HYPERLEUKOCYTOSIS
DR AHMAD AHMADZADEH
HEMATOLOGIST-MEDICAL ONCOLOGIST
Hyperleukocytosis refers to a laboratory abnormality that has
been variably defined as a total leukemia blood cell count
greater than 50 x 109/L (50,000/microL) or 100 x 109/L
(100,000/microL).
leukostasis (also called symptomatic hyperleukocytosis) is a
medical emergency most commonly seen in patients with
acute myeloid leukemia (AML) or chronic myeloid leukemia
(CML) in blast crisis. It is characterized by an extremely
elevated blast cell count and symptoms of decreased tissue
perfusion.
Leukostasis is a pathologic diagnosis in which white cell plugs
are seen in the microvasculature.
Clinically, leukostasis is typically diagnosed empirically when a
patient with leukemia and hyperleukocytosis presents with
respiratory or neurological distress.
Prompt treatment is indicated since, if left untreated, the oneweek mortality rate is approximately 20 to 40 percent.
EPIDEMIOLOGY
The incidence of hyperleukocytosis and leukostasis vary by
leukemia type and patient population.
In general, symptoms of leukostasis are more common in
leukemias with large, poorly deformable blasts, such as acute
myeloid leukemia.
Acute myeloid leukemia : Hyperleukocytosis is present in 10 to
20 percent of patients with newly diagnosed acute myeloid
leukemia (AML). It is more common in patients with
myelomonocytic (FAB-M4) leukemia, monocytic (FAB-M5)
leukemia, or the microgranular variant of acute promyelocytic
leukemia (FAB-M3)
Acute lymphoblastic leukemia : Hyperleukocytosis is seen in 10
to 30 percent of patients with newly diagnosed acute lymphoblastic
leukemia (ALL) .
The incidence appears to be highest in infants, patients between the
ages of 10 and 20 years, males, and those with a T cell phenotype .
Symptoms of leukostasis are rarely seen in patients with ALL and
hyperleukocytosis. Tumor lysis syndrome and disseminated
intravascular coagulation are more common complications related
to the elevated WBC count.
Chronic lymphocytic leukemia : A significant proportion of
patients with chronic lymphocytic leukemia (CLL) present with
hyperleukocytosis. Symptoms of leukostasis are rare unless the
WBC count exceeds 400 x 109/L (400,000/microL).
Chronic myeloid leukemia :
Patients with chronic
myeloid leukemia (CML) typically present with leukocytosis
and a median WBC count of approximately 100 x 109/L
(100,000/microL).
Most
often,
these
are
segmented
neutrophils,
metamyelocytes, and myelocytes. Symptoms of leukostasis
are very uncommon in patients in chronic phase but can be
seen occasionally in patients with myeloid blast crisis and
very elevated blast counts.
pathophysiology
The pathophysiology of leukostasis is not well understood.
There are two main theories, which are not mutually exclusive:
Leukostasis may be due to increased blood viscosity as a direct
complication of a large population of leukemic blasts that are
considerably less deformable than mature leukocytes .With
increasing blast counts, plugs of these more rigid cells can
develop in the microcirculation, thereby impeding blood flow
(leukostasis).
This situation can be worsened by red blood cell transfusions or
the use of diuretics, both of which can increase whole blood
viscosity.
Local hypoxemia may be exacerbated by the high metabolic
activity of the dividing blasts and the associated production of
various cytokines
These cytokines can result in endothelial damage and subsequent
hemorrhage that add to the hypoxic damage already present from
reduced blood flow .
Leukemic blasts can migrate into the surrounding tissues, causing
additional damage .Thus, the lower incidence of clinically
significant leukostasis and vascular injury in patients with CLL and
ALL may be related to the lower metabolic and mitotic rate in the
former and the lack of catabolic enzymes and cytokines in both.
SIGNS AND SYMPTOMS :
Although pathologic evidence of leukostasis can be found in most
organs in patients with extremely high white blood cell (WBC)
counts, the main clinical symptoms of leukostasis and causes of
early death are related to involvement of the central nervous system
(approximately 40 percent) and lungs (approximately 30 percent) .
Pulmonary signs and symptoms include dyspnea and hypoxia with
or without diffuse interstitial or alveolar infiltrates on imaging studies.
Measurement of the arterial pO2 can be falsely decreased in
patients with hyperleukocytosis, since the WBCs in the test tube
utilize oxygen. Pulse oximetry provides a more accurate
assessment of O2 saturation in this setting.
Neurological signs and symptoms include visual changes,
headache, dizziness, tinnitus, gait instability, confusion,
somnolence, and, occasionally, coma.
LABORATORY ABNORMALITIES :
Hyperleukocytosis may result in laboratory abnormalities, which
can be due to interference with laboratory assays or may be a
consequence of the high number of circulating blasts.
