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NCI CANCERLIT® Search: Chronic Lymphocytic Leukemia - May 2002
National Cancer Institute®
Last Modified: May 1, 2002
Table of Contents
1
UI - 11960343
AU - Oudat R; Keating MJ; Lerner S; O'Brien S; Albitar M
TI -
Significance of the levels of bone marrow lymphoid infiltrate in chronic
lymphocytic leukemia patients with nodular partial remission.
SO - Leukemia 2002 Apr;16(4):632-5
AD - Department of Hematopathology, University of Texas MD Anderson Cancer
Center, Houston, TX 77030, USA.
Patients with chronic lymphocytic leukemia (CLL) are considered in
nodular partial remission (nPR) when they are in remission but bone
marrow biopsies show rare nodules. The significance of the level of
residual disease in nPR is not known. We studied 91 previously untreated
CLL patients who were treated with fludarabine alone, fludarabine with
prednisone, or fludarabine with cyclophosphamide and achieved nPR at the
end of six courses. We compared bone marrow lymphoid infiltration before
therapy and at the end of three and six courses of therapy as evaluated
by a pathologist in retrospective fashion with that of the routine
evaluation at the time of performing bone marrow biopsy. We then
compared these results with those obtained by computer-aided
histomorphometry in 28 patients in nPR. There was significant
correlation (P < 0.05) between pathologists as well as between
pathologists and histomorphometry. Upon correlation with clinical
characteristics, there was significant correlation (P 0.01) between
marrow involvement before therapy and white blood cell counts (wbc),
hemoglobin (hgb), absolute lymphocyte counts, and beta2-microglobulin
(beta2-m) but none of these parameters correlated with the lymphoid
infiltrate at the end of three or six courses of therapy. more
importantly, lymphoid infiltration after three and six courses did not
correlate with time to progression (ttp) or overall survival (os).
however, patients with >70% marrow involvement before therapy had a
significantly shorter TTP (P = 0.02). All 91 patients showed similar
results. However, we found reverse correlation between marrow lymphoid
infiltrate at the end of three courses and OS (P = 0.01).
2
UI - 11960344
AU - Bende RJ; Aarts WM; Pals ST; van Noesel CJ
TI -
Immunoglobulin diversification in B cell malignancies: internal splicing
of heavy chain variable region as a by-product of somatic hypermutation.
SO - Leukemia 2002 Apr;16(4):636-44
AD - Department of Pathology, Academic Medical Center, Amsterdam, The
Netherlands.
In this study we describe alternative splicing of somatically mutated
immunoglobulin (Ig) variable heavy chain (V(H)) genes in three distinct
primary B cell non-Hodgkin's lymphomas (B-NHL). In two V4-34 expressing
lymphomas, ie a post-germinal center type B cell chronic lymphocytic
leukemia (B-CLL) and a follicular lymphoma (FL), internally spliced V(H)
gene transcripts were found in which a sequence stretch of 116 bp
between the framework region 1 (FR1) and complementarity determining
region 2 (CDR2) had been deleted. We provide evidence that for this
alternative IgV(H) mRNA processing a known cryptic 5' splice donor site
and a previously unidentified cryptic 3' splice acceptor site were used.
Site-directed mutagenesis showed that the cryptic 3' splice acceptor
site had been activated by specific somatic point mutations. The B-CLL
further harbored a triplication of the rearranged JH3 gene segment
including the putative N region and part of the JH3-JH4 intron sequence.
This triplication probably took place via a repeated mechanism of DNA
double strand break followed by homologous recombination, a mechanism
which was recently proposed also involved in the somatic hypermutation
process and is compatible with the post-germinal center derivation of
this B-CLL. Finally, in a V4-34 expressing diffuse large B cell
lymphoma, we observed alternative IgV(H) mRNA processing using the same
cryptic 5' splice donor site and the normal splice acceptor site of the
CH1-C(mu) exon. The significance of alternative IgV(H) processing in B
cell malignancies and as a potential mechanism of somatic Ig
diversification is discussed.
3
UI - 10779422
AU - Mauro FR; Foa R; Cerretti R; Giannarelli D; Coluzzi S; Mandelli F;
TI -
Girelli G
Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical,
therapeutic, and prognostic features.
SO - Blood 2000 May 1;95(9):2786-92
AD - Dipartimento di Biotecnologie Cellulari ed Ematologia and Dipartimento
di Medicina Sperimentale, University "La Sapienza," Rome, Italy.
mauro@bce.med.uniroma1.it
Fifty-two cases of autoimmune hemolytic anemia (AHA) were observed
within a series of 1203 patients (4.3%) with chronic lymphocytic
leukemia (CLL) followed at a single institution. Nineteen were observed
at the time of CLL diagnosis and 33 during the clinical follow-up.
Ninety percent of the patients with CLL/AHA showed active CLL and 25%
had been treated previously. The antierythrocyte autoantibody (AeAb) was
an IgG in 87% of cases and an IgM in 13%. A lymphocyte count more than
60 x 10(9)/L (P <.00001), age above 65 years (P <.01), and male gender
(P <.01) emerged as independent parameters that correlated significantly
with an increased rate of AHA at CLL diagnosis. Patients previously
treated with chlorambucil (CB) plus prednisone (PDN) and with
fludarabine plus PDN showed a similar rate of AHA (1.8% and 2.5%,
respectively). After steroid therapy associated with CB in case of
active CLL, 70% of patients achieved the complete disappearance of the
AeAb. The actuarial AHA relapse-free survival probability was 54% at 5
years and the median survival probability after AHA was 41 months.
