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NCI CANCERLIT® Search: Chronic Lymphocytic Leukemia - January 2002
National Cancer Institute®
Last Modified: January 1, 2002
Table of Contents
1
UI - 11396717
AU - Sluyter R; Barden JA; Wiley JS
TI -
Detection of P2X purinergic receptors on human B lymphocytes.
SO - Cell Tissue Res 2001 May;304(2):231-6
AD - Department of Medicine, University of Sydney, Nepean Hospital, Penrith,
NSW, Australia. rons@med.usyd.edu.au
B lymphocytes are known to synthesise the P2X7 subtype of the P2X
purinergic receptor family; however, the identification of the other six
P2X subtypes on these cells has been limited by the absence of specific
antibodies. In this study, we used a panel of anti-P2X polyclonal
antibodies and confocal microscopy to examine the presence of each P2X
receptor on human B lymphocytes. We observed that P2X1, P2X2, P2X4 and
P2X7 subtypes, but not P2X3, P2X5 and P2X6 subtypes, are present on B
lymphocytes.
2
UI - 11410425
AU - Podhorecka M; Dmoszynska A; Rolinski J; Wasik-Szczepanek E
TI -
Intracellular interleukin-2 expression by T-cell subsets in B-cell
chronic lymphocytic leukemia.
SO - Haematologica 2001 May;86(5):549-50
3
UI - 11412696
AU - Batlle M; Ribera JM; Oriol A; Rodriguez L; Cirauqui B; Xicoy B; Grau J;
TI -
Feliu J; Flores A; Milla F
[Pneumonia in patients with chronic lymphocytic leukemia. Study of 30
episodes]
SO - Med Clin (Barc) 2001 May 26;116(19):738-40
AD - Servicio de Hematologia-Hemoterapia, Unitat Hematooncologica, Hospital
Universitari Germans Trias i Pujol, Badalona, Universitat Autonoma de
Barcelona, Spain.
BACKGROUND: To analyse the etiology, diagnostic methods and response to
therapy in 30 episodes of pneumonia diagnosed in 17 patients with
chronic lymphocytic leukemia (CLL) between 1995 and 2000. PATIENTS AND
METHOD: In each episode of pneumonia the following data were analysed:
age, gender, treatment of CLL, antiinfectious prophylaxis,
granulocytopenia, CD4/CD8 lymphocytes ratio, hipogammaglobulinemia,
origin of pneumonia (nosocomial or community-acquired), localisation,
respiratory insufficiency, need for mechanical ventilation,
antimicrobial therapy and response. Diagnostic methods included blood
and sputum cultures, fiberoptic bronchoscopy and search for antigens in
urine (Legionella pneumophila serogroup 1, galactomannan, and
Streptococcus pneumoniae). RESULTS: Median age of the series was 60 yr.
(range 50-86) and 12 patients were male. Chlorambucil and prednisone
were used in 13 cases and fludarabine in 8. Granulocytopenia was present
in 14 episodes, hypogammaglobulinemia was seen in 22 and CD4/CD8 ratio
was lower than 1 in 8 out of 14 evaluable cases. Etiology of pneumonia
was established in 16 episodes (53%). Fiberoptic bronchoscopy was the
most useful technique (83% of positive diagnoses) followed by blood
cultures (38%). Two patients were diagnosed of aspergillosis at autopsy.
Pneumococcus was the most frequent agent (5 cases) followed by
Pseudomonas aeruginosa (4), Pneumocystis carinii (2) and Aspergillus
fumigatus (2). One out of the two patients with P. carinii pneumonia had
received fludarabin and the remaining was treated with prednisone for
long time. Ten patients (30%) had died: P. aeruginosa (3 cases), P.
carinii (2), A. fumigatus (2), Mycobacterium xenopi (1), and unknown
microorganism (2). CONCLUSIONS: In this series of CLL patients the
frequency of etiologic diagnosis of pneumonias was good. Pneumococcus
was the most frequent microorganism. Pneumonias caused by opportunistic
microorganisms were associated to the treatment with fludarabin or
prednisone and were associated to a high mortality rate.
4
UI - 11432619
AU - Di Raimondo F; Giustolisi R; Lerner S; Cacciola E; O'Brien S; Kantarjian
TI -
H; Keating MJ
Retrospective study of the prognostic role of serum thymidine kinase
level in CLL patients with active disease treated with fludarabine.
SO - Ann Oncol 2001 May;12(5):621-5
AD - Institute of Hematology, University of Catania, Ospedale Ferrarotto,
Italy. diraimon@sirio-oncology.it
BACKGROUND: Previous studies have shown that the serum thymidine kinase
(TK) level can be used to determine prognosis in patients with
lymphoproliferative diseases, but mainly those with multiple myeloma and
non-Hodgkin's lymphoma. In patients with chronic lymphocytic leukemia
(CLL), TK levels may provide prognostic information independent of stage
and other prognostic factors, but it is still unclear whether they can
be used to predict the response to treatment and length of survival.
