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Hyperleukocytosis: Emergency Management

Article  in  The Indian Journal of Pediatrics · November 2012

DOI: 10.1007/s12098-012-0917-3 · Source: PubMed

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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 Keywords Acute lymphoblastic leukemia . ALL . CML .
leukocyte count exceeding 100,000/mm3. Acute leukemia is Hydration . India . Leukostasis . Priapism
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 Introduction
aggregates, results in stasis in the smaller blood vessels.
This predisposes to neurological, pulmonary or gastrointes- Hyperleukocytosis is defined as peripheral blood leukocyte
tinal complications. In addition, patients are at risk for tumor count exceeding 100,000/mm3 [1]. It typically occurs in
lysis syndrome due to the increased tumor burden. Initial hematological malignancies, including acute lymphoblastic
management includes aggressive hydration, prevention of leukemia(ALL), particularly T-cell ALL, infant ALL or
tumor lysis syndrome, and correction of metabolic abnor- hypodiploid ALL, and acute myeloid leukemia (AML).
malities. A red cell transfusion is not indicated in a hemo- Chronic myeloid leukemia, especially in blast crisis may
dynamically stable child, as it adversely affects the blood present with hyperleukocytosis [2]. Hyperleukocytosis com-
viscosity. Leukapheresis is the treatment of choice for a very plicates the course of leukemia in 5–22 % children [3, 4].
high count, or in patients with symptomatic hyperleukocy-
tosis. The technical expertise required, a relative difficult
venous access in younger children, risk of anticoagulation Differential Diagnosis
and possible non-availability of the procedure in emergency
hours are limitations of leukapheresis. However, it is a Hyperleukocytosis should be differentiated from leukemoid
rewarding procedure and performed with relative ease in reaction, when a high total leukocyte count (TLC) (typically
centers that perform the procedure frequently. An exchange >50,000/mm3) occurs in the presence of non-malignant dis-
transfusion is often a practical option when hyperleukocy- orders. It is observed in certain infections, including pertus-
tosis is complicated with severe anemia. The partial ex- sis, staphylococcus aureus, Pneumococcus, tuberculosis and
change aids in correcting both, without the risk of volume varied inflammatory conditions [5, 6]. Generally, the counts
overload or hyperviscosity, which are the limitations of do not exceed 100,000/mm3. The predominant cells are
hydration and blood transfusion, respectively. Etiology and mature lymphocytes and granulocytes. Differentiation can
management of hyperleukocytosis in relevance to the pedi- be done through history, examination and peripheral smear
atric emergency room is outlined. 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
R. Jain : D. Bansal (*) : R. K. Marwaha raised value of TLC, as the nRBC’s are spuriously counted
Hematology/Oncology Unit, Department of Pediatrics, as leucocytes. The TLC generally is less than 100,000/mm3.
Advanced Pediatrics Center,
Here again, the examination of peripheral smear will con-
Post Graduate Institute of Medical Education and Research,
Chandigarh 160012, India firm the presence of nRBC’s, and a corrected TLC can be
e-mail: [email protected] calculated.
Indian J Pediatr (February 2013) 80(2):144–148 145

Complications of Hyperleukocytosis including intracranial or pulmonary bleeds, vs. 2.5 % with

