Expert Review of Hematology

ISSN: 1747-4086 (Print) 1747-4094 (Online) Journal homepage: http://www.tandfonline.com/loi/ierr20

Hyperleukocytosis and leukostasis: management

of a medical emergency

Sabrina Giammarco, Patrizia Chiusolo, Nicola Piccirillo, Alessia Di Giovanni,

Elisabetta Metafuni, Luca Laurenti, Simona Sica & Livio Pagano

To cite this article: Sabrina Giammarco, Patrizia Chiusolo, Nicola Piccirillo, Alessia Di Giovanni,
Elisabetta Metafuni, Luca Laurenti, Simona Sica & Livio Pagano (2016): Hyperleukocytosis and
leukostasis: management of a medical emergency, Expert Review of Hematology

To link to this article: http://dx.doi.org/10.1080/17474086.2017.1270754

Accepted author version posted online: 14

Dec 2016.

Submit your article to this journal

Article views: 4

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=ierr20

Download by: [The UC San Diego Library] Date: 18 December 2016, At: 17:47
Publisher: Taylor & Francis

Journal: Expert Review of Hematology

DOI: 10.1080/17474086.2017.1270754
Review

Hyperleukocytosis and leukostasis: management of a medical emergency

Giammarco Sabrina1, Chiusolo Patrizia1, Piccirillo Nicola1, Di Giovanni Alessia 1, Metafuni

Elisabetta1, Laurenti Luca1, Sica Simona1, Pagano Livio1.
1
Department of Hematology, Universita’ Cattolica del Sacro Cuore, Rome, Italy

Correspondence to:
Livio Pagano
Department of Hematology, Catholic University
Largo Francesco Vito, 1
I-00168 Roma, Italia
Fax 39-6-3017319
Mail: livio.pagano@unicatt.it

ABSTRACT

Introduction: Hyperleukocytosis is defined as a white blood cell count greater than 100,000/mL in

patients affected by acute leukemia and often it is associated with increased morbidity and

mortality, that can be up to 40% if unrecognized.

Areas covered: Risk factors include younger age, myelomonocytic or monocytic/monoblastic

morphology, microgranular variant of acute promyelocitic leukemia and T-cell ALL, and some

cytogenetic abnormalities. Poor prognosis due to high early death rate secondary to leukostasis.

The mechanisms at the origin of leukostasis are still poorly understood. The management of acute

hyperleukocytosis and leukostasis involves supportive measures and reducing the number of
circulating leukemic blast cells, with careful monitoring of fluid balance, control of uric acid

production and control of urine pH to prevent tumour lysis syndrome.

Expert commentary: Several studies have been performed to ameliorate the outcome of this

setting of patients. The high number of leukocytes may cause 3 main complications: disseminated

intravascular coagulation (DIC), tumor lysis syndrome (TLS), and leukostasis. Although

hyperleukocytosis and tumour lysis syndrome are still a challenge for clinicians, a better prognosis

for these conditions is emerging in the last years.

Keywords
Hyperleucocytosis, leukostasis, leukapheresis, disseminated intravascular coagulation, tumor lysis
syndrome

1. INTRODUCTION

From 5% to 30% of adult patients with acute leukemias present with hyperleukocytosis and

symptoms of leukostasis [1]. Although hyperleukocytosis is commonly defined by white blood

count (WBC)> 100000/µL, it should be noted that WBC levels below this arbitrary threshold can

also cause HL-related complications. Hyperleukocytosis is more common in acute leukemias than

in chronic leukemias. Its incidence ranges from 5% to 13% in adult acute myeloid leukemias (AML)

and 10% to 30% in adult acute lymphoblastic leukemia (ALL) [1-3], while very few case-reports

dealing with chronic leukemia and hyperleukocytosis have been reported in the medical literature

[4-6]. These conditions are a medical emergency that needs prompt recognition and initiation of

therapy to prevent renal and respiratory failure or intracranial haemorrhage. 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 probably due to lower mean lymphoblast cell
volume. In AML leukostasis complications usually occur when the white blood cell (WBC) count is

more than 100x109/L and in ALL when the WBC count exceeds 100x109/L to 200x109/L [7,8].

Risk factors for hyperleukocytosis include younger age, various subsets of leukemia including

myelomonocytic or monocytic/monoblastic morphology, microgranular variant of acute

promyelocitic leukemia and T-cell ALL, and cytogenetic abnormalities like 11q23 rearrangements,

inv(16), presence of the Philadelphia chromosome and molecular FLT3-ITD [1,2,9-11].

The prognostic value of leucocytosis in AML is not clearly defined as in ALL. Several studies

found the peripheral leukocyte count to be a predictor of poor outcome [12-17], while other

authors did not find a strong association [18-21].

However hyperleukocytic acute myeloid leukemia is considered to have a poor prognosis due

to high early death rate secondary to leukostasis [17,18]. It is fundamental to recognize

immediately this setting of patients, because the mortality rate can be up to 40% if unrecognized

[2,22]. As reported in the medical literature, the attempts to reduce early mortality (i.e. during the

first week of therapy) with supportive care and treatment protocols do not seem to have

improved the outcome of these patients. (Table1).

2. CLINICAL FEATURES

Hyperleukocytosis (HL) is commonly defined as a white blood cell count >100 000/µL, caused

by leukemic cell proliferation.

2.1 Leukostasis

Leukostasis is a clinicopathologic syndrome characterized by multiorgan failure, severe

coagulopathy, tumour lysis syndrome and metabolic abnormalities. Although it can affect any

organ system, symptoms usually arise from involvement of the cerebral, pulmonary and renal
microvasculature, leading to intracranial haemorrhage, alteration of alveolar-capillary oxygen

exchange until respiratory failure and renal tubular dysfunction [6].

Most common symptoms include headache, confusion, lethargy, dizziness, blurred vision,

ataxia, papilloedema, retinal haemorrhage and intracranial haemorrhage, regarding CNS system.

