1. Art and Diseño

From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
Serum Levels of Soluble Intercellular Adhesion Molecule 1 Are Increased in
Chronic B-Lymphocytic Leukemia and Correlate With Clinical Stage and
Prognostic Markers
By llse Christiansen, Cecilia Gidlof, AnnaCarin Wallgren, Bengt Simonsson, and Thomas H. Totterman
The serum levels of soluble intercellular adhesion molecule
1 (ICAM-1) were significantly elevated ( P < .001) in patients
with chronic B-lymphocytic leukemia (B-CLL, n = 113) compared with healthy controls (n = 31). SICAM-llevels in B-CLL
were positively correlated to thetumor mass asreflected by
the modified Rai and the Binet staging systems, lymphocyte
counts, and isolated spleno/hepatomegaly. During disease
progression or regression on cytoreductive therapy, the circulating SICAM-l levels changed accordingly. SICAM-l was
also correlated to a kinetic parameter such as the lymphocyte doubling time. Furthermore, the serum SICAM-l levels
were inversely correlated to hemoglobin levels in patients
with earlyclinicalstage,
and this may turn out to be of
prognostic value. SICAM-l wascompared with other serum
markers said to reflect disease activity in B-CLL, ie, soluble
CD23, thymidine kinase, lactate dehydrogenase (LDH), and
P,-microglobulin. SICAM-l wasequally well or better correlated toclinical stage and lymphocyte doubling time. Inunivariate regression analysis,all serum markers but LDH correlated with survival, and in multivariate analysis, SICAM-l
was theonly marker approaching significance foradditional
prognostic information when included after clinicalstage
and lymphocyte doubling time. Based on the present observations, it appears that prospective studies repeatedly monitoring serum SICAM-l in B-CLL are justified.
0 1994 by The American Societyof Hematology.
C
and regulate important cell-stromal and cell-cellinteractions" such as leukocyte adhesion and migration, mitogenand alloantigen-induced T-cell proliferation, T/natural killer
(NK) cellkilling,and
meta~tasis.'"~' Recently, an 82-kD
soluble form of ICAM-I (SICAM-l) was detected in serum
of normalsubjects as well as patientswithinflammatory
conditions such as allograft rejection, rheumatoid arthritis.
systemic lupus erythematosus, and Wegener's granulomatosis. .zx-32 Elevated levels of SICAM-lwere also reported in
malignant disorders including melanoma, Hodgkin's disease
(HD), and childhood acute lymphoblastic leukemia (ALL)?"
We report here that serum sICAM-I levels are elevated
in B-CLL and correlate with the clinical stage, lymphocyte
doubling time (LDT),isolated hepato/splenomegaly, and Hb
level. The prognostic value of SICAM-l was further compared with known serum markers of disease activity such as
sCD23, TK, LDH, and P2m.
HRONICB-LYMPHOCYTICleukemia
(B-CLL)the most common type of leukemia in Western countries -represents a monoclonal expansion of phenotypically
small,slightly immature,and activatedCD5'B
cellsexpressing surface IgMfrequently specific for autoantigen. The
clinical course of B-CLL is quite variable, and consequently,
attempts have been made to find methods for the prediction
of prognosis and timing of therapy. Critical reviews"' of
these methods have clearly established the value of clinical
staging systems'". However, among B-CLL patients reprewill
senting low-risk stages (Rai 0, Binet A),some20%
progress more rapidly, and other methodspredicting progression are needed.' Additional independent prognostic information may be obtained by determination of the blood lymphocyte doubling time,"' hemoglobin (Hb) level," marrow
histopathology," lymphocyte morphology," cytogenetic patterns,'$ and probably also the blood lymphocyte count." A
number of serum markers including lactate dehydrogenase
(LDH)," /?,-microglobulin (,&m)," thymidine kinase (TK),lX
soluble
CD23
(sCD23)," and recently, soluble
CD27
( s C D ~ ~were
) ~ " reported to be positively correlated to clinical stage, but need to be evaluated further.
The intercellular adhesion molecule 1
(ICAM-1, CD54),
a 90-kD member of the Ig supergene family, is the ligand
forthe integrin lymphocyte function-associatedantigen 1
(LFA- I , CD 11a/CD 1
ICAM- ULFA- 1 are widelydistributed among hematopoietic and nonhematopoietic cells
From the Department of Clinical Immunology and Transfusion
Medicine and the Department of Medicine. UniversiQ Hospitul, Uppsala, Sweden.
Submitted April 19, 1994; uccepted July S, 1994.
Supported by grants from the Swedish Cancer Society and
the
Lion's Cancer Fund at the University Hospital, Uppsala, Sweden.
Addressreprintrequests
to Thomas H . Tiitterman,MD,PhD,
Department of Clinical Immunology. University Hospital, S-751 8.5
Uppsala, Sweden.