Infections represented the main cause of morbidity and mortality. IgG
AHA and the occurrence of AHA at the same time of CLL diagnosis emerged
as independent factors significantly correlated with a better survival
probability of AHA/CLL patients. Taken together, this study indicates
that in CLL, AHA is a rare event with no independent effect on survival
for which steroids, associated with CB if required, and a careful
management of infections may successfully control the 2 conditions.
Cooperative studies are needed to better define the optimal steroid
schedule and the therapeutic role of other immunosuppressive agents and
splenectomy. (Blood. 2000;95:2786-2792)
4
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
5
UI - 11920165
AU - Parrado A; Noguera ME; Delmer A; McKenna S; Davies J; Le Gall I; Bentley
TI -
P; Whittaker JA; Sigaux F; Chomienne C; Padua RA
Deregulated expression of promyelocytic leukemia zinc finger protein in
B-cell chronic lymphocytic leukemias does not affect cyclin A
expression.
SO - Hematol J 2000;1(1):15-27
AD - Laboratoire de Biologie Cellulaire Hematopoietique, Universite Paris 7,
France. a.parrado@chu-stlouis.fr
INTRODUCTION: The promyelocytic leukemia zinc finger (PLZF) gene encodes
a transcription factor expressed in myeloid, lymphoid and CD34(+)
progenitor cells. Structurally related to BCL-6, which is involved in
human lymphoma, PLZF may have a role in proliferation, differentiation
and survival of hematopoietic cells, that could be mediated by
transcriptional repression of the cyclin A gene. MATERIALS AND METHODS:
Quantitative competitive reverse transcription-polymerase chain reaction
was used to measure the levels of expression of PLZF and cyclin A in
normal leukocyte subsets (including CD19(+) lymphocytes, n=21) and
malignant B lymphocytes (including B-chronic lymphocytic leukemias
[B-CLL], n=63). Results obtained with this method were confirmed by
Western and Northern blot analysis. Transactivation assays were
performed using an expression construct for PLZF and two cyclin A
promoter luciferase reporters in an Epstein-Barr virus (EBV)-transformed
B-cell line. Cyclin A expression, cell growth kinetics, and cell cycle
were analysed in stable clones of the Burkitt lymphoma (BL) B-cell line
DG75 with inducible expression of PLZF, generated using the
tetracycline-regulated expression system. RESULTS: Expression of PLZF
was 100-fold downregulated in 90% B-CLL (56/63) compared to normal B
lymphocytes (P<0.001). B-CLL patients with the highest levels of PLZF
had a poorer survival (P<0.013). In transactivation assays, PLZF
inhibited the activity of the cyclin A reporters by 50%, demonstrating
that PLZF can repress cyclin A expression in non-malignant B
lymphocytes. However, in B-CLL patients, the level of cyclin A
expression was found to be within the normal range. Altered PLZF
function in B lymphoid malignancies was further corroborated in the
PLZF-regulatable DG75 clones, where induction of PLZF expression did not
significantly alter the levels of cyclin A expression, the cell growth
kinetics, or the cell cycle phase distribution. CONCLUSION: The lower
survival of patients with the highest levels of PLZF suggests that this
protein may be a marker of progression in B-CLL. The absence of
co-ordinated regulation of PLZF and cyclin A genes in B-CLL and in a
malignant B-cell line may indicate a loss of cyclin A control by PLZF in
B-CLL and other B-cell disorders. Deregulation of PLZF could thus play a
role in B-cell malignancy.
6
UI - 11920168
AU - Hetet G; Dastot H; Baens M; Brizard A; Sigaux F; Grandchamp B; Stern MH
TI -
Recurrent molecular deletion of the 12p13 region, centromeric to
ETV6/TEL, in T-cell prolymphocytic leukemia.
SO - Hematol J 2000;1(1):42-7
AD - Unite INSERM U409 and Centre de recherche Claude Bernard, Hopital
Bichat, Paris, France.
INTRODUCTION: T-cell prolymphocytic leukemia is a rare form of mature
leukemia which occurs in adults and in younger patients suffering ataxia
telangiectasia. Among others, complex chromosome aberrations of
chromosome 12 have been described in this disease. We searched for
deletions of the 12p13 region as the result of these chromosome
rearrangements. MATERIAL AND METHODS: Paired leukemic and non-leukemic
cells were obtained from a series of 21 patients suffering T-cell
prolymphocytic leukemia. Loss of heterozygosity was searched for by
microsatellite typing using a fluorescent automated laser DNA sequencer
to analyze the amplification products. Proteins were analyzed by Western
blot. Southern blot analysis of one patient was conducted. RESULTS AND
CONCLUSION: Loss of heterozygosity of the 12p13 region, including the
ETV6 and CDKN1B genes, was detected in nine of these 21 cases (43%).
Western and Southern blot analyses of one case demonstrated a biallelic
deletion which did not include ETV6. Taken together, our results defined
a minimal region of deletion of less than one Mb flanked by the markers
b312C2T7 and D12S320, excluding ETV6 as a candidate gene. Deletion of
the 12p13 region is thus a highly recurrent genetic event in T-cell
prolymphocytic leukemia.
7
UI - 11760820
AU - Roberts JC; Roberts GH
TI -
B-Prolymphocytic leukemia: a case study.
SO - Clin Lab Sci 2001 Fall;14(4):233-7
AD - St Francis Medical Center, Monroe LA 71210, USA.
