Table of Contents
1
UI - 11843800
AU - Chim CS; Loong F; Chung LP
TI -
Chronic lymphocytic leukaemia involving the gallbladder.
SO - Br J Haematol 2001 Dec;115(4):717
AD - University Department of Medicine, Queen Mary Hospital, Hong Kong.
2
UI - 11843801
AU - Rye AD; Stitson RN; Dyer MJ
TI -
Pituitary infiltration in B-cell chronic lymphocytic leukaemia.
SO - Br J Haematol 2001 Dec;115(4):718
AD - Department of Haematology, Leicester Royal Infirmary, Leicester, UK.
3
UI - 11843817
AU - Vuillier F; Maloum K; Thomas EK; Jouanne C; Dighiero G; Scott-Algara D
TI -
Functional monocyte-derived dendritic cells can be generated in chronic
lymphocytic leukaemia.
SO - Br J Haematol 2001 Dec;115(4):831-44
AD - Unite d'Immuno-Hematologie et d'Immunopathologie, Institut Pasteur, 28
rue du Dr Roux, F-75724 Paris Cedex 15, France. vuillier@pasteur.fr
Chronic lymphocytic leukaemia (CLL) remains an incurable disease.
Although modern available treatments are able to induce disease
regression, relapse almost inexorably occurs. Therefore, novel
therapeutic strategies aimed at reducing the disease relapse rate are
very much needed. Among these, the induction of tumour-associated
antigen-specific cytotoxic T lymphocytes (CTL), through either DNA
vaccines or injection of idiotype pulsed dendritic cells (DCs), has been
actively investigated with encouraging preliminary results in B-cell
malignancies. As the CLL B lymphocyte characteristically expresses low
amounts of surface immunoglobulin (Ig) and T cells from these patients
have been reported to display impaired functional activity, there are
concerns related to the possibility of generating specific cytotoxic
antitumoral T cells in this disease. In addition, no information is
presently available regarding the functional ability of CLL-derived DCs.
In the present work, freshly purified monocytes from CLL patients and
normal donors were induced to differentiate in granulocyte-macrophage
colony-stimulating factor (GM-CSF) and interleukin (IL)-4 serum-free
medium and compared for their morphological, phenotypic and functional
characteristics. Our results demonstrate that: (1) functional DCs can be
generated from CLL patients with similar phenotype and function to those
observed from normal donors; (2) in contrast to normal control subjects,
monocyte-derived DCs from CLL patients spontaneously secrete endogenous
IL-10; and (3) interferon (IFN)-gamma in combination with CD40L plays a
major role in priming DCs from CLL patients for IL-12 and IL-15
production. Overall, these results indicate that it is possible to
derive functionally competent DCs from circulating monocytes in CLL
patients.
4
UI - 11843819
AU - Jelinek DF; Tschumper RC; Geyer SM; Bone ND; Dewald GW; Hanson CA;
TI -
Stenson MJ; Witzig TE; Tefferi A; Kay NE
Analysis of clonal B-cell CD38 and immunoglobulin variable region
sequence status in relation to clinical outcome for B-chronic
lymphocytic leukaemia.
SO - Br J Haematol 2001 Dec;115(4):854-61
AD - Department of Immunology, Mayo Graduate and Medical Schools, Mayo
Clinic, 200 1st Street SW, Rochester, MN 55905, USA.
jelinek.diane@mayo.edu
Recent reports suggest that the expression of germline (GL) Ig variable
region heavy-chain genes (VH) is a negative prognostic factor for B-cell
chronic lymphocytic leukaemia (B-CLL) patients and that CLL B-cell CD38
expression may be a surrogate marker of Ig VH gene status. Currently,
however, the usefulness of this surrogate marker is controversial.
Therefore, our goal was to study the ability of CD38 to act as a
surrogate marker for Ig VH somatic mutation (SM), and to identify
differences in overall survival (OS), progression-free survival (PFS)
and response in B-CLL patients based on these two markers. We first
assessed the relationship between CD38 expression and Ig VH status on
131 B-CLL patients, including 66 patients enrolled in three North
Central Cancer Treatment Group Trials. Although the mean percentages of
CD38+ clonal B cells were significantly higher for patients classified
as GL versus SM, CD38 was not a reliable marker for clonal B-cell SM.
Overall, GL patients exhibited significantly shorter OS and PFS times
than SM patients. Despite the inability of clonal B-cell CD38 expression
to predict Ig VH mutation status, patients with < or =30% CD38+ cells
did have shorter PFS and OS times than did CLL patients with < 30% CD38+
cells. Thus, the relationship between CD38 expression and Ig VH mutation
status in B-CLL is not straightforward. Nevertheless, analysis in a
co-operative group clinical trial setting suggests that both B-cell
markers alone or in combination may have clinical usefulness. These data
strongly encourage the study of these biological markers as they relate
to disease heterogeneity in B-CLL.
5
UI - 11807008
AU - Hamblin TJ; Orchard JA; Ibbotson RE; Davis Z; Thomas PW; Stevenson FK;
TI -
Oscier DG
CD38 expression and immunoglobulin variable region mutations are
independent prognostic variables in chronic lymphocytic leukemia, but
CD38 expression may vary during the course of the disease.