The publication costs of this article were defrayedin part by page
chargepayment. This article must thereforebeherebymarked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to
indicate thi.y ,fact.
0 1994 by The American Society of Hematology.
0006-497//94/8409-0013$3.00/0
3010
MATERIALS AND METHODS
Patients and Control Subjects
We studied 1 13 B-CLL patients (75 men and 38 women, mean
age, 69; range, 44 to 88). all fulfilling the diagnostic criteria of the
International Workshop on CLL (IWCLL)." Serum samples were
( I 2 to 460 months) and
collected at varying intervals after diagnosis
stored at -70°C until use. Seventy-one patients were untreated, five
patientsweresplenectomized
only (91,76, 18, 6,and 4 months
before study), and 1S patients had received chemotherapy, but were
off treatment (3 to 240 months). Two of the latter patients had been
splenectomized(39and48monthsearlier).Twenty-two
patients
were on chemotherapy (nine chlorambucil-prednisolone, five COP,
two CHOP, two prednisolone. one cyclosporine-A, one teniposide,
and one prednimustine). Three of these cases had been splenectomized (60, 12, and 2 months before study). At the time of serum
sampling, all I 1 3 patients were restaged according to the systems
of Rai et and
Binet et al.' The LDT's were calculated retrospectively in the 76 untreated patients all having observation times in
excess of l year. All 22 patientsundergoingchemotherapyhad
LDT's 5 1 year before treatment, and were
classified accordingly.
LDT's were
In the IS casesreceivingintermittentchemotherapy,
estimated a minimum of 3 months after treatment. At the time of
serum sampling, analysis of routine hematologic variables including
determination of serum LDH (n = 95) and serum TK (n = 74) were
performed, Repeated sampling of sera was done in I O patients with
disease progression (n = X ) or regression (n = 2).
Blood, Vol 84,No 9 (November l), 1994: pp 3010-3016
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
SICAM-1
3011
IS ELEVATED IN B-CLL
Serum samples from 31 healthy elderly blood donors (mean, 51
years; range, 40 to 60 years) were analyzed for comparison.
Assays
SICAM-l. The SICAM-l levels in serum were determined by
enzyme immunoassay (EIA) kits purchased from British Biotechnology Products Ltd (Oxon. UK). The assay is based on two monoclonal antibodies (MoAbs) directed against different epitopes on the
SICAM-l molecule. The capture MoAb is bound to solid phase and
the detection MoAb is conjugated to horseradish peroxidase (HRP).
3, 3, 5 , 5-tetramethylbenzidine (TMB) is used as substrate. The
colored product was quantified photometrically using a spectrophotometer (Titertek Multiskan MCC1340, Solna, Sweden) set at 450
nm with a correction wavelength of 620 nm. Data were evaluated
by Deltasoft 3.3 MCC software for the Macintosh (both from Apple
Computers, Cupertino, CA). The sensitivity of the assay was 0.35
ng/mL, the interassay coefficient of variance (CV) was less than
7.4% and the intra-assay CV varied between 3.3% and 4.8%. Serum
samples from IO patients were tested fresh and after freeze thawing.
The SICAM-l levels were unaltered.
&microglobulin.
Soluble pzm levels in serum were determined
by EIA kits (T Cell Diagnostics, Inc, Cambridge, UK) based on a
competitive assay in which HRP-labeled Pzm competes with cold
serum ligand for binding to solid phase antiserum. After incubation
with TMB, the colored product was measured using the spectrophotometer set at 450 nm. The sensitivity of the assay was 0.25 pg/mL,
the intra-assay CV was less than 6% and the interassay CV was less
than 13%.
sCD23. sCD23 EIA kits (The Binding Site, Birmingham, UK).
were based on three antibodies. The capture MoAb is bound to solid
phase, and detection involves sheep-antihuman sCD23 followed by
HRP-conjugated antisheep IgG. TMB is used as substrate and the
colored product is measured by spectrophotometry. The intra-assay
precision CV was 4.2% and the interassay CV was 18.9%.
Thymidine kinase. TK is a routine analysis at our institution.
In a radioenzymatic technique (Prolifigen assay; Sangtec Medical,
Bromma, Sweden), TK converts ['251]deoxyuridine into ["'I] deoxyundine monophosphate, and the reaction product, but not the unconverted substrate, is absorbed to a granulate. The radioactivity of the
granulate is then measured after several washings. The mean serum
TK level in healthy adults was 2.4
1.3 U L . TK values above 5
U/L (mean + 2 SD) were considered elevated.
Lactate dehydrogenase. LDH is a routine analysis at our institution. LDH (EC 1.1.l .27) was analyzed on a Hitachi 7 17 spectrophotometer (Boehringer Mannheim Diagnostica, Titzing, Germany) using an LDH reagent from the same manufacturer (Catalogue No.
