From www.bloodjournal.org by guest on January 20, 2015. For personal use only.
A Clinicopathologic
Correlation
Syndrome.
By
A retrospective
blind
eosinophilic
logic
to
the
marrow
findings.
phosphatase
grading
system.
score.
individuals
the
who
did
hematologic
groups
of
based
with
on
which
not
have
all tests
This
the
peripheral
those
clearly
defined
then,
describe
major
multiple
this
organ
designations
disorder,
system
eosi nophilic
have
each drawing
involved.
These
leukemia
dissemi
,2
nated
collagen
disease,7
and
endomyocardial
eosiniphilia.8
Hardy
and
Anderson
blood
and
bone
hematologic
scoring
in this article
may be useful
in prospectively
effective
therapy
in this disorder.
evaluating
Hypereosinophilia
to
eosi nophilic
system
1968,
Since
idiopathic
and
the
with
the Hematology
Institute
Bethesda,
Submitted
Address
symptoms
of
March
infectious
involvement.
Parrillo
is not instituted
4. 1981;
within
1-2
wk,
is noted
hydroxyurea
at
maintain
the
methotrexate,
and
blood
by aspiration
and
Department.
H.R.G.)
National
rate
institutes
of
CPD,
Bethesda,
by Grune
accepted
Md.
& Stratton,
Clinical
20205.
Inc.
July
R.
23. 1981.
Gralnick,
Center,
NIH.
Building
Chief
10,
who
were
number.
and
are
begun
between
on
to
to
6000
a lesser
and
degree
cyclophosphamide,
for
count
was
blood
smears,
bone
preparations
were
stained
biopsy
and
and
of
fibrosis,
A
200-cell
blood
and
on examination
and
of eosinophils.
and
size,
Periph-
biopsy
Romanowsky
prepared
aspiof the
myelopoiesis,
aspirations,
were
and
sections
degree
and
sections
aspirate
peripheral
a modified
and
eosinophilia.
maturation
marrow
with
variation,
and
noted
erythropoiesis
vacuolization,
and
features
evaluated
abnormalities;
specimens
of
response
were
morphological
on all
Other
and
smears
morphological
degree
at NIH
hematologists
of the course
presence
and
obtained
by two
blood
count,
performed
were
smear
marrow
unaware
cellularity,
available.
bone
reviewed
Biopsy
content,
smears
aspirate
days
If progression
modification
included
Peripheral
differential
evaluated
aspirate
and
were
red blood cell (RBC)
size
eral
M.D..
smear
patients.
number,
differential
National
by
therapy
vincristine.
or biopsy,
of the
WBC
outlined
patients
used
have
for
system
infiltration.
dosage
agents
study
evidence
to alternate
count
for
and
symptomatology
initially.
agent,
(WBC)
et al.”
mm
signs
organ
are
a decrease
with
and
were
of the
Evaluation
peripheral
to therapy
NIH
antieosinophil
utilized
cytotoxic
of this
of
of
significant
with
cell
lack
to esoinophilic
1 g/day
blood
the
by Chusid
management
3 mo on this
span
Hematologic
(2)
manifest
of
to
evidence
Specific
regimen
after
Other
the time
busulfan,
drug
white
for
referrable
a dose
mm.
I 0,000/cu
of
et al.’2
60 mg/day
is the
Treatments
Six patients
the diagnosis
as outlined
(3)
plan
involvement
of the disease
for
and
and
admitted
disease;
Schooley
initially
immaturity;
Investigation,
Disease.
to Harvey
0006 -497l/81/5805--0025$Ol.00/0
1012
Pathology
of patients
of I 500 eosinophils/cu
6 mo associated
with
and
unless patients
system
Prednisone,
been
syndrome
eosinophilia;
Rationale
or organ
during
have
as previously
men.
The criteria
eosinophilia
or death
before
et al.’#{176}
and
(M.A.F.
planning
of
granulation,
requests
Service,
5N-236,
© I 981
and
Clinical
of Clinical
This
predicting
or groups
Criteria
hypereosinophilic
causes
other
either
Md.
reprint
Hematology
Service,
Laboratory
of Allergy
Health,
Room
and
in
METHODS
AND
patients
a persistent
than six mo
megakaryocyte
Center
syndromes.
syndrome.
hypereosinophilic
Initial
described
32
( 1)
are:
longer
were
From
scores
abnormalities
useful
individuals
Patients:
evaluation
undertaken
women
and 26 were
platelet
Clinical
of
abnormalities.
seems
MATERIALS
selected
hematologic
parameters
correlated
the severity
of the disease
and responsiveness
The
hematologic
number
cytogenetic
hypereosinophilic
while
low
syndrome
could
be predictive
of either
progression
of
disease
or response
to therapy,
we have studied
retrospectively
all available
admission
hematologic
data of
32 patients
with
hypereosinophilic
syndrome
studied
at the National
Institutes
of Health
(NIH).
In these
to therapy.
and/or
the
require
therapy.
myeloproliferative
scoring
therapy
not
cytotoxic
higher
in
hematologic
other
organ
systems
variably
involved.