SO - Blood 2002 Feb 1;99(3):1023-9
AD - Department of Haematology, Royal Bournemouth Hospital, Castle Lane East,
Bournemouth, BH7 7DW, United Kingdom. terjoha@aol.com
Although the presence or absence of somatic mutations in the
immunoglobulin variable region (IgV(H)) genes in chronic lymphocytic
leukemia (B-CLL) identifies subtypes with very different prognoses, the
assay is technically complex and unavailable to most laboratories. CD38
expression has been suggested as a surrogate marker for the 2 subtypes.
IgV(H) mutations and CD38 expression in 145 patients with B-CLL with a
long follow-up were compared. The 2 assays gave discordant results in 41
patients (28.3%). Multivariate analysis demonstrated that Binet stage,
IgV(H) mutations and CD38 were independent prognostic indicators. Median
survival time in patients whose cells had unmutated IgV(H) genes and
expressed CD38 was 8 years; in those with mutated IgV(H) genes not
expressing CD38, it was 26 years. For those with discordant results,
median survival time was 15 years. Thus, although CD38 expression does
not identify the same 2 subsets as IgV(H) mutations in CLL, it is an
independent risk factor that can be used with IgV(H) mutations and
clinical stage to select patients with B-CLL with the worst prognoses.
Using cryopreserved cells taken at intervals during the course of the
disease, however, changes of CD38 expression over time were demonstrated
in 10 of 41 patients. Causes of the variation of CD38 expression require
further study. Additional prospective studies are required for comparing
CD38 expression with other prognostic factors and for taking sequential
measurements during the course of the disease.
6
UI - 11807009
AU - Tsukada N; Burger JA; Zvaifler NJ; Kipps TJ
TI -
Distinctive features of "nurselike" cells that differentiate in the
context of chronic lymphocytic leukemia.
SO - Blood 2002 Feb 1;99(3):1030-7
AD - Department of Medicine, Division of Hematology/Oncology, University of
California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0663, USA.
A subset of blood mononuclear cells from patients with chronic
lymphocytic leukemia (CLL) can differentiate in vitro into "nurselike"
cells (NLCs) that can protect CLL cells from apoptosis. NLCs express
cytoplasmic vimentin and stromal-derived factor 1 (SDF-1). NLCs also
express CD14, as well as CD11b, CD33, CD40, CD45RO, CD68, CD80, CD86,
HLA-DQ, and HLA-DR, but not CD1a, CD2, CD3, CD11c, CD19, CD45RA, CD83,
CD106, or CD154. Consistent with this phenotype, NLCs failed to
differentiate from blood mononuclear cells that were depleted of CD14+
cells or from isolated CD19+ cells. CD14+ blood cells of healthy donors
could differentiate into cells with the morphology and phenotype of NLCs
when cultured in direct contact with CLL B cells, but not with normal B
cells. Despite expressing antigens in common with blood monocytes,
monocyte-derived dendritic cells, and macrophages, NLCs expressed
significantly higher levels of CD68 than these other cell types.
Consistent with the notion that NLCs are present in vivo, CD14+
splenocytes from CLL patients have NLC morphology and express
significantly higher levels of CD68 than CD14+ splenocytes from persons
without known B-cell malignancy. These findings indicate that although
NLCs may differentiate from blood monocytes, they probably represent a
distinctive hematopoietic cell type that exists in vivo, differentiates
from hematopoietic CD14+ cells in the context of CLL, and in turn
protect CLL cells from apoptosis via a mechanism that is independent of
CD106 (vascular cell adhesion molecule-1). The interaction between CLL
cells and NLCs may represent a novel target for therapy of patients with
this disease.
7
UI - 11807010
AU - Byrd JC; Kitada S; Flinn IW; Aron JL; Pearson M; Lucas D; Reed JC
TI -
The mechanism of tumor cell clearance by rituximab in vivo in patients
with B-cell chronic lymphocytic leukemia: evidence of caspase activation
and apoptosis induction.
SO - Blood 2002 Feb 1;99(3):1038-43
AD - Division of Hematology-Oncology, The Ohio State University, B302
Starling Loving Hall, 320 W 10th Ave, Columbus, OH 43210, USA.
byrd-3@medctr.ohsu.edu
Rituximab is a chimeric monoclonal antibody directed at CD20 with
significant activity in non-Hodgkin lymphoma (NHL) and chronic
lymphocytic leukemia (CLL). A variety of pathways of tumor cytotoxicity
different from cytotoxic chemotherapy have been proposed for this
therapeutic antibody including antibody-dependent cellular cytotoxicity
and complement-mediated cell lysis. This report describes that a
proportion of patients with CLL receiving rituximab treatment have in
vivo activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase
(PARP) cleavage in blood leukemia cells immediately following infusion
of rituximab. This suggests that apoptosis using a pathway similar to
fludarabine and other chemotherapeutic agents is intricately involved in
the blood elimination of tumor cells after rituximab treatment. Patients
having caspase-3 activation and PARP cleavage in vivo had a
significantly lower blood leukemia cell count after treatment as
compared to those without caspase activation. Significant
down-modulation of the antiapoptotic proteins XIAP and Mcl-1 was also
noted, possibly explaining in part how rituximab sensitizes CLL cells to
the cytotoxic effect of chemotherapy in vivo. These findings suggest
that the therapeutic benefit of antibody-based therapy in vivo for
patients with CLL depends in part on induction of apoptosis and provides
another area of focus for studying mechanisms of antibody-resistance in
neoplastic cells.