PATIENTS AND METHODS: To determine whether TK levels can be used to
predict response and survival, we retrospectively examined the serum TK
level in 188 previously treated and untreated patients with active or
advanced CLL who were then treated with fludarabine alone or in
combination with prednisone. The correlation of the TK level with other
prognostic features and with outcome was then assessed. RESULTS: Serum
TK levels were elevated in 92% of the patients, and the levels proved to
associate with previous treatment, stage of disease, and other
tumor-burden related features (i.e., white blood cell counts, absolute
lymphocyte count, bone marrow cellularity). The levels were also
directly associated with indicators of tumor cell turnover (i.e.,
beta2-microglobulin and lactate dehydrogenase levels). Of particular
importance, we found that the TK level was a significant prognostic
indicator of both response to treatment and survival. Specifically, 83%
of patients with a TK level of < 10 U/L responded (complete and partial
response) to treatment with fludarabine, whereas only 45% of patients
with a TK level of > or = 10 U/l responded to treatment (P < 0.01). This
difference was maintained when we separately analyzed untreated and
previously treated patients, and in patients divided according to the
Binet stage. The TK level also added prognostic information about
response to a predictive model based on the hemoglobin and, albumin
levels and the extent of prior treatment. Of further importance, the
median survival rate in patients with a TK level of < 10 U/l was 65%, as
opposed to a rate of 22% in patients with a TK level of > or = 10 U/l (P
= 0.000). CONCLUSIONS: The serum TK level in CLL patients provides
useful prognostic information regarding both response to therapy and
length of survival and should be used in planning appropriate therapy.
In particular, patients with a TK level of > or = 10 U/l have a poor
prognosis and should be considered for aggressive treatment.
5
UI - 11449871
AU - Thompson CA
TI -
Monoclonal antibody licensed for third-line treatment of B-cell chronic
lymphocytic leukemia.
SO - Am J Health Syst Pharm 2001 Jul 1;58(13):1174
6
UI - 11482058
AU - Sokolowska B; Wasik E; Kniaz M; Brzozowska J; Podhorecka M; Sledzinska
TI -
M; Domanski D
Long-term survival among patients with chronic lymphocytic leukemia
(CLL) treated in Department of Hematology, Medical University of Lublin.
SO - Ann Univ Mariae Curie Sklodowska [Med] 2000;55():103-9
AD - Katedra i Klinika Hematologii z Osrodkiem Transplatacji Szpiku Akademii
Medycznej w Lublinie.
7
UI - 11497339
AU - Thurmann PA; Sonnenburg C; Valentova K; Gregora E; Freischlager F;
TI -
Lissner R
Pharmacokinetics of viral antibodies after administration of intravenous
immunoglobulin in patients with chronic lymphocytic leukaemia or
multiple myeloma.
SO - Eur J Clin Pharmacol 2001 Jun;57(3):235-41
AD - University Witten/Herdecke, Hospital Wuppertal GmbH, Germany.
petra.thuermann@klinikum-wuppertal.de
OBJECTIVE: Intravenous immunoglobulin (IVIG) preparations are derived
from human pooled plasma and should fulfil high standards of purity and
viral safety. Introduction of additional purification steps, however,
may result in modulation of the biological properties of
immunoglobulins. Since cleavage of the Fab-fragment leads to a
significant decrease in half-life, the latter provides information about
the integrity of the immunoglobulin G (IgG) molecules. Therefore, a
pharmacokinetic study of a novel preparation is required to determine
safety and disposition in the target population. METHODS: Twenty-seven
patients with chronic lymphocytic leukaemia (CLL) and 12 with multiple
myeloma received intravenous infusions of IVIG containing antibodies
against hepatitis B virus (anti-HBs; n= 15; 8960 IU), cytomegalovirus
(anti-CMV; n = 9; 14,250 U) or varizella-zoster-virus (anti-VZV; n = 15;
6000 IU), respectively. Serum concentrations of viral antibodies were
determined for 71 days during and after infusion. RESULTS: Maximum serum
concentrations of anti-HBs, anti-CMV and anti-VZV were observed at about
4 h (median) after start of the infusion. Total body clearances came to
0.14 +/- 0.08 ml/min (anti-HBs), 0.10 +/- 0.02 ml/ min (anti-CMV) and
0.14 +/- 0.07 ml/min (anti-VZV). The terminal elimination half-lives
were determined to be 25.34 +/- 8.34 days (anti-HBs), 24.66 7.28 days
(anti-CMV) and 31.79 +/- 12.47 days (anti-VZV). Clinical chemistry
parameters including C3- and C4-complement serum concentrations revealed
no pathological changes, seroconversion for hepatitis B and C and HIV
did not occur. CONCLUSIONS: The pharmacokinetic parameters of the IgG
antibodies calculated after administration of the novel IVIG
preparations to patients with CLL and multiple myeloma are in close
agreement with data obtained from healthy volunteers and with values of
native IgG, suggesting that the production process did not impair
clinically relevant characteristics of the viral antibodies.