Respiratory symptoms are tachypnoea, dyspnoea, hypoxia, pulmonary infiltrates and respiratory

failure. In this setting renal failure [23-25] , congestive heart failure, myocardial infarction and

peripheral vascular occlusion [2, 26-29] are also very common manifestations. As shown in the

first studies on hyperleukocytic acute leukemias [30,31], symptoms are related to the mechanical

obstruction of the capillaries of different organ by blasts (Table 2). Two main pathogenetic factors

are responsible for the development of HL: first, a rapid blast proliferation leading to a high

leukemic tumor burden; second, disruption in normal hematopoietic cell adhesion leading to a

reduced affinity in the bone marrow. The high number of leukocytes may cause three main

complications: disseminated intravascular coagulation (DIC), tumor lysis syndrome (TLS) and

leukostasis [32]. Because all these symptoms are unspecific and can have different causes, this

condition is difficult to prove and no agreement upon diagnostic criteria exist. The leukostasis

syndrome can only be proven by autopsy. Pulmonary leukostasis is due to blast cells infiltration

along the lymphatic route surrounding the peribronchial and perivascular regions and within the

alveolar septa or alveolar spaces. Radiological findings concern bilateral interstitial or alveolar

infiltrates. [33,34]. Since these characteristics are not specific for leukemic pulmonary infiltration,

a combination of these High Resolution-CT findings and the information obtained from the clinical

setting may help in achieving a correct diagnosis of chest complication occurring in leukemic

patients. Previous studies are often based on fatal cases and retrospective analysis of the cause

of death [28,31]; Novotny et al [35] developed a helpful approach to recognize the final stage of

leukostasis and patients at risk; it’s a clinical grading score based on the simple evaluation of
severity of symptoms (severe, marked, slight or no limitation) attributed to several organ system.

So it is possible to assign a score to patient : 0-no leukostasis; 1-possible leukostasis; 2-2-probable

leukostasis; 3-highly probable leukostasis.

In our previous study, this leukostasis grading score (LGS) was used to identify high-risk patients

affected by acute leukemia presenting with hyperleukocytosis (WBC exceeding 100 x 109 /L),

diagnosed in our institution from 1995 to 2008. Thirty-three patients out of 558 consecutive

patients presented hyperleukocytosis: we found a statistically significant difference in LGS

according to phenotype when we compare ALL with AML; sorting out ALL, LGS was statistically

higher in AML with monocyte lineage involvement and in patients with early death [36].

2.2 Tumor lysis syndrome

TLS is a potentially life-threatening medical condition occurring in the early phase of diagnosis and

management of high proliferative malignant neoplasms. TLS may occur as a result of spontaneous

cell death, due to the high turn-over of the malignant cells, or as a result of the beginning of the

chemotherapy treatment. It’s characterized by rapid onset of hyperuricemia, hyperkalemia,

hypocalcemia, hyperphosphatemia and renal impairment due to release of intracytoplasmic

components during cellular lysis. It has been developed a classification which distinguishes a

laboratory and a clinical TLS. The laboratory TLS is characterized by the presence of two or more

abnormal laboratory value; instead the clinical TLS is defined by the onset of symptoms such as

fever, renal impairment, cardiac arrhythmia and death, that usually arise in 12 through 72 hours

from the beginning of chemotherapy. [37,38]

2.3 Disseminate intravascular coagulation

DIC is coagulopathy caused by high cell turnover; the cell turnover expose the circulation to high

levels of released tissue factor, which then triggers the extrinsic pathway via factor VII. So the
formation of small clots consume coagulation proteins and platelets, resulting in disruption of

normal coagulation and a severe bleeding tendency. It is characterized by a decrease in platelets

count and fibrinogen, an elevation of D-dimers, and prolongation of prothrombin time and

activated partial thromboplastin time. [39]

3. BIOLOGICAL FEATURES

The underlying mechanisms of leukostasis are poorly understood. A very high number of white

blood cells at diagnosis, the size, stiffness and phenotype of blast cells play an important role in

this subset of patients; although signs of leukostasis rarely occurred in leukemic patients without

markedly elevated leucocyte counts, debate on other mechanisms involved in the pathophysiology

of leukostasis is still open. White blood cells are not deformable such as red cells and blast cell

aggregates can cause vascular occlusion and ischemic tissue injury.

Although high levels of leukemic cells cause plugging of the microcirculation with damage and

disruption of vessel walls and haemorrhages, microvessel occlusion does not depend entirely on

the high blast count alone. There are increasing evidences suggesting that expression and function

of specific adhesion receptors could play an important role in interaction between blast cells and

endothelial cells. It has been demonstrated that leukemic cells can enhance their own adhesion to

the endothelium in vitro by secreting cytokines that alter adhesion molecule activation on

endothelial cells [40]. Production of tumour necrosis factor (TNF) - alfa and interleukin (IL)-1 beta

by leukemic myeloblasts lead to upregulation of several adhesion molecules such as ICAM-1,

VCAM-1 and E-selectin in endothelial cells [41]. This interaction creates a self-perpetuating circuit

which may favour blast cell proliferation, leading to the rapid growth of AML cells in the vascular

compartment, to leukostasis and tissue invasion. Finally other pathways are involved in
endothelial cell activation, like complement system, generation of oxygen-reactive species,

thrombin generation after tissue factor expression and cancer procoagulant secretion by blast

cells [11,22, 42,43]. Moreover AML cells show constitutive release of proteolytic enzymes,

especially matrix metolloproteases P (MMP-9) [44].

4. MANAGEMENT OF LEUKOSTASIS

The management of acute hyperleukocytosis and leukostasis involves supportive measures

and reducing the number of circulating leukemic blast cells. The patient presenting with newly

diagnosed hyperleukocytic acute leukemia should be promptly submitted to vigorous hydration

with intravenous fluids, with careful monitoring of fluid balance, control of uric acid production

using allopurinol or rasburicase, control of urine pH to prevent tumour lysis syndrome [45].