ALL [10]. Metabolic complications occurred more frequently
Hyperleukocytosis is an emergency as it may cause several in patients with ALL than AML. The early mortality was
complications, resulting in morbidity or mortality. Vascular significantly higher in children with AML than ALL [10].
obstruction can occur, leading to organ damage from tissue This difference is likely due to the larger size of blasts in
hypoxia, thrombosis or hemorrhage. Metabolic derange- AML, along with increased adhesiveness. Larger myeloblasts
ments are common due to high blast count. The most com- do not circulate freely in capillaries and small blood vessels,
monly affected organs are central nervous system (CNS) leading to sequestration and vascular damage. The symptoms
and the lungs [2, 7, 8]. A CNS bleed, leukostasis or throm- may be more pronounced, and occur at lower TLC in children
bosis, either independently or in combination, can cause with monocytic leukemia, where the blasts have a higher
CNS symptoms. Manifestations include irritability, altered propensity for adhesiveness and tissue invasion [12].
sensorium, seizures, focal neurological deficits and raised
intracranial pressure. Pulmonary leukostasis may result in
hypoxia, respiratory distress and can require respiratory Investigations
support. Chest radiograph may show presence of diffuse
infiltrates. Other organ systems can also be involved. Gas- Complete blood count with examination of peripheral smear
trointestinal hemorrhage may occur, resulting in bleed, hem- is the initial investigation in a patient with suspected leuke-
atemesis or pain abdomen. Priapism, clitoral engorgement mia, and this would reveal the diagnosis of hyperleukocy-
and dactylitis are the rarer manifestations of leukostasis. tosis as well. It is a good practice to communicate directly
An important complication relating to the high tumor with the pathologist to ensure a timely and reliable report. It
burden in patients with hyperleukocytosis is the tumor lysis is often possible for the pathologist to comment on the likely
syndrome (TLS). TLS may present with isolated lab de- possibility of AML vs. ALL from examination of the pe-
rangement, including hyperuricemia, hyperkalemia, hyper- ripheral smear, including cytochemical stains.
phosphatemia, hypocalcemia or with associated clinical All children, once diagnosed with hyperleukocytosis,
symptoms, including oliguria or anuria, seizures, altered should be evaluated for the attendant complications. Most
sensorium ranging from irritability and confusion to frank importantly, they should be screened for TLS. Serum elec-
coma [9]. The most common time for TLS to occur is within trolytes (including sodium, potassium, calcium, phosphate)
2–3 d following the initiation of chemotherapy, however along with renal functions and uric acid should be requested
spontaneous TLS may occur in the absence of any therapy. immediately. A coagulogram should be performed as dis-
seminated intravascular coagulation may be observed in
AML; association increases the chances of hemorrhage. A
Pathophysiology blood gas analysis should be done to look for acidosis. A
chest radiograph may reveal a mediastinal mass suggesting
Two potential mechanisms have been suggested to explain possibility of T cell-ALL, and pulmonary infiltrates in case
the complications caused by hyperleukocytosis. According of leukostasis or infection. Blood samples for uric acid and
to the traditional explanation, there is an increase in blood blood gas should be transported on ice, and analyzed early,