In a preliminary
attempt
to determine
whether
the degree
and
severity
of the hematologic
manifestation
at initial
evaluation
of patients
with
the
hypereosinophilic
patients,
well with
seen
of
to the
included
eosinophilia
a significant
type
with
disease
introduced
marrow
significantly
of
term
“hypereosinophilic
syndromes”
to encom pass
these
nosologic
entities
and
draw
attention
to the
interrelationships
among
these disorders.9
A constant
feature
of these disorders
has been both
peripheral
had
did
therapy.
required
and
those
who
prednisone
patients
and
used
attention
have
patients
of
to
myelofibrosis
eosinophils
in 1912.’
been
group
to
quotients
as
two
with
and
responded
quotients
similar
R. Gralnick
such
hypereosinophilic
individuals
Harvey
for
by use
HE
IDIOPATHIC
proliferation
of
was initially
recognized
by Stillman
Since
a
who
second
and
of
or
These
and
normalized
performed
study
the
and
scores
therapy
In addition
be
S. Fauci,
hematologic
blood
formulation
also
idiopathic
were
hyper-
Hypereosinophilic
Manifestations
Anthony
a hemato-
B12 levels.
allowed
could
Schooley,
the
determinations.
data
group
T.
utilizing
the
within
One
patients
cytogenetics.
quotient.
patients
syndrome.
T
was
alkaline
hematologic
Robert
undertaken
that
Idiopathic
I. Hematologic
Flaum,
of 32
was
system
bone
leukocyte
A.
study
syndrome
scoring
and
Morris
of the
touch
stain,
as
and
previously
esbed’3
WBC
were
counts,
obtained
hemoglobin
as
previously
determinations,
and
described.’4
Blood,
Vol.
Leukocyte
58.
platelet
counts
alkaline
phos-
No. 5 (November).
1981
From www.bloodjournal.org by guest on January 20, 2015. For personal use only.
HYPEREOSINOPHILIA:
(LAP)
phatase
et al.’5
Dr.
HEMATOLOGIC
scores were
Chromosomal
J. Whang
Vitamin
B,2 was
Dr.
of the
score
system
was
based
known
myeloproliferative
in
I or
abnormalities
the
marrow
were
aggressive
all
abnormal
parameters
to
the
in
score
hematologic
findings
lines
The
of
state.
Table
I were
was
divided
by
bone
bone
criteria
that
found
ranged
total
and
Since
data
points
their
a
for
for
possible
t
test
and
performed
analysis
was
Gehan
test.’
performed
using
Stepwise
by Jennrich
as described
the
Student’s
discriminant
and
was
Sampson.’9
RESULTS
The eosinophils
of these
appearing
eosinophilic
vacuolization,
cells
morphological
maturation
to cells
degranulation,
although
were
and
there
abnormality.
were
primarily
Table
Peripheral
that
1 . Hematologic
Grading
red
blood
cell
morphological
abnormalities
1
platelets
Increased
Myeloid
dyspoiesis
Basophilia
(>200
Immature
WBCs
Myeloblasts
or hypersegmentation
cells/cu
1
mm)
2
or progranulocytes
2
or myelocytes
1
Metamyelocytes
and/or
promyelocytes,
were evident
and
in the
percentage
of
eosinophils
differential
of 33%.
count
seen
in only
were
seen
in five
megakaryocytopoiesis
marrow
patients.
patients,
were
eosinophils
collagen
stains
but
no
identi-
Two
specimens
With
increased.
performed
increase
were
in
17
in reticulin
only
mildly
revealed
Megakaryocytes
marrow
specimens.
ranged
In all
were
were
Of these,
6 revealed
although
the
majority
Correlation
three
biopsy
and aspirate
sections
to markedly
hypercellular.
bone
increase
were
decreased
in
in I 3
Therapy
Requiring
No
Therapy
followed
for a mean
of 36.2
mo/patient
(range
14-90
mo), have required
no specific
therapy.
The hematologic
data are summarized
in Table
2. One
patient
presented
with
less than
1 500 eosinophils/l
initially,
platelets
Decreased
of
and
Six patients,
2
severe
the
Patients
-
to
The
changes
fled.
Bone marrow
from normocellular
increased.
System
Anemia
Moderate
Large
platelets
abnormalities
collagen
fibers.
of the 32 bone
in nuclear
and
blood
smear.
megaloblastic
patients.
fibers,
large,
had partial
had
cytoplasmic
was
no systematic
Abnormalities
hyposegmentation
(blasts,
changes)
in the initial
bone
marrow
from 7% to 57% with a mean
Reticulin
seen in the peripheral
blood smears
ranged
from
normal-sized,
normal-
patients
abnormalities
and nuclear
marrow
cases
Characteristics
Morphological
noneosino-
blasts
with
two-tailed
analysis
of
of
that
patient.
Statistical
of the
presence
The major
abnormalities
of the peripheral
RBCs
were teardrop
forms and nucleated
RBCs.
In the bone
marrow,
disorderly
erythropoiesis
was
uncommon,
every
percentage
the
to
more
pertaining
available
as the
Similar
cytoplasmic
(i.e.,
indicating
Abnormalities
included
promyelocytes,
presence
of myelocytes
and metamyelocytes,
abnormalities
of cytoplasm
(hypergranulanity,
etc.) as well as the aforementioned
nuclear
changes.
bone
the
in
other
not
WBC
marrow
for
defined
phil
bone marrow
aspirate
smear,
although
they were more
readily
identifiable
in the peripheral
blood
smear.