4.1 Supportive care

Prevention strategies include vigorous fluid administration (3 l/mq/day) in order to reduce

waste products concentration, improve renal blood flow and glomerular filtration rate. The use of

diuretics may be helpful to maintain an urinary output of 100 ml/mq/h , but is contraindicated if

hypotension. Close monitoring of fluid balance is strictly recommended. Blood electrolytes and

uric acid concentration tests should be performed at least every six hours for intermediate and

high risk patients. Hyperuricemia should be treated with allopurinol or rasburicase depending on

the uric acid levels.[46]

Transfusion should be avoided unless the patient has symptoms of anemia, because

increasing hematocrit and consequently the whole blood viscosity can lead to development or

worsening of leukostasis [47]. In patients presenting DIC platelet transfusions and substitution of
fresh frozen plasma or fibrinogen should be initiated immediately in order to restore normal

coagulation: impaired coagulation and the associated endothelial damage put the patient at a

considerable risk for severe and fatal bleeding events.

4.2 Cytoreduction

Rapid reduction in the number of circulating blast cells is essential to prevent or delay

establishing of leukostasis (Table 3). It can be obtained by induction chemotherapy, hydroxyurea

and leukapheresis. The need of debulking leukocytoreduction before chemotherapy is gathered

from reports of tumour lysis syndrome with prominent pulmonary and renal manifestations

following initiation of chemotherapy [48-51]. Hydroxyurea 50-100 mg/kg given orally in three or

four doses daily reduces the white blood cell count by 50% to 80% within 24-48 hours without

worsening of clinical signs [2,52]. It can be used as a bridge therapy before a proper induction

regimen in order to reduce the tumor burden and the risk of TLS. However there are no data

indicating that this approach is superior to immediate induction therapy. In all patients eligible for

intensive cure treatment, standard dose or high dose cytarabine plus anthracycline based

treatment should be started as soon as possible.

4.3 Leukapheresis

Apheresis is a general term that refers to the withdrawal of whole blood from the body,

separation and retention of one and more components, with the return of the remaining

components to the patients. The use of modern apheresis devices, named blood cell separators,

allow to separate WBCs and their precursors from patient’s blood by centrifugation, while plasma,

platelets and RBCs are returned to the patient. Apheresis units have the skills necessary to

perform the procedure for collection of peripheral blood stem cells or granulocyte concentrates.
In the setting of therapeutic leukocytapheresis the objective of this procedure is to reduce highly

elevated WBC counts in order to prevent or to treat leukostatic syndrome, in patients affecting by

acute leukemias with hyperleukocytosis. [53]

Another emerging use of the leukapheresis is about the treatment of inflammatory bowel

disease. The mechanical remove of granulocyte and monocyte, utilizing leukocytapheresis, could

reduce the production of inflammatory cytokines. Recent studies demonstrated that patients who

respond to this new approach have a long-term disease course by avoiding drugs. [54]

The use of leukapheresis is still of debating: it is usually started when blast count is more than

100,000/mmc or in the presence of symptoms of leukostasis, and it can reduce the white blood

cell count by 20% to 50% [55,56]. The advantages of its use involve rapid removal of excessive

circulating blasts by mechanical separation and recruitment of marginated leukemic cells into the

intravascular space. There is also an evidence of a possible role of leukapheresis on bone marrow:

this procedure could increase the fraction of bone marrow leukemic cells that are in S-phase, in

order to enhance the efficacy of cell-specific drugs such as cytarabine[57]. It’s necessary to place a

central venous catheter (CVC) because patients may be unstable and more than one procedure

can be necessary. Citrate is the most commonly used anticoagulant during apheresis procedures:

it is rapidly metabolized and thus avoid prolonged anticoagulation. Heparin should not be applied

because of its long-lasting systemic inhibitory effects on coagulation. However citrate binds

calcium and can cause hypocalcemia, including tingling of the perioral area, lightheadedness and

nausea. In rare cases, it can lead to prolongation in the QTc interval [53,58]. Close monitoring of

blood pressure, heart rate and O2 saturation as well as oxygen supply are strongly recommended.

If necessary, prompt transfer of the patient to an intensive care unit, must be possible. Sometimes

it can be necessary to perform the leukapheresis treatment at bedside, in an intensive care unit.
 Leukapheresis can be performed utilizing devices with either continuous or discontinuous

blood withdrawal; in most cases procedures are performed utilizing a continuous flow device. The

blood volume to process should be between 2 and 4 times the patient’s blood volume. The

average of the of the leukocytapheresis product is 600 mL, depending on the type of blood cell

separator used, the patient’s blood volume processed, the patient’s size and the WBC count.

[39,53].

Despite the inability to accurately predict leukostasis complications, leukocytapheresis should

be considered for AML patients with a blast count more than 100x109/L, especially with a

monocytic/monoblastic subtype, and should not delay induction chemotherapy [59-62]. An

important exception would be the case of acute promyelocytic leukemia, in which leukapheresis

should not be used because of the accompanying disseminated intravascular coagulation which is

characteristic for this subtype of AML [63]. This procedure may exacerbate the coagulopathy and

it was associated with a high risk of induction death in one series. [64] Leukocytapheresis offers no

advantage over aggressive induction chemotherapy and supportive care in asymptomatic children

and adults with ALL with WBC counts less than 400x109/L. It should be considered in pulmonary

and CNS symptomatic children with ALL and a WBC count more than 400x109/L [55,65].

Several uncontrolled studies reported that rapid cytoreduction with leukocytapheresis can

improve pulmonary and neurologic manifestations for patients with AML or ALL and symptomatic

leukostasis. These data showed that the use of this safety procedure can reduce early mortality

rate but no effect on long-term survival was documented [55,56,66].

Moreover severe end-organ injury or hemorrhage may not improve, particularly if extensive pre-

existing tissue damage exists: in this setting leukocytapheresis had no significant impact in

reducing the early death rate. The most significant risk factors for incidence of intracranial

haemorrhage and early death were age>65 years, two or more leukostasis sympthoms and the
respiratory distress; [67,68,69]. Leukapheresis can be safely performed in children setting but

without reduction of mortality rate.[70].

