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: Priya Darishini Gunasegaran, Privina Arivalagan

Day, Date

: Tuesday, December 24, 2013


: Prof. Dr. .Hj. Bidasari Lubis, SpA(K)

Chapter 1
1.1 Background
Hyperleukocytosis is defined as peripheral blood leukocyte count exceeding
>100,000/mm3. Acute leukemia is the most common etiology of hyperleukocytosis in
pediatric practice. 1 It is seen in 5% until 20% of newly diagnosed cases of childhood
leukemia and is a poor prognostic factor since it is usually associated with age less
than one year at diagnosis, T-cell immunophenotype, hypodiploidy, and central
nervous system involvement. 2 It is more common in infant ALL, T-cell ALL, AML
M4, M5 and the microgranular variant of APL. 3
Early metabolic complications such as hyperuricemia, hyperkalemia and
hyperphosphatemia secondary to lysis of leukemic blast cells or disseminated
intravascular coagulation can seriously complicate the early course of therapy.


acute leukemias, may cause impairment of organ function (e.g., respiratory failure,
intracranial bleeding, or acute renal failure) and is often associated with profound
metabolic abnormalities and tumor lysis. 3 Early death can be seen in 15% until 66%
of pediatric patients with leukemic hyperleukocytosis.

Recommendations for

standard therapy of these patients include adequate hydration, alkalinization, control

of uric acid production, correction of fluid and electrolyte imbalance, avoidance of
excessive transfusions and a careful use of chemotherapeutic agents. 2
Acute lymphoblastic leukemia (ALL) is a malignant (clonal) disease of the bone
marrow in which early lymphoid precursors proliferate and replace the normal

hematopoietic cells of the marrow. 4 Acute lymphoblastic leukemia (ALL) accounts

for about 77% of cases of childhood leukemia. Its cause is unknown, and genetic
factors may play a role.

In ALL, progressive medullary and extramedullary

accumulations of lymphoblasts are present that lack the potential for differentiation
and maturation. An inhibition of the normal development of hematopoietic cell









weakness,fatigue and paleness secondary to anemia, infection secondary to

leukopenia, and bleeding secondary to thrombocytopenia. 4
The aim of this study is to explore more about the theoritical aspects on
hyperleukocytosis in acute lymphoblastic leukemia and to integrate the theory and
application of hyperleukocytosis in acute lymphoblastic leukemia in daily life as it is
a oncologic emergency.


2.1 Definition
Hyperleukocytosis is defined as a white blood cell (WBC) count of >100 x 109/L
and occurs in 10% to 30% of acute leukaemia.

This extreme leukocyte release is

due to defect of leukocyte release from bone marrow resulting in an increase in

leukocyte count circulating in the blood.

It typically occurs in acute lymphoblastic

leukemia(ALL), particularly T cell ALL, infant ALL or hypodiploid ALL, and acute
myeloid leukemia.(AML) 1
2.2 Epidemiology
Hyperleukocytosis occurs approximately in 9% until 13% of children with acute
lymphoblastic leukemia, in 5% until 20% of children with acute nonlymphoblastic
leukemia, and virtually all children with chronic myleogenous leukemia. It is more
common in infant ALL, acute myeloid leukemia, T-cell ALL with a mediastinal
mass, and hypodiploid ALL. 6
Clinically significant morbidity and mortality are frequently observed in patients
with leukemic hyperleukocytosis. It complicates the course of leukemia in 5% to 22%
children. 1Hyperleukocytosis may result in tumor lysis syndrome and disseminated
intravascular coagulopathy. In addition to well-known complications (eg, acute
respiratory failure, pulmonary hemorrhage, Central nervous system infarction,
hemorrhage), splenic infarction, myocardial ischemia, renal failure due to renal vessel
leukostasis, and priapism have been reported. 7
2.3 Etiology
There are a lot of conditions resulting in leukocytosis. Those are: 8,9
a) Physiological- newborn or strenuous exercise
b) Emotional disorder- fear or agitation
c) Ovulation, labor, pregnancy
d) Acute infections- bacterial, viral, protozoal, fungal, spirochetal