191 353 ). In short, LDH catalyzes pyruvate to lactate + nicotinamide adenine dinucleotide (NAD) in the presence of reduced NAD
(NADH) + H+. Kinetic measurement of NAD at 340 nm proportionally reflects the concentration of LDH. The serum levels in healthy
subjects ranged from 3.8 to 6.7 pkat/L.
RESULTS
Serum SICAM-I Is Elevated in B-CLL
All 113 B-CLL patients and 31 control subjects had detectable serum sICAh4-1 (Fig l). Circulating SICAM-l levels
were significantly elevated ( P = , 0 0 0 9 ) in the patient group
(533 2 293 ng/mL, mean 2 SD) compared with the control
group (329 t 132 ng/mL),althoughvalueswerewidely
scattered in B-CLL. The sICAh4-1 levels in patients representing the lowest Rai stage 0 (395 -C 169 ng/mL) were not
different from controls ( P = .06). However, whenComparing
Binet stage A patients (412 5 205 ng/mL) with controls, a
significant difference was found ( P = .03) (see below).
SICAM-I in Relation to Clinical Staging Systems
When applying the modifiedRai classification system(Fig
2), B-CLL patients representing high-risk stages had significantly higher ( P < .0001) serum levels of SICAM-l (71 1 5
336 ng/mL) compared with intermediate-risk (443 t 217)
1500
1250
Q
1o00,
Q
750
500,
250
Statistical Methods
Data are presented as mean 2 SD. P values less than .05 were
considered significant. Analysis of variance was used to compare
serum SICAM-l levels with the clinical classification systems of Rai
and Binet. The paired Student's t-test was used to compare serum
SICAM-I levels to lymphocyte counts, LDT, and Hb levels. Spearman's correlation coefficient was used to determine the association
between SICAM-land other serum markers,and the association
between lymphocyte count and serum markers. The Cox proportional
hazard regression model was used in univariate and multivariate
analyses.
r *1
**
0
8
CI
8
0
0,
Q0
I
I
Controls
B-CLL
(n=31)
(n=113)
Fig 1. Serum slCAM-1 levels in B-CU patients and healthy controls (P= .OOOS). Horizontal bars indicate mean values.
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
3012
CHRISTIANSEN ET AL
1500
7
*** l
r *** l
I n s ,
0
1250
!l
0
0
8
lo00
8
0
Q
8
750
Serial Determinations of SICAM-I
8
0
500
250
0
0
sionmolecules and their soluble counterparts, we studied
splenomegalyhepatomegaly and
therelationshipbetween
SICAM-l (n = 39, of which only 4 had hepatomegaly, excluding splenectomized cases). Patients with organomegaly
had significantly ( P = ,0006)higher levels of SICAM- 1 (707
i 317 v 430 5 240 ng/mL), as shown in Fig 4B.
A correlation existed between the lymphocyte counts and
serum levelsof sICAM-l ( r = .32, P = .0009) but data
were widely distributed (not shown). Excluding patients on
therapy or off treatment with cytostatics, the same pattern
was seen (not shown).
I
0
(n=23)
8
0
I
1-11
(n=61)
In 10 B-CLL patients, sera were obtained prospectively
at 2 to 8 occasions and analyzed for SICAM-l. According
to the original Rai classification, 8 of 10 patients exhibited
a change in clinical stage (7 progressions and l regression
on therapy). As shown in Fig 5 , a switch in Rai stage was
consistently paralleled by a corresponding change in serum
SICAM-l level in all individuals studied. The same results
were registered using the Binet (9/10 changes in stage) and
IIIh
lo00
(n=29)
I
*** l
0
0
Fig 2. Serum SICAM-l in relation to the corrected Rai classification. B-CLL patients in high-riskstages have significantlyhigher
(P< .OOOl) levels of SICAM-l than patients in low- and intermediaterisk stages. Horizontal bars indicate mean values.
0
0
750
and low-risk (380 -C 185) patients. There was a trend toward
higher sICAM-l levels in the intermediate-risk versus lowrisk group, but the difference wasnot statistically significant.
Using the Binet staging system, we likewise found that the
SICAM-l levels in stage C (739 t- 335 ng/mL) were significantly elevated (P < .0001) compared with stages B and A
(481 t- 245 and 448 t- 233, respectively). Again, no difference was found between stages A and B (data not shown).
Among B-CLL patientsin Binet stage A,a survival advantage has been reported for patients with Hb values greater
than 120 g/L compared with cases having Hb values 120 g/
L or less." Therefore, we compared circulating SICAM-l
levels with Hb levels in 48 stage-A patients. Patients with
Hb values 5 1 2 0 g/L had significantly higher ( P = ,001)
serum SICAM-l levels compared
with patients havinghigher
Hb values (S83 t- 241 v 366 t- 163 ng/mL) (Fig 3).
