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Hyperleukocytic Leukemias and Leukostasis: A Review of

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Pathophysiology, Clinical Presentation and Management

PIERLUIGI PORCU~*,LARRY D. CRIPE~,ELIZABETH w.N G ~ SUMEET
, BHATIA~,
CONSTANCE M. DANIELSONb, ATTILIO ORAZI and LEO J. McCARTHYb

Ohio State University, Columbus, OH, bIndiana University, Indianapolis, IN and Columbia University College of Physicians and Sur-
geons, New York, NY;, USA.

(Revised January 10,2000)

Acute hyperleukocytic leukemias (AHL) are associated with a very high early mortality rate
For personal use only.

mostly due to respiratory failure or intracranial bleeding. The pathophysiological process

leading to these complications is called leukostasis but the biological mechanisms underlying
its development and progression remain unclear. Although traditionally related to over-
crowding of leukemic blasts in the capillaries of the microcirculation, leukostasis is likely to
result from direct endothelial cell damage. This damage is probably mediated by soluble
cytokines released during the interaction between leukemic cells and vascular endothelium
and by the subsequent migration of leukemic blasts in the perivascular space. Leukemic cells
ability to respond to chemotactic cytokines and their expression of specific adhesion mole-
cules are probably more important in determining whether leukostasis will develop than the
number of circulating blasts. This could explain why leukostasis does not develop in all
patients with AHL. The identification of the adhesion molecules, cytokines and receptors
mediating endothelial cell damage in AHL should become a priority if therapeutic improve-
ments are desired. Leukapheresis is widely used but it is unclear whether it provides addi-
tional benefit to a simpler and less invasive intervention with allopurinol, hydroxyurea and
intravenous fluids. Cranial irradiation is not generally recommended. Induction chemother-
apy should be started without delay. It is hoped that specific pharmacological inhibitors of the
interaction between leukemic cells and vascular endothelum will result in an improved out-
come for this very high-risk population.

Keywords: acute leukemia, hyperleukocytosis,leukostasis, leukapheresis

INTRODUCTION leukocytic leukemias (AHL) represent a challenging

therapeutic problem because of a very high risk of
Conventionally and arbitrarily defined as acute leuke- early mortality (20%-40%)92. Although it is debata-
mias with an initial white blood cell count (WBC) or ble whether they represent a distinct subgroup of
blast count greater than 100,000/mm3, acute hyper- leukemias in biological terms, AHL share the distinc-
* Address all correspondence to: Pierluigi Porcu M.D. Division of Hematology/OncologyThe Ohio State University Comprehensive Can-
cer Center B407 Starling Loving Hall 320 West lothAve. Columbus, OH, 43210 Phone: (614) 293-4275 Fax: (614) 293-7529 E-mail:
porcu-1@medctr.osu.edu