Charcot-Leyden
crystals
were commonly
found
in the
thrombocy-
importance
less
specific
From
2 points
anemia,
cytogenetics.
as
with
to findings
precursors
of
were
patients
allocated
(i.e.,
a
grading
syndrome(s).
abnormalities
be
knowl-
assigned
importance
myeloid
quotient
hematologic
hematologic
of
Whang.’6
to any
was
in other
relative
hematologic
outlined
the
and
prior
patient
I . The
cell
1 point
not
or accelerated
patient,
the
blood,
felt
devised
each
myelodysplastic
of other
as
were
hypersegmentation.
laboratories
of Tjio
findings
of immature
and
designated
presence
the
In general,
peripheral
myelofibrosis),
on
or
presence
or
was
in Table
part
2 points.
topenia),
method
and
we designated
indicated
of Rutenberg
in the
by radioimmunoa55ay.l
system
as outlined
experience,
by using
by the
1013
method
performed
information
hematologic
our own
E. Chu
grading
clinical
by the
were
determined
A hematologic
edge
determined
analysis
and
MANIFESTATIONS
but
this
increased
soon
after
admission
and
has persisted
above
1 5OO/tl.
The mean
of the hemoglobin
values
and platelet
counts
were normal
in this
group.
There
were no major
morphological
abnormalities of the RBCs,
nor was there
blood or bone marrow
basophilia,
increase
in mature
WBCs,
or fibrosis.
Bone marrow
Hypercellularity
Mild-moderate
1
Marked
2
Decreased
megakaryocytes
1
Myelofibrosis
Myeloid
(> 1 % of differential)
Myeloblasts-progranulocytes
2
(> 5% of differential)
2
Abnormal
cytogenetics
2
Increased
B,2
1
LAP-abnormal
and/or
were seen in the peripheral
Cytogenetic
abnormalities
in one
patient,
respectively.
common
dyspoiesis
Basophilia
Dyspoiesis
phil WBCs
one patient.
were
seen
_i__
B,2. The
untreated
significantly
apy
for
However,
hypersegmentation
abnormality
was
of
an elevation
noneosino-
blood
of only
and low LAP
The
most
of the
vitamin
mean
hematologic
score
(Table
2) in this
group
was
2.33
(±0.61),
which
differed
(p < 0.005)
from patients
requiring
thenthe
hypereosinophilic
syndrome
(Fig.
1).
the
hematologic
scone
of
patients
who
From www.bloodjournal.org by guest on January 20, 2015. For personal use only.
1014
FLAUM
Table
Penpherie
2.
Hematologic
Findings.
Treatment
Blood
ET AL.
Group
Bone
Other
Marrow
MB
RBC
Patient
1
13.1
2
14.4
3
13.5
4
15.3
5
14.7
6
14.5
WBC
---
Abn
Nb
WBC
-
.0.3
+
6.8
0
5.1
0
6.9
2.3
0
8.1
3.3
0
5.0
1.1
0
12.5
6.0
0
4.1
0/6
Mye#{234}o
---- --
Dysp
9.1
9.6
Mye#{234}o.d
1mm
16.6
O/6t
14.3
Eos
Baso
-
1/6
Cell
Fibro
Mega
Base
Dysp
-
127
NC
-
N
-
317
NC
-
N
-
161
NC
-
N
-
246
NC
ND
N
-
140
NC
ND
N
-
-
242
1
0/6
206
1/6
.9
+1.6
Myed
PIt
PG
--
----
-
N
-
0/6
0/6
-
0/6
Hen,
Eos
Cyto
LAP
B,2
33
N
ND
N
20
N
N
H
1
10
10%
ND
H
3
23
N
L
N
1
14
N
N
N
2
-
-
0/4
%
>5%
-
43
N
N
H
0/6
24
1/6
L 1/4
3/6
#{247}30
Score
5
2
2.33
±5
±61
hemoglobin;
RBC Abn. red blood cell abnormality;
WBC. white blood
cell count.
1O’/cu
mm;
Eos. eosinophils.
1O’/cu
mm; WBC
mm.
white
blood
cat immetisuty:
0-none.
mItamyslocytes.
2 -my&oblasts.
proanulocytes;
Myelo.d
Dysp.. mye4o.d dyspoieess;
Been, basophilsa;
Ptt. platelet
count. 1O’/cu
mm;
Cell. bone marrow
ce4lularity: NC-normoc&lu.
moderately
herceBu.
2 -markedly
hyperceilular;
Myelo-hbro.
myelofibrosis;
Mega.
megakaryocytes;
MB. PG. myeloblasts.
proanulocytes;
Cyto. cytogenetics;
LAP.
Hb.
1 -myelocytes.
1 -mildly
ocytes
to
aahne
tase.
0.
not
es.nt;
#{149}M.an
±
fNurnber
+ .
standard
abnorma’
responded
from the
present; ND. not
error of the msen.
over tot& number
N.
ncrrn&;
1. decreased;
H.
to the
Although
<
increased.
of patients.
to prednisone
was not significantly
untreated
group.
The hematologic
the untreated
group
significantly
different
nisone
therapy
(p
compared
therapy.
detetmaned;
different
quotient
of
was 9.83 ± 2.63, which
also was
from all patients
receiving
pred0.005),
but not significant
when
patient
the
who
mean
responded
(± SEM)
20-
to prednisone
WBC
counts
0
0
0
15-
aciD
w
0
0
0
U)
p<.005
10
quently
received
cant
(0.5 < p
therapeutic
00
30,500
± 5100
per
900vensus4500
in those
patients
0.1).
intervention
cu
mm)
and
3200 per
who
subse-
±
therapy,
<
The
±
these values
were not signifiinterval
from
diagnosis
to
in the
patients
requiring
apy was significantly
shorten
(Gehan
test, Z
p < 0.001) when compared
to the interval
from
nosis
in the untreated
Patients
then=
3.24,
diag-
group.