0
0
0
0
504
250
B
0
0
0
8
0
e
SICAM-I Versus Lymphocyte Doubling Time, Lymphocyte
Count, and Organomegaly
Patients having an LDT less than 1 year had significantly
higher levelsof serum SICAM-l comparedwith cases having
longer LDT's (640 t- 331 v 434 t 213 ng/mL, P = .01)
(Fig 4A).
Neither the modified Rai nor the Binet classification accounts for hepatomegaly andor splenomegaly as single factor. Because this might be relevant when considering adhe-
0
a
Hb > 120 gh
(n=38)
Hb I 120 g/l
(n=10)
Fig 3. Serum SICAM-l in Binet stage A patients related to Hb
levels ( P = .001). The horizontal bars indicate mean values.
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
3013
IS ELEVATED IN B-CLL
SICAM-l
B
A
I yY1 l
1"
l
"
I
I
1250
0
0
8
0
0
8
0
Q8
8
0
B
8
0
0
1000
t
750
e
0
i
8
8
Fig 4. (A) Serum SICAM-l levels are correlated with the lymphocyte
doubling
time (LDT;
P= .01). (B) Patientswith splenomegaly andlor hepatomegaly
have hiaher serum levels of slCAM-l than patients without organomegaly ( P = .0006). Horizontal bars
indicate
mean
values.
(n=60)
I
0
0
0
0
0
1250
1000
I
l
"
"
1500
0
0
0
0
8
Ie
I
8
8
0
-
LDT 2 1 year LDT < 1 year
(n=53)
IWCLL 1992 (10/10 changes in stage) classifications (data
not shown). One patient was treated with peroral 2-chlorodeoxyadenosine (CdA) X 8 according to a recent protocol.
A good partial remission was recorded, the patient changing
in stage from C(IV) to A(0) at the end of therapy. The serum
SICAM-l levels rapidly dropped to normal levels and stayed
low during therapy (from 724 to 325 ng/mL). One B-CLL
patient was monitored before and after splenectomy. Serum
SICAM-1 rapidly dropped from 8 18 to 470 ng/mL after the
operation (data not shown).
1"'
I
/4
Organomeg. No Organomeg.
(n=64)
(n=39)
SICAM-I Compared With Other Serum Markers
Among serum markers claimed to be associated with clinical stage and disease activity in B-CLL, we chose to consider
sCD23, TK, P2m, andLDH
and compared these with
SICAM-1 (Tables 1 through 3). The correlation between each
individual serum marker and the corrected Rai classification
is shown in Table 1. SICAM-lwas equal or superior to
sCD23, TK, and LDH. No significant correlation between
P2m and corrected Rai stage was registered. Table 2 shows
the correlation between each individual serum marker and
the LDT. With the exception of LDH, the other serum markers (SICAM-l, sCD23, TK, and P2m) were correlated to
LDT,with marginal significance for P2m. Table 3 shows
the criss-cross correlations between serum levels of the five
markers and the lymphocyte count. SICAM-l wasmost
strongly correlated to TK and sCD23, followed by P2m and
the lymphocyte count. No correlation was seen with LDH.
SICAM-I and Prognosis
0
0
I
n
1
I11 IV
Fig 5. Serialanalysis of serum SICAM-l in eight patients
changing in Rai
stage
(seven
progressing and one regressing
on therapy).
Table 4 shows the prognostic value (survival) of SICAM1 and the four other serum markers in univariate and multivariate Cox regression analysis. A significant ( P < .002)
survival advantage was registered in patients with lower serum SICAM-l levels. However, no cutoff value was found.
With the exception of LDH, the other markers sCD23, TK,
and P2m also showed significant correlation to survival. Mul-
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
CHRISTIANSEN ET AL
301
Table 1. Rai Staging System Correlated With Different Serum Markers
Rai Stage
I + II
0
SICAM-l (ng/mL)
sCD 23 (pglmL)
O m (pg/mL)
TK (U/L)
LDH(pkat!L)
PValues
380 -t 185' (n = 22)
339 2 283 (n = 22)
5.23 2 9.24 (n = 22)
2.60 5 0.99 (n = 13)
6.04 t 1.39 (n = 20)
443
724
4.92
7.50
6.34
111
2 217 (n = 62)
t 688 (n = 61)
2 6.45 (n = 61)
2 5.84 (n = 43)
5 1.63 (n = 54)
711
1,796
7.97
25.5
9.88
+ IV
0
5 336 (n = 29)
2 1,466 (n = 291
f 6.08 (n = 29)
2 29.89 (n = 18)
f 5.29 (n = 21)
VI
+ II
0 VIII
NS
NS
NS
NS
NS
+
IV
1.0001
<.0001
NS
,0001
1.0001
I
t
II V I I I
i-
IV
,0001
.ooo 1
NS
1.0001
1.0001
Abbreviation: NS, not significant.