The case study reported is of a patient initially misdiagnosed as
chronic lymphocytic leukemia. Immunophenotyping studies ultimately
identified the nature of the disease as B-cell prolymphocytic leukemia
with concomitant warm autoimmune hemolytic anemia. The leukemia and
hemolytic anemia were refractory to all conventional treatments
administered. The patient survived a significantly shorter period of
time than the median time of three years reported in the literature. The
patient expired from complications resulting from B-cell PLL, warm
autoimmune hemolytic anemia, and combination chemotherapy.
8
UI - 11921024
AU - Smith E; Hallman JR; Pardasani A; McMichael A
TI -
Multiple herpetic whitlow lesions in a patient with chronic lymphocytic
leukemia.
SO - Am J Hematol 2002 Apr;69(4):285-8
AD - Department of Dermatology, Wake Forest University School of Medicine,
Winston-Salem, North Carolina, USA.
Herpetic whitlow, a herpes simplex virus infection involving the digits,
most commonly presents as a vesicular eruption involving a single digit.
Diagnosis of herpetic whitlow can usually be made with the history of
exposure, the characteristic vesicular eruption, and a positive Tzank
smear and/or viral culture. We describe a case of herpetic whitlow in a
patient finishing 6 cycles of chemotherapy for refractory chronic
lymphocytic leukemia that presented with a bilateral, multi-digit,
crusted eruption of the hands. This is an illustrative case of an
immunocompromised host status altering appearance and course of
cutaneous disease such that the history and physical exam alone may not
help in diagnosing atypical presentations of herpetic infections. This
case underscores the necessity for clinico-histopathologic correlation.
Copyright 2002 Wiley-Liss, Inc.
9
UI - 11880188
AU - Bessler H; Bergman M; Salman H; Cohen AM; Fenig E; Djaldetti M
TI -
Factor(s) released from irradiated B-CLL cells induce apoptosis in
leukemic lymphocytes.
SO - Cancer Lett 2002 May 8;179(1):103-8
AD - Laboratory for Immunology and Hematology Research, Rabin Medical Center,
Golda Campus, Petah Tiqva and the Sackler School of Medicine, Tel Aviv
University, Tel Aviv, Israel.
Photon irradiation of peripheral blood lymphocytes from 25 patients with
untreated B-chronic lymphocytic leukemia (B-CLL) induced an increase in
apoptotic response by 270%. No significant increase in apoptosis was
observed after irradiation of peripheral blood mononuclear cells from 15
healthy volunteers. Supernatants (sups) derived from irradiated leukemic
cells incubated with non-irradiated autologous cells induced a 75%
enhancement in number of apoptotic cells, as compared with sups from
non-irradiated CLL cells. The level of tumor necrosis factor alpha, a
cytokine known to prevent apoptosis, was reduced in the sups of
irradiated CLL cells in comparison to that of non-irradiated
lymphocytes. The interleukin (IL)-10 level, an IL reported to induce
apoptosis, was similar in the sups of irradiated and non-irradiated
lymphocytes from B-CLL patients. No change in IL-2 levels was observed.
The significance of these findings and the role of factor(s) in the sups
of irradiated leukemic lymphocytes as inducers of apoptosis are
discussed.
10
UI - 11917501
AU - Hara T; Choraku M; Hashimoto N; Kosaka M; Wakatsuki S
TI -
[A longer prognosis of B-CLL with mutation of IgVH gene]
SO - Nippon Naika Gakkai Zasshi 2002 Feb 10;91(2):743-5
AD - Tokushima Prefecture Hospital of Kaifu, Tokushima.
11
UI - 11979092
AU - Asplund SL; McKenna RW; Howard MS; Kroft SH
TI -
Immunophenotype does not correlate with lymph node histology in chronic
lymphocytic leukemia/small lymphocytic lymphoma.
SO - Am J Surg Pathol 2002 May;26(5):624-9
AD - University of Texas Southwestern Medical School, Dallas, Texas, USA.
Sheryl.Asplund@UTSouthwestern.edu
The presence of prominent proliferation centers (PCs) in lymph nodes
(LNs) involved with chronic lymphocytic leukemia/small lymphocytic
lymphoma (CLL/SLL) has been associated with atypical blood smear
morphology. Atypical CLL has in turn been associated with variant
immunophenotypes and poor outcome. However, the significance of abundant
PCs remains controversial. We have analyzed the flow cytometric
immunophenotypic features of 54 CLL/SLL LNs and correlated these
findings with the morphologic and clinical features. The LN histology
was assigned to one of two groups based on the prominence of PCs: Group
I LNs contained scattered small, sometimes ill-defined PCs in a
background of monotonous small round lymphocytes. Group II LNs had
increased numbers and sizes of PCs resulting in an obviously nodular
appearance at low magnification. Flow cytometry was performed using
broad three- or four-color antibody panels that included anti-CD5, CD19,
CD20, CD23, CD38, FMC7, and surface immunoglobulin (sIg). The intensity
of expression of all markers was scored semi-quantitatively using
isotypic controls and internal positive and negative populations as
standards. There were 32 group I and 22 group II LNs that, by
definition, expressed CD19, CD5, and CD23. Little variability was seen
in the intensity of expression of CD19, and the majority of cases
expressed CD23 brightly. CD5 varied from very dim to an intensity
similar to that of normal T cells; the majority had an intermediate
level of CD5 expression. FMC7 was expressed to a significant extent in
11 cases (21%). CD20 was relatively bright in 17 cases (32%). sIg was
dim in 29 cases (55%) and moderate or bright in 24 cases (45%). CD38 was
expressed significantly in 25 cases (47%). There was no correlation
between histologic group and intensity of expression of any individual
marker or with an immunophenotypic atypia score based on FMC7, CD20, and
sIg. There was also no correlation between morphology or immunophenotype
and clinical features. These findings do not support the interpretation
that the prominence of proliferation centers in CLL/SLL LNs defines
biologically distinct subtypes.