Responding
to Prednisone
Of the 26 patients
who were placed
on conticostenoid
therapy,
9 responded
adequately
to prednisone.
An
adequate
response
to therapy
is defined
as lack
of
progression
of disease
or subjective
and
objective
improvement
in signs and symptoms
of disease
activity. Five of the six female
patients
are included
in the
prednisone-nesponsive
0
0
0
(9600
± 1600
versus
eosinophilcounts(4l00
cu mm)
were
higher
time for this
I 1 yn). The
group.
The
group
is 50 mo/patient
hematologic
data
mean
follow-up
(range
for this
I-
presented
in Table
group
is noteworthy.
w
to moderate
bone marrow
hypencellulanity
(5
patients)
and low on high LAP (6 patients).
No peripheral
blood
WBC
immaturity
on abnormality
in platelet
count
on
I
5-
0
cytogenetics
was
3. The heterogeneous
Most commonly
10 mo to
group
are
noted.
Further,
there
nature
of the
noted
were mild
was
no increase
in either
fibrosis
on myeloblasts
and progranulocytes
in
the bone marrow.
The hematologic
scone in this subgroup
was 3.44 ±
0.77, a value that did not differ significantly
from the
F’
‘J
No Therapy
Required
Theapy
Required
Fig. 1 .
Hematologic
score comparing
the patients
requiring
no
therapy
versus
patients
requiring
therapy.
The treated
group of
patients
included
those patients
receiving
prednisone
or cytotoxic
therapy.
The bar and brackets
represent
the mean
±
SEM. The
mean hematologic
score of the treated
group was 8.81 and for the
group requiring
no therapy
2.33.
untreated
patients,
but
was
from the patients
who required
2). The hematologic
quotient
significantly
different
cytotoxic
therapy
(Fig.
showed
similar
differ-
ences (Fig. 3). The mean WBC
higher
when
compared
to
(19,600
± 3400
versus
9600
was not significantly
different
count was significantly
the
untreated
group
± 1600,
p < 0.05)
but
when compared
to the
cytotoxic
therapy
group
(19,600
±
3400
versus
From www.bloodjournal.org by guest on January 20, 2015. For personal use only.
HYPEREOSINOPHILIA:
HEMATOLOGIC
Table
Penpher
1015
MANIFESTATIONS
at
3.
Hema tologic
Findi ngs. Pr edniso
ne Responders
Blood
Merrow
Bone
Other
MB
RBC
Patient
WBC
Myeloid
WBC
Eos
1mm
Dysp
Base
7
11.0
-
43.6
25.7
0
+
-
3B7
1
ND
N
-
-
8
9
14.0
-
9.6
2.4
0
-
-
332
NC
-
H
-
-
12.9
-
17.9
6.4
0
-
-
349
1
ND
L
-
10
13.9
-
19.2
9.8
0
+
-
216
1
ND
L
11
a.7
+
19.2
7.1
0
-
-
532
1
-
12
16.5
-
12.0
4.1
0
-
-
403
NC
13
12.6
-
16.9
13.4
0
-
-
208
14
11.5
+
25.7
10.5
0
-
-
15
16.7
-
12.0
1.6
0
+
+
13.1
2/9
19.6
9.2
3/9
1/9
320
±3.4
±2.4
±.1
(21,900
±
4500/cu
LAP
B,,
-
51
N
H
N
5
-
10
N
N
N
0
-
-
57
N
H
H
4
-
+
-
42
N
L
H
6
N
-
-
-
31
N
L
N
6
ND
N
-
-
-
46
ND
L
N
1
NC
-
N
+
-
-
3B
ND
L
N
3
234
1
-
N
-
-
22
5
221
NC
-
N
-
-
-
5/9
0/5
L
1/9
1/9
0/9
mm).
20’
0
0
0
ocx:
>5%
2/9
N
H
N
N
N
H
1
34
0/7
L
3/9
3.44
±6
3/9
H
1/9
3/9
Requiring
Seventeen
mo/patient
Cytotoxic
patients,
(range
±77
Therapy
followed
1-108
Score
7
H
Patients
for a mean
mo)
required
period
of 38
cytotoxic
then-
apy.
When
compared
to the group
responding
to
prednisone,
the patients
in this treatment
category
received
prednisone
for a significantly
shorten
period
of time
no
15
Hem
%
Cyto
eosinophil
not differ
untreated
therapy
Base
PG
Eos
±37
36,200
± 7300,
p > 0.05).
The mean of the
count
was 9200
±
2400/cu
mm and did
significantly
when
compared
to either
the
group
(4100
± 900/cu
mm),
or the cytotoxic
group
Cell
Mye#{234}o.d
Dyap
Abn
0/9
PIt
Mye#{234}oFibro
Mega
Hb
(Gehan
test,
significant
Z
=
difference
treatment
responded
therapy
between
those
to and those that
(Wilcoxon
test, U
is clear
that
prednisone
3.76,
p
in
duration
=
<
0.001).
of
We
found
prednisone
patients
who
ultimately
ultimately
failed cytotoxic
26,p
> 0.10);
however,
responders
had
a scone
it
of 6 on
w
0
n.s.