1
 2 PIERLUIGI PORCU et al.
tion of a dramatic clinical presentation and a gener-
ally unfavorable outcome. It is recognized that
severity of symptoms and outcome in AHL depend in
large measure on 1) the type of leukemia, the degree
of leukocytosis and the percentage of circulating
blasts, 2) the patient's age and performance status, and
3) the coexistence of coagulation disorders and meta-
bolic abnormalities. The incidence of symptomatic
hyperleukocytosis is greater in acute myeloid leuke-
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mia (AML) than in acute lymphoblastic leukemias
ALL)^. Symptoms may arise from the involvement
of any organ system but intraparenchymal brain hem-
orrhages and respiratory failure account for the
majority of early deaths. A direct role in determining
these complications has been attributed to diffuse cer-
ebral and pulmonary microcirculatory failure from
sludging of leukemic blasts into capillary vessels, a
phenomenon known as leuko~tasis~'~. In spite of sig-
nificant advances in supportive care and chemother-
For personal use only.
apy, very little progress has been made in the
management of established leukostasis. Leukapher-
esis, introduced more than 20 years ago6, does not
seem to have produced a significant reduction in early
mortality rate. Its use, however, is generally recom-
mended because of the quick cytoreductive effect and
several anecdotal reports of dramatic responses7-".
Although complete remission rate may not be signifi-
cantly lower in AHL compared to non-hyperleuko-
cytic acute leukemias, many have reported a higher
risk of relapse and shorter survival'2-'8. Whether this
underscores a fundamental biological difference or
simply reflects the enormous initial load of leukemic
TABLE I Factors associated with hyperleukocytosis in AML and ALL
AML
Age < 1 year
FAB M4, M5
APL microgranular variant (M3v)
llq23 rearrangements
inv( 16)(pl3q22)
Chromosome 6 abnormalities
Expression of lung resistance protein (LRP)
cells is unknown. The clinical challenge posed by
AHL is therefore twofold. First, the pathophysiology
of hyperleukocytosis and leukostasis needs to be elu-
cidated to establish the relative value of the treatment
modalities currently in use and to guide the develop-
ment of more effective therapies. Second, the clinical
and biological characteristics of AHL should be stud-
ied in order to confirm or refute their unfavorable
long-term prognosis, so that risk-adapted therapy can
be applied.
We recently reported a retrospective analysis of the
management of a large cohort of adults with hyperleu-
kocytic AML, focusing on the cytoreductive role of
leukapheresis''. Our study confirmed the high rate of
early deaths (29.1%) in these patients but failed to
demonstrate an improvement in early mortality rate
with the use leukapheresis compared to historical
controls, even in the group with clinically evident leu-
kostasis. This suggests that immediate leukoreduction
may be necessary but not sufficient to treat leukosta-
sis and prevent early death. The goal of this review is
to offer a contemporary perspective of the clinical and
biological problems associated with AHL. The inci-
dence, pathophysiology and prognosis of AHL is
reviewed in light of molecular and clinical data gath-
ered by the authors over the last 15 years and availa-
ble from the literature. We also present the current
evidence regarding the mechanisms determining leu-
kostasis in AHL and speculate about potential biolog-
ical targets for therapy. Finally, we critically discuss
the therapeutic role played by leukapheresis and other
cytoreductive measures.
~
ALL
Age < 1 year
Male sex
T-cell phenotype
Leukemic cell ploidy < 50 chromos
CNS involvement
llq23 rearrangements
Ph'-positive ALL
Loss of p16 expression
 MANAGEMENT OF ACUTE LEUKEMIA WITH HYPEIUEUKOCYTOSIS
INCIDENCE, BIOLOGICAL CORRELATES
AND CLINICAL COURSE OF AHL
Acute Myeloid Leukemia
The frequency of hyperleukocytosis in AML is varia-
ble, ranging from 5% to 13% in adult AML and from
12% to 25% in pediatric AML'23143'5320-23. In our
series, this subgroup represents 18% of all adult AML
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diagnosed between 1984 and 1997 (Table 11). Pub-
lished figures may underestimate the true incidence of
hyperleukocytic AML because many of these patients
are treated off protocol and die shortly after diagnosis.
Moreover, patient stratification based on initial WBC
count is often limited to a generic cut-off, which
ranges between 30,000/mm3 and 50,000/mm3. Since
a statistical analysis of response and survival for the
subset of patients with hyperleukocytosis is often not
available, it remains unsettled whether hyperleukocy-
For personal use only.
tosis is an independent predictor of response and sur-
vival.
The clinical and biological characteristics predic-
tive of hyperleukocytosis in AML have not been sys-
tematically investigated. With the exception of
congenital or infant leukemia, typically presenting
with massive tumor cell burden and extensive cutane-
ous and visceral involvement, there is no other associ-
ation with specific age groups. Further, the frequency
of hyperleukocytosis in congenital and infant leuke-
mias may be more related to the predominance of
myelomonocytic subtypes of AML and to the high
frequency of chromosome 1lq23 rearrangements than
age itself. Likewise, except for one pediatric study by
Creutzig et a12', where an association between male
sex and hyperleukocytosis was found, current data do
not indicate any gender preference. Age, however, has
a significant impact on prognosis in hyperleukocytic
AML19.
Among the French-American-British (FAB) sub-
types of AML, myeloid leukemias with monocytic
differentiation (M4, M5) and the microgranular vari-
ant (M3v) of acute promyelocytic leukemia (APL)
have been linked to hyperleukocytosis. Cuttner et
al.24 first reported this association and suggested that
the clinical manifestations of hyperleukocytosis are
3
secondary to the migration of leukemic monocytes
into extramedullary sites were further proliferation
and tissue damage occurs. Acute myelomonocytic
leukemias with atypical eosinophils (M4Eo) often
present with very high WBC counts and organomeg-
aly. M4Eo represents 5-10% of all AML cases and is
typically associated with inversion of chromosome 16
[inv( 1 6 ) ( ~ 1 3 q 2 2 ) ] ~Complete
~. remission rate and
survival in M4Eo are significantly better compared to
other subtypes of AML, suggesting that karyotype
rather than hyperleukocytosis determines outcome26.
Very high WBC counts, organomegaly and extramed-
ullary disease are also nearly always present in poorly
differentiated monoblastic leukemias (M5a), 30% to
40% of these patients presenting with WBC counts
greater than 100,000/mm3.Unlike M4Eo, this sub-
type is associated with unfavorable cytogenetics and a
very high incidence of relapse. While the association
between hyperleukocytosis and myelomonocytic
leukemias is established, it should be noted that in our
series", as well as in other reports14,15,21723 predomi-
nance of M4 and M5 subtypes was not observed, nei-
ther in the entire group nor in the early death group
(Table 11).
The cytogenetic abnormalities observed in hyper-
leukocytic AML reflect the relatively high incidence
of myelomonocytic subtypes. In addition to
inv( 16)(p13q22), the most common abnormalities
described in these patients have been rearrangements
of chromosome 1lq23. Originally described as
t(4;11)(q21;q23) in a subset of childhood ALL char-
acterized by age <1 year, high incidence of CNS
involvement, hyperleukocytosis and expression of
mixed lineage marker^^^,^^, 11q23 rearrangements
have now been detected in 40-50% of infant AML,
5-10% of de-novo adult AML and in more than 70%
of AML following chemotherapy with topoisomerase
I1 inhibitor^^^. In adults, the vast majority of AML
with llq23 rearrangements is FAB-M4/M5, often
with mixed lineage markers and hyperleukocytosis.
The clinical implications of 1lq23 rearrangements in
adult AML remain to be completely established.
There is evidence that rearrangements between 1lq23
and a large family of partner genes mat results in a
spectrum of clinical presentations, with diverse clini-
 4 PIERLUIGI PORCU et al.

cal features (including hyperleukocytosis) and kocytic AML. Chromosome 16q22 rearrangements
prognosis30.Our cytogenetics data (Table 111) support and gains or losses at chromosome 6 were also fre-
the observation that 1lq23 rearrangements are the quently observed.
most common chromosomal abnormality in hyperleu-

TABLE I1 Patient characteristics and treatment results in hyperleukocytic AML in 8 published series

Porcu Ventura Dutcher Creutzig Bunin Cuttner Hug Vaughan

(1997) (1988) (1987) (1987) (1985) (1983) (1983) (1981)
No. of patients 48 61 41 65 73 22 46 18
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Fraction of total AML 18% na 11.6% 22.1% 22% na 11.5% na

M4/5 predominant No No na Yes No Yes No na
Agea 41.2 50 45 9 8.5 43.5 Adults 51
M:F ratio 1.6:1 1S:l 1:l.l 1.1:l 1.1:l na na 1:1.2
WBC counta 201,000 155,250 175,000 198,000 167,000 173,000 145,000 87,000
% blasts 78% na 95% na na 81% 92% 100%
Platelet counta 35,000 na 53,000 58,000 30,000 61,500 58,000 50,250
Hematocrita 0.27 na na na 0.21 0.28 0.25 na
Coagulopathy 40% 16.4% 43% na 17.8% na na 38.8%
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Renal failure 16.6% na na na 5.4% na na 16.6%

Hepatosplenomegaly 30% 41.1% 44% >50% na na na na
Neurological Symptoms 26% 5.8% 12.1% 24.6% 12.5% 9% 6.5% na
Respiratory Distress 33.3% 42% na na 8.2% 9% 10.8% na
CNS leukemia 2% na 2.4% na 21.9% na na na
Early Deaths (<I4 days) 29.1% 20% 20% 31% 23.2% 22.7% 13% 33.3%
Cause of deathb B>L L>B B>L B>L B>L B=L L>B L>B
WBC predictive' No No na Yes Yes na na No
Median time from 3.5 days na na 3 days na 5 days 6 days I ?5 days
Dx to death (range 0-7) (range 0-9) (range 1-13) (range 2-8) (range &6)
% leukapheresed 100% 71.7% 26.8% 1.5% 1.3% 100% 61% None
CR rate 69% 56% 47.6% na na 68% 52% 56%
na: not available

a. #Median.
b. L=respiratory failure; B=neurological.
c. Initial WBC count predictive of early death.