Leukocytapheresis should reach a WBC count of less than 100x109/L in asymptomatic AML

patients and of less than 50x109/L in symptomatic ones. [55,71]. Chemotherapy should not be

postponed and it is required to prevent rapid reaccumulation of circulating blasts [50].

Leukapheresis is an option for the initial management of hyperleukocytosis; however no impact on

long-term outcome has been shown [52,66].

Hyperleukocytosis is still an adverse prognostic indicator affecting early mortality, particularly

in patients presenting with symptoms secondary to leukostasis; the overall survival of the first 28

days after presentation is not different between patients managed either by leukapheresis or

hydroxyurea [39,51,66,72].

5. CONCLUSIONS

Hyperleukocytic acute leukemias are a medical emergency that needs prompt recognition and

initiation of therapy to prevent renal and respiratory failure or intracranial haemorrhage. Several

studies have been performed to ameliorate the outcome of this setting of patients. Although

hyperleukocytosis and tumour lysis syndrome are still a challenge for clinicians, a better prognosis

for these conditions is emerging in the last years.

6. EXPERT COMMENTARY

Hyperleukocytosis (HL) is a laboratory abnormality, commonly defined by a white blood cell

count >100 000/µL, caused by leukemic cell proliferation. In untreated acute myeloid leukemia

(AML), ∼5% to 20% of patients present with HL. In a patient with HL, underlying diseases other
than AML, such as acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia, and chronic

myeloid leukemia, particularly in acceleration or blast crisis, should be considered as differential

diagnosis.

The high number of leukocytes may cause 3 main complications: disseminated intravascular

coagulation (DIC), tumor lysis syndrome (TLS), and leukostasis. DIC is caused by high cell turnover

and associated high levels of released tissue factor, which then triggers the extrinsic pathway via

factor VII.

TLS may occur as a result of spontaneous or treatment-induced cell death. TLS is characterized

by rapid onset of hyperuricemia, hyperkalemia, hypocalcemia, hyperphosphatemia and renal

impairment following release of intracytoplasmic components during cellular lysis.

Leukostasis is explained by 2 main mechanisms. The rheological model is based on a

mechanical disturbance in the blood flow by an increase of viscosity in the microcirculation, due to

the higher size of blasts and to their lesser deformability. However, the observation that there is

no clear correlation between the leukocyte count and the severity and frequency of leukostatic

complications points toward additional cellular mechanisms involved in the genesis of leukostasis

such as interactions between leukemic cells and the endothelium, mediated by adhesion

molecules.

Although it can affect any organ system, symptoms usually arise from involvement of the

cerebral, pulmonary and renal microvasculature, leading to intracranial haemorrhage, alteration

of alveolar-capillary oxygen exchange until respiratory failure and renal tubular dysfunction.

The management of acute hyperleukocytosis and leukostasis involves supportive measures

and reducing the number of circulating leukemic blast cells. The patient should be promptly

submitted to vigorous hydration with intravenous fluids, with careful monitoring of fluid balance,
control of uric acid production using allopurinol or rasburicase, control of urine Ph to prevent

tumour lysis syndrome.

Rapid reduction in the number of circulating blast cells can be obtained by induction

chemotherapy, hydroxyurea and leukapheresis. The need of debulking leukocytoreduction before

chemotherapy is gathered from reports of tumour lysis syndrome with prominent pulmonary and

renal manifestations following initiation of chemotherapy. The mechanical removal of leukocytes

by leukapheresis has become routinely available in many hematologic treatment centers. However

the use of leukapheresis in HL patients is still under debate. First, the majority of the leukemic

burden is located in the bone marrow. These cells are rapidly mobilized into the peripheral blood

shortly after a successful leukapheresis. Second in the most cases, patient need to place a CVC for

several reasons: inadequate access can compromise the efficacy of the apheresis, patients with AL

may be unstable and more than one procedure can be necessary. Third, the use of citrate as

anticoagulant, although it is rapidly metabolized, it binds calcium and can cause hypocalcemia, and

in rare cases, it can lead to prolongation in the QTc interval. Finally a beneficial clinical effect of

leukapheresis on early clinical outcomes could not be shown consistently in clinical trials.

Leukapheresis is a valid option for the initial management of hyperleukocytosis, although no

impact on long-term outcome has been shown. Chemotherapy should not be postponed and it is

required to prevent rapid reaccumulation of circulating blasts.

7. FIVE-YEAR VIEW

Hyperleukocytosis represent a medical emergency that needs prompt recognition and

initiation of therapy to prevent renal and respiratory failure or intracranial haemorrhage. The

clinical presentation depends largely on the lineage and the number of circulating leukemic blasts.
 Since initial report more than eighty years ago, medical management and therapeutic options

have improved and now they are currently used in the daily practice. Immediate initiation of

cytoreductive treatment in this chemosensitive disease is mandatory and should not be delayed.

Leukapheresis is a valid option for the initial management of hyperleukocytosis and it has become

routinely available in many hematologic treatment centers because the mechanical removal of

leukocytes, before starting chemotherapy, can prevent tumour lysis syndrome with prominent

pulmonary and renal manifestations.

Lack of clinical trials does not allow to identify the role of leukapheresis in early and long term

outcome; in our centre hyperleukocytosis management is well coded according to internal and

international guidelines and leukapheresis is routinely used in patients with leukostasis symptoms

with clinical improvement and with the aim to reduce the risk of TLS, after the start of

chemotherapy. We found no impact on long term outcome, probably because hyperleukocytosis

represent itself a poor prognostic factor. It would be necessary a multicenter clinical trial to better

defined the role of leukapheresis on early on long outcome and to code the its use in this medical

emergency.

8. KEY ISSUES

• Hyperleukocytosis is laboratory abnormality, commonly defined by white blood count

(WBC)> 100000/µL; it should be noted that WBC levels below this arbitrary threshold

can also cause HL-related complications;

• Risk factors for hyperleukocytosis include younger age, various subsets of leukemia

including myelomonocytic or monocytic/monoblastic morphology, microgranular

variant of acute promyelocitic leukemia and T-cell ALL, and cytogenetic abnormalities
 like 11q23 rearrangements, inv(16), presence of the Philadelphia chromosome and

molecular FLT3-ITD.