8
UI - 11807020
AU - Ghazal H
TI -
Successful treatment of pure red cell aplasia with rituximab in patients
with chronic lymphocytic leukemia.
SO - Blood 2002 Feb 1;99(3):1092-4
AD - Kentucky Cancer Clinic, 200 Medical Center Dr, Suite 3-0, Hazard, KY
41701, USA. hassan@tgtel.com
Pure red cell aplasia (PRCA) is a rare complication in patients with
chronic lymphocytic leukemia (CLL). It is characterized by
reticulocytopenia and by an absence of red cell precursors in the bone
marrow. Unlike autoimmune hemolytic anemia, which is characterized by an
increased number of reticulocytes, positive Coombs test findings, and a
high serum level of lactate dehydrogenase. Two patients with B-cell CLL
are reported to have developed PRCA, one while on chemotherapy with
fludarabine and one seeking treatment for de novo PRCA. Both responded
dramatically to therapy with monoclonal antibody rituximab (Rituxan) in
a short period of time and continued to be transfusion-independent.
These are the first 2 reported patients for whom rituximab treatment for
PRCA in CLL was successful, and this treatment deserves further
investigation.
9
UI - 11822361
AU - Iannitto E; Ammatuna E; Marino C; Cirrincione S; Greco G; Mariani G
TI -
Sustained response of refractory chronic lymphocytic leukemia in
progression complicated by acute hemolitic anemia to anti-CD20
monoclonal antibody.
SO - Blood 2002 Feb 1;99(3):1096-7
10
UI - 11841407
AU - Chevallier P; Penther D; Avet-Loiseau H; Robillard N; Ifrah N; Mahe B;
TI -
Hamidou M; Maisonneuve H; Moreau P; Jardel H; Harousseau JL; Bataille R;
Garand R
CD38 expression and secondary 17p deletion are important prognostic
factors in chronic lymphocytic leukaemia.
SO - Br J Haematol 2002 Jan;116(1):142-50
AD - Laboratoire d'Hematologie, Institut de Biologie, Centre Hospitalier
Universitaire, Nantes, France.
CD38 expression and chromosomal abnormalities are novel prognostic
factors in chronic lymphocytic leukaemia (CLL). However, their value
remains undetermined. CD38 was evaluated in 123 patients and chromosomal
aberrations in 111 cases with fluorescence in situ hybridization (FISH).
CD38 expression was found in 27% of the cases. In addition, seven out of
32 CD38- patients became CD38+ during evolution of the disease.
Chromosomal abnormalities included isolated 13q deletion (40%), 12q
trisomy (14%), 11q deletion (without 17p deletion) (14%) and 17p
deletion (7%). CD38 expression was significantly associated with Binet
stages B and C, atypical morphology and 11q deletion. On univariate
analysis of survival estimates, advanced Binet stages, CD38+ phenotype,
atypical morphology and 11q or 17p deletions were associated with
shorter event-free survival (EFS), treatment-free interval (TFI) and
overall survival (OS). Multivariate analysis identified both Binet
stages and CD38 as independent prognostic factors with regard to EFS and
TFI. However, CD38 appeared as an independent factor for OS when
restricted to Binet stage A. Chromosomal aberrations were re-evaluated
during evolution in 31 cases. The 17p deletion was the most frequent new
chromosomal abnormality (35%) and significantly associated with death
(64%). In conclusion, CD38 expression and secondary 17p deletion are
important poor prognostic indicators, especially in Binet stage A CLL.
11
UI - 11803359
AU - Castagna L; Nozza A; Bertuzzi A; Siracusano L; Timofeeva I; Santoro A
TI -
Allogeneic peripheral blood stem cell transplantation with reduced
intensity conditioning in primary refractory prolymphocytic leukemia:
graft-versus-leukemia effect without graft-versus-host disease.
SO - Bone Marrow Transplant 2001 Dec;28(12):1155-6
AD - Department of Medical Oncology and Hematology, Instituto Clinico
Humanitas, 56 via Manzoni, 20089 Rozzano, Milan, Italy.
A patient with progressive prolymphocytic leukemia (PLL) received an
allogeneic stem cell transplant using a reduced intensity conditioning
regimen to avoid prohibitive toxicities. Early in the post-transplant
period, a high donor-derived CD8+ count was observed. One year from
transplantation, the patient was in complete remission, fully donor
chimeric and with a normal performance status, suggesting that this
approach may represent a useful treatment option in patients with
refractory PLL.
12
UI - 11840283
AU - Hulkkonen J; Vilpo L; Hurme M; Vilpo J
TI -
Surface antigen expression in chronic lymphocytic leukemia: clustering
analysis, interrelationships and effects of chromosomal abnormalities.
SO - Leukemia 2002 Feb;16(2):178-85
AD - Department of Microbiology and Immunology, University of Tampere Medical
School and Laboratory Center of Tampere University Hospital, Tampere,
Finland.