8
UI - 11484993
AU - Vartholomatos G; Kapsali E; Dokou E; Bourantas KL
TI -
Lack of HLA-DR expression in a patient with B-chronic lymphocytic
leukemia.
SO - J Exp Clin Cancer Res 2001 Jun;20(2):305-6
AD - Unit of Molecular Biology, University Hospital of Ioannina, Greece.
We describe a rare case of a patient with chronic lymphocytic leukemia
(CLL) whose immunophenotype analysis revealed lack of HLA-DR in B-cells.
9
UI - 11593539
AU - Peng L; Bradley CJ; Wiley JS
TI -
P2Z purinoceptor, a special receptor for apoptosis induced by ATP in
human leukemic lymphocytes.
SO - Chin Med J (Engl) 1999 Apr;112(4):356-62
AD - Department of Laboratory Medicine, First Hospital, West China University
of Medical Sciences, Chengdu 610041, China.
OBJECTIVE: To investigate the role of purinergic P2Z receptors for
apoptosis of human leukemic lymphocytes mediated by extracellular
adenosine triphosphate (ATP). METHODS: A total of 13 B-chronic
lymphocytic leukemia (CLL) patients were studied. Exposure of leukemic
lymphocytes with (n = 8) or without (n = 5) P2Z receptors to ATP,
benzoylbenzoic-ATP (BzATP), 2-methylthio-ATP (2MeSATP), adenosine-5'
[gamma-thio] triphosphate (ATP-gamma S), and other nucleosides for 8 h
in vitro. Apoptosis was detected by electron microscopy (EM), agarose
gel electrophoresis, and the quantitative assay-TdT assay. RESULTS:
Apoptosis was detected only in leukemic lymphocytes with P2Z receptors.
Using a quantitative assay, ATP-induced DNA strand breaks were found to
occur specifically with BzATP, ATP and 2MeSATP, but not for analogue
ATP-gamma S nor other nucleosides. Meanwhile, ATP-induced DNA
fragmentation was fully blocked by pretreatment with oxidized ATP
(OxATP), a compound recently shown to block P2Z receptors. Also, it is
shown that the Ca2+/calmodulin complex plays a role in the regulation of
the apoptosis induced by ATP on CLL cells, because an antagonist of this
complex, 1-[N, O-bis
(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN-62)
was found to inhibit the ATP-induced apoptosis. Furthermore, choline, an
inhibitor of phospholipase D (PLD), is first shown to partially inhibit
ATP-induced apoptosis. CONCLUSION: These data indicate that P2Z
receptors on lymphocytes play an important role in the apoptosis induced
by ATP in vitro.
10
UI - 11588025
AU - Leporrier M; Chevret S; Cazin B; Boudjerra N; Feugier P; Desablens B;
TI -
Rapp MJ; Jaubert J; Autrand C; Divine M; Dreyfus B; Maloum K; Travade P;
Dighiero G; Binet JL; Chastang C; French Cooperative Group on Chronic
Lymphocytic Leukemia
Randomized comparison of fludarabine, CAP, and ChOP in 938 previously
untreated stage B and C chronic lymphocytic leukemia patients.
SO - Blood 2001 Oct 15;98(8):2319-25
AD - Service d'Hematologie, CHU Caen, France. leporrier-m@chu-caen.fr
To comparatively assess first-line treatment with fludarabine and 2
anthracycline-containing regimens, namely CAP (cyclophosphamide,
doxorubicin plus prednisone) and ChOP (cyclophosphamide, vincristine,
prednisone plus doxorubicin), in advanced stages of chronic lymphocytic
leukemia (CLL), previously untreated patients with stage B or C CLL were
randomly allocated to receive 6 monthly courses of either ChOP, CAP, or
fludarabine (FAMP), stratified based on the Binet stages. End points
were overall survival, treatment response, and tolerance. From June 1,
1990 to April 15, 1998, 938 patients (651 stage B and 287 stage C) were
randomized in 73 centers. Compared to ChOP and FAMP, CAP induced lower
overall remission rates (58.2%; ChOP, 71.5%; FAMP; 71.1%; P <.0001 for
each), including lower clinical remission rates (CAP, 15.2%; ChOP,
29.6%; FAMP, 40.1%; P =.003). By contrast, median survival time did not
differ significantly according to randomization (67, 70, and 69 months
in the ChOP, CAP, and FAMP groups, respectively). Incidences of
infections (< 5%) and autoimmune hemolytic anemia (< 2%) during the 6
courses were similar in the randomized groups, whereas fludarabine
induced, compared to ChOP and CAP, more frequent protracted
thrombocytopenia (P =.003) and less frequent nausea-vomiting (P =.003)
and hair loss (P <.0001). For patients with stage B and C CLL first-line
fludarabine and ChOP regimens both provided similar overall survival and
close response rates, and better results than CAP. However, there was an
increase in clinical remission rate and a trend toward a better
tolerance of fludarabine over ChOP that may influence the choice between
these regimens as front-line treatments in patients with CLL.