0
U)
0
80-
p <.001
0
0
0
0
10
00
-I
0
70-
n.s.
p<.001
00
Z60
0
I-
COD
W
I
p
<
0
w
I
5-
0
00
0
ci
00
0
40
0
-
-J
20’
00
u
No Therapy
Prednusone
Cytotoxic
Required
Responders
Therapy
Required
Hematologic
scores
comparing
patients
requiring
no
therapy.
those who responded
to prednisone
and those requiring
cytotoxic
therapy.
The mean hematologic
score for the patients
requiring
no therapy
was 2.33. for the patients
who responded
to
prednisone
3.44.
and for the group
requiring
cytotoxic
therapy
1 1 .7. The bars and brackets
represent
the mean
±
SEM.
The
differences
between
the untreated
group
and the prednisone
responders
was not significant.
while comparison
of the cytotoxic
therapy
group against
either
the prednisone
responders
or the
untreated
group was significant
at p < 0.001.
Fig.
2.
0
0
I
10
-
±
No Therapy
Required
Prednisone
Responders
Cytotoxic
Therapy
Required
Fig. 3.
Hematologic
quotient
comparison
of the same groups
as Fig. 2. The hematologic
quotient
for patients
who required
no
therapy
was 9.81 #{149}
for the patients
who responded
to prednisone
therapy
was 14.8 and for the patients
requiring
cytotoxic
therapy
was 53.8. The bar and brackets
represent
the mean ± SEM.
From www.bloodjournal.org by guest on January 20, 2015. For personal use only.
1016
FLAUM
ET AL.
100
.
(I)
Fig.
of the
patients
who responded
tQ prednisone
versus
patients
who required
cytotoxic
therapy.
Ninety
percent of patients
requiring
cytotoxic
therapy
had
a score
greater
than 6. while
1 00% of
prednisone
responders
had a
score
of 6 or less. Two patients
who
required
cytotoxic
therspy had scores
of 5 or 6. The
data
indicate
that
scores
greater
than 6 are associated
with
an aggressive
form
of
disease.
while
scores
less than
I
4.
Comparison
hematologic
-J
0
w
060
U
I
40
,_30
O.--.O
z
.
20
Prednisone
.
Responders
Cytotoxic
Therapy
(9)
Required
(17)
10
a-
I
1
2
3
4
5
6
7
8
9
1011
1213
HEMATOLOGIC
adequate
16, Table
and
6
4).
Therapeutically,
three
subgroups.
group
patients
can
be divided
did not receive
into
an
no further
patient
to the
therapy
due
to age
and
debili-
patients
(nos. 17 and
on cytotoxic
therapy
4, responded
to cytotoxic
therapy.
T able 4.
Periptier
Hemat
5 are
busulfan
The
respond
(no. 25).
remaining
four
to cytotoxic
data
of
patients
in the
associated
who either
for therapy
prednisone.
with
all
with
patients
had no requirement
or responded
hydroxyurea,
(no.
20)
patients
therapy
of
and
while
one
another
(nos. 29-32)
(hydroxyurea).
the
patients
cytotoxic
therapy
failed
who
summarized
in Table
blood
abnormalities
to
to
The
required
4.
appeared
group.
Greaten
than 75% of patients
demonstrated
anemia
and RBC
abnormalities,
and
more
than
60%
demonstrated
abnormalities
in platelet
counts,
dyspoiesis
of noneosinophil granulocytes,
and basophilia.
WBC
immaturity
19,
but
occurred
less
frequently.
cytes
were present
in the
patients
and metamyelocytes
Myeloblasts
and
peripheral
and
blood
myelocytes
progranuloin 3 of 17
in 4 of
I 7 patients.
Seven
ologic
were
treated
cyclophosphamide
in
died prior to delivery
of a course
of therapy
that could
be evaluated
for its efficacy.
These
patients
received
myleran
and 6-mencaptopunine.
Nine patients,
including
the other
female,
nos. 2028 in Table
I
19 20
cytotoxic
therapy
are
Multiple
peripheral
(no.
18) died within
days
of being
NIH and prior to institution
of chemo-
therapy.
The two remaining
Table
4) were placed
directly
I
patients
received
hematologic
trial of cytotoxic
therapy.
One patient
(no.
4) failed
to respond
to a trial of prednisone
received
ty. One
admitted
this
Four
I
15 16 17 18
SCORE
less while
over 90% of the patients
who eventually
required
cytotoxic
therapy
had a scone greater
than
(Fig.