Chronic lymphocytic leukemia (CLL) is a phenotypically distinguishable
form of B-lymphoid leukemias. The regularity of surface membrane antigen
expression patterns, their interrelationships as well as the effects of
the three frequent chromosomal aberrations, ie 11q deletion, 13q
deletion and trisomy 12, were investigated in 35 classic CLL cases by
flow cytometry. The two-way cluster analysis of 31 individual antigens
revealed three expression patterns: (1) most cells in most cases
positive (CD5, CD19, CD20, CD23, CD27, CD40, CD45, CD45RA); (2) most
cells in most cases negative (CD10, CD14, CD34, CD122, CD154, mIgG); and
(3) a mixed pattern with a variable number of positive cases and a
variable percentage of positive cells in individual cases (CD11c, CD21,
CD22, CD25, CD38, CD45RO, CD79b, CD80, CD95, CD124, CD126, CD130, FMC7,
mIgD, mIgkappa, mIglambda, mIgM). The expressions of several antigens
were strongly interdependent, even when antigens belonged to entirely
different gene families. Such antigen pairs were: CD11c/CD21; CD19/CD45;
CD19/CD79b; CD22/CD45RA; CD23/Igkappa; CD25/mIgM; CD27/CD45; CD45/CD79b;
CD45RA/Igkappa. In contrast, the expression of some antigens was
mutually exclusive, the best examples being CD45RA/CD45RO, CD38/CD80 and
CD45RA/CD80. Deletion of chromosome arm 11q attenuated expression of
splicing variant CD45RA, but enhanced CD45RO expression. In contrast,
cases of trisomy 12 were associated with enhanced CD45RA and attenuated
CD45RO expression. Similarly, trisomy 12 was associated with enhanced
CD27 and mIgkappa expression. The variable levels of signaling surface
membrane antigens, their interactions and interference by genetic
aberrations are likely to affect the clinical progression and drug
response of CLL.
13
UI - 11840292
AU - Depil S; Roche C; Dussart P; Prin L
TI -
Expression of a human endogenous retrovirus, HERV-K, in the blood cells
of leukemia patients.
SO - Leukemia 2002 Feb;16(2):254-9
AD - Laboratoire d'Immunologie, Faculte de Medecine, Lille, France.
Human endogenous retroviral sequences (HERVs) are believed to be
possible pathogenic agents in carcinogenesis. HERV-K is the most
biologically active form, since members of this family have intact open
reading frames for the gag, pol or env genes. Antibody response against
HERV-K peptides has been reported in leukemia patients, suggesting a
possible overexpression of this sequence in leukemic cells. Using
real-time quantitative RT-PCR (TaqMan), we found that in six of the
eight leukemia samples we collected, transcriptional activity of
HERV-K10-like gag gene was 5- to 10-fold higher than in normal
peripheral blood mononuclear cells (PBMCs) or mononuclear cells from
cord blood. The overexpression was marked enough to be detected by
Northern blot. In addition, there was no significant variation of HERV-K
expression in normal PBMCs after exposure to different factors (PHA,
gamma irradiation, 5-azacytidine) that potentially modulate HERV
expression. This suggests that HERV-K relative overexpression in
leukemia samples might be specifically associated with tumor
development. The origin of these transcriptional variations is therefore
worth being investigated further.
14
UI - 11842391
AU - Keating MJ; O'Brien S; Albitar M
TI -
Emerging information on the use of rituximab in chronic lymphocytic
leukemia.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):70-4
AD - Leukemia Department, The University of Texas M. D. Anderson Cancer
Center, Houston, TX 77030, USA.
Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC
Pharmaceuticals, San Diego, CA) is a chimeric monoclonal antibody that
targets mature B cells in most lymphoid B-cell malignancies. While
rituximab was approved by the US Food and Drug Administration for the
treatment of recurrent B-cell lymphoma, initial studies suggested that
it had less activity in small lymphocytic lymphoma, the nodal
counterpart of chronic lymphocytic leukemia (CLL). Two studies have now
investigated the activity of higher-dose and more intensive therapy with
rituximab in CLL. They have shown a dose-response relationship and a
higher response rate than previously seen in the lower-dose studies.
This is presumably caused by the overcoming of lower antigen density on
CLL cells compared with lymphoma cells, and the shorter half-life of
rituximab in small lymphocytic lymphoma. There is now evidence that CD20
is shed into the plasma in patients with CLL, which may explain the
shorter half-life of the antibody in small lymphocytic lymphoma/CLL. The
higher dose may then be effective in overcoming this so-called "antigen
sink." Toxicity was uncommon except in previously untreated patients and
those with atypical forms of CLL such as mantle cell lymphoma and
prolymphocytic leukemia. There is now evidence in vitro of additive or
synergistic activity of rituximab with a variety of chemotherapeutic
agents including fludarabine and cyclophosphamide. Combinations of
fludarabine with rituximab or these two drugs combined with
cyclophosphamide have given very high complete response rates in series
of patients with both previously untreated and treated CLL. It is
apparent that rituximab is playing a significant role in the management
of patients with CLL as salvage therapy and is a potential potentiating
agent for combined chemoimmunotherapy strategies for front-line or
relapsed patients with CLL. Copyright 2002 by W.B. Saunders Company.
15
UI - 11842392
AU - Nabhan C; Rosen ST
TI -
Conceptual aspects of combining rituximab and Campath-1H in the
treatment of chronic lymphocytic leukemia.
SO - Semin Oncol 2002 Feb;29(1 Suppl 2):75-80
AD - Division of Hematology/Oncology, Department of Medicine, Northwestern
University Medical School, Robert H. Lurie Comprehensive Cancer Center,
Chicago, IL 60611, USA.