12
UI - 11418459
AU - Rawstron AC; Kennedy B; Evans PA; Davies FE; Richards SJ; Haynes AP;
TI -
Russell NH; Hale G; Morgan GJ; Jack AS; Hillmen P
Quantitation of minimal disease levels in chronic lymphocytic leukemia
using a sensitive flow cytometric assay improves the prediction of
outcome and can be used to optimize therapy.
SO - Blood 2001 Jul 1;98(1):29-35
AD - Haematological Malignancy Diagnostic Service, Leeds General Infirmary,
Leeds, United Kingdom. andy.rawstron@newscientist.net
Previous studies have suggested that the level of residual disease at
the end of therapy predicts outcome in chronic lymphocytic leukemia
(CLL). However, available methods for detecting CLL cells are either
insensitive or not routinely applicable. A flow cytometric assay was
developed that can differentiate CLL cells from normal B cells on the
basis of their CD19/CD5/CD20/CD79b expression. The assay is rapid and
can detect one CLL cell in 10(4) to 10(5) leukocytes in all patients. We
have compared this assay to conventional assessment in 104 patients
treated with CAMPATH-1H and/or autologous transplant. During CAMPATH-1H
therapy, circulating CLL cells were rapidly depleted in responding
patients, but remained detectable in nonresponders. Patients with more
than 0.01 x 10(9)/L circulating CLL cells always had significant (> 5%)
marrow disease, and blood monitoring could be used to time marrow
assessments. In 25 out of 104 patients achieving complete remission by
National Cancer Institute (NCI) criteria, the detection of residual bone
marrow disease at more than 0.05% of leukocytes in 6 out of 25 patients
predicted significantly poorer event-free (P =.0001) and overall
survival (P =.007). CLL cells are detectable at a median of 15.8 months
(range, 5.5-41.8) posttreatment in 9 out of 18 evaluable patients with
less than 0.05% CLL cells at end of treatment. All patients with
detectable disease have progressively increasing disease levels on
follow-up. The use of sensitive techniques, such as the flow assay
described here, allow accurate quantitation of disease levels and
provide an accurate method for guiding therapy and predicting outcome.
These results suggest that the eradication of detectable disease may
lead to improved survival and should be tested in future studies.
13
UI - 11699197
AU - D'Arena G; Musto P; Cascavilla N; Dell'Olio M; Di Renzo N; Perla G;
TI -
Savino L; Carotenuto M
CD38 expression correlates with adverse biological features and predicts
poor clinical outcome in B-cell chronic lymphocytic leukemia.
SO - Leuk Lymphoma 2001 Jun;42(1-2):109-14
AD - Division of Hematology, IRCCS Casa Sollievo della Sofferenza Hospital,
71013 San Giovanni Rotondo, Italy. ematologia@operapadrepio.it
CD38 identifies a surface molecule with multi-functional activity. Its
prognostic importance in B-cell chronic lymphocytic leukemia (B-CLL) is
currently under investigation in view of the fact that two different
groups have recently indicated that CD38 expression could be an
independent prognostic marker in B-CLL. We analyzed the
clinico-biological features of 61 immunologically typical (CD5+CD23+)
B-CLL patients stratified according to the CD38 expression. Twenty-two
(36%) patients expressed CD38 in more than 30% of CD19-positive cells
and were considered as CD38-positive B-CLL. Atypical morphology (p
0.02), peripheral blood lymphocytosis (p 0.01) and diffuse
histopathologic bone marrow pattern (p 0.003) were findings found to be
closely associated with CD38 expression. On the other hand, A and B
Binet stages (p 0.02) and interstitial bone marrow involvement (p 0.005)
were more represented in the CD38-negative B-CLL group. Trisomy 12 was
detected more frequently in the CD38-positive B-CLL group, while 13q14
deletions mainly occurred in CD38-negative group (p 0.005). Finally,
median survival of CD38-positive B-CLL patients was 90 months, while it
was not reached at 180 months in CD38-negative patients. Taken together,
our data strongly suggest that the evaluation of CD38 expression may
identify two groups patients with B-CLL greatly differing in their
clinico-biological features.
14
UI - 11699204
AU - Stahl D; Lacroix-Desmazes S; Sibrowski W; Kazatchkine MD; Kaveri SV
TI -
Broad alterations of self-reactive antibody-repertoires of plasma IgM
and IgG in B-cell chronic lymphocytic leukemia (B-CLL) and B-CLL related
target-restricted autoimmunity.
SO - Leuk Lymphoma 2001 Jun;42(1-2):163-76
AD - INSERM U430, Universite Pierre et Marie Curie, Hopital Broussais, Paris,
France. stahld@uni-muenster.de
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by a
malignant CD5+ B-cell clone. The leukemic clone commonly expresses IgM
antibodies exhibiting reactivity toward a wide range of self-antigens.
However, B-CLL associated autoimmunity is typically restricted to
self-antigens expressed by blood cells, and mediated by IgG
autoantibodies of polyclonal origin. In the present study, we addressed
the question whether self-reactive antibody repertoires of plasma IgM
and IgG are disturbed by monoclonal immunoglobulins of B-CLL patients,
and whether antibody repertoires of patients exhibiting B-CLL associated
target-restricted autoimmune disease (AID) differ from those of B-CLL
patients without AID. We investigated antibody repertoires at a global
level, using a technique of quantitative immunoblotting that allows for
the quantitative screening of antibody reactivities in complex antibody
mixtures toward a large panel of antigens derived from homologous tissue
extracts, followed by multiparametric statistical analysis of the data.