11
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
UI - 11596014
AU - Cortes J; O'Brien S; Loscertales J; Kantarjian H; Giles F; Thomas D;
TI -
Koller C; Keating M
Cyclosporin A for the treatment of cytopenia associated with chronic
lymphocytic leukemia.
SO - Cancer 2001 Oct 15;92(8):2016-22
AD - Department of Leukemia, The University of Texas, M. D. Anderson Cancer
Center, Houston, Texas, USA. jcortes@mdanderson.org
BACKGROUND: Autoimmune cytopenias are a frequent complication in
patients with chronic lymphocytic leukemia (CLL). Anecdotal reports
suggest that cyclosporin A (CsA) may be beneficial for patients with
CLL-associated pure red cell aplasia. In the current study, the authors
investigated the use of CsA in the management of anemia or
thrombocytopenia of presumed autoimmune etiology associated with CLL.
METHODS: Thirty-one patients with CLL and anemia or thrombocytopenia of
presumed autoimmune etiology were treated with CsA at a dose of 300
mg/day. Sixteen patients (52%) had anemia (hemoglobin
UI - 11597735
AU - Pettitt AR; Moran EC; Cawley JC
TI -
Homotypic interactions protect chronic lymphocytic leukaemia cells from
spontaneous death in vitro.
SO - Leuk Res 2001 Nov;25(11):1003-12
AD - Department of Haematology, University of Liverpool, Liverpool, UK.
andrew.pettitt@rlbuh-tr.nwest.nhs.uk
Chronic lymphocytic leukaemia (CLL) cells are long-lived in vivo but
undergo spontaneous apoptosis when cultured in vitro. Since CLL cells
associate intimately with one another at sites of tissue involvement, we
examined the hitherto unproven possibility that homotypic interactions
between the malignant cells might reduce their propensity to undergo
spontaneous cell death. In a series of experiments in which highly pure
CLL-cell populations were cultured on a non-adherent surface, cell
viability was found to increase markedly with the level of crowding at
the bottom of the culture vessel. The effect was observed among unevenly
distributed cells within a single culture vessel and did not require
direct cell-cell contact. This indicates that cell survival was being
regulated in an autocrine fashion by locally acting soluble products.
Conditioned medium from crowded CLL cells enhanced the survival of
autologous non-crowded cells, indicating that at least some of the
autocrine survival factors produced by CLL cells could accumulate in the
extracellular environment. In addition, the survival of non-crowded CLL
cells was markedly enhanced by co-culturing them with an excess of
autologous fixed cells. This protective effect of direct cell-cell
contact was mediated by specific surface structures since it was
abrogated by pre-treating the fixed cells with neuraminidase. Our
results provide the first direct demonstration that the survival of
cultured CLL cells is enhanced by homotypic interactions. We speculate
that these protective effects may contribute to the accumulation of CLL
cells in vivo, and that further elucidation of the underlying mechanisms
may lead to novel therapeutic strategies.
UI - 11597727
AU - Morabito F; Mangiola M; Oliva B; Stelitano C; Callea V; Deaglio S;
TI -
Iacopino P; Brugiatelli M; Malavasi F
Peripheral blood CD38 expression predicts survival in B-cell chronic
lymphocytic leukemia.
SO - Leuk Res 2001 Nov;25(11):927-32
AD - Centro Trapianti di Midollo Osseo, Dipartimento di Ematologia, Azienda
Ospedaliera 'Bianchi-Melacrino-Morelli', 89100 Reggio, Calabria, Italy.
morctmo@tin.it
CD38 expression was investigated in 161 untreated patients with B-cell
chronic lymphocytic leukemia (B-CLL). A score system, devised ad hoc by
integrating the percentage and the mean fluorescence intensity (MFI)
values of CD38(+) cells, indicated that B-CLL patients with a CD38 score
< or =3 are characterized by a significantly longer survival compared to
those with a CD38 score >3 (P=0.0026). Thirty-seven percent of patients
with a CD38 score < or =3 and 58% of those with a score >3 were dead at
10 years. Multivariate analysis indicates that only the CD38 score
successfully predicts survival (P=0.0028), with an estimated 3.8-fold
greater risk of death for those cases with CD38 score >3.
UI - 11597732
AU - Roue G; Lancry L; Duquesne F; Salaun V; Troussard X; Sola B
TI -
Upstream mediators of the Fas apoptotic transduction pathway are
defective in B-chronic lymphocytic leukemia.
SO - Leuk Res 2001 Nov;25(11):967-80
AD - UPRES-EA 2128, UFR de Medecine, Universite de Caen, CHU Cote de Nacre,
14032 Cedex, Caen, France.
Data concerning the presence and the functionality of Fas receptor in
malignant B-cells are controversial. We have analyzed Fas molecules on
B-cells from patients with B-chronic lymphocytic leukemia (B-CLL) cells.