Monoclonal antibody-based therapy has emerged as a novel approach in the
treatment of hematologic malignancies. The safety and tolerability of
monoclonal antibodies make these compounds attractive and easy to
administer, even in elderly, heavily pretreated patients. Chronic
lymphocytic leukemia is an incurable disease with few therapeutic
options once patients fail purine analogue-based therapy. Two monoclonal
antibodies have shown activity in this disease. The first is rituximab
(Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC
Pharmaceuticals, San Diego, CA), a chimeric human-mouse anti-CD20
antibody. The second is Campath-1H, a humanized form of a rat antibody
active against CD52. We hypothesize that combining both antibodies in
patients who have failed conventional therapies and express both CD20
and CD52 might have enhanced efficacy and therapeutic benefit. This
concept is being explored at our institution in the context of a phase
I/II clinical trial. The outcome and feasibility of this combination
opens the way for future combination therapies using novel biologic
agents. Copyright 2002 by W.B. Saunders Company.
16
UI - 11857008
AU - Molica S; Vitelli G; Levato D; Ricciotti A; Digiesi G
TI -
Clinicoprognostic implications of increased serum levels of vascular
endothelial growth factor and basic fibroblastic growth factor in early
B-cell chronic lymphocytic leukaemia.
SO - Br J Cancer 2002 Jan 7;86(1):31-5
AD - Department of Hematology, Azienda Ospedaliera Pugliese-Ciaccio,
Catanzaro, Italy. smolica@libero.it
To assess the relative merit of increased serum levels of vascular
endothelial growth factor and basic fibroblastic growth factor in
predicting the risk of disease progression of patients with early B-cell
chronic lymphocytic leukaemia we analyzed 81 Binet stage A patients
whose sera were taken at the time of diagnosis and evaluated for the
presence of vascular endothelial growth factor and basic fibroblast
growth factor using an enzyme-linked immunosorbent assay. Serum levels
of vascular endothelial growth factor positively correlated with Rai
sub-stages (P=0.03), peripheral blood lymphocytosis (P=0.03), bone
marrow histology (P=0.04) and beta2-microglobulin (beta2-m) (P=0.006).
When dealing with basic fibroblast growth factor only a correlation with
Rai sub-stages (P=0.02) could be found. Different cut-offs set on the
basis of a stratification in quartiles, failed to demonstrate any
correlation between serum levels of basic fibroblast growth factor and
disease progression. In contrast, patients with increased serum levels
of vascular endothelial growth factor (above median value, 203 pg
ml(-1)) had a three times increased risk of disease progression,
although, in multivariate analysis only Rai sub-stages (P=0.0001) and
lymphocyte doubling time (P=0.002) retained their prognostic
significance. Low levels of vascular endothelial growth factor were
indicative of good clinical outcome in the subgroup of patients with
either low (P=0.02) or high (P=0.03) beta2-m concentration. Finally, the
highest prognostic power was obtained when serum vascular endothelial
growth factor and beta2-m were examined in combination. Median of
progression-free survival of patients who had both serum vascular
endothelial growth factor and beta2-m higher than median value was only
13 months, in contrast median progression-free survival of patients with
one marker increased (i.e. above the 50th percentile) was 40 months.
Patients with both markers below the median experienced the best
clinical outcome (median progression-free survival not reached at 40
months). In conclusion, serum levels of either vascular endothelial
growth factor or basic fibroblast growth factor are high in patients
with early chronic lymphocytic leukaemia, however, only vascular
endothelial growth factor predicts behaviour of disease and helps to
refine the prognosis of stage A patients.
17
UI - 11808164
AU - Imamura N
TI -
[Chronic lymphocytic leukemias]
SO - Nippon Rinsho 2001 Nov;59 Suppl 7():537-47
AD - Department of Hematology & Oncology, Division of Clinical Research,
Research Institute for Radiation Medicine & Biology, Hiroshima
University.
18
UI - 11872081
AU - Robak T; Urbanska-Rys H; Strzelecka B; Krykowski E; Bartkowiak J;
TI -
Bionski JZ; Kordek R; Warzocha K
Plasmablastic lymphoma in a patient with chronic lymphocytic leukemia
heavily pretreated with cladribine (2-CdA): an unusual variant of
Richter's syndrome.
SO - Eur J Haematol 2001 Nov-Dec;67(5-6):322-7
AD - Department of Hematology and Department of Oncology, Medical University
of Lodz, Poland. robaktad@csk.am.lodz.pl
Patients with chronic lymphocytic leukemia (CLL) may develop a
large-cell transformation known as Richter's syndrome (RS). RS usually
presents as diffuse large-cell lymphoma (DLCL) or its immunoblastic
variant, and it can be recognized simultaneously with CLL or even 23 yr
after its diagnosis. We describe an unusual case of CLL treated with
cladribine (2-CdA) in whom DLCL of the plasmablastic type (PBL)
developed 4 yr after CLL (Rai IV) diagnosis and 1.5 yr after the 10th
course of 2-CdA treatment. Immmunologic, cytogenetic, and molecular
studies performed at the time of CLL and PBL coappearance indicated that
both tumors originated from different B-cell progenitors. Both
malignancies were refractory to VAD (vincristine, doxorubicin,
dexamethasone)-based chemotherapy, and only partial response was
achieved with CHOP (cyclophosphamide, doxorubicin, vincristine,
prednisone) salvage treatment. However, the patient died 6 months after
the occurrence of RS due to rapid progression of PBL. This is the first
description of a CLL patient who developed an unusual plasmablastic
variant of RS. Recently, the PBL entity has been identified among DLCL
associated with the human immunodeficiency virus (HIV) infection. We
suggest that in our CLL patient heavily pretreated with 2-CdA, PBL arose
as a second clone due to the prolonged and severe state of the host's
immunosuppression. Overall survival with current strategies is poor, and
further insight into the natural history, biology, and treatment of PBL
are needed.