viscosity, secondary to high TLC and leukocyte aggregates, as the high TLC may result in false lowering of uric acid and
resulting in stasis in the smaller blood vessels. The second hypoxemia.
proposed mechanism is of adhesive interactions between the
damaged endothelium of the vessel and leukemic blasts,
precipitating leukostasis. The toxins and cytokines released Management
by the vascular endothelium exacerbate the situation [1, 2].
Clinically significant hyperleukocytosis usually occurs in Initial management is directed towards aggressive hydration,
the presence of a TLC exceeding 300,000/mm3 in ALL, and use of allopurinol for prevention of TLS, and prevention or
more than 200,000/mm3 in AML. However, several factors correction of metabolic abnormalities. The definitive manage-
may result in symptoms at a lower TLC. These include ment involves reduction of the tumor load by chemotherapy.
severe anemia, thrombocytopenia, renal dysfunction, super- An outline of management is illustrated in Fig. 1.
imposed infection, dehydration and acidosis. The CNS
events and pulmonary leukostasis are more common in Fluids
children with AML, while TLS is observed with a higher
frequency in ALL [9–11]. In an analysis of 234 children All patients should be initiated on continuous intravenous
with hyperleukocytosis from St Jude hospital, 19 % of hydration with potassium and calcium free fluids (N/2 or N/
children with AML had hemorrhagic complications, 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 blood cell transfusion is not indicated in a hemodynamically
is twice the maintenance, and can be increased in a symptom- stable child, as it increases the blood viscosity. In case of
atic patient who persists to have a high TLC. The fluid rate severe anemia, with impending congestive cardiac failure,
depends on the tumor burden as well as the hemoglobin (Hb). leukapheresis or exchange transfusion are better options. Coa-
If the Hb is ‘reasonable’ (≈7–8 g/dL or more), higher fluid gulopathy may be observed in children with AML (particu-
volumes can be administered, while monitoring for fluid over- larly promyelocytic variant). If present, it should be corrected
load and urine output. If the Hb is very low (less than ≈6 g/dL), by transfusion of 10–15 mL/kg of fresh frozen plasma.
less fluids should be given, as higher volumes may precipitate
congestive heart failure. There is no role of routine use of Prevention of Tumor Lysis
diuretics in hyperleukocytosis, as the goal is hemodilution
and reduction of viscosity. Diuretics are however indicated if Aggressive hydration therapy administered for hyperleuko-
there is co-existing TLS and fluid overload. cytosis, aids in the prevention of TLS as well. The reader
may wish to read a recent review on TLS [13]. Briefly,
Transfusion of Blood Products Allopurinol is started in all children, at a dose of 250–
500 mg/m2/d (maximum 800 mg/d) in three divided doses.
Platelets should be transfused at counts below 20,000/mm3 Tablet Zyloric is available in 100 and 300 mg strengths. In
to prevent CNS bleed, or in the presence of any active case of established TLS with raised uric acid, the preferred
mucosal or visceral bleeds [1]. A platelet transfusion does therapy is with recombinant urate oxidase, administered intra-
not increase the blood viscosity significantly. Packed red venously, at a dose of 0.05–0.2 mg/kg, to be repeated if
Indian J Pediatr (February 2013) 80(2):144–148 147