We observed a large variability, both of percentage of Fas-positive
cells and of intensity of Fas level. Fas triggering was inefficient in
inducing apoptosis whatever the number of Fas-positive B-cells, the
amount of Fas receptors. B-cells were also resistant to etoposide
treatment, but able to undergo apoptosis after dexamethasone treatment.
We suggest that the Fas apoptotic pathway is altered in B-CLL patients
at the initial step(s) of apoptotic machinery.
UI - 11672767
AU - Odero MD; Soto JL; Matutes E; Martin-Subero JI; Zudaire I; Rao PH;
TI -
Cigudosa JC; Ardanaz MT; Chaganti RS; Perucho M; Calasanz MJ
Comparative genomic hybridization and amplotyping by arbitrarily primed
PCR in stage A B-CLL.
SO - Cancer Genet Cytogenet 2001 Oct 1;130(1):8-13
AD - Department of Genetics, University of Navarra, C/ Irunlarrea s/n,
31008-, Pamplona, Spain. modero@unav.es
Cytogenetic analysis is useful in the diagnosis and to assess prognosis
of B-cell chronic lymphocytic leukemia (B-CLL). However, successful
cytogenetics by standard techniques has been hindered by the low in
vitro mitotic activity of the malignant B-cell population. Fluorescence
in situ hybridization (FISH) has become a useful tool, but it does not
provide an overall view of the aberrations. To overcome this hurdle, two
DNA-based techniques have been tested in the present study: comparative
genomic hybridization (CGH) and amplotyping by arbitrarily primed PCR
(AP-PCR). Comparative genomic hybridization resolution depends upon the
400-bands of the human standard karyotype. AP-PCR allows detection of
allelic losses and gains in tumor cells by PCR fingerprinting, thus its
resolution is at the molecular level. Both techniques were performed in
23 patients with stage A B-CLL at diagnosis. The results were compared
with FISH. The sensitivity of AP-PCR was greater than CGH (62% vs. 43%).
The use of CGH combined with AP-PCR allowed to detect genetic
abnormalities in 79% (15/19) of patients in whom G-banding was not
informative, providing a global view of the aberrations in a sole
experiment. This study shows that combining these two methods with FISH,
makes possible a more precise genetic characterization of patients with
B-CLL.
UI - 11675331
AU - Del Poeta G; Maurillo L; Venditti A; Buccisano F; Epiceno AM; Capelli G;
TI -
Tamburini A; Suppo G; Battaglia A; Del Principe MI; Del Moro B; Masi M;
Amadori S
Clinical significance of CD38 expression in chronic lymphocytic
leukemia.
SO - Blood 2001 Nov 1;98(9):2633-9
AD - Cattedra e Divisione di Ematologia, Universita Tor Vergata, Ospedale
S.Eugenio, Roma, Italy. g.delpoeta@tin.it
B-cell chronic lymphocytic leukemia (B-CLL) follows heterogeneous
clinical courses, and several biological parameters need to be added to
the current clinical staging systems to predict which patients will
experience an indolent or an aggressive outcome. This study analyzed
CD38 expression by flow cytometry and soluble APO1/Fas (sAPO1/Fas),
Bcl-2 (sBcl-2), and CD23 (sCD23) proteins by immunoenzymatic methods to
evaluate their effect on the clinical course of 168 unselected B-CLL
patients. Intermediate/high risk modified Rai stages were characterized
by a higher CD38(+) B-cell number (P =.0002) and higher sCD23 levels (P
<.0001). Moreover, CD38(+) B-cell percentages were significantly and
directly associated both with beta(2)-microglobulin and sCD23
concentrations (P <.0001 and P =.002, respectively). Both a higher tumor
burden (lymphadenopathy/splenomegaly) and a lymphocyte doubling time
less than 12 months were significantly associated with higher CD38(+)
percentages (P <.0001 and P =.0001, respectively). With regard to
clinical outcome, progression-free survival was significantly longer
(75% versus 37% at 5 years; P =.00006) in patients with lower CD38(+)
B-cell percentages. Furthermore, the risk of partial or no response to
fludarabine increased with increasing CD38 expression (P =.003), and a
shorter overall survival (50% versus 92% at 8 years; P <.00001)
characterized patients with more than 30% CD38(+) B-cell number. The
predictive value of CD38 expression was maintained among the patients
within the Rai intermediate risk group and was confirmed in multivariate
analysis. Thus, the percentage of CD38(+) B cells appears to be an
accurate predictor of clinical outcome and therefore could be used to
indicate when more novel chemotherapeutic approaches are needed.