e) Metabolic causes- diabetic coma, acidosis, anoxia, azotemia, acute gout,

thyroid storm, burns, seizures
f) Drugs- steroid, epinephrine, endotoxin, lithium, serotonin, histamine, heparin,
g) Poisoning- lead, mercury, camphor
h) Acute hemorrhage
i) Malignant neoplasm- carcinoma, sarcoma, lymphoma
j) Connective







inflammatory bowel disease

k) Hematological diseases- splenectomy, functional asplenia, leukemia adnd
mieloproliferative disorders, hemolytic anemia, transfusion reaction
l) Megaloblastic anemia during therapy
2.4 Risk Factors
Risk factors for hyperleukocytosis include younger age (it is most commonly
seen in infants), certain types of leukemia (microgranular variants of acute
promyelocytic leukemia [AML-M3v], acute myelomonocytic leukemia [AML-M4],
acute monocytic leukemia [AML-M5], and T-cell ALL), and cytogenetic










Newly diagnosed or recurrent leukemia is a risk factor. Besides that, patient with
elevated white blood cell count are at a higher risk. The risk of complication increases
as the white blood cell count increases >100 000 /mm3. A higher risk is found in
infant ALL, acute myeloid leukemia, T-cell ALL with a mediastinal mass, and
hypodiploid ALL. 6
2.5 Patogenesis
The Pathogenesis of leukostasis is determined by: 12
a) Sluggish flow with stasis
b) Aggregation of leukaemic cells
c) Formation of microthrombi

d) Release of toxic granules

e) Endothelial damage
f) Oxygen consumption by leukocytes
g) Tissue invasion
2.6 Pathophysiology
Hyperleukocytosis (WBC count >100 X 109/L, or >100 X 103/L) occurs in
leukemia and myeloproliferative disorders. This is certainly due to its inherent
autonomous growth potential of malignant cells. Hyperleukocytosis often causes
vascular occlusion, resulting in ischemia, hemorrhage, and edema of the involved
organs. 3,4
The pathophysiology of leukocytosis stems from production, maturation and
survival of leukocytes. Stem cells give rise to erythroblast, myeloblast and

75% of nucleated cells in the bone marrow are committed to the

production of leukocytes.


At any time, 90% WBCs remain in storage in the bone

marrow, with 7% to 8% in the tissue compartment and the remainder in circulation.

This large storage pool allows for a rapid increase in WBCs. In addition, a percentage
of circulating WBCs is marginated along blood vessel walls and is mobilized by
inflammatory stimuli. The main two causes of leukocytosis is a normal bone marrow
response to external stimuli or the effect of a primary bone marrow disorder. 9
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 total leukocyte count 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. 13,14
Clinically significant hyperleukocytis occurs in the presence of 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 total leukocyte count. This include severe anemia,
thrombocytopenia, renal dysfunction, super imposed infection, dehydration and
acidosis. The central nervous system events and pulmonary leukostasis are more
common in children with AML, while Tumor Lysis Syndrome is observed with a
higher frequency in ALL. 13,14
2.7 Clinical Manifestation
Symptoms of hyperleukocytosis are mainly caused by leukostasis, which is a
clinico pathology syndrome caused by circulating leukemic blast cells in the


Suggestive symptoms such as headache, vision blurring,

exertional dyspnoea to respiratory distress, hypoxia, mild confusion and somnolence

to stupor and coma supports the presence of medical emergency therefore number of
white blood cell should be lowered immidiately.


The clinical presentation depends

largely on the lineage and the number of circulating leukemic blasts. Despite a higher
incidence and degree of hyperleukocytosis in ALL vs AML, clinically manifest
hyperleukocytosis is not commonly seen in ALL. 10

Leukostasis is usually associated with a very high number of circulating blasts

(ie, hyperleukocytosis), but leukostasis has also been described with blast counts of
less than 50,000/mm. 17 Earlier leukostasis was thought to be due presence of critical
leukocrit (fractional leukocyte volume) and increased viscosity. Now, there is
increased evidence that, interaction of
endothelium and blast cell leading to aggregation of blast cells in microcirculature. It
is due to difference in expression of adhesion molecules in lymphoblast and
myeloblast cell surfaces. The adhesion molecules expressed on the leukaemic blast
cells and their hemotactic response to the cytokines in the vascular microenvironment
is more important than cell number.18
General symptoms of ALL can include weight loss, severe night sweats,
tiredness, fever, and loss of appetite 4,10