Arterial pO2 can be falsely decreased because of the enhanced
metabolic activity of the malignant cells, even when the specimen is
appropriately placed on ice during transport to the laboratory. Pulse
oximetry provides a more accurate assessment of O2 saturation.
The platelet count may be overestimated by automated blood cell
counters because fragments of blasts on blood smear can be
mistakenly counted as platelets. A manual platelet count and careful
review of the peripheral smear is appropriate in such settings.
Approximately 80 percent of patients with leukostasis are febrile,
which may be due to inflammation associated with leukostasis or
concurrent infection. Since an infectious cause cannot be easily
excluded, we treat empirically for infection in all such patients.
Less common signs or symptoms of leukostasis include
electrocardiographic signs of myocardial ischemia or right ventricular
overload, worsening renal insufficiency, priapism, acute limb
ischemia, or bowel infarction .
Occasionally, patients develop dyspnea and worsening hypoxemia
following the initiation of chemotherapy due to the lysis of leukemic
cells trapped in the lungs (eg, acute lysis pneumopathy)
Serum potassium can be spuriously elevated due to its release from
leukemic blasts during the in vitro clotting process. Potassium levels
measured from heparinized plasma samples, rather than serum,
can circumvent this effect.
Disseminated intravascular coagulation (DIC) occurs in up to 40
percent of patients .
DIC presents with various degrees of thrombin generation (eg,
decreased fibrinogen) and increased fibrinolysis (eg, elevated fibrin
degradation products and D-dimer). DIC may develop or worsen
following chemotherapy.
Spontaneous tumor lysis syndrome (TLS) is present in up to 10
percent of patients with leukostasis.
Laboratory evidence of tumor lysis syndrome includes increased
elevated serum concentrations of uric acid, potassium, and
phosphate, often accompanied by hypocalcemia. TLS may develop
or worsen following chemotherapy.
DIAGNOSIS : Leukostasis (symptomatic hyperleukocytosis) is
diagnosed empirically when a patient with leukemia and a white
blood cell (WBC) count over 100 x 109/L (100,000/microL) presents
with symptoms thought to be due to tissue hypoxia, most commonly
respiratory or neurological distress.
The diagnosis requires a high degree of suspicion, and some
patients have pathologically proven leukostasis at WBC counts below
this level.
Pathologically, leukostasis is diagnosed when a biopsy of involved
tissue demonstrates white cell plugs in the microvasculature .
A pathologic diagnosis of leukostasis is rarely obtained because of
the risks associated with biopsy of affected tissues.
MANAGEMENT
Leukostasis (symptomatic hyperleukocytosis) constitutes
a medical emergency, and efforts should be made to
rapidly stabilize the patient and lower the white blood cell
count.
In most cases, rapid cytoreduction can be achieved with
induction chemotherapy, which should be administered in
conjunction with prophylaxis for tumor lysis syndrome.
Adequate fluid resuscitation to prevent dehydration and
ensure good urine flow is important.
Cytoreduction :
Twenty to 40 percent of patients with symptomatic hyperleukocytosis
die within the first week of presentation .
The mortality rate appears to be unrelated to the level of the white
blood cell count, but patients with symptoms (eg, respiratory distress
or neurological compromise) have a significantly worse prognosis
when compared with patients who have hyperleukocytosis alone.
Cytoreduction can be achieved through the use of chemotherapy
( hydroxyurea or remission induction chemotherapy) or
leukapheresis.
While both modalities rapidly decrease the circulating white blood
cell count, chemotherapy also destroys leukemia cells in the bone
marrow and is the only treatment proven to improve survival. There
have been no prospective trials or large observational studies
comparing these two options for the treatment of hyperleukocytosis
and leukostasis.
In general, we propose the following approach to patients with
hyperleukocytosis:
For patients with symptomatic or asymptomatic hyperleukocytosis,
we suggest initial treatment with induction chemotherapy rather
than hydroxyurea or leukapheresis. This should be accompanied
by tumor lysis syndrome prophylaxis with aggressive hydration and
allopurinol.
Our preference for induction chemotherapy is primarily based upon
the knowledge that such therapy is also a necessary step toward the
successful treatment of patients with leukemia. There is little evidence
to confirm that decreasing the white blood cell (WBC) count alone will
reduce
the
early
mortality
rate.
An exception to this approach may occur in patients who cannot start
induction chemotherapy immediately. Such patients include those who
have poor venous access, renal insufficiency, or other severe
metabolic disturbances, and those with delays in initiating prophylaxis
for tumor lysis syndrome (TLS).
