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PubMed1985

Spleen irradiation in chronic lymphocytic leukemia (CLL): palliation in patients unfit for splenectomy.

In 22 patients with CLL given 30 courses of spleen irradiation, 23 responses were observed (77%, 95% confidence limits, 58-90%). Response was defined as reduction in palpable spleen size accompanied by relief of symptoms (pain, abdominal discomfort, and sweating) or improvement in hypersequestration or hemolytic anemia. Reduction in leukocyte count alone was not regarded as response. All responses were partial. The median response duration was 1 year. Subsequently, three patients underwent splenectomy. The median survival from the beginning of spleen irradiation was 2.5 years (range: 1 month-greater than 5 years). Only six patients had minor side effects from the gastrointestinal tract. The hematologic effect was most pronounced on the white blood cell count, but also the platelet count was affected. It is concluded that spleen irradiation is a gentle and effective alternative in CLL patients suffering from splenomegaly (pain and hypersplenism), refractory to chemotherapy and glucocorticosteroids and unfit for splenectomy. Splenic irradiation may also be used with benefit preoperatively before splenectomy in patients with excessive splenomegaly and hypersplenism.

Adult↗

PubMed1984

Chromosome studies in patients with T-CLL chronic lymphocytic leukemia and expansions of granular lymphocytes.

Chromosome analyses were carried out in eight patients with lymphoproliferative disorders of mature T and NK cells. Three cases were characterized by an abnormal expansion of granular lymphocytes (GL), one by a lymphoma of GL with leukemic spread, and four by an OKT4-T-CLL. In four patients cytogenetic studies were performed on bone marrow cells; in seven patients peripheral blood lymphocytes were examined by either direct preparations or PHA-stimulated cultures. Six patients displayed a normal karyotype. Two cases belonging to the OKT4-T-CLL group had a chromosome number ranging from 44 to 47, with multiple numerical and structural clonal anomalies. Clonal anomalies could be a feature of patients with the more aggressive clinical course.

Adult↗

PubMed1995

Detection of two Epstein-Barr-virus (EBV)-carrying leukemic cell clones in a patient with chronic lymphocytic leukemia (CLL).

The leukemic-cell population of one CLL patient, PG, was found to contain a sub-set of EBV-genome-carrying cells. It was detected directly by the expression of EBNA (EBV-encoded nuclear antigen) and by its capacity to grow in vitro. The proportion of EBNA-positive cells (0.1%) was maintained constantly during the period of this study, the final 3 years of the patient's life. EBV-carrying clonal sibling B-cell lines were established on 5 occasions. They had identically rearranged JH bands and chromosomal markers corresponding to the ex vivo CLL cells. Analysis of the viral episomes in the lines proved that they were the descendants of one cell. On the last occasion of blood sampling, 8 B-cell lines were established; 4 of these contained the same clonal markers as the previous lines, while 4 other lines belonged to another clone with identical JH rearrangement. Their abnormal karyotypes were different from the first clone. The chromosomal markers were only partly identical, suggesting secondary diversifications. The EBV sub-strain carried by this group of lines was different from the sub-strain of the first clone, as judged by the EBNA size distributions (EBNOtype) and EBV-DNA analysis. Analysis of the terminal repeat in the viral episomes also showed that the first and the second set of clones represented 2 independent EBV-infection events in vivo.

B-Lymphocytes↗

PubMed2005

Differential effects on CLL cell survival exerted by different microenvironmental elements.

Selected microenvironmental stimuli confer to leukemic cells a growth advantage and an extended survival. We aimed at dissecting the differential support provided by the different cellular components of the microenvironment where CLL cells accumulate. To this end we cultured purified CLL cells in vitro in the presence or absence of different accessory cells (stromal cells, autologous T lymphocytes) and/or soluble molecules (IL-4, sCD40L) and assessed the leukemic cell response in terms of cell viability and chemoattracting capacity. The results indicate that both T lymphocytes and stromal cells are involved in sustaining the survival of leukemic B cells, but indicate that their support is different in terms of time of onset and duration. T cells have a short-term support activity while stromal cells provide long-term support.

B-Lymphocytes↗

PubMed1989

Long-range restriction map of a region of human chromosome 19 containing the apolipoprotein genes, a CLL-associated translocation breakpoint, and two polymorphic MluI sites.

The apolipoprotein gene cluster on human chromosome 19 (APOC1, APOC2, APOE) has been localised by pulsed-field gel electrophoresis to within 200 kb of a chronic lymphocytic leukemia-associated translocation breakpoint. A restriction map covering 1300 kb around these loci has been constructed and contains two polymorphic MluI sites, which appear to show Mendelian inheritance. The orientation of the map on the chromosome has been established as 19cen - CLL breakpoint - APOC2 - 19qter. Pedigree analysis using APOC2, a probe derived from the CLL breakpoint, and other localised markers on 19q suggests that the myotonic dystrophy locus is distal to APOC2 on 19q.