I
14
score
Findin gs. Cytotoxic
ie Blood
Thera
py Group
Bone Merrow
Other
MB
RBC
Patient
Hb
Abn
-
WBC
Eos
WBC
mm
MyeIo.d
Dysp
Been
PIt
C.U
MyeloFibro
Mega
Baso
Myelosd
Dyap
Hem
PG
%
>5%
Eos
Cyto
LAP
B,2
Score
16
12.6
17.7
12.4
0
+
-
129
2
+
N
-
-
-
21
N
L
N
17
10.2
ND
80.0
59.2
0
ND
-
158
2
+
L
ND
ND
ND
ND
N
I
ND
18
9.4
ND
68.7
24.7
1
ND
+
786
2
ND
N
ND
ND
ND
ND
Ph’
ND
ND
40.5
34.4
0
ND
-
ND
5%
L
H
26.5
21.5
0
44
N
N
H
5
22.1
14.1
2
+
57
N
N
H
16
70.0
2
18
1
24.2
1
--
248
NC
ND
N
ND
ND
ND
1
ND
L
-
-
-
+
112
ND
ND
L
+
+
+
+
320
2
ND
N
+
+
-
57
30%
H
H
+
+
178
1
-
L
ND
ND
ND
ND
N
L
H
11
+
+
128
2
ND
L
-
+
-
34
N
I
H
15
0
-
+
530
2
ND
L
-
-
-
14
24%
L
N
10
0
-
+
266
NC
ND
N
+
-
-
36
10%
N
H
8
6.4
0
ND
+
182
1
+
N
+
-
-
29
N
L
N
B
11.4
8.6
0
+
-
109
2
-
L
+
-
-
56
N
H
H
12.5
6.1
0
#{247}
132
1
+
L
-
+
+
36
ND
N
H
13
10.5
13.3
21
12.2
22
11.0
+
23
13.1
+
16.8
24
11.2
f
69.0
25
15.2
+
43.5
25.7
26
13.7
+
39.1
30.5
27
15.4
ND
13.4
28
13.9
+
29
15.4
0
6.8
31
11.6
32
10.7
12.1
±.6
+
+
+
10/3
-
113.0
3.1
7.9
-
-
9
1.2
0
+
-
36
2
+
L
-
+
-
31
76%
N
H
15
9.4
2
+
-
101
2
ND
I
-
+
-
45
N
H
H
15
23.0
15.6
1
+
+
12772
+
L
+
+
+
24
30%
ND
H
20
36.2
21.9
7/17
2/13
37
7/16
L
12/15
+7.3
+4.6
9/13
10/17
226
±45
14/16
6/8
11/17
6/13
7/13
±5
7/15
3/iS
chemotherapy.
6
15.2
H
Recennng
8
10
301
19
20
30#{149}
ND
11
11.65
±1.04
From www.bloodjournal.org by guest on January 20, 2015. For personal use only.
HYPEREOSINOPHILIA:
HEMATOLOGIC
The bone marrow
14 of the
MANIFESTATIONS
demonstrated
16 patients
hypercellulanity
in whom
able for evaluation.
Fibrosis
mens,
while
megakaryocytes
Myeloid
Increase
dyspoiesis
also
in myeloblasts
occurred
in only
specimens
occurred
commonly
and progranulocytes
Abnormal
evaluation
in the
B,2,
and
common
findings.
The
patients
who
responded
to
from
lower
incidence
brosis
(2/8).
(1 /3)
and
bone
marrow
The mean WBC count was
and
The mean
as a whole
count
hematologic
was
did
(50 versus
66, p
patients
chemotherapy
demonstrated
creased
megakanyocytes,
maturation
vitamin
all
3
>
±
mm.
was
0.10).
failed
to respond
thrombocytopenia,
abnormalities
of
to
demyeloid
in the bone
marrow,
and
elevation
B,2 levels.
Myelofibnosis
was demonstrated
patients
in
whom
biopsies
were
of
in
available.
Further,
the 2 patients
who
had
greater
than
5%
myeloblasts
and prognanulocytes
fell into this treatment
failure
category.
The mean
of the hematologic
sconeandquotient,
tively,
was
15.8
not
significantly
±
l.5and66.3
±
different
from
therapy
responsive
group.
The
mean
count
of these
4 patients
was 13,500
eosinophil
count
was
8000
±
patient
was receiving
chemotherapy
these
values
were
Discriminant
±
involvement
important
syndromes.
system
that
WBC
mm;
One
that
Analysis
analysis,
utilizing
hematocount,
yielded
classification
These
values
resulted
in the
No Therapy
Required
Prednisone
Responders
advanced
in group,
laboratory
patient
table,
that
two
one
from
heterogeneity
of
to patient
suggested
to
responders
the
two
In order
to apply
the hematoto each
patient,
we devised
the
which allowed
for “comparison”
score.
It is important
to restate
individuals
who
were
of the hematologic
scoring
involved
in
system,
Total
therapy
the
analy-
sis of the initial
laboratory
data,
and interpretation
of
the bone marrow
and peripheral
blood smears
had no
prior knowledge
of the patients’
courses.
We feel that
this type of objective
grading
system
can be implein other
with the
studies
of individuals
or
hypeneosinophilic
syndromes.
groups
of
The morphological
abnormalities
of the eosinophils
in this disorder,
notably
increased
size, irregular
cytoplasmic
granulation
and vacuolization,
and nuclear
hypoand hypersegmentation,
have been commented
on previously.2’20
In our study,
the abnormalities
in the
Classification
Matrix
Cytotoxic Therapy
Responders
Cytotoxic
Therapy
Nonresponders
Percent
Correct
5
1
0
0
83
3
6
0
0
67
therapy
responders
Cytotoxic
us
to subdivide
the hypeneosinobasis of hematologic
findings.
hematologic
picture
would
be
Prednisone
Cytotoxic
the
and
the
system
No therapy
required
one
in subclassifying
the
hypereosinophilic
We arbitrarily
set a hematologic
scoring
included
findings
in the peripheral
blood,
their initial
admission.
logic scoring
system
hematologic
quotient,
of each
hematology
mented
patients
5.
in the
bone
marrow,
and certain
other
studies
previously
shown
to be useful
in classifying
hematologic
disondens, i.e., B,2 levels, cytogenetics,
LAP.