If induction chemotherapy must be delayed, our approach to
hyperleukocytosis depends upon whether or not the patient is having
symptoms of hyperleukocytosis (ie, leukostasis):
For patients without symptoms of leukostasis who must have
induction chemotherapy delayed, we suggest cytoreduction with
hydroxyurea rather than leukapheresis. Cytoreduction with
hydroxyurea can precipitate or exacerbate hyperuricemia and
occasionally precipitate TLS, therefore such patients also need
intravenous hydration and TLS prophylaxis.
For patients with symptoms of leukostasis who must have
induction chemotherapy delayed, we suggest initial cytoreduction
with leukapheresis in combination with hydroxyurea to lower or
stabilize the WBC count.
Induction chemotherapy:
Induction chemotherapy is an essential component of the successful
treatment of patients with leukemia. In the setting of
hyperleukocytosis, induction chemotherapy serves to both rapidly
decrease the circulating WBC count and target the leukemia cells in
the bone marrow. Induction therapy typically substantially reduces
the WBC count within 24 hours.
Patients with hyperleukocytosis are at higher risk of developing tumor
lysis syndrome with induction chemotherapy. This syndrome is best
prevented via appropriate treatment with intravenous hydration to
ensure adequate urine flow,allopurinol or rasburicase to reduce
serum uric acid levels, and correction of any electrolyte disturbances
or causes of reversible renal failure.
Hydroxyurea:
We typically reserve hydroxyurea for patients with asymptomatic
hyperleukocytosis who are unable to receive immediate induction
chemotherapy. Hydroxyurea, given at a total dose of 50 to 100
mg/kg per day orally, reduces the WBC count by 50 to 80 percent
within 24 to 48 hours The usual hydroxyurea dose is 2 to 4 grams
orally every 12 hours, which is continued until the WBC count is
below 50 x 109/L (50,000/microL).
Side effects of hydroxyurea are usually minimal and are typically
limited to patients who are exposed to hydroxyurea for a prolonged
period. Rare complications include fever and abnormal liver function
tests.
Hydroxyurea should NOT be used in pregnancy or in women who
are breastfeeding
Leukapheresis:
The role of leukapheresis as an adjunct to the treatment of all
patients with hyperleukocytosis is controversial. It is not clear
whether survival is improved in patients treated with leukapheresis
when compared with patients who receive cytoreductive
chemotherapy promptly.
Although intensive leukapheresis, with procedure times often lasting
many hours, has been reported to produce improvement in
pulmonary and central nervous system symptoms, there are
theoretical and practical limitations to its benefits. It is precisely the
patient in whom leukostasis is most likely to occur, that is, the
patient with a high and rapidly rising blast count, in whom the
technical limitations of leukapheresis are relevant.
Although some clinicians advocate its use for patients with
asymptomatic hyperleukocytosis, we typically reserve leukapheresis
for patients with symptomatic hyperleukocytosis who must have
induction chemotherapy postponed.
Our preference to reserve leukapheresis for this selected patient
population is primarily based upon the known risks associated with
leukapheresis described below and an unclear benefit. Anecdotal
reports have claimed dramatic responses but larger retrospective
analyses have demonstrated conflicting effects on early mortality
rates .
Given the paucity of data concerning the efficacy of leukapheresis in
reducing early mortality and/or improving overall survival,
leukapheresis cannot be recommended for routine therapy as a
form of tumor "debulking" in patients with high blast counts.
patients with symptomatic leukocytosis have an extremely high
mortality rate without immediate therapy .
When both respiratory failure and neurologic compromise are
present, the death rate at one week reaches 90 percent .
Therefore, if facilities are available, we suggest leukapheresis for
patients with leukemic blast counts greater than 50 to 100 x 109/L
(50 to 100,000/microL) and associated symptoms as a temporizing
measure until chemotherapy can be initiated.
It is difficult to predict the percent leukocyte count reduction in
individual patients, but sessions are usually planned for four- to
five-hour collections with repeat sessions as needed.
It is generally agreed that leukapheresis should NOT be used for
patients with acute promyelocytic leukemia because it may worsen
the intrinsic coagulopathy associated with this subtype of
leukemia. Placement of large intravenous leukapheresis catheters
in these patients has been associated with venous thrombosis or
hemorrhage.
A small number of platelets are inevitably removed with the
leukemic blasts, resulting in worsening thrombocytopenia.
The effect is generally transient with WBC counts typically
rebounding after leukapheresis is discontinued unless
chemotherapy is begun.
It is unclear whether leukapheresis can reverse vascular damage
already sustained from leukostasis. In addition, symptomatic
leukostasis can still develop after the WBC count has been
lowered by leukapheresis.