• This condition is a medical emergency that needs prompt recognition and initiation of

therapy because the high number of leukocytes may cause 3 main complications:

disseminated intravascular coagulation (DIC), tumor lysis syndrome (TLS), and

leukostasis.

• DIC is caused by high cell turnover and associated high levels of released tissue factor,

which then triggers the extrinsic pathway via factor VII.

• TLS is characterized by rapid onset of hyperuricemia, hyperkalemia, hypocalcemia,

hyperphosphatemia and renal impairment following release of intracytoplasmic

components during cellular lysis.

• Leukostasis is explained by an increase of viscosity in the microcirculation, due to the

higher size of blasts and to their lesser deformability, and by additional cellular

mechanisms such as interactions between leukemic cells and the endothelium,

mediated by adhesion molecules.

• The management of acute hyperleukocytosis and leukostasis involves supportive

measures and reducing the number of circulating leukemic blast cells, with careful

monitoring of fluid balance, control of uric acid production and control of urine Ph to

prevent tumour lysis syndrome.

• Rapid reduction in the number of circulating blast cells can be obtained by induction

chemotherapy, hydroxyurea and leukapheresis.

• The mechanical removal of leukocytes by leukapheresis has become routinely

available in many hematologic treatment centers. It allows a rapid reduction in the

 number of circulating blast cells and to prevent tumour lysis syndrome with prominent

pulmonary and renal manifestations

Funding

This paper was not funded.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity

with a financial interest in or financial conflict with the subject matter or materials discussed in the

manuscript. This includes employment, consultancies, honoraria, stock ownership or options,

expert testimony, grants or patents received or pending, or royalties.