Since
this was
a retrospective
study,
it was readily
obvious
that
all
patients
might
not have all studies
performed
during
that
Table
and
from
development
chemo-
3000/cu
mm.
at the time
As noted
made
in the group
therapy.
In only
to prednisone
response
group
and
cytotoxic
responder
to nonnesponder.
that we might
be able
philic
syndrome
on the
We felt that the entire
the
obtained.
Stepwise
discniminant
logic score and eosinophil
functions
for each group.
a patient
clinical
5.8,respec-
of the
4100/cu
5.
an
DISCUSSION
The
for this subgroup
who
was
connect
group
with
of the classification
idiopathic
hypeneosinophilic
syndrome(s)
great
variability
in progression
of organ
.
Each of the four
not
myelofidyspoiesis
11,000/cu
1 1 I ± I .4, a value
that did not differ
significantly
from
that
of the patients
who did not respond
to
chemotherapy
(0.05
<
p < 0.1).
The
mean
of the
hematologic
quotients
was likewise
not statistically
significant
in Table
a
6500/cu
±
presented
of classification
was
respond
to cytotoxic
agents
(3/9),
myeloid
39,400
are
the nontherapy
patient
from
were
cytotoxic
of cases
into the
79%.
The
results
of
instances
by demonstrating
23,000
score
matrix
(>5%)
LAP
classification
accuracy
no error
cytogenetics,
of thrombocytopenia
eosinophil
avail-
in 54%.
abnormal
differed
mm
in
were
occurred
in 6 of 8 speciwere decreased
in 65%.
2 patients.
the group
1017
0
1
7
1
78
0
0
0
4
100
79
From www.bloodjournal.org by guest on January 20, 2015. For personal use only.
1018
eosinophil
series
were
not
these
various
subgroups
syndromes.
significant
of the
Little
attention
has been
noneosinophil
granulocytes
immaturity.
Morphologically,
clear
and
cytoplasmic
given
save
Red
blood
to abnormalities
for the presence
abnormalities
of
maturation
were
cell morphological
an indicator
in delineating
hypeneosinophilic
of
of
nu-
evident
in I 2 of 28 patients
teardrop
blood.
patients
forms
and
nonmoblasts
in the peripheral
These
changes
were
seen
primarily
in the
requiring
more aggressive
therapy.
Similarly,
the
incidence
disease
of
and
was
somewhat
reponted.2’
syndrome
anemia
increased
present
in 53%
lower
incidence
The concurrence
and enythnocytosis
Thrombocytopenia
cases and thnombocytosis
by Benvenisti
and
16%,
respectively,
decreased
of our
decreased
patients.
than
was
Ultmann.2
An incidence
was
found
in our
were
and
decreased
with the severity
failed
and
megakaryocytes.
An elevated
WBC
count
has been recognized
as an
indicator
of a poor prognosis.
In patients
with a WBC
count
greaten
than
100,000/cu
mm, the 9-mo survival
was 25%.
Both the WBC and eosinophil
counts
in our
series
showed
a trend
requiring
therapy
and
to higher
statistically
ences were evident
when
untreated
were compared
cytotoxic
therapy.
Data
from
the
counts
in
significant
those patients
to the patients
literature
patients
differ-
who remained
who required
is inconclusive
regarding
the level on significance
of vitamin
B,2 in hypereosinophilic syndromes,22’23
while in our patients
vitamin
B,2
was elevated
in 60% with
an 80% incidence
in the
group of patients
who required
cytotoxic
therapy.
Cytogenetic
analysis
had
been
both
normal24
and abnormal
authors
have considered
these
of the
neoplastic
29 patients
sis. Seven
showed
of these
nature
of this
reported
to
reveal
kanyotypes.2531
Many
findings
to be indicative
disorder.
Eight
abnormalities
in cytogenetic
patients
required
cytotoxic
of our
analytherapy.
Further,
of the 3 patients
who failed a trial of hydnoxyurea, 2 were shown
to have aneuploidy.
It appears
that
the finding
of abnormal
chnomosomal
analysis
is both
the
leukemoid
and
were
reaction,
myelofibrosis,
CGL.’3
and
possibly
found
Although
differences,
frequency
ing more
myeloid
the
in a
phase
of
there
were
no striking
intergroup
was
a tendency
to increased
abnormality
in the patients
requirtherapy.
Seven
of the I 0 patients
there
of LAP
aggressive
in the chemotherapy
had low LAP scones.
Myelofibrosis
has
associated
metaplasia
accelerated
group
who
been
seen
had
with
either
abnormal
values
previously2’3334
course
on blastic
transformation.
with increases
in myeloblasts
and
of the
reviewed
who
with
is
This
in 3 patients.
extent
that all patients
had
both
thrombocytopenia
values
been
of 3 1% and
series,
and
found
disorder
of
previously
found
in two-thirds
in 3% of the cases
The
findings
of thnombocytopenia
marrow
magakanyocytes
correlated
to the
severity
of the hypeneosinophilic
has also been reported.2’
megakaryocytes
of disease
chemotherapy
with
aggressive
to therapy.
low LAP
number
of our patients.
LAP
is well known
to be
reduced
in chronic
granulocytic
leukemia
(CGL)32
while
elevations
are present
in disparate
disorders,
including
In our
for
abnormalities
were
consisted
primarily
of
and
of a more
of a poor response
Both
high
and
appreciated
both in the peripheral
blood and bone marrow.20
series,
these findings
correlated
with a requirement
more intensive
therapy.
a
ET AL.