* Mean 5 standard deviation.
Table 2. Lymphocyte Doubling Time Correlated
With Serum Markers
Lymphocyte Doubling Time
<lyr
SICAM-l
575
sCD23 (pg/mL) 1,216
732
P2m (pg/mL)
17
TK (U/L)
7.8
LDH (pkaVL)
P Values
2 1 yr
2 297* (n = 48) 444 2 248 (n = 65).01
f 1,158 (n = 48)709 2 910 (n = 64).01
2 793 (n = 47)
464 2 615 (n
? 23 (n = 34)5.8
f 5.6 (n = 40)
6.6 2 2.5 (n = 55)
2 3.9 (n = 40)
=
65).05
.004
NS
Abbreviation: NS, not significant.
* Mean 2 SD.
tivariate analysis was performed with two, three, or four
prognostic factors against each serum marker. The results
were identical, and therefore, only the analyses testing the
corrected Rai staging plus LDT versus each serum marker
are shown (Table 4).The highest P value was obtained for
SICAM-l, although this did not reach significance ( P = .08)
in the present patient material.
DISCUSSION
The most commonly used methods for predicting prognosis in B-CLL are clinical staging systems that estimate the
static tumor mass:7,L5,37 whereas additional information is
obtained by studying the kinetics of leukemic cell expansion,
ie, lymphocyte doubling time," the lymphocyte and marrow
morphol~gy,'~
and
~ ' ~cytogenetic aberration^.'^ The prediction of prognosis is particularly difficult in patients representing early clinical stages," and serial monitoring of different
serum marker~l~.~'
and activated lymphocyte phenotypes3'
reflecting disease activity have been proposed.
The present investigation is, to our knowledge, the first
to show that serum levels of 82-kD SICAM-l are elevated
in B-CLL and correlate with survival in univariate analysis.
However, elevated serum levels of SICAM-l have recently
been described in patients with other hematopoietic tumors
such as HD34-36a
and childhood ALL,36and also in malignant
melanoma3333y.
In HD patients, serum SICAM-l levels were
related to tumor mass, B symptoms, circulating interleukin2 (IL-2) receptor (CD25) levels, and disease-free survival.
In melanoma, increased SICAM-l serum levels" and tumor
cell ICAM-l expression4"were typical for metastatic disease.
In the case of HD, it was shown by histochemistry that the
malignant cells overexpress ICAM-1,35and that HDcell lines
release SICAM-l when exposed to various c y t o k i n e ~ . ~ ~
In the present study, the serum SICAM-l levels inBCLL patients were positively correlated to the tumor mass as
reflected by the modified Rai and Binet stagings, lymphocyte
counts and isolated splenomegaly/hepatomegaly.In patients
repeatedly monitored during disease progression or regression on cytoreductive therapy, the circulating SICAM-l levels changed accordingly. SICAM-l was also correlated to a
kinetic parameter represented by the lymphocyte doubling
time. This indicates that SICAM-l maynot simply reflect
the static tumor mass in B-CLL. Further, the serum SICAM1 levels were inversely correlated to Hb levels in patients
with early clinical stage, and this may turn out to have prognostic significance." We also compared SICAM-l with other
serum markers said to reflect disease activity in B-CLL, ie,
sCD23, TK, LDH, and P2m.L6"9SICAM-l was equally well
or better correlated with clinical stage and LDT.In univariate
regression analysis, all serum markers but LDH correlated
with survival, andin multivariate analysis, SICAM-I was
the only markerapproaching significance ( P = .08) for prognostic information when included after clinical stage and
lymphocyte doubling time. Based on all the present observa-
Table 3. Correlation of SICAM-l With Other Serum Markers and Lymphocyte Count
Lymphocyte Count
SICAM-l
sCD 23
&m
TK
SICAM-1
sCD 23
0.32' ( P = ,0009)
0.41 ( P < .0001)
0.47
-
0.47 ( P < ,0001)
0.45
( P < ,0001)
0.42 ( P < .0001)
P m
0.06 (NS)
0.21 (NS)
0.06 (NS)
0.52 ( P < ,0001)
0.47 ( P < ,0001)
0.45 ( P = ,0001)
TK
LDH
( P i ,0001)
0.45 ( P < ,0001)
0.52 ( P < .0001)
0.47
0.18 (NS)
Abbreviation: NS, not significant.
Spearman's correlation coefficient.