We demonstrate that self-reactive antibody repertoires of plasma IgM and
IgG are broadly altered in patients with B-CLL, that alterations in
self-reactive antibody repertoires are not restricted to B-CLL patients
exhibiting AID, and that target-restricted autoimmunity in B-CLL
patients is associated with altered antibody repertoires not restricted
to the target organ. We conclude that monoclonal alterations of
immunoglobulin production in B-CLL are associated with broad defects of
self-reactive antibody repertoires. Our observations suggest that the
application of therapeutic IVIg preparations might influence B-CLL by
restoring normal self-reactive antibody repertoires in plasma.
15
UI - 11699207
AU - Tsimanis A; Shvidel L; Klepfish A; Shtalrid M; Kalinkovich A; Berrebi A
TI -
Over-expression of the functional interleukin-11 alpha receptor in the
development of B-cell chronic lymphocytic leukemia.
SO - Leuk Lymphoma 2001 Jun;42(1-2):195-205
AD - Department of Hematology, Kaplan Medical Center, POB 1, Rehovot, 76100,
Israel. Yehudats@netvision.net.il
Several cytokines have been found to play a role in the pathogenesis of
B-CLL. In the present study using reverse-transcriptase polymerase chain
reaction (RT-PCR), FACS analysis and immunofluorescence we have shown
the constitutive expression of IL-11 and IL-11R alpha in B-chronic
lymphocytic leukemia (B-CLL). The expression level of IL-11R alpha in
B-CLL cells is much higher than in PBL of normal donors. Recombinant
human IL-11 (rhIL-11) activates B-CLL cells, leading to morphologic
alterations of the cells and increase in cell number and size.
Short-term cultivation in the presence of rhIL-11 did not lead to
quantitative changes in the ratio of the living vs apoptotic and dead
cells. However, in contrast to rhIL-6, pretreatment with rhIL-11, did
not cause B-CLL cells to be resistant to the action of dexamethasone.
These data suggest an essential role for the IL-11/IL11 R alpha system
in the pathogenesis of the malignant B-CLL cells.
16
UI - 11699221
AU - Gu B; Dao LP; Wiley J
TI -
Impaired transendothelial migration of B-CLL lymphocytes: a defect
linked to low L-selectin expression.
SO - Leuk Lymphoma 2001 Jun;42(1-2):5-12
AD - Sydney University, Department of Medicine, Nepean Hospital, Penrith, NSW
2750, Australia.
The emigration of lymphocytes from blood into lymph nodes is regulated
by the expression of the adhesion molecule, L-selectin on the lymphocyte
surface which arrests the rolling of the cell on the vessel wall and
allows firmer adhesive interactions to develop. The expression of
L-selectin on B-CLL lymphocytes is less than half that on normal
lymphocytes and this difference correlates with an impaired capacity of
B-CLL lymphocytes to migrate beneath a monolayer of human umbilical vein
endothelial cells. Both the B-cell and T-cell lymphocytes from normal
subjects and B-CLL patients show down-regulation of L-selectin and CD23
after transendothelial migration. The reduced expression of L-selectin
on B-CLL lymphocytes leads to a relative "trapping" of these cells in
the vascular space and is one factor contributing to the elevation of
peripheral lymphocyte count.
17
UI - 11699227
AU - Ishibe N; Sgambati MT; Fontaine L; Goldin LR; Jain N; Weissman N; Marti
TI -
GE; Caporaso NE
Clinical characteristics of familial B-CLL in the National Cancer
Institute Familial Registry.
SO - Leuk Lymphoma 2001 Jun;42(1-2):99-108
AD - Genetic Epidemiology Branch, Division of Cancer Epidemiology and
Genetics, National Cancer Institute, National Institutes of Health, 6120
Executive Blvd., MSC 7236, Rockville, MD 20852, USA.
In an ongoing study, families with two or more living cases of B-CLL in
first-degree relatives have been recruited through physician and
self-referral. Since 1967, 28 kindreds with 73 cases of B-CLL have been
enrolled within the National Cancer Institute (NCI) Familial B-CLL
Registry. Medical, clinical, and demographic information have been
obtained from private physicians, patient interview, hospital records,
and death certificates. We used SEER Registry data to compare
characteristics of sporadic B-CLL to familial B-CLL. The mean age at
diagnosis was approximately 10 years younger among familial cases (57.9
+/- 12.1) than that observed in sporadic cases (70.1 +/- 11.9). A higher
percentage of second primary tumors among familial CLL cases compared to
reports in sporadic was also observed (16% vs. 8.8%). However, the
transformation rate to non-Hodgkin's lymphoma does not appear to be
different from that reported for sporadic cases. In conclusion, we
observed some differences between familial and sporadic cases; whether
any of these characteristics affect survival time or severity of disease
is unknown. The study of families with multiple B-CLL cases will aid in
delineating the genes and environmental factors that may play a role in
the development of both forms of B-CLL.
18
UI - 11871387
AU - Esteve J; Villamor N; Colomer D; Montserrat E
TI -
Different clinical value of minimal residual disease after autologous
and allogenic stem cell transplantation for chronic lymphocytic
leukemia.
SO - Blood 2002 Mar 1;99(5):1873-4
19
UI - 11916516
AU - Kivekas I; Hulkkonen J; Hurme M; Vilpo L; Vilpo J
TI -
CD80 antigen expression as a predictor of ex vivo chemosensitivity in
chronic lymphocytic leukemia.
