Hyperleukositosis

Bidasari Lubis- Olga Rasiyanti Siregar

Divisi Hematology – Oncology / Child Health

Departement
Medical Faculty –University of Sumatera Utara

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Introduction

1. Hyperleukositosis
2. Leukostasis
3. Leucocytosis
4. Leukemoid reaction
5. Leukapheresis

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The formation of neutrophil and
monocytes phagocytes

HIS2-K9 (2020) 4
HIS2-K9 (2020) 5
Neutrophil kinetics

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Hyperleukositosis

• Peripheral blood leukocyte count>100.000/mm3

• Hyperleukocytosis occurs :
- Almost all children with CML , especially “ Blast crisis “
- (8 - 13%) of children with ALL ( particularly T-cell with mediastinal mass, Infant
ALL) and (5 - 25%) of children with AML  Acute Hyperleukocytic
Leukemia ( AHL )  Leukapheresis , Leucocytoreduction

Pizzo PA,Poplack DG..Pediatric Oncology 7 th ed.2016

J.Transci 2018:57(1):4-7

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Symptoms associated with Hyperleukositosis

• Respiratory symptoms: • Ocular symptoms :

dyspnea,tachypnea,hypoxia,Acute papilledema ,small artery or vena
Respiratory Distress Syndrome, distention
Respiratory failure • Skin symptoms : cyanosis,
• Neurologic symptoms : focal plethora
deficits, headache ,confusion,
delirium , ataxia, stroke,seizure
• Genitourinary symptoms :
Perkin JC,Davis JE.Hematology/Oncology Clinics of North
priapism,renal failure America ,2017

• Cardiac symptoms : cardiac

ischemia , pulmonary edema

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Complication Hyperleukocytosis :

Three main complication :

1. Leukostasis : clinicopathologic syndrome , characterized by
multiorgan failure, severe coagulopathy, TLS, metabolic abnormalities
2. Tumor Lysis Syndrome ( TLS ) : result of spontaneous of treatment
intercell cell death. TLS  rapid onset of hyperuricemia
,hyperkalaemia,hypocalcemia,hyperphosphatemia ,renal impairment ,
following release of intracytoplasmic component during cellular lysis.
3. DIC : caused by high cell turnover and associated high level of released
tissue factor  trigger external pathway via FVII
S Giammarco et al. Expert review of hematology ,2016

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Leukostasis

• Called : symptomatic hyperleukocytosis

• most commonly :Acute Myeloid Leukemia or Chronic Myeloid Leukemia in
blast crisis.
• Characterized : extremely elevated blast cell count  Leukemic blast –
endothelial cell interaction  decreased tissue perfusion  prompt
recognition  medicical emergencyinitiation of therapy to prevent renal
and respiratory failure or intracranial haemorrhage
• The underlying mechanisms of hyperleukocytosis and leukostasis are
poorly understood

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Pathogenesis
High numbers of circulating
blasts leads to sludging,
obstruction of capillaries and
subsequent tissue malperfusion.
In addition, circulating blasts
induce endothelial adhesion
receptor expression (ie E
selectin, P selectin ICAM-1)
leading to further adhesion and
sludging.  
From Rollig et al, Blood 2016

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Disseminated Intravascular Coagulation

• Associated high level of released Tissue factor

• Trigger external pathway via F VII
• Laboratory : decreased platelet count ,
fibrinogen ,
elevated D-dimer
prolongation PT , APTT

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Tumor Lysis Syndrome
(TLS)
Generally occurs with a high tumor burden
and with initiation of cytotoxic therapy (i.e.
induction chemotherapy)
Can also occur spontaneously with high
tumor burden (i.e. hyperleukocytosis)
The risk of developing tumor lysis syndrome
(TLS) varies with the type of
leukemia/lymphoma:
Extremely high risk: Burkitt Lympoma
(bulky or advanced stage)/Leukemia
High Risk: T cell Leukemia/lymphoma, ALL
with WBC >100K, AML with WBC >50K
Intermediate Risk: Stage III/IV Non-Burkitt
NHL, Burkitt lymphoma (not bulky or
advanced)/Leukemia, ALL with WBC 50-
100K, AML with WBC 10-50K
Low Risk: All other patients not meeting
above criteria

Stanford Pediatric Critical Care

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 Pathogenesis TLS

Pession et al.Biologic:Targets & Therapy 2008:2(1)