0.42 ( P < ,0001)
( P < ,0001)
0.45
0.24 ( P0.12
= .02)
-
( P = .0001)
(NS)
LDH
0.18 (NS)
0.24 ( P = .02)
0.12 (NS)
-
0.50 ( P < ,0001)
0.50 ( P < ,0001)
-
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
3015
SICAM-l IS ELEVATED IN B-CLL
Table 4. Prognostic Value of dCAM-1 and Other Serum Markers
Teated in the Cox Proportional Hazard Regression Model
~~
SICAM-l
sCD23
D2m
TK
LDH
Univariate Analysis ( P value)
Multivariate Analysis ( P value)
,002
<.002
.08
,006
,002
.068
.23
.30
.27
.95
tions, we think that a prospective study repeatedly monitoring serum SICAM-l in B-CLL is justified.
The cellular origin of SICAM-l in B-CLL is presently
unknown. Soluble ICAM-l is thought to be released from
the cell surface through proteolytic cleavage:'"'
Some 40%
of B-CLL patients were reported to have surface ICAM-lI
leukemic cells in the blood.43 However, in our experience
the surface expression of ICAM-1 on circulating B-CLL
cells is low and poorly correlated with serum SICAM-l levels (unpublished observations). Further, circulating B-CLL
cells are arrested in the GO phase of the cell cycle," and the
proliferative tumor cell compartment is likely represented
by the bone marrow, lymph nodes, and spleen. Several inflammatory mediators including IL-1, tumor necrosis factor
a (TNFa),interferon 7 , and IL-4 enhance cell surface expression of ICAM-1,'" 45-48 and B-CLL cells have been reported to
releaseatleast TNFa, E-1, andpossibly IL-2."-5' Furthermore, T-cells and NK-cells in these patients are phenotypically a~tivated.~'
Thus, circulating SICAM-l in B-CLL may originate from
either tumor cells, regulatory cell types, or both, and this is
presently under investigation.
ACKNOWLEDGMENT
We are grateful to Dr J. Bring and A. Taube at the Department of
Statistics, Uppsala University, for their expert help with the statistical
analysis.
REFERENCES
1. Montserrat E, Rozman C: Chronic lymphocytic leukemia:
Prognostic factors and natural history, in Rozman C (ed): Bailliere's
Clinical Hematology, v01 6. London, UK, BalliBre Tindall, 1993, p
849
2. Rai KR: Progress in chronic lymphocytic leukemia: A historical perspective, in Rozman C (ed): BailliBre's Clinical Hematology,
v01 6. London, UK, Ballikre Tindall, 1993, p 757
3. Dighiero G, Travade P, Chevret S, Fenaux P, Chastang C,
Binet JL, the French Cooperative group on CLL: B-cell chronic
lymphocytic leukemia: Present status and future directions. Blood
78:1901, 1991
4. Foon K A , Rai KR, Gale R P Chronic lymphocytic leukemia:
New insights into biology and therapy. Ann Int Med 113: 525, 1990
5. Montserrat E, Rozman C: Prognostic factors in chronic
lymphocytic leukemia, in Polliack A, Catovsky D (eds): Chronic
Lymphocytic Leukemia. Chur, Switzerland, Harwood, 1988, p 111
6. Rai K, Sawitsky A, Cronkite E, Chanana AB, Levy RN, Pasternack BS: Clinical staging of chronic lymphocytic leukemia. Blood
46:219, 1975
7. Binet JL, Auguier A, Dighiero G, Chastang C, Piquet H, Goasguen J, Vaugier G, Potron G, Colona P, Thomas M, Tchernia G,
Jacqiullat C, Boivin P, Lesty C, Duault MT, Monconduit M: A new
prognostic classification of chronic lymphocytic leukemia derived
from a multivariate analysis. Cancer 48:198, 1981
8. Rai KR: A critical analysis of staging in CLL, in Gale RP, Rai
KR(eds): Chronic Lymphocytic Leukemia: Recent Progress and
Future Directions. New York, NY, Liss, 1987, p 253
9. Chronic lymphocytic leukemia: Proposals for a revised prognostic staging system. Report From The International Workshop on
CLL. Br J Haematol 48:365, 1981
10. Montserrat E, Sanchez-Bison0 J, Vifiolas N,Rozman C: Lymphocyte doubling time in chronic lymphocytic leukemia: Analysis
of its prognostic significance. Br J Haematol 62567, 1986
11. French Cooperative Group on Chronic Lymphocytic Leukemia: Natural history of stage A chronic lymphocytic leukemia untreated patients. Br J Haematol 76:45, 1990
12. Rozman C, Hernandez-Nieto L, Montserrat E, Brugues R:
Prognostic significance of bone marrow patterns in chronic lymphocytic leukemia. Br J Haematol 47529, 1981
13. Melo JV, Catovsky D, Galton DAG: The relationship between
chronic lymphocytic leukaemia and prolymphocytic leukaemia.