TABLE I11 Karyotypes of hyperleukocytic AML and ALL

AMLa
UPN#1 46,XY; t( 1;9;1l)(p36;p22;q23)
UPN#2 46,XY
UPN#3 46,XX
UPN#4 46,XX; inv(16)(p13q22)
UPN#5 45,XX; t(2; 1 l)(q37.2;q24.2)//del(16)(q22)//-19
 MANAGEMENT OF ACUTE LEUKEMIA WITH HYPERLEUKOCYTOSIS 5

AMLa
UPN% 45,X; t(5;9;22)(q13;q34;q1 1)//t(9; 1l)(p22;q23)
UPNR 46,XX; t(4; 1l)(q2 1 ;q23)
UPNW 46,XY
UPNB 4 5 , x x ; -7
UPN#10 46,XY
UPN#l1 46,XX
UPN#l2 46,XY t( 1; 1l)(q42;q21)//t(2; 12)(pl5;pl3)//inv(9)(q21q34)
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UPN#l3 46,XY
UPN#14 46,XX; t(9; 1l)(p22;q23)
UPN#I 5 46,XX; de1(6)(p23q25)
UPN#16 46,XX
UPN#17 45,XX; -7//del( 1l)(q23)//add(6)(p23)
UPN#I 8 46,XY; t(9;l l)(p22;q23)
UPN#19 46,XX; t(9;l l)(p22;q23)
UPNRO 46,XY inv(16)(p13q22)
UPNR 1 46,XY
UPNR2 46,XY
For personal use only.

UPN#23 46,XX; t( 1;1l)(p32;q23)

UPN#24 46,XX
UPNR5 46,XY
UPNR6 46,XX
UPN#27 46,XY inv(16)(p13q22)
UPNR8 46,XX; -7//+8
UPN#29 46,XY
ALL^
UPN#I 46,XY de1(9)(p21p24)
UPNR 46,XY t(5; 14)(q3l;q32)
UPNB 46,XY
UPN#4 46,XY de1(9)(p21p24)
UPN#5 46,XY del(s)(ql5q35)//del(6)(q15q27)//de1(9)(q2lq34)
UPN% 46,X; -X//+7//de1(9)(p2 lp24)
UPNR 47,XY del( l)(q25q32)//inv(5)(pl5qll)//+8//de1(9)(p13)//-16
UPNW 46,XY t(4;l l)(q21;q23)
UPN#9 46,XY t(4;11)(q21;q23)
UPN#lO 46,XX; del(6)(q13q23)
UPN#I 1 46,XY (4;11)(q21;q23)
UPN#I 2 46,XX; de1(6)(q23q25)
UPN#I 3 46,XY de(6)(q21q25)
UPN#14 46,XX; t(4;l l)(q21;q23)

