasing expertise and experience of the
transfusion medicine services.
Chemotherapy It is important to remember that leukaphe-
resis or exchange transfusion is not the definitive therapy.
They are temporary measures, which aid in stabilizing the
patient, while establishing diagnosis and initiating chemother-
apy. Chemotherapy must be initiated as early as possible.
However, starting regular dose, multi-agent chemotherapy in
patients with hyperleukocytosis may result in life-threatening
metabolic derangements and TLS. This is particularly true for
147
children with ALL, who have a high risk of TLS, and may
develop renal shut down necessitating dialysis, with full dose
chemotherapy given upfront. In patients with AML, on the
other hand, regular chemotherapy can often be administered
even with a high TLC, as the metabolic complications are less
common. Lower doses of steroids alone may be given to
children with ALL, while continuing hyper-hydration and
other measures for control of hyperleukocytosis. In a study
of 15 children with ALL and hyperleukocytosis, intravenous
prednisone started at a low dose and gradually escalated over
5 d to full dose, led to significant reduction in TLC by day 3,
without developing severe metabolic complications [20]. In
authors experience, 2–3 d of steroids in patients with ALL as a
single agent chemotherapy along with aggressive fluid thera-
py, as against initiation of multi-agent chemotherapy, is often
successful in preventing TLS.
Monitoring forms an integral part of management of a
child with hyperleukocytosis. Clinical as well as lab parame-
ters should be recorded. Vitals should be monitored frequently
(q 3–4 hourly). Monitoring includes observation for respira-
tory distress and any hemodynamic instability which may
indicate a bleed or congestive cardiac failure. Sensorium
should be evaluated periodically as the earliest manifestations
of a CNS event are generally headache or persistent vomiting.
Adequate fluid intake and urine output (2–4 ml/kg/h) should
be ensured. Urinary catheterization is not recommended in a
conscious and hemodynamically stable child. It leads to un-
necessary discomfort and increases the risk of infection. Lab
monitoring includes daily or more frequent complete blood
counts, and evaluation for TLS (serum electrolytes including
K, Ca, iP, uric acid, urea and creatinine) every 8–12 hourly.
Coagulogram should be repeated if initially deranged.
Indian Experience
In a study from Delhi, Arya et al reported 38 % of patients
with T-cell ALL to have hyperleukocytosis; the survival of T-
cell ALL was equivalent to B-lineage ALL [21]. The inci-
dence of hyperleukocytosis was 11 % in children with ALL in
a study from Tata Memorial Hospital, Mumbai; leucocyte
count at diagnosis did not affect the incidence of off therapy
relapses [22]. Another study from the same center however
reported a high TLC (>60,000/mm3) to be a poor prognostic
marker in children with ALL [23]. From the authors center,
hyperleukocytosis was documented in 111 (14.6 %) of 762
patients [24]. Significant lymphadenopathy (45 %), mediasti-
nal adenopathy (26 %) and superior vena cava-obstruction
(9 %) were accompanying clinical features. TLS was observed
in 33 % and CNS complications (altered sensorium, raised
intracranial pressure, stroke or intracranial hemorrhage) in
19 %. The estimated mean survival for the entire cohort was
significantly inferior to that of other ALL patients [24]. With
148
improved supportive care and risk-stratified chemotherapy the
outcome is very likely to improve in the future.
Conflicts of Interest None.
Role of Funding Source None.
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