Analysis of survival and prognostic features. Br J Haematol 65:23,
1987
14. Juliusson G, Gahrton G: Chromosomal aberrations in B-cell
chronic lymphocytic leukemia. Pathogenetic and clinical implications. Cancer Genet Cytogenet 45:143, 1990
15. Vallespi T, Montserrat E, Sancz MA: Chronic lymphocytic
leukemia: Prognostic value of lymphocyte morphological subtypes.
A multivariate analysis in 146 patients. Br J Haemtol 77:478, 1991
16. Lee J, Dixon D, Kantarjian H, Keating M, Talpaz M: Prognosis of chronic lymhocytic leukemia: A multivariate regression analysis of 325 untreated patients. Blood 69:929, 1987
17. Simonsson B, Wibell L, Nilsson K: &microglobulin in
chronic lymphocytic leukemia. Scand J Haematol 24 174, 1980
18. Kallander CFR, Simonsson B, Hagberg H, Gronowitz JS:
Serum deoxythymidine kinase gives prognostic information in CLL.
Cancer 54:2450, 1984
19. Sarfati M,Bron D, Lagneaux L, Fonteyn C, Frost H, Delaspesse G: Elevations of IgE-binding factors in theserum of patients
with B-cell derived chronic lymphocytic leukemia. Blood 71:94,
1988
20. Van Oer's MHJ, Pals ST, Evers LM, Van der Schoot CE,
Koopman G, Bonfrer JMG, Hintzen RQ, Von der Borne AEG, Van
Lier RAW: Expression and release of CD27 in human B-cell malignancies. Blood 82:3430, 1993
21. Marlin SD, Springer TA: Purified intercellular adhesion molecule-l (ICAM-I) is a ligand for lymphocyte function associated
antigen 1 (LFA-I). Cell 512313, 1987
22. Makgoba MW, Sanders ME, Ginther Luce EG, Dustin ML,
Springer TA, Clark EA, Mannoni P, Shaw S: ICAM-I a ligand for
LFA-l dependent adhesion of B, T and myeloid cells. Nature 33 1:86,
1988
23. Larson, RS, Springer TA: Structure and function of leucocyte
integrins. Immunol Rev 114: 181, 1990
24. Pardi R, Inverrardi L, Bender JR: Regulatory mechanisms in
leukocyte adhesion: Flexible receptors for sophisticated travellers.
Immunol Today 13:224, 1992
25. Dougherty GJ, Murdock S, Hogg N: The function of human
intercellular adhesion molecule-l (ICAM-1) in the generation of an
immune response. Eur J Immunol 18:35, 1988
26. Dustin ML, Springer TA: Lymphocyte function associated
antigen-] (LFA-I) interaction with intercellular adhesion molecule1 (ICAM-l) is one of at least three mechanisms for lymphocyte
adhesion to cultured endothelial cells. J Cell Biol 107:321, 1988
27. Smith CN, Martin SD, Rothlein R, Toman C, Anderson DC:
Cooperative interactions of LFA-I and Mac-l with intercellular ad-
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
3016
hesion molecule-l in facilitating adherence and transendothelial migration of human neutrophils in vitro. J Clin Invest 83:2008, 1989
28. Rothlein R, Mainolti EA, Czaikowski M, Marlin SD: A form
of circulating ICAM-I in human serum. J Immunol 147:3788, 1991
29. Adams DH, Mainolti E, Elias E, Neuberger JM, Rothlein R:
Detection of circulating intercellular adhesin molecule- 1 after liver
transplantation-Evidence of local release within the liver during
graft rejection. Transplantation 55:83, 1993
30. Kling E, Bieg S, Boehme M, Scherbaum WA: Circulating
intercellular adhesion molecule-l as anew disease marker in patients
with systemic lupus erytromatosis. Clin Invest 71:299, 1993
3 1. Cush JJ, Rothlein R, Lindsley HB, Mainolfi EA, Lipsky PE:
Increased levels of circulating intercellular adhesion molecule 1 in
the sera of patients with rheumatoid arthritis. Arthritis Rheum
36: 1098, I993
32. Hauschild S, Scmitt WH, Kekow J, Szymkowiak C, Gross
WL: Elevated serum levels of ICAM-1 in Wegener’s Granulomatosis. lmmun Infekt 20:84, 1992
33. Harning R, Mainolti E, Bystryn JC, Henn M, Meluzzi VJ,
Rothlein R: Serum levels of circulating intercellular adhesion molecule 1 in human malignant melanoma. Cancer Res 51:5003, 1991
34. GNSS HJ, Dolken G, Brach M, Mertelsmann R, Herrman F
Serum levels of circulating ICAM-l are increased in Hodgkin’s
disease. Leukemia 7: 1245, 1993
35. Pizzolo G, Vinante F, Nadali G, Ricetti MM, Morosato L,
Marrocchela R, Vincenzi C: ICAM- I tissue overexpression associated with increased serum levels of its soluble form in Hodgkin’s
disease. Br J Haematol 84:161, 1993
36. Pui CH, Luo X, Evans W, Martin S, Rugg A, Wilimus J,
Crist WM, Hudson M: Serum intercellular adhesion molecule-l in
childhood malignancy. Blood 82:895, 1993
36a. Christiansen I, Kalkner KM, Enblad G, Gildhof C, Glimelius
B, Totterman TH: Soluble ICAM-I in Hodgkin’s disease: A promising independent predictive marker for relapse. (submitted)
37. Chronic lymphocytic leukemia: Recommendations for diagnosis, staging and response criteria. International Workshop on CLL.