2.8 Diagnosis
Complete blood count with the examination of peripheral smear is the initial
investigation of a patient with suspected leukemia, which also reveals
hyperleukocytosis. By examining the peripheral smear , including cytochemical
stains, the likely possibility of AML vs ALL can be seen. All children, once
diagnosed with hyperleukocytosis should be attended for possible complications.
Most importantly, screening for TLS should be done. Serum electrolytes(sodium,
potassium, calcium, phosphate) along with renal functions and uric acid should be
requested immediately. 13
Laboratory evalution should include careful assesement for thrombocytopenia,
coagulopathy, and tumor lysis syndrome. Platelets may have to be counted manually,
since a spurious elevation of the automated platelet count can occur due to the
presence of fragments of
white and red blood cells.

Fever is common. Although fever can be traced to

infection in very few (< 5%) of these patients, 11 infection needs to be ruled out, since
acute hyperleukocytosis can mimic several viral, bacterial, and fungal syndromes. 1,9
A coagulogram should be performed as disseminated intravascular coagulation
may be observed in AML; the 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 the posibilty of T-cell ALL and pulmonary infiltrates
in case of leukostasis or infection.19
Bone marrow aspiration and biopsy may be necessary to differentiate leukemia
from a benign condition (leukemoid reaction), if the patient has persistent
leukocytosis. Leukocyte alkaline phosphatase (LAP) score was used to differentiate
chronic myelocytic leukemia from benign leukocytosis in the past. 7
2.9 Differential Diagnosis
Hyperleukocytosis should be differentiated from leukemoid reaction when a high
TLC(typically >50,000/mm3) occurs in the presence of non malignant disorders. It is








Pneumococcus, tuberculosis and varied inflammatory conditions.


Generally the

counts do not exceed 100 000/mm . 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 can also raise the
TLC erroneously. This is generally observed in Thalasemia major and neonates. 10
Below is the distinguishing features between a leukemoid reaction and true
leukemia: 8

Leukemoid reaction



Evidence of infection






Anemia, Trombocytopenia

Bone marrow

Normal, hypercellular



megakaryocytes, decreased
erythroid precursors

alkaline High

These are the differentials of hyperleukocytosis: 3

Acute Lymphoblastic Leukemia

Acute Myelocytic Leukemia




Down Syndrome

Hypereosinophilic Syndrome

Leukocyte Adhesion Deficiency




Polycythemia Vera

Sickle Cell Anemia

2.10 Management
The management of acute hyperleukocytosis and leukostasis involves supportive
measures and reducing the number of circulating leukemic blast cells. Initial
management is directed towards aggressive hydration, use of allupurinol for
prevention of TLS, and prevention or correction of metabolic abnormalities. The
definite management involves reduction of the tumor load by chemotherapy.
Leukapheresis or exchange blood transfusion is a treatment of choice with hydration,
urine alkalization, and administration of allopurinol or rasburicase (uric acid oxydase)
to reduce serum uric acid and minimize tumor lysis syndrome. When rasburicase is
used, urine alkalinization is not recommended. 3
Supportive measures should include:
a) Vigorous hydration with intravenous fluids. - Intravenous fluids should be used
judiciously, however, with careful monitoring of the fluid balance in patients with
coexisting cardiopulmonary comorbidities who might be prone to pulmonary
decompensation in the setting of leukostasis. 17
b) Alkalinization of the urine to prevent acute uric acid nephropathy. Allupurinol
inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine.
It reduces synthesis of uric acid without disrupting biosynthesis of vital purines and
also reduces plasma concentration and urine excretion of uric acid; simultaneously
increasing plasma concentration and urine excretion of more soluble oxypurine
precursors. 5