a. 23/48 hyperleukocytic AML patients were successfully karyotyped

b. 14/18 hyperleukocytic ALL patients were successfully karyptyped
 6 PIERLUIGI PORCU el al.
Few studies specifically have focused on the
response to therapy and long term survival of adult
patients with hyperleukocytic AML. As noted, the
independent prognostic value of hyperleukocytosis in
AML is controversial because of its close linkage
with other established or putative unfavorable mark-
ers, such as karyotype, extramedullary and CNS
involvement, expression of multidrug resistant pheno-
type and antecedent hematological disorders. On mul-
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tivariate regression analysis, the association is
observed in some studies but not in others. However,
establishing the true prognostic impact of hyperleuko-
cytosis in AML is important because these patients
represent a sizable fraction of all AML cases, they are
young and they may be candidates for allogeneic
bone marrow transplantation. In the absence of other
poor prognostic factors such as older age and unafora-
ble karyotype (13 of 29 patients in our series had nor-
mal karyotype) accurate risk stratification may be
For personal use only.
difficult.
One of the most informative studies on hyperleuko-
cytic AML remains that of Dutcher et al. l2 who retro-
spectively compared the clinical course and outcome
of 353 adult patients with AML, stratified in three
groups according to the initial WBC count
(<50,0W/mm3, 50- 100,000/mm3, >1O0,000/mm3).
The group with hyperleukocytosis represented 11.6%
of the total. FAB subclassification was not reported.
The incidence of early deaths was significantlyhigher
in the hyperleukocytic group (20%) compared to the
others (10% and 2.3%). These patients also experi-
enced a lower CR rate, required more cycles of induc-
tion chemotherapy with Ara-C and Daunorubicin, and
had significantly shorter disease-free and overall sur-
vival. Only one of 41 patients presenting with hyper-
leukocytosis was alive at 10 years. Another striking
observation was that this subgroup showed no
improvement in overall survival when evaluated by
year of treatment (1971-1977 vs 1978-1982). The
Southwest Oncology Group (SWOG) has also
reported similar results in a large study of BMT in
first remission for adult AML31. Patients with hyper-
leukocytosis represented 11.3% of the study popula-
tion. Multivariate analysis revealed age and WBC
count to be the only factors associated with complete
remission. The median overall and disease-free sur-
vival of patients with hyperleukocytosiswere only 2.9
and 4.3 months respectively, compared to 7.4 and
16.6 months for patients with normal WBC counts.
About 70% of the patients with hyperleukocytosis
had relapsed at 12 months and their estimated 7-year
disease-free survival was only 14% as opposed to
33% for the group with normal WBC counts. While
the SWOG study suffer from lack of cytogenetics
data, a recent European study of elderly AML found
that unfavorable cytogenetics and hyperleukocytosis
had and independent adverse effect on complete
remission rate, although not disease-free survival32.
The prognostic role of hyperleukocytosis in AML
may also depend on the chemotherapy regimen used.
Two of three North-American randomized studies
suggesting an advantage for idarubicin over daunoru-
bicin in AML, found that while a WBC count
>50,000/mm3 exerted a negative effect on CR rate
(both studies) and overall survival (one study) in the
daunorubicin arm, it had no impact in the idarubicin
-33-35 . These studies did not specifically address
the hyperleukocytic subgroup, but concluded that ida-
rubicin may be a better induction anthracyclin, espe-
cially in patients with hyperleukocytosis.
Acute Lymphoblastic Leukemia
A more consistent association between hyperleukocy-
tosis and distinct clinical, immunophenotypic and
cytogenetic findings exists for ALL. Likewise, the
poor prognostic value of hyperleukocytosis in both
pediatric and adult ALL is well established2. Finally,
estimates of the incidence of hyperleukocytosis in
ALL may be more accurate than for AML, because of
a lower early mortality rate (2-6%). The clinical
implications of hyperleukocytosis in ALL are differ-
ent from those in AML21. Leukostasis is rarely seen
in ALL and the immediate management focuses pri-
marily on the prevention and treatment of tumor lysis
syndrome (TLS) and disseminated intravascular
coagulation (DIC). The challenge in hyperleukocytic
ALL lies in the development of strategies to over-
come the high risk of relapse rather than preventing
 MANAGEMENT OF ACUTE LEUKEMIA WITH HYPERLEUKOCYTOSIS
leukostasis-related early deaths. Overall, the inci-
dence of hyperleukocytosis in ALL ranges between
10% and 30% and appears to be higher in two age
groups. As in AML, infants often present with
extreme leukocytosis, extramedullary involvement,
and massive hepat~splenomegaly~~. A second peak of
hyperleukocytic ALL has been reported in the second
decade of life. The clinical and laboratory features
associated with hyperleukocytosis have been
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described (Table IV)374'. Harousseau et al.39 found
an association with the presence of a mediastinal
mass, male sex, massive hepatosplenomegaly and
expression of T-cell markers. More recently Eguig-
uren et ale4' reported that patients with hyperleukocy-
tosis represented 18% of all cases of pediatric ALL
referred to St. Jude Children Hospital between 1984
and 1988. Hyperleukocytosis was significantly asso-
ciated with age less than I year, T-cell markers, leuke-
mic cell ploidy < 50 chromosomes, presence of a
For personal use only.
mediastinal mass and CNS leukemia at diagnosis. The
correlation with immunophenotype was very strong,
with up to 38% of T-ALL patients having initial WBC
counts greater than 100,000/mm3. Early death rate
was only 1.5%. For adult ALL data are less consist-
ently available. In a large German study16, 16.9% of
adult ALL patients presented with hyperleukocytosis.
Predominance of male sex and T-cell phenotype was
again noted, but early mortality was not reported. At
Indiana University, hyperleukocytosis was observed
in 14% of patients with adult ALL patients treated
between 1985 and 1997 (unpublished data). We also
observed a higher proportion of males (ratio 5.8:1)
and T-cell phenotype, but not a higher prevalence of
CNS leukemia. Median age for the hyperleukocytic
patients was 23 years, significantly lower than the
non-hyperleukocytic group (61 years). The early mor-
tality rate in our series was about 5% (1/18 patients).
In ALL, hyperleukocytosis has most consistently
been observed in patients with 1lq23 rearrangements,
usually t(4;l l)(q21;q23), and in patients with
t(9;22)(q34;qlI) (Ph'-positive ALL). These two
translocations are associated with very poor progno-
sis, both in adult and in children, and tend to occur in
pre-B and common-type ALL, respectively4245.
I
Another translocation linked to hyperleukocytosis
and defining a poor risk subset of ALL is
t( 1;19)(q23;p13),which occurs in approximately 25%
of pediatric pre-B ALL46. More recent studies have
confirmed the poor prognosis associated with a bal-
anced t( l ; 19) rearrangement, but questioned the asso-
ciation with h y p e r l e u k o c y t ~ s i s ~In~ *our
~ ~ series
. of
hyperleukocytic adult ALL (1 8 patients), the most
common cytogenetic abnormalities were
t(4;l l)(q21;q23) and deletions of chromosome 6 and
chromosome 9 (de19p21) (Table 111). More recently, a
strong association between homozygous deletions of
the p16 gene (also known as MTSl or CDKN2) and
several adverse prognostic features in ALL, including
hyperleukocytosis has been The p 16
gene is located on chromosome 9p2 1, a region deleted
in 7-13% of ALL cases. It encodes an inhibitor of the
CyclinD-Retinoblastoma signaling pathway that acts
as a negative regulator of cellular proliferation5'.
Loss of function of both p16 alleles results in altered
regulation of cell cycle progression and accelerated
cell division. Molecular studies on fresh leukemia
cells from ALL patients have confirmed the poor
prognosis associated with homozygous p16 deletions
and the linkage to hyperleukocyt~sis~~. The incidence
of p16 deletions is higher in T-ALL (25-83%) than in
B-ALL (10%).
The WBC count is one of the most important prog-
nostic factors in pediatric ALL, with a near linear cor-
relation between degree of leukocytosis and
long-term survival. Although there is no definite
cut-off, patients with WBC count >50,000/mm3 have
a particularly poor prognosis, and very few children
with hyperleukocytosis are long-term survivors. In
the study by Eguiguren et a14', the estimated 4-year
event-free survival (EFS) was 52% for the hyperleu-
kocytic group versus 79% for the rest of the group.
EFS was even worse (34%) for the subgroup with
presenting WBC count >200,00O/rnm3. These data
have been confirmed recently by the NCI-sponsored
risk classification for pediatric ALL53. In adult ALL,
hyperleukocytosis does not seem to affect complete
remission rate but is associated with a shorter dura-
tion of remission and overall survival'6,'8.
 8 PIERLUIGI PORCU el al.