AnnIntMed 110:236, 1989.
38. Totterman TH, Carlsson M, Simonsson B, Bengtsson M, Nilsson K: T-cell activation and subset patterns are altered in B-CLL
and correlate with the stage of the disease. Blood 74:786, 1989
39. Altomonte A, Colizzi F, Esposito G, Maio M: Circulating
intercellular adhesion molecule 1 as a marker of disease progression
in cutaneous melanoma. N Engl J Med 327:959, 1992
40. Johnson JP, Stade BG, Holzmann B, Schwable W, Riethmuller G: De novo expression of intercellular adhesion molecule- 1
CHRISTIANSENET
AL
in melanoma correlates with increased risk for metastasis. Proc Natl
Acad Sci USA 86:641, 1989
41. Rothlein R, Czajkowski M, O’Neill MM, Marlin SD. Mainolti
E, Merluzzi VJ: Induction of intercellular adhesion molecule I 011
primary and continuos cell lines by pro-inflammatory cytokines.
Regulation by pharmacological agents and neutralizing antibodies.
J Immunol I41 :1665, 1988
42. Seth R, Raymond FD, Makgoba MW: Circulating ICAM-I
isoforms: Diagnostic prospects for inflammatory and immune disorders. Lancet 338:83, 1991
43. Maio M, Pinto A, Carbone A, Zagonel V, Gloghini A, Marotta
G, Cirillo D, Colombatti A, Ferrara F, Del Vecchio L, Ferrone S:
Differential expression of CDS4/intercellular adhesion molecule- l
in myeloid leukemias and in lymphoproliferative disorders. Blood
76:783, 1990
44. Andreeff M, Darzynkiewicz Z, Sharpless TK, Clarkson BD.
Melamed MR: Discrimination of human leukemia subtypes by flow
cytometric analysis of cellular DNA and RNA. Blood 55:282, 1980
45. Dustin ML, Rothlein R, Bhan AK, Dinarello CA, Springer
TA: Induction by IL-I and interferon-y: Tissue distribution, biochemistry and function of natural adherence molecule (ICAM-I). J
lmmunol 137:245, 1986
46. Pober JS, Gimbrone MA, Lapiene LA, Mendrick DL, Fiers
W, Rothlein R, Springer TA: Overlapping patterns of activation of
human endothelial cells by interleukin-l, tumor necrosis factor and
immune interferon. J Immunol 137:1893, 1986
47. Olive D, Lopez M, Blaise D, Viens P, Stoppa AM, Brandely
M, Mawas C, Mannoni P, Maraninchi D: Cell surface expression of
ICAM-I (CD54) and LFA-3 (CD%), two adhesion molecules, is
upregulated on bone marrow leukemic blasts after in vivo administration of high-dose recombinant interleukin-2. J Immunother
10:412, 1991
48. Carlsson M, Soderberg 0, Nilsson K: Interleukin-4 enhances
homotypic adhesion of activated B-chronic lymphocytic leukemia
(B-CLL) cells via a selective up-regulation of CD54. Scand J Immuno1 37515, 1993
40. Cordingley I T , Hoffbrand AV, Heslop HE, Turner M, Bianchi A, Reittie JE, Vyakarnam A, Brenner MK: Tumor necrosis factor
as an autocrine tumour growth factor for chronic B-cell malignancies. Lancet 8592:969, 1988
50. Pistoia V, Cozzolino F, Rubartelli A, Toraia M, Roncella S,
Ferranini M:In vitro production of interleukin 1 by normal and
malignant human B lymphocytes. J Immunol 136:1688, 1986
S I. Rossi JF, Commes T, Jourdan M: Interleukin-2 production i n
B-cell chronic lymphocytic leukemia. Blood 66:840, 1985
From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
1994 84: 3010-3016
Serum levels of soluble intercellular adhesion molecule 1 are
increased in chronic B-lymphocytic leukemia and correlate with
clinical stage and prognostic markers [see comments]
I Christiansen, C Gidlof, AC Wallgren, B Simonsson and TH Totterman
Updated information and services can be found at:
http://www.bloodjournal.org/content/84/9/3010.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American
Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.