HYPERLEUKOCYTOSIS DR AHMAD AHMADZADEH HEMATOLOGIST-MEDICAL ONCOLOGIST.
LEUKOCYTAPHERESIS FOR THE TREATMENT OF … · LEUKOCYTAPHERESIS FOR THE TREATMENT OF...
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LEUKOCYTAPHERESIS FOR THE TREATMENT OF
HYPERLEUKOCYTOSIS SECONDARY TO ACUTE
LEUKEMIA
Nicole Aqui, M.D.
Chief, ApheresisServices
Division of Transfusion Medicine
Department of Pathology and Laboratory Medicine
University of Pennsylvania
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Learning Objective
• To gain an understanding of the pathophysiology of
leukostasis and the role of leukocytapheresis as a
therapeutic intervention
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Hyperleukocytosis
• White blood cell (WBC) count
greater than 100 x 109/L*
• Seen in 5 – 25% of patients with
acute leukemia
• Risk factors include younger
age, certain cytogenetic
abnormalities, and monocytic
differentiation subtypes (acute
myelomonocytic leukemia and
acute monoblastic and
monocytic leukemia)
Mauro MJ. N Engl J Med 2003;349:767-767.
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Hyperleukocytosis
• Poor prognosis
• High early mortality
• Lower complete remission rate*
• Decreased disease free survival*
• Can lead to…
• Tumor lysis syndrome
• Disseminated intravascular coagulopathy (DIC)
• Leukostasis
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Leukostasis - Pathophysiology
• Multifactorial
• Increased viscosity
• Occlusion of small
vessels by leukemic
blasts
• Tissue infiltration
Lichtman and Rowe, Blood (1982)
*True leukocrit (TRUE) is corrected
for trapped plasma.
*
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Leukostasis - Pathophysiology
• AML >> CML, ALL, CLL
• Size of blasts
• Blasts secrete cytokines that increase activation of endothelial cells
and induce adhesion molecules, promoting adhesion of blast cells
to vascular endothelium
• Symptoms can be seen in WBC as low as 50 x 109/L in AML. Often
not seen until > 300 x 109/L in CML, ALL
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Leukostasis - Symptoms
• Leukostasis is a clinical diagnosis
• Pulmonary
• Tachypnea, dyspnea, hypoxia
• Neurologic
• Mental status changes, delirium, confusion, headache, dizziness,
tinnitus
• Vascular
• Myocardial ischemia/infarction, priapism, retinal
hemorrhage/thrombosis
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Leukostasis – End organ damage
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Management of Hyperleukocytosis
• Cytoreduction
• Chemotherapy
• Leukocytapheresis
• Aggressive hydration
• Prevention of tumor lysis syndrome
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Leukocytapheresis – Technical Aspects
• Access
• Peripheral
• CVC (preferred) – dialysis-compatible dual or triple lumen
• Medcomp, Quinton Instruments, Hickman
• “Dose”
• 1.5 – 2 blood volumes
• Use pre-, mid-CBC and patient tolerance as a guide
• Frequency
• q12-24 hours
• Treatment of leukostasis: WBC count < 50 x 109/L
• Prophylaxis in asymptomatic patient: WBC count < 50 x 109/L
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Side Effects
• Blood loss
• Due to contaminating red cells in buffy coat. The more difficult it is
to obtain interface, the more red cell loss.
• Extracorporeal volume (ECV) varies according to apheresis
instrument, but can be as high as 285 ml
• Transfusions prior to leukocytapheresis may worsen hyperviscosity
(pRBC HCT 60-70%)
• Can give pRBCs as volume replacement at the end of the
procedure
• Platelet loss
• Generally not as severe as RBC loss
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Efficacy of Leukocytapheresis • Immediate cytoreduction
• Several studies have shown no effect overall survival
• Conflicting evidence of effect on early mortality
Pastore F, Pastore A, Wittmann G, Hiddemann W, et al. PLoS ONE (2014)
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Effect of leukocytapheresis on early death
• Meta-analysis
• 21 studies
• WBC > 100 x 109/L
Oberio et al. Leukemia Research (2014)
Potentially relevant refs
Identified through database
search (n = 5701)
Citations screened by
title/abstract (n = 4876)
Full text refs retrieved for
further evaluation (n = 42)
Studies included in meta-
analysis (n = 21)
Articles excluded (n = 4835)
Excluded (n = 21)
Did not use WBC criteria for
hyperleukocytosis
Selected population
Published < 1980
Did not describe early
mortality
< 5 patients
Publication not in English
Duplicates removed
(n = 825)
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Effect of leukocytapheresis on early death
Oberio et al. Leukemia Research (2014)
Subgroups Number of
studies
(patients)
Proportion of
patients with
early death
p value
Leukapheresis 0.67
Universal 5 (157) 25.6
Selected 9 (263) 18.9
Never 1 (45) 17.8
Hydroxyurea/Low
dose chemo
0.23
Universal 8 (430) 22.8
Selected 1 (32) 33.3
Never 2 (278) 10.3
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Effect of leukocytapheresis on early death
Study Leukapheresis
Events (Total)
No
Leukapheresis
Events (Total)
Odds Ratio
Bug 2007 4 (25) 9 (28) 0.40
Chang 2007 12 (28) 13 (47) 1.96
Giles 2001 9 (71) 17 (75) 0.50
Inaba 2008 1 (36) 16 (70) 0.10
Sung 2012 1 (16) 3 (73) 1.56
Ventura 1998 7 (61) 10 (24) 0.18
Oberio et al. Leukemia Research (2014)
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Role of Leukocytapheresis in APL?
• Acute promyelocytic leukemia with translocation between
chromosomes 15 and 17 (APL), is associated with DIC
and thrombocytopenia, thus these patients are
predisposed to bleeding complications.
• A study to examine treatments for leukocytosis associated
with RA syndrome found that low-dose chemotherapy or
leukapheresis was frequently a trigger event for fatal or
near-fatal hemorrhage. These patients did worse than
those who received no treatment at all. (Vahdat et al, Blood 1994)
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ASFA 2013 Guidelines
Indication Condition Recommendation Category
Hyperleukocytosis
secondary to leukemia
Leukostasis Grade 1B I
Prophylaxis Grade 2C III
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Conclusions
• Leukostasis secondary to hyperleukocytosis is a
potentially life-threatening complication of acute
leukemias that carries a poor prognosis, thus is a true
emergency.
• The role of leukocytapheresis for cytoreduction is still
unclear. Though patients often experience symptomatic
relief, there appears to be no effect on long-term survival
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Conclusions
• The decision to perform leukocytapheresis should in no
way delay more definitive treatment, i.e. hydroxyurea
and chemotherapy.
• In the absence of prospective trials, institutions should
develop their own standardized criteria for the
treatment of asymptomatic patients.
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Acknowledgments UPENN Transfusion Medicine Faculty
• Don Siegel, MD PhD
• Una O’Doherty, MD PhD
• Taku Kambayashi, MD PhD
UPENN Transfusion Medicine Staff
• Robin Brown
• Crystal Williamson
UPENN Apheresis Staff
• Leah Irwin, Nurse Manager
• Christa Eisenmann
• Lita Jamensky
• Melissa Murter
• Jane Mason
• Felicia Morrison
• Jennifer Green
• Marcia Hole
• Kevin Schnell
• Karen Fogle