Supportive care :
• The following supportive care measures should be considered for
all patients with hyperleukocytosis:
Symptomatic leukostasis can be precipitated by increases in whole
blood viscosity following red blood cell transfusions. Such
transfusions should be withheld, if possible, until the blast count is
reduced. If a transfusion is necessary, it should be given slowly,
administering a single unit of red blood cells over a few hours, or
during the leukapheresis procedure.
• Hydration is encouraged and diuretics are discouraged.
• Patients with hyperleukocytosis are at risk of tumor lysis syndrome
(TLS), although this syndrome is less common in patients with AML
than in those with ALL or Burkitt leukemia/lymphoma. TLS is best
prevented with intravenous hydration to ensure adequate urine flow,
allopurinol to reduce serum uric acid levels, and the correction of
any electrolyte disturbances or causes of reversible renal failure.
Coagulation abnormalities, including disseminated intravascular
coagulation (DIC), further increase the risk of local hemorrhage.
Specific treatment aimed at the DIC should be considered.
Patients should also receive prophylactic platelet transfusions to
maintain a count of greater than 20 to 30,000/microL until the WBC
count has been reduced and the clinical situation has been
stabilized.
The risk of intracranial hemorrhage is greatest after the WBC count
has been markedly reduced, suggesting that a reperfusion injury
may occur when the circulation is restored to previously hypoxemic
or ischemic capillary beds. Thus, aggressive platelet support and
correction of coagulopathy should continue for several weeks during
the remission induction period.
In addition, patients with leukostasis often require specialized,
symptom-directed supportive care including mechanical ventilation
for respiratory failure and/or stroke.
Is there a role for cranial irradiation?
Some centers advocate low dose cranial irradiation (eg, 400 cGy in
a single fraction), in order to prevent further proliferation of leukemic
cells in central nervous system sites.
there are no comparative studies to determine whether the results
with cranial irradiation are superior to those with chemotherapy
alone, and we do not advocate the routine use of cranial irradiation
in this setting. Nevertheless, it could be considered for patients with
serious central nervous system symptoms related to leukostasis.
PROGNOSIS :
The prognostic impact of hyperleukocytosis and leukostasis
(symptomatic hyperleukocytosis) depends upon the type of
leukemia (acute myeloid leukemia or acute lymphoblastic leukemia)
and the presence of symptoms.
The initial mortality rate for patients with acute myeloid leukemia
(AML) and leukostasis has been estimated at 20 to 40 percent and
appears to be unrelated to the severity of the hyperleukocytosis .
If patients survive the initial period, they tend to have somewhat
lower remission rates. Remission durations are also shorter,
possibly because of a larger initial tumor mass, but more likely
related to the biology and intrinsic chemotherapy resistance of the
leukemia .
In patients with acute lymphoblastic leukemia (ALL),
hyperleukocytosis is rarely complicated by leukostasis and the early
death rate is less than 5 percent in childhood ALL .
The challenge of leukostasis management in ALL involves
preventing tumor lysis syndrome, disseminated intravascular
coagulation, and the higher risk of relapse (approximately 50
percent by four years) .
SUMMARY
Hyperleukocytosis is a laboratory abnormality that has been variably defined
as a total white blood cell (WBC) count greater than 50 x 109/L
(50,000/microL) or 100 x 109/L (100,000/microL).
leukostasis (also called symptomatic hyperleukocytosis) is a medical
emergency that is most commonly seen in patients with acute myeloid
leukemia (AML) or chronic myeloid leukemia (CML) in blast crisis and is
characterized by an extremely elevated WBC count and symptoms of
decreased tissue perfusion.
The main clinical symptoms of leukostasis and causes of early death are
related to involvement of the central nervous system and lungs.
Clinically, leukostasis is diagnosed empirically when a patient with leukemia
and a blast cell count over 50 to 100 x 109/L (100,000/microL) presents with
respiratory or neurological distress.
The initial management of a patient with hyperleukocytosis is directed at
rapid lowering of the WBC count.
For patients with symptomatic or asymptomatic hyperleukocytosis, we
suggest initial cytoreduction with induction chemotherapy rather than
hydroxyurea or leukapheresis
For patients with asymptomatic hyperleukocytosis who must have
induction chemotherapy delayed, we suggest cytoreduction with
hydroxyurea rather than leukapheresis .
For patients with symptoms of leukostasis who must have induction
chemotherapy delayed, we suggest initial leukapheresis in addition to
hydroxyurea (if possible) to lower or stabilize the WBC count .
Red blood cell transfusions should be withheld, if possible, until the blast
count is reduced. If a transfusion is necessary, it should be administered
slowly.
Most patients with hyperleukocytosis are candidates for tumor lysis
syndrome prophylaxis with aggressive intravenous hydration and
allopurinol or rasburicase to decrease serum uric acid levels.
Coagulation abnormalities require aggressive treatment with platelet
transfusions and coagulation factors.
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