c) Prevention of tumor lysis syndrome

Allopurinol should be given orally or intravenously (in cases of intractable nausea
and vomiting) to prevent tumor lysis syndrome. Recombinant urate oxidase
(rasburicase) is an alternative drug to prevent tumor lysis and manage hyperuricemia
in patients who cannot tolerate allopurinol. Rasburicase converts uric acid to
allantoin, which is 5 to 10 times more soluble than uric acid and therefore is rapidly
excreted by the kidneys. 17
d) DIC or thrombocytopenia
Transfusions should be avoided unless the patient has symptoms of anemia and the
hemoglobin is less than 7 to 8 g/dL. Increasing the erythrocrit (fractional erythrocyte
volume) and, consequently, the whole blood viscosity can lead to the development
and worsening of leukostasis if the leukocrit is already high in patients with acute
hyperleukocytosis. 17,22
Prompt reduction in the number of circulating blast cells (leukocytoreduction) is
essential to prevent leukostasis in patients with acute hyperleukocytosis and to treat
or halt the progression of established leukostasis. Still, clinical deterioration and
death can occur despite a significant reduction in the white blood cell count.10
Leukocytoreduction can be achieved by induction chemotherapy, hydroxyurea, and
leukapheresis. Prompt initiation of induction chemotherapy remains the mainstay of
treatment of acute hyperleukocytosis and leukostasis. Hydroxyurea given at dosages
of 50 to 100 mg/kg/day in three or four divided doses has been shown to reduce the
leukocyte count by 50% to 60% within 24 to 48 hours and should be started at the
time of initial diagnosis and continued until the count has decreased to safer
f) Radiation
Cranial radiation has been used to control neurologic symptoms secondary to
leukostasis, especially in patients with ALL.24 However, lack of controlled trials and


the significant toxicity associated with whole-brain irradiation preclude its routine use
for the treatment of this syndrome. 25
g) Leukapheresis
Leukapheresis involves the removal of circulating blast cells with re-infusion of
leukocyte-poor plasma. Although there are no evidence based guidelines for when to
start leukapheresis, it is usually started in patients with AML when the blast count is
more than 100,000/mm3 or in the presence of symptoms of leukostasis, irrespective
of the blast count.26,27 In ALL, leukapheresis is usually not done unless symptoms of
leukostasis develop or the blast count exceeds 100,000 to 200,000/mm3.28-30

Advantages - A single session of leukapheresis decreases the white blood cell

count by 20% to 50%. It immediately removes circulating blasts, and it may
also recruit marginated leukemic cells into the intravascular space.10 It also
permits the infusion of blood products (eg, platelets) and correction of
metabolic abnormalities.

Disadvantages- The placement and maintenance of central venous catheters

may cause complications. Also, the treatment requires specialized equipment
and trained personnel, and it is not widely available.


It can also worsen the

thrombocytopenia as a significant number of platelets are often removed with

the WBCs with this procedure. If it is not well orschestrated it may delay the
initiation of appropriate supportive care and definitive chemotherapy.
The optimal timing of leukapharesis and its use in symptomatic patients with
WBCs count <100 000/mm3 remains controversial. It is also unclear whether
leukapharesis should be used in patients with hyperleukocytosis but no clinical signs
of leukostasis. 31
2.11 Complications
Although leukostasis can affect any organ system, symptoms usually arise from
involvement of the pulmonary and cerebral microvasculature, and most early deaths
are due to respiratory failure and intracranial hemorrhage.


Coagulopathy (21%),


neurologic features (6%), pulmonary leukostasis (11%) and metabolic complications

(32%) had been observed before the initiation of chemotherapy. 32
Leukostasis, primarily in the lungs and central nervous system, is a frequent
complication in acute leukemia and is associated with increased early mortality in the
treatment of both adults and children with the disease.33 Pathological definition:
Morphological evidence of intravascular accumulation of leukaemic blasts
occupying most or all of the vascular lumen, with or without the presence of fibrin.
It is thought that sludging of leukaemic blasts in capillary vessels lead to diffuse
cerebral, pulmonary and renal microcirculatory failure, resulting in tissue hypoxia,
infarct or haemorrhage can occur as a result. 34
Lung involvement in leukaemia is primarily due to a) leukostasis of vessels and
b) true leukaemic infiltration of interstitium and alveoli 11,17 Patients can present with
symptoms ranging from exertional dyspnea to severe respiratory distress. However,
chest radiography may be normal or may reveal varying degrees of diffuse interstitial
or alveolar infiltrates.18
Arterial blood gas samples should be interpreted cautiously, as a spuriously low
arterial oxygen tension (pseudohypoxemia) can result from rapid consumption of
plasma oxygen by the markedly increased number of white blood cells.
oximetry can more accurately assess oxygenation status in this setting.