UI - 11675354
AU - Jones DT; Ganeshaguru K; Virchis AE; Folarin NI; Lowdell MW; Mehta AB;
TI -
Prentice HG; Hoffbrand AV; Wickremasinghe RG
Caspase 8 activation independent of Fas (CD95/APO-1) signaling may
mediate killing of B-chronic lymphocytic leukemia cells by cytotoxic
drugs or gamma radiation.
SO - Blood 2001 Nov 1;98(9):2800-7
AD - Department of Hematology, Royal Free and University College Medical
School, Royal Free Campus, London, United Kingdom.
Ligation of the cell-surface Fas molecule by its ligand (Fas-L) or
agonistic anti-Fas monoclonal antibodies results in the cleavage and
activation of the cysteine protease procaspase 8 followed by the
activation of procaspase 3 and by apoptosis. In some leukemia cell
lines, cytotoxic drugs induce expression of Fas-L, which may contribute
to cell killing through the ligation of Fas. The involvement of Fas,
Fas-L, and caspase 8 was studied in the killing of B-cell chronic
lymphocytic leukemia (B-CLL) cells by chlorambucil, fludarabine, or
gamma radiation. Spontaneous apoptosis was observed at 24-hour
incubation, with additional apoptosis induced by each of the cytotoxic
treatments. Although Fas mRNA expression was elevated after exposure to
chlorambucil, fludarabine, or gamma radiation, Fas protein levels only
increased after irradiation. Therefore, Fas expression may be regulated
by multiple mechanisms that allow the translation of Fas mRNA only in
response to restricted cytotoxic stimuli. None of the cytotoxic stimuli
studied here induced Fas-L expression. An agonistic anti-Fas monoclonal
antibody (CH-11) did not significantly augment apoptosis induction by
any of the death stimuli. A Fas-blocking antibody (ZB4) did not inhibit
spontaneous, chlorambucil-, fludarabine-, or radiation-induced
apoptosis. However, procaspase 8 processing was induced by all cytotoxic
stimuli. These data suggest that the Fas/Fas-L signaling system does not
play a major role in the induction of apoptosis in B-CLL cells treated
with cytotoxic drugs or radiation. However, Fas-independent activation
of caspase 8 may play a crucial role in the regulation of apoptosis in
these cells.
UI - 11678895
AU - Goddard RV; Prentice AG; Copplestone JA; Kaminski ER
TI -
Generation in vitro of B-cell chronic lymphocytic
leukaemia-proliferative and specific HLA class-II-restricted cytotoxic
T-cell responses using autologous dendritic cells pulsed with tumour
cell lysate.
SO - Clin Exp Immunol 2001 Oct;126(1):16-28
AD - Plymouth Postgraduate Medical School, Derriford Combined Laboratory,
Derriford Hospital, Plymouth, UK. ruth.goddard@phnt.swest.nhs.uk
Immunotherapy using dendritic cells has shown encouraging results in
both haematological and non-haematological malignancies. In this study,
monocyte-derived dendritic cells from patients with B-CLL were cultured
for 6 days in the presence of IL-4 and GM-CSF. Autologous B-CLL T-cells
were cultured alone or with B-CLL lysate-pulsed and unpulsed autologous
dendritic cells. IFN-gamma secretion was assessed using ELISA.
Cytotoxicity was assessed, after 21 days in culture and re-stimulation,
using flow cytometry with and without blockade by anti-HLA class I,
anti-HLA class II, anti-CD4, anti-CD8 and anti-TCRalphabeta monoclonal
antibodies. B-CLL T cells stimulated with B-CLL lysate-pulsed autologous
dendritic cells showed a significant (P = 0.0004) increase in IFN-gamma
secretion and a significant (P = 0.0008) increase in specific
cytotoxicity to autologous B-cell targets, but none to autologous T cell
or B cell targets from healthy individuals. B-CLL T cells cultured with
(non-B-CLL) B-cell lysate-pulsed B-CLL dendritic cells showed no
significant response. Pulsing dendritic cells from healthy volunteers
with an autologous (non-B-CLL) B-cell lysate did not stimulate
proliferation, cytokine production or cytotoxicity by autologous T
cells. Pulsing B-CLL dendritic cells with allogeneic B-CLL lysates and
culturing with autologous T-cells elicited cytotoxicity against
autologous B-CLL targets in some cases, but not in others. Cytotoxicity
was significantly reduced by blocking with anti-HLA class II (P =
0.001), anti-TCRalphabeta (P = 0.03) and anti-CD4 (P = 0.046)
antibodies. Phenotyping of the responding T-cell population demonstrated
the majority to be CD4 positive. Our data demonstrate that HLA class
II-restricted proliferative and cytotoxic T-cell responses to B-CLL can
be generated using autologous dendritic cells pulsed with tumour cell
lysate.
UI - 11678896
AU - Porakishvili N; Roschupkina T; Kalber T; Jewell AP; Patterson K; Yong K;
TI -
Lydyard PM
Expansion of CD4+ T cells with a cytotoxic phenotype in patients with
B-chronic lymphocytic leukaemia (B-CLL).