FLAUM
a
rapidly
and
has
progressive
The
two
progranulocytes
patients
had
concomitant
myelofibnosis,
one of whom
has subsequently
developed
blastic
transformation.
Myelofibnosis was demonstrated
in each of the three
patients
who
had
biopsies
hydroxyurea
performed
therapy.
in the
Myelofibnosis,
group
that
failed
in the hypereo-
sinophilia
syndrome,
is thus
associated
with
progressive
and less therapeutically
responsive
den. A similar
situation
exists in CGL.’3
The compilation
logic
score,
of these entities
its derivative,
and
a more
disor-
to form a hematothe
hematologic
quotient,
allows
one to separate
those
patients
who
require
no therapy
or prednisone
therapy
from those
who will subsequently
require
chemotherapy.
As can
be seen
from
Fig.
3, all
patients
who
did
not
receive
therapy
had hematologic
scones
of 5 on less with
a
mean
scone of 2.33,
while
only 30% of patients
who
were felt to require
prednisone
on cytotoxic
agents
had
scones
group
in this range.
was 8.8 1 The
.
the untreated
many
of the
absent
in
group
factors
this
comparison
demonstrates
in myeloblasts
however,
is 6 or less,
while
required
cytotoxic
therapy
were
mean of the hematologic
quotients
and
are
No
patient
with
that
were
a score
hypersegmyeloid
progranulocytes.
evident
when
a
are made.
Figure
2
score of all predni90%
of patients
who
above
this value.
The
is also significantly
different.
In comparing
patients
with
with
those
greaten
than
6, several
evident.
latter
score
in
i.e.,
RBC
abnormalities;
blood and bone marrow
of treatment
groups
that the hematologic
responders
this
of the fact
this scone
myelofibnosis;
dyspoiesis
and
of the bone marrow
noneosinophil
cells; and increase
Greater
differences,
sone
score
of
hematologic
is a reflection
that
comprise
subgroup,
peripheral
WBC immaturity;
basophilia;
mentation
The
mean
low mean
scores
of 6 on less
differences
were
of 6 or less
had
WBC
From www.bloodjournal.org by guest on January 20, 2015. For personal use only.
HYPEREOSINOPHILIA:
HEMATOLOGIC
immaturity
myelofibrosis,
in
blasts
and
progranulocytes.
peripheral
previously
blood
recognized
classification
The
philic
syndrome
Some
have
the peripheral
on an elevated
blood,
bone
marrow
percentage
of myeloThe
has
been
considered
a major
the
our
data,
syndrome
into
a
phase.
The benign
who
have
divide
benign
phase
phase
consists
increased
the
counts
second
group,
comprised
of
the
two
accelerated
subgroups.
accelerated
individuals
(oven
low hematologic
scones and quotients,
no specific
therapy
or respond
to
not
respond
to
steroid
therapy.
In
cell
do
addition,
the
subgroups
of
syndrome
and
bone
marrow
and
phase
patients
or
by a
and
peripheral
decreased
megakaryothere
appears
to be a
with
have
the
been
able
values
at the
time
would
not
who
In this last group
eosinophilic
form
plastic
syndrome.
hypeneosinophilic
to
require
of their
therapy
predict
from
the
of presentation
those
therapy
corti-
or only
disease,
and those
who
to control
their disease.
of patients,
their
of myelopnolifenative
these
disease
may be an
on myelodys-
ACKNOWLEDGMENT
B,2, LAP,
individuals
have biochemical
evidence,
i.e.,
cytogenetics,
to suggest
that they truly have
proliferative
disorder.
These
patients
require
therapy
to control
their disease.
The second
in
thrombocytopenia,
In the accelerated
costenoids
for control
require
more intensive
be
of
patients
who tend to have abnormalities
of other
series
and generalized
hyperplasia
of the marrow,
group
of
chemo-
progranulocytes
patients
require
The
phase,
appears
to
The
first,
a group
to be that
to cytotoxic
of patients
is characterized
of myelofibnosis,
myeloblasts,
hematologic
I 500/z1),
and who
prednisone.
appears
responsive
true continuum
ofdiseases;
we have seen one patient
in
the accelerated
group
who developed
acute
leukemia.
In this study
we were
able
to define
separate
was
hypereosinophilic
and
an
of those
eosinophil
of leuke-
syndrome
phase
not
are
therapy.
This group
very high incidence
blood,
cytes.
of controversy.
a form
the
of
has
been
indicator.”
hypereosino-
issue
syndrome
we can
the accelerated
patients
who
significance
WBC
immaturity
as a poor prognostic
of the idiopathic
mia,2
while
others
doubted
that
even a neoplastic
proliferation.7’3536
From
1019
MANIFESTATIONS
a myelocytotoxic
group
of
The authors
statistical
inant
wish
to thank
analysis,
analysis,
David
Robertson,
Lynda
Ray
and
Laurie
crisis
in
chronic
and
M.D.
AIling,
Arthur
M.D.
for assistance
for performing
Tuchman
with
discrim-
for secretarial
assistance.
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1981 58: 1012-1020
A clinicopathologic correlation of the idiopathic hypereosinophilic
syndrome. I. Hematologic manifestations
MA Flaum, RT Schooley, AS Fauci and HR Gralnick
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