Neurologic manifestations can range from mild confusion and somnolence to

stupor and coma. Focal central nervous system deficits may herald intracranial
hemorrhage.17 Retinal hemorrhage, retinal vein thrombosis, myocardial infarction,
acute limb ischemia, and renal vein thrombosis have all been described with
leukostasis and acute hyperleukocytosis. Disseminated intravascular coagulation
(DIC) occurs in 30% to 40% of patients with AML and in 15% to 25% of patients
with ALL. 10 Though more common in AML-M3 (also known as acute promyelocytic
leukemia), DIC can occur in all subtypes of acute leukemia. 17
Dying leukaemic blasts release uric acid in addition to potassium and phosphate.
Elevated uric acid and phosphate may precipitate in the renal tubules resulting in


secondary renal failure. Tumour Lysis syndrome (TLS) is a triad of electrolyte

disturbance with hyperuricaemia, hyperphosphataemia and hyperkalemia. This is
more common in ALL compared with AML


. TLS can be prevented by

hyperhydration with intravenous fluids and either rasburicase (uric acid oxidase) or
allopurinol. 17
The nature and severity encountered in the cancer patient with tumor lysis are
influenced by: 35
a)The timing and intensity of chemotherapy
b)The magnitude of intracellular ion and solute release, imcluding urate precursors,
phosphates and potassium
c)Prophylactive measures such as hydration
d)Acid-base status
e)Glomerular filtration rate
Not only does hyperuricemia and hyperphosphataemia result from tumor lysis
syndrome, they also contribute to oliguric acute renal failure in patients with tumor
lysis. 35
Hyperuricaemia may occur spontaneously or as a complication of the rapid
destruction of tumor cells due to chemotherapy. It is characterized by increase in
blood uric acid levels exceeding 7 mg / dl and can reach 20 mg / dl and more.

Usually developing 48 to 72 hours after therapy, it is caused by increased purine

metabolism due to enhanced catabolism of nucleic acids, a consequence of increased
turnover or cancer chemotherapy that aggravates cell lysis and causes rapid release of
purine metabolites.


Uric acid is the end product of purine metabolism and is

excreted by the kidneys. In the liver, xanthine and hypoxanthine is catalysed by

xanthine oxidase into uric acid. 5,36 A total of approximately 98% of uric acid ionized
at physiological acid-base state (pK acid Uric 5.6). Solubility of uric acid is very bad
at acidic urine circumstances but relatively insoluble in the plasma. If the renal
excretion capability is exceeded, there will be uric acid nephropathy. 5


Hyperkalemia refers to excess of potassium in the bloodstream. It is considered

to be the most dangerous consequence of TLS. 41 Mild-moderate hyperkalemia is
characterized by levels serum potassium exceeding

5.5 mEq / L, and severe

hyperkalemia when serum potassium levels are found to exceed 6 mEq / L and or has
been a change in the electrocardiogram (ECG). 5 It is suggested that due to stress on
cellular metabolism in addition to chemotherapy and radiotherapy as well as reduced
ATP levels may cause potassium to leak out of tumour cells before complete lysis,
resulting in early elevated levels of potassium concentration in the serum. 37 In severe
circumstances cardiac arrhythmias may occur such as asystole, tachycardia









neuromuscular disorder such as weakness of muscles, paresthesia, muscle spasms and

flaccid ascending paralysis. Nausea, vomiting, diarrhea and anorexia also can occur.
An ECG with serum potassium levels exceeding 7 mEq / L is in the form of high T





Hyperphosphatemia results from rapid release of intracellular phosphates into the

peripheral blood during acute degradation of malignant cells, which may contain up
to four times more organic and inorganic phosphates as compared to normal cells.