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 Laboratory criteria of TLS

Uric acid Increase of more than 25% from baseline if available or

Values 476 mol/L 8 mg/dL
Potassium Increase of more than 25% from baseline if available or
Values 6.0 mmol/L 6 mEq/dL
Phosphorus Increase of more than 25% from baseline if available or
Values 1.45 mmol/L 4.5 mg/dL for adults patients
Values 2.1 mmol/L 6.5 mg/dL for pediatric patients
Calcium Decrease of more than 25% from baseline if available
or Values 1.75 mmol/L 7 mg/dL
Modifi ed from Cairo and Bishop (2004).

Pession et al.Biologic:Targets & Therapy 2008:2(1)

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Prevention of TLS Treatment laboratory and clinical TLS

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Management Tumor Lysis Syndrome

Rasburicase
Aggressive hydration
• Recombinant urate oxidase
Allupurinol
• Catalyzes the oxidation uric acid to
Rasburicase allantoin
• 5-10 x urine soluble
• T/Hyperuricemia , high risk of TLS
• Dose : 0.1-0.2 mg/Kg
• Contra indication : Def. G6PD
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Leukemoid
reaction

• High total leucocyte count (TLC) typically > 50.000/mmᴲ , do

not exceed 100.000/mmᴲ
• Non malignant disorders

• Several causes :

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Management hyperleukocytosis and leukostasis
1. Hydration and allopurinol with alkalinization
( D5 1/4NS + 40 mEq/L Sodium bicarbonate or sodium acetat : 2-4 times maintenance fluid rate )
2.Cytoreduction : of circulating leukemic blast cells by :
- induction chemotherapy
- hydroxyurea,
- low-dose chemotherapy
- leukapheresis.
• The measures such as hydroxyurea, low-dose chemotherapy, and leukapheresis shouldn’t be considered
to correct the laboratory abnormalities in patients with hyperleukocytosis who have no signs or symptoms.
• No evidence to compare the effectiveness of the two therapies

Pizzo PA ,Poplack DG .Pediatric Oncology ,7 th ed,2016

Kirkmaz S.Transfusion and apheresisScience,2018;57

J.Clinical Apheresis 2016

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Management hyperleukocytosis and leukostasis

3. Monitoring for tumor lysis

• Rasburicase generally given for uric acid >8 mg/dL
• Twice maintenance fluids without potassium with goal UOP 2-3 cc/kg/hr
4. Leukapheresis: Role in treatment of hyperleukocytosis is controversial as the
evidence is quite limited
• One study of 53 patients at St. Jude's with ALL and hyperleukocytosis
(WBC 200 to 1 M) demonstrated similar rates of adverse events in the 9
that received leukapheresis compared with the 42 that did not receive
leukapheresis
• Can exacerbate DIC in APML

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Management hyperleukositosis

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Therapeutic leukapheresis
• indicated : symptomatic
hyperleukocytosis
• most frequent in newly diagnosed
acute myeloid leukaemia (10 – 20   be no effect on long-term survival.
%) and acute lymphoblastic
leukaemia (10 – 30  %) and is a
potentially life-threatening
condition
• Leukocytapheresis for the treatment of
hyperleukocytosis secondary to acute
leukemia Nicole Aqui,Una O. Hematology 2014
Because there are no prospective, randomized studies, and
retrospective studies report conflicting results, the role of
leukocytapheresis for cytoreduction is still unclear. Although
patients often experience symptomatic relief, there appears to
• The Management of Hyperleukocytosis in
2017: Do We Still Need Leukapheresis?
J.tranfus Apher Sci 2018;57(1):4-7

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 J.Clinical Apheresis 2016

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HO-2020 Indian J Pediatr 2013;80(2):144-148 25
Take Home Massage

• High morbidity index  Optimal management is still uncertain

• The underlying mechanisms of hyperleukocytosis and leukostasis are
poorly understood. The management of hyperleukocytosis and leukostasis
involves supportive measures and reducing the number of circulating
leukemic blast cells by induction chemotherapy, hydroxyurea, low-dose
chemotherapy, and leukapheresis. 
• Recommendation :intensive chemotherapy should be implemented as
quickly as possible in treatment-eligible patients, in parallel with supportive
measures for DIC and TLS.

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