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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
Article views: 4
Download by: [The UC San Diego Library] Date: 18 December 2016, At: 17:47
Publisher: Taylor & Francis
DOI: 10.1080/17474086.2017.1270754
Review
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
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
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
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
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
promyelocitic leukemia and T-cell ALL, and cytogenetic abnormalities like 11q23 rearrangements,
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
However hyperleukocytic acute myeloid leukemia is considered to have a poor prognosis due
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
2. CLINICAL FEATURES
Hyperleukocytosis (HL) is commonly defined as a white blood cell count >100 000/µL, caused
2.1 Leukostasis
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
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.
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
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].
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
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
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
count and fibrinogen, an elevation of D-dimers, and prolongation of prothrombin time and
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
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
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,
4. MANAGEMENT OF LEUKOSTASIS
and reducing the number of circulating leukemic blast cells. The patient presenting with newly
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].
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
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
4.2 Cytoreduction
Rapid reduction in the number of circulating blast cells is essential to prevent or delay
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
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
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].
be considered for AML patients with a blast count more than 100x109/L, especially with a
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
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
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
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
6. EXPERT COMMENTARY
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
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
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
of alveolar-capillary oxygen exchange until respiratory failure and renal tubular dysfunction.
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
Rapid reduction in the number of circulating blast cells can be obtained by induction
chemotherapy is gathered from reports of tumour lysis syndrome with prominent pulmonary and
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.
impact on long-term outcome has been shown. Chemotherapy should not be postponed and it is
7. FIVE-YEAR VIEW
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
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
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
(WBC)> 100000/µL; it should be noted that WBC levels below this arbitrary threshold
• Risk factors for hyperleukocytosis include younger age, various subsets of leukemia
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:
leukostasis.
• DIC is caused by high cell turnover and associated high levels of released tissue factor,
higher size of blasts and to their lesser deformability, and by additional cellular
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
• Rapid reduction in the number of circulating blast cells can be obtained by induction
Funding
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
REFERENCES
*Article of 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)
Legend: d.n.s. data not shown; OS overall survival; AML acute myeloid leukemia; CML chronic
myeloid leukemia; ALL acute lymphoblastic leukemia
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