Hyperphosphatemia can lead to acute renal failure as a result of precipitation with

calcium in renal tubules. The concentration of calcium in serum quickly decreases as
precipitation with phosphate occurs. Precipitation of calcium phosphate occurs when
the solubility product of calcium and phosphate is exceeded, leading to hypocalcemia
along with organ damage associated with calcium deposition. 37
Hypocalcemia is a metabolic disorder that is a direct consequence of
hyperphosphatemia as symptoms associated with hyperphosphatemia are manisfested
indirectly through its effect on calcium. 5 Hypocalcemia can result in both neurologic
and cardiac symptoms. Neurologic symptoms include muscle cramps, tetany and
seizures. When calcium phosphate precipitates in cardiac system serious
dysrhythmias can occur. 37


2.12 Prognosis
ALL patients with hiperleukositosis are included in high-risk groups that they have a
worse prognosis compared with those who have leukocyte count <50 000/ul. Besides
prognosis influenced by the number of leukocytes, there are several factors such as
age, phenotype, and cytogenetic response to prednisone administration. Morbidity
and mortality is higher in patients with leukocytes> 50.000/ul and as causes of death
that occur in the induction phase chemotherapy is generally due to sepsis and severe
bleeding. 5



Hyperleukocytosis is defined as peripheral blood leukocyte count exceeding

>100,000/mm3. This extreme leukocyte release is due to defect of leukocyte release
from bone marrow resulting in an increase in leukocyte count circulating in the blood.
According to our case report, HS, 13 year old, came with chief complaint
paleness which became more severe since a month ago. Patient objected having any
bleeding currently and history of bleeding (-). Patient is having menstrual bleeding
for this past 5 days with volume of blood produced is very less. Fever (+) occurred 3
months ago, high type fever that reduced with fever medicines but relapse again.
Vomiting (+) since this past 3 days, preceded by nauseated feeling, 3x/day with
volume aqua cup. The contents of vomit is food that she ate shortly before.
Cough (-), flu (-), spasm (-), decreased appetite (+) and decreased body weight (+)
2 kg in 3 months. History of in contact with peroxide (+). Family members with
similar complaints(-).History of pregnancy, patient is the only child for her parents.
Mother was 24 years old when she was pregnant. During her pregnancy she always
control to midwife. Fever during pregnancy (-). DM (-).Hypertension(-). History of
consuming medicines during pregnancy (-).History of consuming herbs (-). Normal
delivery assisted by midwife with infant birth weight 3700g. Cried as soon as the
baby was born and was declared healthy by the midwife. Urination (+)
normal.Defecation (+) normal.




Definition: Hyperleukocytosis is defined Patients leukocyte count was

as a white blood cell (WBC) count
exceeding >100,000/mm3.
Epidemiology: Hyperleukocytosis occurs Patient



approximately in 9% until 13% of Hyperleukocytosis





lymphoblastic lymphoblastic Leukemia





diseases- Patient




asplenia, Lymphoblastic Leukemia


disorders, hemolytic anemia, transfusion


Risk factor : Newly diagnosed or Patient was diagnosed with leukemia 3

recurrent leukemia is a risk factor



months ago
clinical -Patient has weakness, fatigue and

presentation is dominated by progressive paleness secondary to anemia




paleness -Due to ALL patient has experienced

secondary to anemia, infection secondary weight loss, tiredness, fever and loss of
to leukopenia, and bleeding secondary to apetite.
-Suggestive symptoms such as headache,
vision blurring, exertional dyspnoea to




confusion and somnolence to stupor and

-General symptoms of ALL can include







tiredness, fever, and loss of appetite.

Test and Diagnosis: -All children, once

diagnosed with hyperleukocytosis should
be attended for possible complications.
Most importantly, screening for TLS




electrolytes(sodium, potassium, calcium,

phosphate) along with renal functions and





- Laboratory evalution should include
careful assesement for thrombocytopenia,
coagulopathy, and tumor lysis syndrome.
- A blood gas analysis should be done to
look for acidosis.





intravenous fluids, Alkalinization of the







nephropathy, Recombinant urate oxidase

(rasburicase) is an alternative drug to





hyperuricemia in patients who cannot

tolerate allopurinol.