19
UI - 11840260
AU - Durig J; Naschar M; Schmucker U; Renzing-Kohler K; Holter T; Huttmann A;
TI -
Duhrsen U
CD38 expression is an important prognostic marker in chronic lymphocytic
leukaemia.
SO - Leukemia 2002 Jan;16(1):30-5
AD - Department of Haematology, Medical Faculty, University of Essen, Essen,
Germany.
Employing a multicolour flow cytometry assay, 133 B-chronic lymphocytic
leukaemia (B-CLL) cases were analysed for surface expression of CD38.
Based on a cut-off value of 20%, CLL patients were categorised into a
CD38-positive (> or = 20%, n = 56) and a CD38-negative subgroup (< 20%,
n = 77) and separately analysed for clinical and laboratory parameters.
Patients in the CD38-positive cohort were characterised by an
unfavourable clinical course with a more advanced disease stage, poor
responsiveness to chemotherapy, short time to initiation of first
treatment and shorter survival. In contrast, the CD38- negative group
required minimal or no treatment, remained treatment-free for a longer
time period and had prolonged survival (P < 0.05). CD38 expression was a
robust marker in the majority of patients in that it was stable over
time and not significantly influenced by chemotherapy. In conclusion,
our data confirm recent studies suggesting a role of CD38 as a predictor
of clinical outcome in patients with B-CLL.
20
UI - 11840261
AU - Van Den Neste E; Cardoen S; Husson B; Rosier JF; Delacauw A; Ferrant A;
TI -
Van den Berghe G; Bontemps F
2-Chloro-2'-deoxyadenosine inhibits DNA repair synthesis and potentiates
UVC cytotoxicity in chronic lymphocytic leukemia B lymphocytes.
SO - Leukemia 2002 Jan;16(1):36-43
AD - Laboratory of Physiological Chemistry, Christian de Duve Institute of
Cellular Pathology (ICP), Brussels, Belgium.
2-Chloro-2'-deoxyadenosine (CdA) is a deoxyadenosine analogue which
targets enzymes involved in DNA synthesis, and hence might interfere
with the resynthesis step of DNA repair. We tested this hypothesis in
resting B cell chronic lymphocytic leukemia (B-CLL) lymphocytes, after
firstly characterizing unscheduled DNA synthesis occurring in these
cells. We observed that the spontaneous incorporation of
[methyl-3H]thymidine (dThd) into DNA of B-CLL cells was not completely
inhibitable by hydroxyurea (HU) which blocks DNA replication. In
addition, in the presence of HU, dThd incorporation could be upregulated
by UVC radiation or DNA alkylation, without re-entry of the cells into S
phase. CdA was found to inhibit both spontaneous and upregulated DNA
synthesis in B-CLL cells. Phosphorylation of CdA was essential to exert
this effect. We finally observed a strong synergistic cytotoxicity
between UV light and CdA, which was correlated with activation of
caspase-3 and high molecular weight DNA fragmentation, two markers of
apoptosis. Taken together, these observations indicate that in B-CLL
cells CdA inhibits unscheduled DNA synthesis which represents the
polymerizing step of a repair process responsive to DNA aggression.
Inhibition of this process by CdA, together with a combined activation
of the apoptotic proteolytic cascade by CdA and UV, may explain their
synergistic cytotoxicity.
21
UI - 11840262
AU - Pers JO; Berthou C; Porakishvili N; Burdjanadze M; Le Calvez G; Abgrall
TI -
JF; Lydyard PM; Youinou P; Jamin C
CD5-induced apoptosis of B cells in some patients with chronic
lymphocytic leukemia.
SO - Leukemia 2002 Jan;16(1):44-52
AD - Institut de Synergie des Sciences et de la Sante, Brest University
Medical School, Brest, France.
Although B chronic lymphocytic leukemia (B-CLL) is characterized by
prolonged survival of CD5(+) B cells in vivo, these cells apoptose
spontaneously in vitro. The effect of CD5 ligation on apoptosis was
studied in 27 newly diagnosed patients with B-CLL, in relation to the
expression of surface IgM (sIgM), CD79b, CD38, CD72 and CD19. B cells
from 15 patients (group I) were resistant to anti-CD5-induced apoptosis,
whereas apoptosis above spontaneous levels was seen in the remaining 12
studied (group II). Group II was then subdivided on the basis of
differences in the time required to reach maximum apoptosis: whilst B
cells from seven patients underwent apoptosis by 18 h, those from the
remaining five needed 36 h to apoptose. The expression of sIgM, CD5,
CD79b and CD38 was higher in group II than group I, suggesting that
signaling for apoptosis might operate via CD79, and that CD38 expression
was required. As shown by flow cytometry and confirmed by Western
blotting, apoptosis was associated with a decrease in the ratios of
Bcl-2/Bax and Bcl(XL)/Bax, due to an increase in the level of Bax, but
no change in that of Bcl-2. This heterogeneous apoptotic response to CD5
ligation offers an explanation for the incomplete success of anti-CD5
monoclonal therapy, and might help identify patients who would respond
to such treatment.