SO - Leuk Res 2002 May;26(5):443-6
AD - Leukemia Research Laboratory, Department of Clinical Chemistry,
Laboratory Center, Tampere University Hospital and University of Tampere
Medical School, P.O. Box 2000, FIN-33521, Tampere, Finland.
We investigated the correlation between expression of 31 surface
membrane antigens and chemosensitivity of peripheral blood mononuclear
cells from 36 patients with CLL. The sensitivity of CLL cells to nine
drugs (2'-chlorodeoxyadenosine, cisplatin, chlorambucil, cyclosporin A,
doxorubicin, fludarabine, prednisolone, verapamil and vincristine) and
two types of irradiation (gamma and UV-irradiation) was determined from
dose-response curves of 4-day cultures ex vivo. The results indicated
that the CLL cases responding to purine analogs (2'-chlorodeoxyadenosine
and fludarabine) can be identified according to CD80 expression: all
resistant cases had low or negative CD80 expression. No other
correlations were revealed. CD80 may be a surrogate chemosensitivity
marker for purine analogs.
20
UI - 11916525
AU - Zhou R; Frostvik Stolt M; Kronenwett U; Gruber A; Liliemark J; Liliemark
TI -
E
Real-time RT-PCR for the determination of topoisomerase II mRNA level in
leukaemic cells.
SO - Leuk Res 2002 May;26(5):487-94
AD - Department of Oncology-Pathology, Cancer Center Karolinska at CCK,
Karolinska Institute and Hospital, R8:00, SE-171 76 Stockholm, Sweden.
rong.zhou@cck.ki.se
We developed a real-time RT-PCR assay for the quantification of
topoisomerase II (topo II) mRNA level. It was applied on peripheral
leukaemic cells from 23 patients with acute myelogenous leukaemia (AML)
and 23 with chronic lymphocytic leukaemia (CLL). RNA template dilutions
from 0.25 to 25ng per reaction were used as standard curves for topo
IIalpha, beta and the internal control 18S rRNA. About 57% (26/46) and
26% (12/46) of the specimens had detectable topo IIbeta and alpha mRNA,
respectively. The correlation between these two factors was rho=0.7 and
P=0.0001. No relationship between topo IIalpha or beta mRNA level and
response to chemotherapy was found in AML patients (n=19 assessable for
response).Our method is rapid and convenient for quantification of topo
IIalpha and beta mRNA levels, and could be suitable for investigation in
a larger population.
21
UI - 11769960
AU - Keating MJ
TI -
Progress in CLL, chemotherapy, antibodies and transplantation.
SO - Biomed Pharmacother 2001 Nov;55(9-10):524-8
AD - The University of Texas M. D. Anderson Cancer Center, Department of
Leukemia, Houston 77030, USA.
Over the last decade, major advancements in our understanding of chronic
lymphocytic leukemia (CLL) and its variants have occurred. It has become
apparent that there is diversity in types of CLL including those
patients that do or do not have hyper-mutation of their immunoglobulin
genes. Mutated genes confer a favorable prognosis. One of the major
advances in our therapy has been the discovery of the activity of purine
analogs, which have been demonstrated to be more active than
conventional therapy in achieving complete remission, prolonged
remission duration, and a suggestion of improved survival. More
recently, based on information that purine analogs inhibit DNA repair,
rational combinations have been developed. In particular, fludarabine
plus cyclophosphamide appeared to have added activity compared to either
drug given alone or in sequence. This has led to a higher response rate,
longer time to progression, and an improvement in survival in patients
treated following prior alkylating agents. Two monoclonal antibodies,
Rituximab and Campath-1H, have become available for clinical use and
research. Rituximab has modest activity as a single agent, with higher
response rates being noted in patients who receive more intensive
regimens. Rituximab has been successfully combined with chemotherapy,
and in association with fludarabine plus cyclophosphamide (FCR) has a
very high response rate and the ability to obtain polymerase chain
reaction (PCR) negativity for the immunoglobulin heavy chain region.
Campath-1H is very active as a single agent and is being recommended for
treatment for patients with fludarabine refractory disease and will
receive increased attention as a research agent in earlier-stage
patients. Autologous and allogeneic bone marrow transplantation have
emerged as significant treatments in CLL. The ability to achieve
responses in bone marrow and peripheral blood with newer regimens has
given the opportunity to collect stem cells from patients. There is a
suggestion that intensification of remissions with autologous transplant
can lead to PCR negativity and prolonged remissions. Allogeneic
transplantation has been demonstrated to be effective with a strong
suggestion of graph versus leukemia effect. This has been utilized in
the development of non-ablative marrow allogenaic bone marrow transplant
programs. Non-ablative transplants appear to be as effective as ablative
transplants in the most recent analysis. Thus, multiple modalities have
been brought together to achieve high-quality complete remissions in
CLL, giving the prospect of improved survival.
22
UI - 11869948
AU - De Fanis U; Dalla Mora L; Romano C; Sellitto A; Tirelli A; Lucivero G
TI -
Altered constitutive and activation-induced expression of CD95 by B- and
T-cells in B-cell chronic lymphocytic leukemia.
SO - Haematologica 2002 Mar;87(3):325-7
Expression of CD95, a molecule involved in activation-induced cell death
(AICD), might contribute to explain accumulation of leukemic B-cells and
functional impairment of T-cells in B-cell chronic lymphocytic leukemia
(B-CLL). There-fore, we compared constitutive and activation-induced
expression of CD95 and CD69 by B- and T-cells in CLL patients and in
healthy donors.