REFERENCES

*Article of interest

**Article of considerable interest

1. Majhail NS, Lichtin A Acute leukemia with a very high leukocyte count: confronting a medical
emergency Clev Clin J Med 2004;71(8):633-7
2. Porcu P, Farag S, Marcucci G et al. Leukocytoreduction for acute leukemia Ther Apher 2002;6(1).15-
23
3. Hoelzer D, Thiel E, Buchner A.et al. Prognostic factors in a Multicenter Study for Treatment of Acute
Lymphoblastic Leukemia in Adults. Blood, 1988; 71: 123-131.
4. Cukierman T., Gatt M.E., Libster D. et al. Chronic lymphocytic leukaemia presenting with extreme
hyperleukocytosis and thrombosis of the common femoral vein. Leuk Lymphoma 2002
Sep;43(9):1865-8.
5. Resende L.S.R., Coradazzi A.L., Rocha-Junior C., Zanini J.M., Niéro-Melo L. Sudden bilateral deafness
from hyperleukocytosis in chronic myeloid leukaemia. Acta Haematol 2000; 104:46-49.
6. Lichtman MA, Rome JM Hyperleukocytic leukemias: rheological, clinical, and therapeutic
considerations Blood 1982;60(2):279-83
7. Bunin NJ, Pui CH. Differing complications of hyperleukocytosis in children with acute lymphoblastic
or acute nonlymphoblastic leukemia. J Clin Oncol. 1985; 3(12): 1590-5rcd
8. Eguiguren JM, Schell MJ, Crist WM et al. Complications and outcome in childhood acute
lymphoblastic leukemia with hyperleukocitosis. Blood 1992; 79: 871-875.
9. Porcu P, Cripe LD, Ng EW et al. Hyperleukocytic leukemias and leukostasis: a review of
pathophysiology, clinical presentation and management Leuk Lymphoma 2000;39(1-2):1-18
10. Dutcher JP, Schiffer CA, Wiernik PH Hyperleukocytosis in adult acute nonlymphocytic leukemia:
impact on remission rate and duration, and survival J Clin Oncol. 1987;5(9):1364-72
11. Blum W, Porcu P Therapeutic apheresis in hyperleukocytosis and hyperviscosity syndrome Semin
Thromb Hemost. 2007;33(4):350-4
12. Appelbaum FR, Kopecky KJ Long-term survival after chemoterapy for acute myeloid leukaemia
Cancer Suppl 1997;80:2199-204
13. Bloomfield CD, Lawrence D, Byrd JC et al. Frequency of prolonged remission duration after high-
dose cytarabine intensification in acute myeloid leukemia varies by citegenetic subtypes Cancer Res
1998;58:4173-9
14. Anderson JE, Kopecky KJ, Willman CL et al. Outcome after induction chemotherapy for older
patients with acute myeloid leukaemia is not improved with mitoxantrone and etoposide compared
to cytarabine and daunorubicin: a Southwest Oncology Group study Blood 2002;100:3869-76
15. Chen CC, Yang CF, Yang MH et al. Pre-treatment prognostic factors and treatment outcome in
elderly patients with de novo acute myeloid leukaemia Ann Oncol 2005;16:1366-73
16. Gupta V, Chun K, Yi Ql et al. Disease biology rather than age is the most important determination of
survival of patients > 60 years with acute myeloid leukaemia treated with unform intensive therapy
Cancer 2005;103:2082-90
17. Marbello L, Ricci F, Nosari AM et al. Outcome of hyperleukocytic adult acute myeloid leukemia: a
single-center retrospective study and review of literature. Leuk Res 2008; (32): 1221-1227.
18. Greenwood MJ, Seftel MD, Richardson C et al. Leukocyte count as a predictor of death during
remission induction in acute myeloid leukaemia Leuk Lymphoma 2006;47:1245-52
19. Flasshove M, Meusers P, Schütte J et al. Long-term survival after induction therapy with idarubicin
and cytosine arabinoside for de novo acute leukaemia Ann Hematol 2000;79:533-42
20. Wahlin A, Markevarn B, Golovleva I et al. Improved outcome in adult acute myeloid leukemia is
almost entirely restricted to young patients and associated with stem cell transplantation Eur J
Haematol 2002;68:54-63
21. Behringer B, Pitako JA, Kunzmann R et al. Prognosis of older patients with acute myeloid leukemia
receiving either induction or non-curative treatment: a single-center retrospective study Ann
Hematol 2003;82:381-9
22. van Buchen MA, te Velde J, Willemze R et al. Leukostasis, an underestimated cause of death in
leukaemia Blut 1988;56(1):39-44
23. Takazoe K, Abe A, Kawamura T, Watanabe S, et al. Persistent renal failure in acute myelomonocytic
leukaemia: possible role of massive leukaemia infiltration in the renal interstitium. Nephron.
1996;73(4):728-9.
24. Tobelem G, Jacquillat C, Chastang C, Auclerc MF, Lechevallier T, et al. Acute monoblastic leukemia:
a clinical and biologic study of 74 cases. Blood. 1980 Jan;55(1):71-6.
25. Muggia FM, Heinemann HO, Farhangi M, Osserman EF. Lysozymuria and renal tubular dysfunction
in monocytic and myelomonocytic leukemia. Am J Med. 1969 Sep;47(3):351-66
26. Lichtman MA, Heal J, Rowe JM Hyperleukocytic leukemia: rheological and clinical features and
management Clin Haematol 1987;1:725-46
27. Frankel DH, Larson RA, Lorincz AL et al. Acral lividosis-a sign of myeloproliferative diseases.
Hyperleukocytosis syndrome in chronic myelogenous leukemia Arch Dermatol 1987;123:921-4
28. Würthner JU, Köhler G, Behringer D Leukostasis followed by hemorrhage complicating the initiation
of chemotherapy in patients with acute myeloid leukemia and hyperleukocytosis: a clinicopathologic
report of four cases Cancer. 1999 15;85(2):368-74
29. Cohen Y, Amir G, Da’as N et al. Acute myocardial infarction as the presenting symptom of acute
myeloblastic leukemia with extreme hyperleukocytosis Am J Hematol 2002;71:47-9
30. Vernant JP, Brun B, Mannoni P, Dreyfus B. Respiratory distress of hyperleukocytic graulocytic
leukemias. Cancer 1979 Jul; 44(1):264-8.
31. McKee LC Jr, Collins RD Intravascular leukocyte thrombi and aggregates as a cause of morbidity and
mortality in leukemia Medicine (Baltimora) 1974;53:463-78
32. Röllig C, Ehninger G. How I treat hyperleukocytosis in acute myeloid leukemia. Blood. 2015 May
21;125(21):3246-52
33. Tanaka N, Matsumoto T, Miura G, Emoto T, Matsunaga N. HRCT findings of chest complications in
patients with leukemia. Eur Radiol. 2002 Jun;12(6):1512-22.
34. Potenza L, Luppi M, Morselli M, Tonelli S et al. Leukaemic pulmonary infiltrates in adult acute
myeloid leukaemia: a high-resolution computerized tomography study. Br J Haematol. 2003
Mar;120(6):1058-61.
35. Novotny JR, Müller-Beiβenhirtz H, Herget-Rosenthal S et al. Grading of symptoms in hyperleukocytic
leukaemia: a clinical model for the role of different blast types and promyelocytes in the
development of leukostasis syndrome Eur J Haematol 2005;74:501-10
36. Piccirillo N, Laurenti L, Chiusolo P et al. Reliability of leukostasis grading score to identify patients
with high-risk hyperleukocytosis Am J Hematol 2009 Jun;84(6):381-2
37. Tosi P, Barosi G, Lazzaro C, Liso V, Marchetti M, Morra E, Pession A, Rosti G, Santoro A, Zinzani PL,
Tura S. Consensus conference on the management of tumor lysis syndrome. Haematologica. 2008
Dec;93(12):1877-85.
38. Pession A, Masetti R, Gaidano G, Tosi P, Rosti G, Aglietta M, Specchia G, Porta F, Pane F. Risk
evaluation, prophylaxis, and treatment of tumor lysis syndrome: consensus of an Italian expert
panel. Adv Ther. 2011 Aug;28(8):684-97.
39. Ganzel C, Becker J, Mintz PD, Lazarus HM, Rowe JM. Hyperleukocytosis, leukostasis and
leukapheresis: practice management. Blood Rev. 2012 May;26(3):117-22.

40. Sissolak G, Hoffbrand AV, Mehta AB, Ganeshaguru K. Interferon-alpha inducible 2'-5' oligoadenylate
synthetase transcripts in lymphoid and myeloid leukemias. Leukemia. 1993 May;7(5):712-6.
41. Hatfield KJ, Bedringsaas SL, Ryningen A, Gjertsen BT, Bruserud O. Hypoxia increases HIF-1α
expression and constitutive cytokine release by primary human acute myeloid leukaemia cells. Eur
Cytokine Netw. 2010 Sep;21(3):154-64.
42. Stucki A, Rivier AS, Gikic M et al. Endotelial cell activation by myeloblasts: molecular mechanisms of
leukostasis and leukemic cell dissemination Blood 2001;97(7):2121-9
43. van Buchem MA, Hogendoorn PC, Bruijn JA, Kluin PM. Endothelial activation antigens in pulmonary
leukostasis in leukemia. Acta Haematol. 1993;90(1):29-33
44. Reikvam H, Hatfield KJ, Oyan AM, Kalland KH, Kittang AO, Bruserud O. Primary human acute
myelogenous leukemia cells release matrix metalloproteases and their inhibitors: release profile and
pharmacological modulation. Eur J Haematol. 2010 Mar;84(3):239-51.
45. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T et al. Diagnosis and management of
acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf
of the European LeukemiaNet. Blood. 2010 Jan 21;115(3):453-74.
46. Criscuolo M, Fianchi L, Dragonetti G, Pagano L. Tumor lysis syndrome: review of pathogenesis, risk
factors and management of a medical emergency. Expert Rev Hematol. 2016;9(2):197-208