22
UI - 10342064
AU - Cobeta-Garcia JC; Domingo-Morera JA; Martinez-Burgui J
TI -
RS3PE syndrome and chronic lymphoid leukaemia.
SO - Clin Exp Rheumatol 1999 Mar-Apr;17(2):266-7
23
UI - 10939806
AU - Stoppa-Lyonnet D; Lauge A; Sigaux F; Stern MH
TI -
No germline ATM mutation in a series of 16T-cell prolymphocytic
leukemias.
SO - Blood 2000 Jul 1;96(1):374-6
24
UI - 11706875
AU - Singer C; Goldstone T
TI -
Chronic lymphocytic leukaemia.
SO - Clin Med 2001 Sep-Oct;1(5):350-3
AD - Royal United Hospital, Bath.
25
UI - 11857346
AU - Chun HH; Castellvi-Bel S; Wang Z; Nagourney RA; Plaeger S;
TI -
Becker-Catania SG; Naeim F; Sparkes RS; Gatti RA
TCL-1, MTCP-1 and TML-1 gene expression profile in non-leukemic clonal
proliferations associated with ataxia-telangiectasia.
SO - Int J Cancer 2002 Feb 20;97(6):726-31
AD - Department of Pathology, School of Medicine, University of California at
Los Angeles, Los Angeles, CA 90095-1732, USA.
We analyzed the role of 4 genes, TCL-1, MTCP-1, TML-1 and ATM, in the
early pathogenesis of T cell leukemia, with particular interest in the
characteristics of long-standing non-leukemic clonal proliferations in
ataxia-telangiectasia (A-T) patients. Five patients were studied: 4
patients had A-T (2 of whom had non-leukemic clonal proliferations
[ATCP]), 1 had B cell lymphoma and 1 had T-ALL; a fifth patient with
T-PLL did not have A-T. We measured the levels of expression for TCL-1,
MTCP-1 and TML-1. TCL-1, not expressed in unstimulated mature T cells,
was upregulated in the peripheral blood leukocytes (PBL) of the 2 A-T
patients with ATCP. It was also expressed in the malignant cells of the
A-T patient with B cell lymphoma and the T-PLL cells of the patient
without A-T. In the same cells, MTCP-1 type A was expressed equally in
all 5 patients, as well as in the controls; MTCP-1 type B transcripts
were not observed. TML-1, also not expressed in unstimulated T cells,
was expressed in the PBL of one A-T patient with ATCP and in the
leukemic cells of the non-A-T T-PLL patient. These expression patterns
were compared to cellular immunophenotypes. The non-leukemic clonal T
cell populations had the characteristics of immature T cells. We
conclude that TCL-1 and TML-1 play a role in cell proliferation and
survival but are not pivotal genes in the progression to malignancy,
even when the ATM gene is mutated. Additional genetic alterations must
occur to initiate tumorigenesis. Copyright 2001 Wiley-Liss, Inc.
26
UI - 11850081
AU - Wong KF; So CC
TI -
Chronic lymphocytic leukemia with a novel der(8;15)(q10;q10)
translocation.
SO - Cancer Genet Cytogenet 2002 Jan 15;132(2):159-60
AD - Department of Pathology, Queen Elizabeth Hospital, SAR, Hong Kong,
China. kfwong@ha.org.hk
A 71-year-old male was found to have chronic lymphocytic leukemia.
Cytogenetic study of the leukemic lymphocytes shows a
46,XY,der(8;15)+15. The der(8;15) is a novel chromosomal abnormality in
human malignancies. The resulting loss of 8p and trisomy 15q are both
unusual chromosomal changes in chronic lymphocytic leukemia.
27
UI - 11867687
AU - de la Fuente MT; Casanova B; Moyano JV; Garcia-Gila M; Sanz L;
TI -
Garcia-Marco J; Silva A; Garcia-Pardo A
Engagement of alpha4beta1 integrin by fibronectin induces in vitro
resistance of B chronic lymphocytic leukemia cells to fludarabine.
SO - J Leukoc Biol 2002 Mar;71(3):495-502
AD - Departamento de Inmunologia, Centro de Investigaciones Biologicas, CSIC,
Velazquez 144, 28006 Madrid, Spain.
B-cell chronic lymphocytic leukemia is characterized by the accumulation
of malignant B lymphocytes as a result of abnormal survival signals
operating in vivo. Previously, we showed that adhesion of B-CLL cells to
the fibronectin fragment H89, a ligand for alpha4beta1 integrin,
prevents their spontaneous apoptosis in vitro. We have now studied
whether alpha4beta1/H89 interaction affected the response of B-CLL cells
to the therapeutic drug fludarabine. B-CLL cells cultured on H89 during
treatment with fludarabine showed significantly higher mean viability
(P<0.05) than cells cultured on the control polylysine for all doses of
drug tested. Similar results were obtained with the EHEB cell line.
