LEUKOCYTAPHERESIS FOR THE TREATMENT OF … · LEUKOCYTAPHERESIS FOR THE TREATMENT OF...

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

Learning Objective

• To gain an understanding of the pathophysiology of

leukostasis and the role of leukocytapheresis as a

therapeutic intervention

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.

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

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.

*

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

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

Leukostasis – End organ damage

Management of Hyperleukocytosis

• Cytoreduction

• Chemotherapy

• Leukocytapheresis

• Aggressive hydration

• Prevention of tumor lysis syndrome

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

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

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)

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)

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

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)

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)

ASFA 2013 Guidelines

Indication Condition Recommendation Category

Hyperleukocytosis

secondary to leukemia

Leukostasis Grade 1B I

Prophylaxis Grade 2C III

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

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.

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