TABLE IV Patient characteristics and treatment results in hyperleukocytic ALL

Porcu Eguiguren Maurer Bunin Wald Harousseau

(unpublished) ( I 992) ( 1988) (1985) ( I 982) (1980)

No of Patients 18 64 124 161 28 141

Fraction of total ALL 14% 18% 8.4% 13% 6.1% na
Age 23 <10 <10 7 <18 <I5
M:F ratio 5.8:l 1.2:1 2:1 2:1 1:l 1.5:l
WBC count (x mm3) 319,000 na >200,000 193,000 na na
Platelet count (x mm3) 45,000 na na 20,000 na 40,000
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Hematocrit 0.32 na na 0.22 na 0.32

Coaugulopathy 23% 15.6% 6.4% 5% na na
Neurological Symptoms 15% 4.6% 3% na na na
Respiratory distress 20% na na 0 na na
CNS leukemia 15% 19% na 18% na na
Early deaths 5% 1.5% 5.6% 4.9% 5% 12.7%
Cause of death B Toxicity B B=L=M B B
Time from Dx to death 2 days Day 49 na na 2.5 na
% leukapheresed 100% 31% 15.3% 4.3% 0 na
For personal use only.

CR rate 78% 94% 91% na na 71%

B=death from brain hemorrhage; L=death from respiratory distress: M=death form metabolic complications