23
UI - 11877305
AU - Kennedy B; Rawstron A; Carter C; Ryan M; Speed K; Lucas G; Hillmen P
TI -
Campath-1H and fludarabine in combination are highly active in
refractory chronic lymphocytic leukemia.
SO - Blood 2002 Mar 15;99(6):2245-7
AD - Haematological Malignancy Diagnostic Service, Institute of Pathology,
Algernon Firth Building, University of Leeds, Leeds LS2 9JT, West
Yorkshire, UK. medbk@leeds.ac.uk
Campath-1H (alemtuzumab) is the most effective monoclonal antibody in
single-agent use in B-cell chronic lymphocytic leukemia (CLL) with
reported response rates of 33% to 70%. Combination therapy is now the
conventional treatment for most hematologic malignancies. Monoclonal
antibody treatments may sensitize tumor cells to subsequent
chemotherapy. We report the combination of Campath-1H with fludarabine
in patients with CLL refractory to each agent used singly. Six patients
who had received a median of 8 courses of fludarabine (range, 4-10
courses) and 16 weeks of Campath-1H (range, 8-32 weeks) were treated.
Five patients responded, including one who had a complete response by
National Cancer Institute criteria. The responses observed were better
in each patient than responses after each agent used singly. Complete
morphologic bone marrow responses were seen in 3 patients, including
eradication of disease measured by sensitive flow cytometry in 2.
Campath-1H combined with fludarabine is a highly promising novel therapy
for refractory CLL.
24
UI - 11877310
AU - Tobin G; Thunberg U; Johnson A; Thorn I; Soderberg O; Hultdin M; Botling
TI -
J; Enblad G; Sallstrom J; Sundstrom C; Roos G; Rosenquist R
Somatically mutated Ig V(H)3-21 genes characterize a new subset of
chronic lymphocytic leukemia.
SO - Blood 2002 Mar 15;99(6):2262-4
AD - Department of Genetics and Pathology, Uppsala University, SE-751 85
Uppsala, Sweden.
Recent studies on the immunoglobulin variable heavy chain (IgV(H)) genes
have revealed that B-cell chronic lymphocytic leukemia (B-CLL) consists
of at least 2 clinical entities with either somatically mutated or
unmutated V(H) genes. We have analyzed the V(H) gene mutation status and
V(H) gene usage in 119 B-CLL cases and correlated them to overall
survival. A novel finding was the preferential use of the V(H)3-21 gene
in mutated cases, whereas biased V(H)1-69 gene usage was found in
unmutated cases as previously reported. Interestingly, the subset of
mutated cases using the V(H)3-21 gene displayed distinctive
genotypic/phenotypic characteristics with shorter average length of the
complementarity determining region 3 and clonal expression of lambda
light chains. In addition, this mutated subset showed significantly
shorter survival than other mutated cases and a similar clinical course
to unmutated cases. We therefore suggest that B-CLL cases with mutated
V(H)3-21 genes may constitute an additional entity of B-CLL.
25
UI - 11902141
AU - Zupo S; Cutrona G; Mangiola M; Ferrarini M
TI -
Role of surface IgM and IgD on survival of the cells from B-cell chronic
lymphocytic leukemia.
SO - Blood 2002 Mar 15;99(6):2277-8
26
UI - 11839681
AU - Moon E; Lee R; Near R; Weintraub L; Wolda S; Lerner A
TI -
Inhibition of PDE3B augments PDE4 inhibitor-induced apoptosis in a
subset of patients with chronic lymphocytic leukemia.
SO - Clin Cancer Res 2002 Feb;8(2):589-95
AD - Department of Medicine, Section of Hematology and Oncology, Boston
Medical Center, 650 Albany Street, Boston, MA 02118, USA.
PURPOSE: cAMP phosphodiesterase (PDE) 4 is a family of enzymes the
inhibition of which induces chronic lymphocytic leukemia (CLL)
apoptosis. However, leukemic cells from a subset of CLL patients are
relatively resistant to treatment with the PDE4 inhibitor rolipram,
particularly when this drug is used in the absence of an adenylate
cyclase stimulus such as forskolin. Elevated cAMP levels induce
compensatory up-regulation of several cyclic nucleotide PDE families in
other model systems. We here examine the hypothesis that CLL cells that
survive treatment with rolipram do so as a result of residual PDE
activity that is not inhibited by this drug. EXPERIMENTAL DESIGN: We
examined by Western analysis the effect of rolipram treatment on CLL
expression of PDE3B, PDE4A, PDE4B, PDE4D, and PDE7A. We also examined
the ability of rolipram (PDE4 inhibitor) or cilostamide (PDE3
inhibitor), alone or together, to induce apoptosis or elevate cyclic AMP
in leukemic cells from patients with CLL. RESULTS: Rolipram increased
levels of PDE4B and, to a variable extent, PDE4D. When combined with
forskolin, rolipram also increased levels of a second family of PDEs,
PDE3B. Addition of the specific PDE3 inhibitor, cilostamide, modestly
augmented rolipram-induced apoptosis in five of seven
"rolipram-resistant" CLL samples. CONCLUSIONS: Although this work
confirms that PDE4 appears to be the most important PDE target for
induction of apoptosis in CLL, combination therapy with PDE3 and PDE4
inhibitors or use of dual-selective drugs may be of benefit in a subset
of relatively PDE4-inhibitor resistant CLL patients.
27
UI - 11997030
AU - Nardini E; Rizzi S; Capello D; Vitolo U; Gaidano G; Menard S; Balsari A
TI -
Most immunoglobulin heavy chain switch mu rearrangements in B-cell
chronic lymphocytic leukemia are internal deletions.