SO - Clin Exp Immunol 2001 Oct;126(1):29-36
AD - Department of Immunology & Molecular Pathology, Royal Free and Middlesex
Hospital Medical School, London, UK. n_porakishvili@hotmail.com
Abnormal CD4/CD8 ratios and T-cell function have previously been shown
in patients with B-chronic lymphocytic leukaemia (B-CLL). We have
demonstrated that CD4+ T cells containing both serine esterase and
perforin (PF) are increased in the blood of these patients. Using flow
cytometry, we have shown that the CD4+ PF+ cells were CD57+ but lacked
expression of CD28, suggesting a mature population. The same phenotype
in CD8+ T cells is characteristic of mature cytotoxic T cells. However,
in contrast to the CD8+ T cells, the CD4+ T cells were more frequently
CD45RO positive than CD45RA positive, indicating prior antigen
experience. In contrast, this population lacked expression of either
CD69 or HLA-DR, arguing that they were not activated or that they are an
abnormal population of T cells. Their constitutive cytokine levels
showed them mainly to contain IL4 and not IFNgamma, suggesting a Th2
phenotype. The role of the CD4+ PF+ T-cell population is at present
uncertain. However, this potentially cytotoxic T-cell population could
contribute both to enhancing survival of the B-CLL tumour cells through
production of IL4, and to the immunodeficient state frequently seen in
patients with this tumour, independent of drug treatment.
UI - 11681413
AU - Aalto Y; El-Rifa W; Vilpo L; Ollila J; Nagy B; Vihinen M; Vilpo J;
TI -
Knuutila S
Distinct gene expression profiling in chronic lymphocytic leukemia with
11q23 deletion.
SO - Leukemia 2001 Nov;15(11):1721-8
AD - Department of Medical Genetics, Haartman Institute and Helsinki
University Central Hospital, University of Helsinki, Finland.
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with
regard to its clinical course. The limitations of the methods currently
available for prognostic assessment in CLL do not allow accurate
prediction of the risk of disease progression in individual patients.
The recently developed cDNA array technique provides a unique
opportunity to study gene expression in various malignancies. To
identify new molecular markers for prognostication of CLL patients, we
analyzed cDNA arrays by using hierarchical clustering and standard
statistic t-test on 34 CLL patients. We found significant expression
differences in 78 genes compared to the reference tonsillar B
lymphocytes. A cluster of genes, LCP1, PARP, BLR1, DEK, NPM, MCL1,
SLP76, STAM, HIVEP1, EVI2B, CD25, HTLF, HIVEP2, BCL2, MNDA, PBX3, EB12,
TCF1, CGRP, CD14, ILB, GZMK, GPR17 and CD79B, was associated (P < 0.05)
with the unfavorable 11q deletion and also with the unfavorable Binet
stages B and C. We present here gene expression profiling that is
associated with CLL patients with the 11q23 deletion. Many of the genes
in the cluster have not previously been shown to be related to the
initiation or progression of CLL. These novel findings provide
fundamental information for further attempts to understand the
interaction of the clustered genes in the leukomogenesis of CLL in order
to better design treatments aimed at specific molecular target(s).
UI - 11679181
AU - Potti A; Ganti AK; Koch M; Mehdi SA; Levitt R
TI -
Identification of HER-2/neu overexpression and the clinical course of
lung carcinoma in non-smokers with chronic lymphocytic leukemia.
SO - Lung Cancer 2001 Nov;34(2):227-32
AD - Department of Medicine, University of North Dakota School of Medicine,
Fargo, ND 58102, USA. apotti@medicine.nodak.edu
Patients with CLL have an excess risk of developing second primary
malignancies. The etiology of this excess risk is unclear, and has been
thought to be related to smoking. HER-2/neu overexpression has evolved
as a prognostic/predictive factor in some solid tumors. We reviewed our
experience with non-smokers who had CLL and subsequently developed lung
carcinoma, in an effort to better understand the clinical course of
these patients, and to evaluate the role of HER-2/neu overexpression. We
reviewed the records of all patients who had a diagnosis of both CLL and
lung carcinoma between 1986 and 2000. HER-2/neu overexpression was
estimated by immunohistochemistry (IHC) using the Hercep test (DAKO). An
IHC score of 2+ or greater was considered positive. Overall survival was
calculated from the date of diagnosis of lung carcinoma by the
Kaplan-Meier product limit method. Fourteen non-smokers in whom a
diagnosis of CLL was made at least 6 months prior to the diagnosis of
lung carcinoma were identified. The median age for diagnosis of CLL in
this group was 67 years while that for lung carcinoma was 70 years. The
lung carcinomas included 10 non-small cell (NSCLC) and four small cell
(SCLC) carcinomas. Nine specimens (six NSCLC and three SCLC) showed
HER-2/neu overexpression. Interestingly, 90% of patients with advanced
stage cancer (stage IIIB/IV NSCLC or extensive SCLC) overexpressed
HER-2/neu. The presence of CLL did not alter outcome in patients with
early stage lung cancer. However, after adjustment for age and
performance status, patients with advanced stage NSCLC and CLL had a
worse than expected outcome. HER-2/neu overexpression (independent of
smoking) may be involved in the development/progression of lung cancer
in patients with CLL, and has an associated worse outcome. It is
appropriate to consider heightened surveillance of CLL patients for lung
carcinoma.