PATHOPHYSIOLOGY, CLINICAL hyperleukocytosis and respiratory or neurological dis-

MANIFESTATIONS AND PROGNOSIS
OF LEUKOSTASIS
Leukostasis is best defined as a pathological entity. It
is usually but not invariably associated with
extremely elevated numbers of circulating leukemic
blasts. According to McKee and Collins54, leukosta-
sis is the morphological evidence of intravascular
accumulation of leukemic blasts occupying most or
all of the vascular lumen, with or without the presence
of fibrin. This pathological definition fails to provide
clues to the underlying mechanisms but remains the
best available because the clinical and radiographic
manifestations of leukostasis are difficult or impossi-
ble to discern form those of other common infectious
or hemorrhagic complication of acute leukemia. The
lack of reliable clinical criteria is a major problem in
the diagnosis and clinical investigation of this syn-
drome. In practice, leukostasis is empirically diag-
nosed when patients present with acute leukemia,
tress. However, the issue is complicated by the fact
that some patients may have clinically suspected or
pathologically proven leukostasis with leukemic blast
counts significantly lower than 100,000/mm3.55,56
Pathophysiology
While the reasons for the extraordinary expansion of
the circulating leukemic cell pool in AHL remain
unknown, potential mechanisms leading to leukosta-
sis have been explored. Several years ago Litchmann
proposed a pathophysiological model of leukostasis,
based on the rheological consequences of
hyperleukocyt~sis~~. The model provided a rational
explanation for the different incidence of leukostasis
in AML and ALL but failed to clarify many clinical
and pathological observations. Litchmann determined
that the viscosity of leukocyte suspensions in vitro
increases dramatically when the fractional volume of
leukocytes (also known as leukocrit) exceeds 12-15
 MANAGEMENT OF ACUTE LEUKEMIA WITH HYPERLEUKOCYTOSIS
mL/dL57. The concentration of leukocytes necessary
to produce such leukocrits is a function of the mean
cell volume (MCV) of the cells. Since, on average,
leukemic myeloblasts have twice as large an MCV as
leukemic lymphoblasts, it takes twice the number of
lymphoblasts than myeloblasts to result in a critical
leukocrit. This could well explain the different inci-
dence of leukostasis in AML and ALL, for the same
degree of leukocytosis. However, leukemic blast con-
Leuk Lymphoma Downloaded from informahealthcare.com by University of Minnesota on 08/31/13
centrations necessary to reach leukocrit of 12-15
mL/dL (300,000-450,000/mm3 for AML and
600,000-8000-000/mm3 for ALL), are rarely seen.
Therefore, changes in whole blood viscosity probably
play a very small role in this syndrome and additional
factors, possibly related to the adhesive or invasive
properties of leukemic blasts, may be more important.
L i t ~ h m a n nand
~ ~ others58 established that whole
blood viscosity is not increased in AHL because the
increase of the leukocrit is usually counterbalanced
For personal use only.
by a fall of the erythrocrit (fractional volume of eryth-
rocytes). This observation has important management
implications, as packed RBC transfusions in asympto-
matic patients with AHL have been associated with
rapid development of l e u k o ~ t a s i sand
~ ~ should there-
fore be avoided. Since whole blood viscosity is not
elevated in the great majority of AHL, Litchmann et
al. proposed that leukostasis is the result of increased
blood viscosity in the microcirculation and produced
experimental evidence that flow in capillary glass
tubes is severely impaired at high concentrations of
leukemic cells57. The viscosity of the blood in the
microcirculation, however, cannot be directly meas-
ured in vivo and this mechanism of disease remains
speculative. Furthermore, many observations suggest
that leukostasis is not simply related to leukemic blast
concentration or to the biomechanical properties of
the cells. In autoptic studies, blast aggregates and
thrombi are more often seen in the lungs, brain and
heart, suggesting some degree of organ ~ p e c i f i c i t y ~ ~ .endothelial cells61,62.
Furthermore, many cases of clinically suspected or
pathologically proven leukostasis have been reported
in patients with lower blast counts55356.Although
experimental evidence is limited, there are indications
that leukemic blast-endothelial cell interactions, lead-
ing to vascular wall disruption and bleeding, may be
9
triggered by locally released chemoattractant factors
which ultimately determine the distribution and
severity of the damage6M2. Complement-induced
granulocyte aggregation and leukostasis is well docu-
mented as a mechanism of disease63 and could play a
role in the hyperleukocytic syndrome as well64. More
recently, interesting data have begun to emerge from
the investigation of the expression and function of
adhesion receptors in leukemic c e l l ~ ~ ~It- is~ estab-
l.
lished that adhesion molecule up- and down-regula-
tion are important mechanisms leading to
physiological and pathological l e u k o c y t ~ s i s There
.~~
is also good evidence that specific adhesion mole-
cules such as ICAM-1 and P-Selectins mediate neu-
trophil-induced acute lung injury in ~ e s p i s ~ ~ , ~ ~ ,
suggesting that blockage of the interactions between
these molecules and their receptors may prevent vas-
cular damage in the microcirculation. Stucki et a1.62
found upregulated expression of several adhesion
molecules (CD54, CD62E, CD62P, CD106) in
endothelial cell of AML patients with leukostasis, fol-
lowing interaction with leukemic blasts. The leukos-
tasis associated with the retinoic acid syndrome
seen in patients with APL treated with all-trans retin-
oic acid (ATRA), appears to be related to
ATRA-induced changes in the number and type of
adhesion receptors on leukemic cells75. Another
intriguing observation is that hemodynamic flow con-
ditions and local hypoxemia play a major influence
on the process of leukocyte adhesion to endothelium
in vivo, by modulating the expression of adhesion
molecules and chemokines such as CD54, CD62E,
CD106, and i n t e r l e ~ k i n - 8 ~ Conditions
~~. associated
with turbolent flow result in a different pattern of
adhesion receptors, compared to conditions of physio-
logic laminar flow, suggesting a mechanism by which
hyperleukocytosis could directly affect the outcome
of the local interactions between leukemic blasts and
Clinical manifestations
The clinical and laboratory manifestations of hyper-
leukocytosis in AML are different from those in
 10 PIERLUIGI PORCU et al.
bone fide leukostasis occurring in ALL
only with extraordinary elevations of the WBC count.
Once leukostasis has developed, signs and symptoms
are usually related to the involvement of the respira-
tory or central nervous system (CNS). Patients may
have respiratory distress, hypoxemia, and diffuse
interstitial or alveolar infiltrates on chest radiographs,
although occasionally there may be no obvious radio-
graphic abnormalitiesg1. The presence of hypoxemia
Leuk Lymphoma Downloaded from informahealthcare.com by University of Minnesota on 08/31/13
needs to be carefully documented because hyperleu-
kocytosis can lead to spurious hypoxemia if the blood
sample is not immediately refrigerated on ice before
blood gas a n a l y s i ~ ~Presenting
~ , ~ ~ . neurological signs
may include confusion, somnolence, stupor, delirium,
occasionally coma. Patients frequently complain of
headache, dizziness, tinnitus, gait instability, blurred
vision or visual field defects. On exam, papilledema,
retinal veins distention, retinal hemorrhages and,
For personal use only.
occasionally, cranial nerve defects and neck stiffness
may be foundg4. Some of these findings are clearly
related to focal areas of CNS hemorrhage, rather than
from microcirculatory sludging. Additional but less
common clinical findings include neck vein disten-
tion, gallop rhythm and electrocardiographic signs of
right ventricular overload, myocardial ischemia, pria-
pism, acute limb ischemia, bowel infarctions and
renal vein t h r o r n b o s i ~ ~Fever
~ - ~ ~is. a near ubiquitous
finding. It is frequently high (>39*C) and may not be
due to infections, as cultures are nearly always nega-
tive. In our experience (Table I1 and Table IV), neuro-
logical symptoms were found in 30% of AML and
15.3% of ALL, respiratory distress in 38.5% and 23%
respectively, fever (>38.5%) in 82% and 69%. Chest
radiographic abnormalities were present in approxi-
mately 50% of the patients with respiratory symptoms
suggestive of leukostasis. Conversely, about 20% of
patients without respiratory symptoms had diffuse
interstitial infiltrates on CXR. Coagulation abnormal-
ities were very common and evidence of DIC was
present in 40% of AML and 23% of ALL. Thrombo-
cytopenia is the rule and automated cell analyzers
may underestimate its severity, because WBC frag-
ments are often counted as plateletsg8. Manual plate-
let counts should be performed when in doubt.
Approximately 16% of AML but none of the ALL
had renal failure at presentation. Evidence of sponta-
neous tumor lysis syndrome was seen in both AML
(10%) and ALL (18%). Only about 5% of patients
had positive blood cultures.
Prognosis
The short-term outcome of AML patients who present
with hyperleukocytosis has been and remains gener-
ally poor. The search for clinical or laboratory fea-
tures associated with a higher risk of mortality has
revealed that while several symptoms are predictive
of imminent demise, the absolute WBC count or the
number of circulating blasts is not19. It is not entirely
surprising that the degree of hyperleukocytosis is not
predictive for early death. It is known that some AML
patients with extremely elevated blast counts remain
totally asymptomatic and others with similar or lower
blast counts crush and die within hours from presenta-
tion. Since predicting which patients with hyperleu-
kocytic AML will develop leukostasis is a difficult
and dangerous exercise, all patients routinely receive
aggressive leukocytoreduction, including leukapher-
esis. However, additional host- or tumor-related fac-
tors, besides hyperleukocytosis, must play a role in
determining clinical outcome and their identification
should become a priority. Many have reported that
respiratory distress and neurological symptoms repre-
sent very ominous signs and few of these patients sur-
vive, regardless of how heroic a treatment they
receiveg9-. In the 48 patients with hyperleukocytic
AML described in our original study, five clinical
characteristics were significantly associated with
early death: age, respiratory distress, renal failure,
neurological symptoms and presence of coagulopa-
thy. Only 5 of 19 patients with respiratory distress
(26.3%), and only 4 of 13 patients with neurological
symptoms (30.7%) survived during the first week of
treatment (Table V). When both respiratory distress
and neurological symptoms were present, the odds of
death were greater than 90%. The cause of death was
predominantly cerebrovascular.
 MANAGEMENT OF ACUTE LEUKEMIA WITH HYPERLEUKOCYTOSIS 11

TABLE V Clinical characteristics and outcome in hyperleukocytic AML

Death within 1 week 14/48pts (29.1%) Survival within 1 week 34/48pts (70.9%) P value
Initial WBC ( x l O g ~ )
Median 250 187 0.093
Range 140-506 101-405
Initial blasts (xlO/L)
Median 207 160 0.172
Range 42475 45-379
Leuk Lymphoma Downloaded from informahealthcare.com by University of Minnesota on 08/31/13

Platelet count (xlO/L)

Median 56 58 0.352
Range 16-450 10-760
Age (years)
Median 48 34 0.032
Range 19-77 18-79
Gender
Male 9 21 0.662
Female 5 13
For personal use only.