47. Zuckerman T, Ganzel C, Tallman MS, Rowe JM. How I treat hematologic emergencies in adults with
acute leukemia. Blood. 2012 Sep 6;120(10):1993-2002.
48. Myers TJ, Cole SR, Klatsky AU et al. Respiratory failure due to pulmonary leukostasis following
chemotherapy of acute non-lymphocytic leukemia Cancer 1983;53:1808-13
49. Dombret H, Hunault M, Faucher C et al. Acute lysis pneumopathy after chemotherapy for acute
myelomonocytic leukemia with abnormal marrow eosinophils Cancer 1992;69:1356-61
50. Tryka AF, Godleski JJ, Fanta CH Leukemic cell lysis pneumopathy after chemotherapy: a
complication of treated myeloblastic leukemia Cancer 1982;50:2763-70
51. Grund FM, Armitage JO, Burns CP. Hydroxyurea in the prevention of the effects of leukostasis in
acute leukemia. Arch Int Med 1977; 137: 1246-7
52. Porcu P, Danielson CF, Orazi A et al. Therapeutic leukapheresis in hyperleukocytosis leukaemias:
lack of correlation between degree of cytoreduction and early mortality rate Br J Haematol 1997;98-
433-6
53. Hölig K, Moog R. Leukocyte Depletion by Therapeutic Leukocytapheresis in Patients with Leukemia.
Transfus Med Hemother. 2012 Aug;39(4):241-245
54. Saniabadi AR, Tanaka T, Ohmori T, Sawada K, Yamamoto T, Hanai H. Treating inflammatory bowel
disease by adsorptive leucocytapheresis: a desire to treat without drugs. World J Gastroenterol.
2014 Aug 7;20(29):9699-715.
55. Giles FJ, Shen Y, Kantarjian HM, Korbling MJ et al. Leukapheresis reduces early mortality in patients
with acute myeloid leukemia with high white cell counts but does not improve long- term survival.
Leuk Lymphoma. 2001 Jun;42(1-2):67-73.
• An important study showing the impact of leukapheresis in reducing early mortality rate, but no
effect on long-term survival were reported
56. Thiébaut A, Thomas X, Belhabri A, Anglaret B, Archimbaud E. Impact of pre-induction therapy
leukapheresis on treatment outcome in adult acute myelogenous leukemia presenting with
hyperleukocytosis. Ann Hematol. 2000 Sep;79(9):501-6.
• An important study showed an early death rate much lower(4%) than that reported in the
literature (30-50%), in a cohort of 53 patients with a diagnosis of hyperleukocitic acute leukemia,
submitted to leukocytapheresis
57. Powell BL, Gregory BW, Evans JK, White JC, Lyerly ES, Chorley HM, Russell GB, Capizzi RL.
Leukapheresis induced changes in cell cycle distribution and nucleoside transporters in patients with
untreated acute myeloid leukemia. Leukemia. 1991 Dec;5(12):1037-42.
• This study emphasizes another possible role of leukapheresis: the procedure could increase the
fraction of bone marrow leukemic cells that are in S-phase, and so it could enhance the efficacy
of chemotherapy.
58. Aqui N, O'Doherty U. Leukocytapheresis for the treatment of hyperleukocytosis secondary to acute
leukemia. Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):457-60
59. Szczepiorkowski ZM, Winters JL, Bandarenko N et al. Guidelines on the use of therapeutic apheresis
in clinical practice--evidence-based approach from the Apheresis Applications Committee of the
American Society for Apheresis J Clin Apher. 2010;25(3):83-177
60. De Santis GC, de Oliveira LC, Romano LG, Almeida Prado Bde P Jr, Simoes BP, Rego EM, Covas DT,
Falcao RP.Therapeutic leukapheresis in patients with leukostasis secondary to acute myelogenous
leukemia. Clin Apher. 2011;26(4):181-5.
61. Bruserud Ø, Liseth K, Stamnesfet S, Cacic DL, Melve G, Kristoffersen E, Hervig T, Reikvam H.
Hyperleukocytosis and leukocytapheresis in acute leukaemias: experience from a single centre and
 review of the literature of leukocytapheresis in acute myeloid leukaemia. Transfus Med. 2013
Dec;23(6):397-406.
62. Pham HP, Schwartz J. How we approach a patient with symptoms of leukostasis requiring emergent
leukocytapheresis. Transfusion. 2015 Oct;55(10):2306-11.
63. Vahdat L, Maslak P, Miller WH Jr, Eardley A et al. Early mortality and the retinoic acid syndrome in
acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha
isoform, and CD13 expression in patients treated with all-trans retinoic acid. Blood. 1994 Dec
1;84(11):3843-9. Review.
64. Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, Naoe T, Lengfelder E,
Büchner T, Döhner H, Burnett AK, Lo-Coco F. Management of acute promyelocytic leukemia:
recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009 Feb
26;113(9):1875-91.
65. Abla O, Khanani MF, Hitzler JK et al Complications of hyperleukocytosis and leukapheresis in
pediatric acute leukemia Blood 2004;104:(abstract) 1963.
66. Bug G, Anargyrou K, Tonn T et al. Impact of leukapheresis on early death rate in adult acute
myeloid leukemia presenting with hyperleukocytosis Transfusion 2007;47:1843-50