Analysis of the expression of Bcl-2-family proteins after 48 h of
fludarabine treatment revealed that Bcl-xL levels were significantly
higher (P<0.05) for cells cultured on H89 than on polylysine and
correlated (r=0.56, P<0.05) with the increased cell viability observed
on H89 cultures. These results indicate that Bcl-xL is involved in the
survival signals induced by alpha4beta1 ligation and may contribute to
the progressive drug resistance observed in B-CLL.
28
UI - 11243240
AU - Stankovic T; Taylor AM; Yuille MR; Vorechovsky I
TI -
Recurrent ATM mutations in T-PLL on diverse haplotypes: no support for
their germline origin.
SO - Blood 2001 Mar 1;97(5):1517-8
29
UI - 11760651
AU - Sinkovics J; Horvath J
TI -
[Molecular biology investigations in chronic lymphocytic leukemia]
SO - Orv Hetil 2001 Oct 21;142(42):2338-9
30
UI - 11841432
AU - Moran EC; Kamiguti AS; Cawley JC; Pettitt AR
TI -
Cytoprotective antioxidant activity of serum albumin and autocrine
catalase in chronic lymphocytic leukaemia.
SO - Br J Haematol 2002 Feb;116(2):316-28
AD - Department of Haematology, Royal Liverpool University Hospital,
Liverpool, UK.
Chronic lymphocytic leukaemia (CLL) cells are long lived in vivo but
undergo spontaneous apoptosis when cultured in vitro. Intriguingly, CLL
cells also appear to have a specific susceptibility to oxidative stress
- a potent inducer of apoptosis. Here, we show that serum albumin can
function as a cytoprotective antioxidant of potential relevance to
circulating CLL cells, and that autocrine catalase - a hydrogen
peroxide-inactivating enzyme that may be released extracellularly - can
perform a similar role under the crowded conditions that prevail at
sites of tissue involvement. Albumin lowered oxidative stress in
cultured CLL cells and inhibited spontaneous and reactive
oxidant-induced apoptosis. Maximal effects were observed at a
concentration of 10 mg/ml - fourfold lower than that in plasma and
twofold higher than that in standard culture medium containing 10% fetal
calf serum. Oxidative stress and spontaneous apoptosis were also
decreased by cell crowding and by conditioned medium (CM) from crowded
CLL cells, indicating that these processes were subject to autocrine
regulation. CLL cells were found to express catalase and release enzyme
activity into the culture medium. Exogenous catalase decreased oxidative
stress and spontaneous apoptosis, and the anti-apoptotic effect of CM
from crowded CLL cells was abrogated by the specific catalase inhibitor,
3'-amino-1,2,4-triazole. Together, these data strongly implicate
autocrine catalase as a cytoprotective antioxidant. Oxidative stress in
CLL cells was greatly diminished by ruthenium red - an inhibitor of
mitochondrial reactive oxidant production - and by the glutathione (GSH)
precursor N-acetylcysteine, suggesting that the GSH peroxidase
antioxidant system may be compromised by lack of available substrate.
Our findings highlight the importance of endogenous reactive oxidants in
regulating CLL-cell apoptosis, and help to explain why CLL cells survive
for prolonged periods in vivo despite their vulnerability to oxidative
stress and spontaneous apoptosis when cultured in vitro.
31
UI - 11841436
AU - Thomas R; Ribeiro I; Shepherd P; Johnson P; Cook M; Lakhani A;
TI -
Kaczmarski R; Carrington P; Catovsky D
Spontaneous clinical regression in chronic lymphocytic leukaemia.
SO - Br J Haematol 2002 Feb;116(2):341-5
AD - Department of Haematology, Western General Hospital, Edinburgh, UK.
Chronic lymphocytic leukaemia (CLL) is a B-cell disorder, which has a
median survival of over 10 years from diagnosis for stage A disease. The
natural history of stage A disease is generally indolent or only slowly
progressive. It is less well known that CLL may undergo spontaneous
regression. We report a series of 10 such cases (eight stage A and two
stage B) followed at our institutions.
32
UI - 11888034
AU - Rao RD; Morice WG; Phyliky RL
TI -
Hemophagocytosis in a patient with chronic lymphocytic leukemia and
histoplasmosis.
SO - Mayo Clin Proc 2002 Mar;77(3):287-90
AD - Division of Hematology and Internal Medicine, Mayo Clinic, Rochester,
Minn 55905, USA.
We present a case of hemophagocytosis in the setting of a disseminated
Histoplasma infection in a patient with B-cell chronic lymphocytic
leukemia (CLL). A 68-year-old man with CLL presented with progressive
pancytopenia and fevers after therapy with cyclophosphamide and
fludarabine phosphate. Extensive evaluation for a source of infection
revealed a pulmonary nodule. A biopsy specimen taken from the nodule
showed granulomas containing Histoplasma organisms. A bone marrow biopsy
specimen demonstrated disseminated histoplasmosis and intense
hemophagocytosis. Antifungal therapy with amphotericin B was initiated,
and the fevers and cytopenias resolved. Hemophagocytic syndrome is an
uncommon condition with many origins. It is characterized by a
proliferation of histiocytes with phagocytosis of formed elements of
blood. Clinical manifestations include signs and symptoms of immune
activation and decreased peripheral blood cell counts. This condition is
often underdiagnosed because clinicians are unfamiliar with it.
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