Coagulopathy
Present 9 (64.2%) 10 (17.6%) 0.001
Respiratory distress
Present 14 (100%) 5 (14.7%) 0.001
Renal Failure
Present 6 (42.8%) 1(29%) 0.001
Neurological symptoms
Present 9 (64.2%) 4(11.7%) 0.001

Short-term prognosis is remarkably better for adult
and patients with ALL, early mortality rate being only
2 4 % . Clinical features associated with a higher risk
of early death in ALL include WBC count greater
than 250,000/mm3 and neurological c o m p r o m i ~ e ~ ~ .by leukapheresis or by chemotherapy, suggesting that
Almost all early deaths in hyperleukocytic ALL are
due to intracranial bleeding.
TREATMENT OF AHL
There is a common misconception that most deaths
due to leukostasis occur in the initial few hours after
admission and at the peak of hyperleukocytosis. In
fact, large numbers of patients with AHL develop
clinically evident leukostasis only two or three days
post admission, sometimes after cytoreductive meas-
ures, including induction chemotherapy, have been
initiated. Clinical deterioration and death may occur
after the WBC has been significantly reduced, either
while leukocytoreduction may be an important step in
the management of leukostasis, additional ,measures
are required to reduce the number of early deaths.
However, while the lack of progress in the acute man-
agement of hyperleukocytosis over the last 20 years
underscores the need for new treatment modalities,
very little research has been conducted on the factors
responsible for its development and progression.
Thus, without an improved knowledge of the cellular
and molecular mechanisms involved in leukostasis,
treatment advances in this field will continue to be
delayed.
 12 PIERLUIGI PORCU et al.
The current treatment of AHL focuses on aggres-
sive supportive care, prompt cytoreduction, and occa-
sionally cranial irradiation to prevent or treat
l e u k o ~ t a s i s ~Cytoreduction
~-~~. has traditionally been
achieved with leukapheresis, hydroxyurea and con-
ventional induction chemotherapy. Swift initiation of
induction chemotherapy is considered the absolute
mainstay of treatment in all cases of AHL but there
has been some controversy as to the initial role of leu-
Leuk Lymphoma Downloaded from informahealthcare.com by University of Minnesota on 08/31/13
kapheresis and hydroxyurea. The need for initial
cytoreduction is inferred from several reports of acute
tumor lysis syndrome, with prominent pulmonary
manifestations, following initiation of chemotherapy
in patients with AHL (acute lysis p n e ~ m o p a t h y ) ~ ~ - ~ *until
Hydroxyurea, given orally at the dose of 50-
100 mg/kg/day, is very efficient in reducing the WBC
count even in the presence of massive hyperleukocy-
tosis. Several clinical studies have shown that hydrox-
yurea reduces the WBC count by 50-80% within 24-
For personal use only.
48 hrs, without causing tumor lysis pneumopathy or
worsening disseminated intravascular coagulation
(DIC)993'00.Hydroxyurea, 1-2 grams PO q 6 hours,
should be started immediately in all patients with
hyperleukocytic AML and continued until the WBC
count has decreased to safer levels. With the advent of
continuous flow and automated cell separators, some
have argued that leukapheresis is more important than
hydroxyurea as the initial cytoreductive
r n e a s ~ r e ~ ~ ' ~The~ ' -two
' ~ ~approaches,
. however, are
probably best used in combination. The advantage of
leukapheresis is based on the assumption that circu-
lating blasts are cleared more rapidly and that multi-
ple procedures can eventually recruit leukemic cells
from the extravascular space into the intravascular
space, thus reversing established leukocyte aggre-
gates in the cerebral and pulmonary microcirculation.
Additionally, the physical removal of large number of
leukemic cells and the ability to administer fresh
plasma and fluids during a single procedure, are
believed by many to significantly reduce the risk of
hemorrhage and tumor lysis syndrome4'.
The disadvantage of leukapheresis is that it
requires the placement of large bore, central venous
catheters, is available only in selected centers and
thrombocytopenia is often made worse, as platelets
are removed together with the leukemic blasts. Fur-
thermore, although based on very reasonable assump-
tions, leukapheresis is empirical, lacks
standardization, and is limited by a very poor under-
standing of the factors affecting the efficiency of
cytoreduction in different types of leukemia and vari-
ous clinical circumstances. Although guidelines about
the indication for leukapheresis have been
published94, there are no widely accepted criteria on
when to begin, when to stop, and what clinical or lab-
oratory parameters to use to direct treatment. In most
centers, leukapheresis is initiated in AML when the
WBC count is above 100,000/mm3 and continued
. it has been reduced to 50,000/mm3or less. Many
do not perform leukapheresis in ALL unless the WBC
count is greater than 250,000-300,000/mm3, and
alternative, non-invasive, approaches have been
advocated, especialy in ~ h i l d r e n ' ~ ~ -It' ~is~ .well
known that occasionally WBC counts rebound
quickly after leukapheresis and that in some patients
the WBC count cannot be reduced even with multiple
procedures. It is also unclear whether leukapheresis
should be used as a preventive measure in patients
with hyperleukocytosis but no clinical signs of leuko-
stasis, or to manage established leukostasis. This
dilemma has significant practical implications
because the procedure is expensive, requires the
prompt mobilization of specialized blood bank per-
sonnel and if not well orchestrated may actually delay
the initiation of appropriate anti-leukemic therapy.
Because there is very little published clinical investi-
gation of the most appropriate use of leukapheresis in
AHL, in 1995 we undertook a detailed analysis of the
role of leukapharesis in adult patients with hyperleu-
kocytic AML.
One of our objectives was to identifying the safe
level of cytoreduction that one should aim at when
using this procedure. However, when the achieved
percent and absolute leukocytoreductions were com-
pared in patients who survived the first week of ther-
apy and in patients who died from leukostasis, no
difference was found (Table VI). Moreover, there was
no difference between the two groups in the WBC