needed. It is more effective than allopurinol in preventing and children with ALL, who have a high risk of TLS, and may
treating TLS, and decreasing the need for dialysis. A small case develop renal shut down necessitating dialysis, with full dose
series has shown its efficacy in preventing TLS in spite of a chemotherapy given upfront. In patients with AML, on the
very high TLC [3, 14]. (Inj Rasburicase1.5 mg; ≈ Rs 12,000). other hand, regular chemotherapy can often be administered
Reduction of TLC is necessary to prevent morbidity and even with a high TLC, as the metabolic complications are less
mortality in symptomatic leukostasis and preventing tumor common. Lower doses of steroids alone may be given to
lysis prior to initiating chemotherapy. It can be done by children with ALL, while continuing hyper-hydration and
leukapheresis or exchange transfusion. other measures for control of hyperleukocytosis. In a study
Leukapheresis is the treatment of choice for a very high of 15 children with ALL and hyperleukocytosis, intravenous
TLC (>2–3 lakh), or in patients with symptomatic hyper- prednisone started at a low dose and gradually escalated over
leukocytosis [15]. It is the removal of circulating leukocytes 5 d to full dose, led to significant reduction in TLC by day 3,
from the blood and re-infusion of the leukodepleted blood. without developing severe metabolic complications [20]. In
A single leukapheresis decreases the TLC by 20–50 %. authors experience, 2–3 d of steroids in patients with ALL as a
Most patients require a single procedure; rarely more than single agent chemotherapy along with aggressive fluid thera-
two procedures are necessary [8, 16]. The difficult venous py, as against initiation of multi-agent chemotherapy, is often
access in younger children, technical difficulty of the pro- successful in preventing TLS.
cedure in small children, particularly those less than 15 kg, Monitoring forms an integral part of management of a
risk of anticoagulation, inadequate experience and non- child with hyperleukocytosis. Clinical as well as lab parame-
availability of the procedure in emergency hours are the ters should be recorded. Vitals should be monitored frequently
limitations. (q 3–4 hourly). Monitoring includes observation for respira-
Exchange transfusion can be done with fresh whole blood or tory distress and any hemodynamic instability which may
with a mix of packed red blood cells and plasma (in a ratio of 2– indicate a bleed or congestive cardiac failure. Sensorium
3:1), with platelet supplementation. Recommended volume should be evaluated periodically as the earliest manifestations
varies from 70 to 150 mL/kg, with an aim to reduce the blasts of a CNS event are generally headache or persistent vomiting.
by at least 50 % [17, 18]. It is a safe procedure even in neonates Adequate fluid intake and urine output (2–4 ml/kg/h) should
or infants with hyperleukocytosis, and in neonates can be be ensured. Urinary catheterization is not recommended in a
performed through the umbilical catheterization [19]. It is par- conscious and hemodynamically stable child. It leads to un-
ticularly beneficial when hyperleukocytosis is accompanied necessary discomfort and increases the risk of infection. Lab
with severe anemia. The partial exchange aids in correcting monitoring includes daily or more frequent complete blood
both, without the risk for volume overload or hyperviscosity, counts, and evaluation for TLS (serum electrolytes including
which are the limitations of hydration and blood transfusion, K, Ca, iP, uric acid, urea and creatinine) every 8–12 hourly.
respectively. In the authors experience, a partial exchange with Coagulogram should be repeated if initially deranged.
~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 Indian Experience
comparison between exchange transfusion and leukapheresis
on efficacy and safety. However, there is data to suggest that In a study from Delhi, Arya et al reported 38 % of patients
both the procedures may be equally efficacious in reducing the with T-cell ALL to have hyperleukocytosis; the survival of T-
TLC, with a mean reduction in TLC of 50–60 % with either. cell ALL was equivalent to B-lineage ALL [21]. The inci-
The choice between the two would depend on the clinical dence of hyperleukocytosis was 11 % in children with ALL in
scenario, with age, weight, ease of procedure and availability a study from Tata Memorial Hospital, Mumbai; leucocyte
of equipment being some of the deciding factors [18]. In the count at diagnosis did not affect the incidence of off therapy
authors’ institute, leukapheresis is increasingly preferred, in relapses [22]. Another study from the same center however
parallel with the increasing expertise and experience of the reported a high TLC (>60,000/mm3) to be a poor prognostic
transfusion medicine services. marker in children with ALL [23]. From the authors center,
Chemotherapy It is important to remember that leukaphe- hyperleukocytosis was documented in 111 (14.6 %) of 762
resis or exchange transfusion is not the definitive therapy. patients [24]. Significant lymphadenopathy (45 %), mediasti-
They are temporary measures, which aid in stabilizing the nal adenopathy (26 %) and superior vena cava-obstruction
patient, while establishing diagnosis and initiating chemother- (9 %) were accompanying clinical features. TLS was observed
apy. Chemotherapy must be initiated as early as possible. in 33 % and CNS complications (altered sensorium, raised
However, starting regular dose, multi-agent chemotherapy in intracranial pressure, stroke or intracranial hemorrhage) in
patients with hyperleukocytosis may result in life-threatening 19 %. The estimated mean survival for the entire cohort was
metabolic derangements and TLS. This is particularly true for significantly inferior to that of other ALL patients [24]. With
148 Indian J Pediatr (February 2013) 80(2):144–148

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12. van Furth R, van Zwet TL. Cytochemical, functional, and prolif-
Conflicts of Interest None. erative characteristics of promonocytes and monocytes from
patients with monocytic leukemia. Blood. 1983;62:298–304.
13. Rajendran A, Bansal D, Marwaha RK, Singhi SC. Tumor lysis
Role of Funding Source None. syndrome. Indian J Pediatr. 2012 Jul 1. [Epub ahead of print].
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for the management of pediatric and adult tumor lysis syndrome:
an evidence-based review. J Clin Oncol. 2008;26:2767–78.
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