UI - 11690583
AU - Almeda FQ; Adler S; Rosenson RS
TI -
Metastatic tumor infiltration of the pericardium masquerading as
pericardial tamponade.
SO - Am J Med 2001 Oct 15;111(6):504-5
UI - 11684275
AU - Adamson PJ; Zola H; Nicholson IC; Pilkington G; Hohmann A
TI -
Antibody against CD20 in patients with B cell malignancy.
SO - Leuk Res 2001 Dec;25(12):1047-50
AD - Child Health Research Institute, Women's and Children's Hospital,
University of Adelaide, 72 King William Road, Adelaide 5006, Australia.
Cancer patients may make antibodies against antigens on the surface of
their malignant cells due either to the expression of unique antigens or
to dysregulated responses to self antigens. Patients with B cell
malignancy frequently produce autoantibodies and may therefore be a
source of immunoglobulin genes for the production of phage display
antibody libraries directed against tumour-associated antigens. Patients
with autoimmune disease have circulating antibodies against lymphocyte
surface antigens, and may also provide a good starting point for the
production of a library of lymphocyte-reactive antibody structures. In
this study, plasma and serum samples from patients with B cell
malignancy or Sjogren's syndrome and from healthy controls were screened
for antibodies against the B cell membrane antigens CD20. While the
majority of samples showed very low reactivity, some individuals did
show significant and reproducible binding to CD20. To identify a good
donor for library construction, it would be advisable to screen donors
for antibody against the antigens of interest.
UI - 11695311
AU - De Roux-Serratrice C; Serratrice J; Granel B; Horschowski N; Genty I;
TI -
Weiller-Merli C; Arnoulet C; Disdier P; Weiller PJ
[Chronic lymphoid hemopathy mimicking a "dermatologic non-disease"]
SO - Rev Med Interne 2001 Oct;22(10):1001-2
UI - 11691637
AU - Rondeau G; Moreau I; Bezieau S; Petit JL; Heilig R; Fernandez S;
TI -
Pennarun E; Myers JS; Batzer MA; Moisan JP; Devilder MC
Comprehensive analysis of a large genomic sequence at the putative
B-cell chronic lymphocytic leukaemia (B-CLL) tumour suppresser gene
locus.
SO - Mutat Res 2001 Dec;458(3-4):55-70
AD - INSERM U463, Institut de Biologie de l'Hotel-Dieu, Centre Hospitalier
Universitaire, 44093 Cedex, Nantes, France.
In many haematological diseases, and more particularly in B-cell chronic
lymphocytic leukaemia (B-CLL), the existence of a tumour suppressor gene
located within the frequently deleted region 13q14.3, has been put
forward. A wide candidate region spanning from marker D13S273 to D13S25
has been proposed and an extensive physical map has been constructed by
several teams. In this study, we sequenced a minimal core deleted region
that we have previously defined and annotated it with flanking available
public sequences. Our analysis shows that this region is gene-poor.
Furthermore, our work allowed us to identify new alternative
transcripts, spanning core regions, of the previously defined candidate
genes DLEU1 and DLEU2. Since their putative involvement in B-CLL was
controversial, our present study provide support for reconsidering the
DLEU1 and DLEU2 genes as B-CLL candidate genes, with a new definition of
their organisation and context.
UI - 11698021
AU - Rodig SJ; Dorfman DM
TI -
Splendore-Hoeppli phenomenon.
SO - Arch Pathol Lab Med 2001 Nov;125(11):1515-6
AD - Department of Pathology, Brigham and Women's Hospital, 75 Francis St,
Boston, MA 02115, USA.
UI - 11698290
AU - Bernal A; Pastore RD; Asgary Z; Keller SA; Cesarman E; Liou HC;
TI -
Schattner EJ
Survival of leukemic B cells promoted by engagement of the antigen
receptor.
SO - Blood 2001 Nov 15;98(10):3050-7
AD - Immunology Program, Weill Graduate School of Medical Sciences of Cornell
University, and Department of Medicine, Weill Medical College of Cornell
University, New York, NY 10021, USA.
Chronic lymphocytic leukemia (CLL) is an incurable leukemia
characterized by the slow but progressive accumulation of cells in a
CD5+ B-cell clone. Like the nonmalignant counterparts, B-1 cells, CLL
cells often express surface immunoglobulin with the capacity to bind
autologous structures. Previously there has been no established link
between antigen-receptor binding and inhibition of apoptosis i
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