count achieved either at the time of death or at the
time of discontinuation of leukapheresis. These
 MANAGEMENT OF ACUTE LEUKEMIA WITH HYPERLEUKOCYTOSIS
results were interpreted as indicating that outcome
was independent of the efficiency of leukapheresis, as
measured by these parameters. Further, achieving a
predetermined WBC count (<100,000/mm3) did not
seem to prevent the development of clinical leukosta-
sis and death, indicating that either leukapheresis
should be targeted to a lower but yet to be defined
WBC count or that leukostasis, once established, can-
not be reversed even with most dramatic leukocytore-
Leuk Lymphoma Downloaded from informahealthcare.com by University of Minnesota on 08/31/13
ductions. Our conclusion was that no safe level of
leukocytoreduction could be identified in these
patients and that leukapheresis should be used with a
clear understanding that early deaths and leukostasis
may still occur, after safe WBC counts have been
achieved. A corollary conclusion was that the value
of leukapheresis in the management of this syndrome
couldnt be considered established. The use of leuka-
pheresis in hyperleukocytic ALL is even more contro-
versial because of the low incidence of leukostasis
For personal use only.
and early mortality. In pediatric ALL, one analysis of
the effect of initial management of hyperleukocytosis
suggested an advantage for leukapheresis in the sub-
group of patients with severe hyperuricemia and renal
failure, where the incidence of severe electrolyte
abnormalities was reduced from 32% to 5%41. This
effect was thought to depend on the rapid physical
removal of leukemic cells. In this, as in other studies,
no significant benefit on mortality from CNS
hemorrrhage was seen. However, cerebrovascular
leukostasis may occur in ALL and has been occasion-
ally observed in the absence of severe
hyperleukocytosis5508.In some of these cases, leu-
kapheresis has been successful in controlling estab-
lished neurological sympt~rns~.
The role of cranial irradiation in AHL is debated,
both in children and in adults. Some reviews on the
management of AML recommend adding cranial irra-
diation to leukapheresis in the management of hyper-
leukocytosis based on historical data or the personal
opinion of the writer. Clinical protocols in AML
often have paragraphs encouraging, but not mandat-
ing, the use of cranial irradiation in patients with neu-
rological symptoms. In practice, cranial irradiation is
rarely performed in adult AML because of its incon-
13
venience, toxicity and the absolute lack of data about
its efficacy. Its use is likely to be ultimately aban-
doned. In children ALL, prophylactic or therapeutic
whole brain irradiation is currently discouraged,
because of the acute and chronic neuropsychiatric
.
complications associated with it In adults, the pro-
cedure is occasionally employed in a desperate
attempt to control neurological symptoms, usually
with little success. The prophylactic use of cranial
irradiation in adult ALL is also not generally advo-
cated.
The use of drugs with mechanisms of action differ-
ent from the conventional cytotoxic or cytostatic
compounds has not been systematically investigated
in the approach to hyperleukocytosis. However it is
likely that future therapeutic advances will mainly
come from these agents. Awaiting the development of
new targeted molecules such as adhesion receptor
antagonists, one potentially helpful and already avail-
able drug to investigate is dexamethasone. Dexameth-
asone inhibits up-regulation of CD 18, L-selectins and
interleukin-8 receptors on myeloid leukemic cells and
of E-selectins and ICAM-1 on endothelial cells in
vitrol 12-1 15. These actions are believed to represent
an essential component of the powerful antiinflamma-
tory effects of corticosteroids116. Furthermore, dex-
amethasone has been shown to be effective in
controlling the hyperleukocytosis associated with the
ATRA syndrome in acute promyelocytic leukemia
(APL)I7. Its beneficial effect in this condition is
believed to result from modulation of adhesion mole-
cules on APL cells. Finally, it is likely that the leuko-
cytosis and the vasculoprotective effects seen with
high dose (or high-potency) steroids are also related
to changes in the expression of adhesion
molecules I8. Controlled clinical trials of dexametha-
sone, as an adjunctive therapeutic measure in AHL
may therefore be warranted. Ultimately, it is hoped
that a better knowledge of the surface molecules and
chemotactic cytokines involved will result in the
development of specific pharmacological inhibitors
of the interactions between leukemic blasts and vas-
cular endothelium, leading to a more effective therapy
and a reduction in the number of early deaths.
 14 PIERLUIGI PORCU et al.
TABLE VI Outcome in AHL according to results of leukapheresis
Death within I week 14/48 pts (29.1%)
Percent reduction (%)
Median 57.4
Range 3.5-91.2
Absolute reduction (x109k)
Median 124
Range 8-301
Leuk Lymphoma Downloaded from informahealthcare.com by University of Minnesota on 08/31/13
Final WBC count (x109k)
Median 91
Range 21-374
CONCLUSIONS
There has been very little improvement in the man-
agement of hyperleukocytosis and leukostasis in
For personal use only.
AML and ALL in the last 20-30 years. The early
mortality rate for hyperleukocytic AML continues to
be unacceptably high and even though the potential to
achieve remission is probably similar to that of
non-hyperleukocytic patients, many die of complica-
tions during induction chemotherapy. The current
standard of care should be the immediate initiation of
intravenous fluids, allopurinol, hydroxyurea and the
aggressive correction of coagulopathy and thrombo-
cytopenia. If leukapheresis is available, it should be
started but only after the above steps have been taken.
Guidelines as to how long to perform leukapheresis
and when to stop it are not available at this time.
Unfortunately there is no evidence that any of these
measures have produced a reduction in the number of
early deaths. Induction chemotherapy should be
started as soon as possible. More specific pharmaco-
logical inhibition of the interaction between leukemic
cells and vascular endothelium should be researched.
It is hoped that this will result in improved outcome
for these patients.
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