SO - FEBS Lett 2002 May 8;518(1-3):119-23
AD - Department of Experimental Oncology, Molecular Targeting Unit, National
Cancer Institute, Via Venezian 1, 20133, Milan, Italy.
We investigated 38 cases of B-cell chronic lymphocytic leukemia (B-CLL)
for the presence of non-productive rearrangements in the S(mu) regions
and defined for the first time the molecular nature of these
rearrangements. Southern blot analysis revealed S(mu) region
rearrangements in 13 cases (34%) and polymerase chain reactions (PCRs)
indicated that these rearrangements consisted of internal deletions of
the S(mu) region. Long-distance PCRs localized the S(mu) deletions in
the V(H)DJ(H) rearranged allele in most cases. We investigated if S(mu)
deletions were related to V(H) somatic mutations that, together with
isotype switch recombination, are indicative of the B-cell maturation
stage. No significant correlation between the presence of S(mu)
deletions and V(H) somatic mutations was found, indicating that the two
processes are independent in B-CLL. Moreover no significant correlation
between S(mu) deletions and prognosis was observed. Having shown that
S(mu) internal deletions are not chromosome translocations rules out
their involvement in the onset of malignancy, while their localization
in the V(H)DJ(H) rearranged alleles suggests a possible role in the
stabilization of the isotype of the expressed immunoglobulin.
28
UI - 10477712
AU - Damle RN; Wasil T; Fais F; Ghiotto F; Valetto A; Allen SL; Buchbinder A;
TI -
Budman D; Dittmar K; Kolitz J; Lichtman SM; Schulman P; Vinciguerra VP;
Rai KR; Ferrarini M; Chiorazzi N
Ig V gene mutation status and CD38 expression as novel prognostic
indicators in chronic lymphocytic leukemia.
SO - Blood 1999 Sep 15;94(6):1840-7
AD - Department of Medicine, North Shore University Hospital, Manhasset, NY,
USA.
Cellular immunophenotypic studies were performed on a cohort of randomly
selected IgM(+) B-chronic lymphocytic leukemia (B-CLL) cases for which
Ig V(H) and V(L) gene sequences were available. The cases were
categorized based on V gene mutation status and CD38 expression and
analyzed for treatment history and survival. The B-CLL cases could be
divided into 2 groups. Those patients with unmutated V genes displayed
higher percentages of CD38(+) B-CLL cells (>/=30%) than those with
mutated V genes that had lower percentages of CD38(+) cells (<30%).
Patients in both the unmutated and the >/=30% CD38(+) groups responded
poorly to continuous multiregimen chemotherapy (including fludarabine)
and had shorter survival. In contrast, the mutated and the <30% CD38(+)
groups required minimal or no chemotherapy and had prolonged survival.
These observations were true also for those patients who stratified to
the Rai intermediate risk category. In the mutated and the <30% CD38(+)
groups, males and females were virtually equally distributed, whereas in
the unmutated and the >/=30% CD38(+) groups, a marked male predominance
was found. Thus, Ig V gene mutation status and the percentages of
CD38(+) B-CLL cells appear to be accurate predictors of clinical outcome
in B-CLL patients. These parameters, especially CD38 expression that can
be analyzed conveniently in most clinical laboratories, should be
valuable adjuncts to the present staging systems for predicting the
clinical course in individual B-CLL cases. Future evaluations of new
therapeutic strategies and drugs should take into account the different
natural histories of patients categorized in these manners.
29
UI - 10477713
AU - Hamblin TJ; Davis Z; Gardiner A; Oscier DG; Stevenson FK
TI -
Unmutated Ig V(H) genes are associated with a more aggressive form of
chronic lymphocytic leukemia.
SO - Blood 1999 Sep 15;94(6):1848-54
AD - Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK.
terjoha@aol.com
Despite having several characteristics of naive B cells, chronic
lymphocytic leukemia (CLL) cells have been shown in some cases to have
somatically mutated Ig variable region genes, indicating that the cell
of origin has passed through the germinal center. A previous study of
patients with CLL found an association between lack of somatic mutation
and trisomy 12 and, therefore, possibly with a less favorable prognosis.
We have sequenced the Ig V(H) genes of the tumor cells of 84 patients
with CLL and correlated our findings with clinical features. A total of
38 cases (45.2%) showed >/= 98% sequence homology with the nearest
germline V(H) gene; 46 cases (54.8%) showed >2% somatic mutation.
Unmutated V(H) genes were significantly associated with V1-69 and D3-3
usage, with atypical morphology; isolated trisomy 12, advanced stage and
progressive disease. Survival was significantly worse for patients with
unmutated V(H) genes irrespective of stage. Median survival for stage A
patients with unmutated V(H) genes was 95 months compared with 293
months for patients whose tumors had mutated V(H) genes (P =.0008). The
simplest explanation is that CLL comprises 2 different diseases with
different clinical courses. One, arising from a memory B cell, has a
benign course, the other, arising from a naive B cell, is more
malignant.
30
UI - 10787241
AU - Hamblin TJ; Orchard JA; Gardiner A; Oscier DG; Davis Z; Stevenson FK
TI -
Immunoglobulin V genes and CD38 expression in CLL.
SO - Blood 2000 Apr 1;95(7):2455-7
31
UI - 11263438
AU - Thunberg U; Johnson A; Roos G; Thorn I; Tobin G; Sallstrom J; Sundstrom
TI -
C; Rosenquist R
CD38 expression is a poor predictor for VH gene mutational status and
prognosis in chronic lymphocytic leukemia.
SO - Blood 2001 Mar 15;97(6):1892-4
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