67. Chang MC, Chen TY, Tang JL, Lan YJ, Chao TY, Chiu CF, Ho HT.Leukapheresis and cranial irradiation
in patients with hyperleukocytic acute myeloid leukemia: no impact on early mortality and
intracranial hemorrhage. Am J Hematol. 2007 Nov;82(11):976-80.
• Of importance this retrospective analysis of 75 patients with hyperleukocytic AML, which
identified the most significant risk factors for incidence of intracranial haemorrhage and early
death: age>65 years, two or more leukostasis sympthoms and the respiratory distress; in this
setting leukocytapheresis had no significant impact in reducing the early death rate
68. Pastore F, Pastore A, Wittmann G, Hiddemann W, Spiekermann K. The role of therapeutic
leukapheresis in hyperleukocytotic AML. PLoS One. 2014 Apr 14;
69. Oberoi S, Lehrnbecher T, Phillips B, Hitzler J, Ethier MC, Beyene J, Sung L. Leukapheresis and low-
dose chemotherapy do not reduce early mortality in acute myeloid leukemia hyperleukocytosis: a
systematic review and meta-analysis. Leuk Res. 2014 Apr;38(4):460-8.
• Of considerable importance is this meta-analysis included twenty-one studies, with a total of
1500 adult and pediatric patients. The study showed no difference in early mortality rate
between the use of leukapheresis or the use of hydroxyurea and low-dose chemotherapy.
70. Sung L, Aplenc R, Alonzo TA, Gerbing RB, Gamis AS. Predictors and short-term outcomes of
hyperleukocytosis in children with acute myeloid leukemia: a report from the Children's Oncology
Group. Haematologica. 2012 Nov;97(11):1770-3.
• This study showed how leukapheresis can be safely use also for pediatric patients
 71. Kuruvilla JG, Greenwood MD, Hogge DE et al Outcome for patients with acute myelogenous
leukemia and hyperleukocytosis requiring urgent leukapheresis at diagnosis Blood 2002;100:
(abstract) 4598.
72. Kuo KHM, Callum J, Brandwein j et al. Management of hyperleukocytosis in acute myelogenous
leukemia using hydroxyurea rather than leukapheresis Blood 2006;108: (abst 2007)

Table 1: Hyperleukocytic Leukemias: a review of literature

No of Observati Disease Medi Medi Early Early Leukaphere Chemother Both Media
patien on an an deat deaths sed apy n OS
ts time age WBC hs due to patients (mont
(rang (x leukosta h)
e) 109/L) sis
(rang
e)
Berg J et 17 d.n.s AML 54 152 1 0 3 d.n.s d.n.s d.n.s.
al (1979) (7%) (23%)
Hug V et 46 1973-79 AML 54 152 6 6 (13%) 28 18 28 6
al (1983) (100- (13% (60%) (39%) (60%
200) ) )
Cuttner 22 d.n.s. AML 43 166 3 3 22 22 22 d.n.s.
J et al (13% (13%) (100%) (100%) (100
(1983) ) %)
Lester TJ 43 1974-83 AML 48 154 11 7 35 1 35 4
et al (17- (102- (25% (63%) (81%) (2%) (81%
(1985) 76) 438) ) )
Dutcher 41 1971-82 AML 45 175 8 5 11 d.n.s d.n.s d.n.s.
JP et al (20% (57%) (26%)
(1987) )
Porcu P 48 1984-95 AML/C 41 201 14 14 48 48 48 d.n.s
et al ML-BC (8-79) (101- (27% (27%) (100%) (100%) (100
(1997) 506) ) %)
Thiébau 53 1985-95 AML 59 160 2 1 (2%) 53 53 53 10
t A et al (16- (100- (4%) (100%) (100%) (100
(2000) 78) 480) %)
Giles et 71 1992- AML d.n.s d.n.s d.n.s
al (2001) 1999 d.n.s d.n.s d.n.s d.n.s d.n.s
Bug G et 53 1995- AML 50 151 13 4 27 36 27 7
al 2005 (20- (103- (25% (7%)
(2007) 78) 399) )
Chang 75 1998- AML 48 d.n.s. 15 3 22 37 dns 1.5
MC.et al 2005 (16- (40%
(2007) 85) )
Marbell 45 1995- AML 56 159 8 2 0 45 0 10
o L et al 2005 (17- (102- (17% (4%) (100%)
(2008) 80) 452) )
De 15 1998- AML 46 200 7 d.n.s. 15 11 11 0.3
Santis 2008 (22- (88- (46%
GC et al 78) 400) )
(2011)
Bruseru 16 d.n.s. 7 AML 40 309 2 1 16 16 16 d.n.s.
d O et 5 ALL (1-88) (104- (12% (6%)
al, 3 CML 935) )
(2013) 1 CLL
UCSC 45 2011-15 40 AML 53 92 6 2 11 45 11 11
experien 5 (22- (50- (13% (4%) (24%) (100%) (24%
ce ALL 85) 270) ) )

Legend: d.n.s. data not shown; OS overall survival; AML acute myeloid leukemia; CML chronic
myeloid leukemia; ALL acute lymphoblastic leukemia

Table 2: Sympthoms’ frequency of hyperleukocytosis in the literature

Reference Signs and Symptoms Frequency (%)

Porcu et al. Ther Apher 2002 27

Marbello et al Leuk Res 2008 13

Neurological symptoms
Oliveira et al Med Onc 2009 45

Novotny et al Eur J Hematol 2005 3

Blurred vision
Novotny et al Eur J Hematol 2005 4
Confusion/delirium/somnolence
Wurthner et al Cancer 1999 case report
Retinal hemorrhage
Wurthner et al Cancer 1999 case report
Intracranial hemorrhage
Porcu et al. Ther Apher 2002 39
Pulmonary symptoms
Marbello et al Leuk Res 2008 29

Novotny et al Eur J Hematol 2005 16

Dyspnea
Thiebaut et al Ann Hematol 2000 9
Pulmonary infiltrate
Porcu et al. Ther Apher 2002 14
Renal failure
Novotny et al Eur J Hematol 2005 1

Novotny et al Eur J Hematol 2005 3

Arrythmia
Cohen et al Am J Hematol 2002 case report
Myocardial infarction
Novotny et al Eur J Hematol 2005 1
Ischemic necrosis
Porcu et al. Ther Apher 2002 39
DIC
Novotny et al Eur J Hematol 2005 2
Table 3: Management of hyperleukocytosis
What to do
Vigorous hydratation (2 L/m2/day) and
careful monitoring of fluid balance
Control of uric acid production using
AT ADMISSION allopurinol or rasburicase
Urine alkalinisation using sodium
bicarbonate
Reduction of circulating blast cells
Why
Improve intravascular volume,
enhance renal blood flow and
promote urinary escretion
Decrease the risk of uric acid
crystallization in the kidneys
Reduce tendency to uric acid
precipitation in renal tubules
Prevent multiple organ failure