Apolipoproteins↗

PubMed1987

T-helper phenotype chronic lymphocytic leukemia (Thp-CLL): characterization of an Italian case with particular biological findings.

A patient with Chronic Lymphocytic Leukemia (CLL) characterized by an expansion of helper phenotype mature T lymphocytes is here described. The phenotype of these cells was OKT3+, OKT4+, Leu 9+, 5/9+, OKT8-, Tac- and functional studies showed a strong helper activity on B cell differentiation; an "in vivo" presence of an IgG-lambda paraproteinaemia has been demonstrated. Cytogenetic studies showed multiple clonal, numerical and structural rearrangements which included a tandem t(14;14) (q11;32) translocation. Hybridization showed HTLV I related specific bands indicating the presence of exogenous sequences related to prototype virus but derived from a different Retrovirus (HTLV 1c). The clinical course was aggressive and unsuccessful treatments with various polichemotherapeutic protocols, associated with multiple leukaphereses, were performed. The authors underline that despite the morphological, immunological, biological and virological heterogeneity, the common feature of T-helper CLL is the inexorable clinical course which needs a new therapeutic approach.

Antibodies, Viral↗

PubMed2002

[Progressive multifocal leukoencephalopathy (PML) in chronic lymphatic leukemia (CLL). Review of the literature and case report].

Progressive multifocal leukoencephalopathy (PML) is an infectious disease of the central nervous system caused by the JC virus. Progressive multifocal leukoencephalopathy represents a reactivation of the JC virus after long-standing immunosuppression. Also, PML plays an important role as an opportunistic infection in patients with AIDS. The average time of survival in patients with PML in combination with chronic lymphatic leukemia (CLL) (n = 17 in the literature) is 4.3 months, and therapeutic options are not established. We report the case of a patient with CLL and PML. Clinical symptoms are slight hemiparesis of the right side, mainly appearing as a disturbance of motor function. In MRI, a typical subcortical lesion was shown, and JC virus DNA was positive in the CSF by PCR. Because of first positive results in treatment of PML in patients with AIDS, therapy with cidofovir was started. After treatment for 16 months, symptoms are stable, the PML-induced lesions in MRI are in regression, and JC virus DNA is not detectable in the CSF.

Antiviral Agents↗

PubMed2006

Cyclin E but not bcl-2, bax or mcl-1 is differentially expressed in ZAP 70-positive and ZAP 70-negative B-CLL cells.

The clinical course of chronic lymphocytic leukemia is variable. While some patients have indolent disease, others require aggressive treatment within a short time after diagnosis. Differences in the expression of proteins regulating cell cycle and apoptosis may be responsible for the heterogeneous course of the disease. Recently, protein ZAP 70 [zeta-chain (T-cell receptor) associated protein kinase 70 kDa] has been found to be differentially expressed within two biologic subgroups, characterized by the presence or absence of somatic mutations in specific immunoglobulin heavy-chain variable region genes. In the present work, we analyzed highly purified B-CLL cells from 60 patients for ZAP 70 expression and the expression of cyclin E, bcl-2, bax, and mcl-1 as well as the ratios of bcl-2/bax and mcl-1/bax. The results indicate that cyclin E is expressed significantly higher in ZAP 70-positive as in ZAP 70-negative samples. We did not observe significant differences within the expression of Bcl-2 family member proteins. We conclude that higher cyclin E expression in samples of ZAP 70-positive patients may reflect a larger proliferating compartment in vivo compared to ZAP 70-negative patients and that cyclin E may add prognostic information in this context for patients with B-CLL.

Adult↗

PubMed2005

Mobilization of peripheral blood stem cells in CLL patients after front-line fludarabine treatment.

Autologous peripheral blood stem cell transplantation is performed in an increasing number of chronic lymphocytic leukaemia (CLL) patients who are in the first remission following fludarabine treatment. There are contradictory data about the adverse impact of fludarabine on stem cell harvest. We analysed retrospectively mobilization results in 56 poor-risk CLL patients (median age: 56 years) who underwent first-line treatment with fludarabine and cyclophosphamide. The mobilization, consisting of cyclophosphamide 3 g/m(2) and granulocyte colony-stimulating factor (G-CSF) 10 microg/kg per day, was performed with a median of 77 days following the last fludarabine course. The target yield was >or=2.0x10(6) CD34+ cells/kg. The procedure was successful in 23 (41%) patients. A median of 3.3x10(6) CD34+ cells/kg was collected per patient. The successful mobilization was associated with a longer interval from the last chemotherapy (>2 months). The mobilization result was not influenced by the number of fludarabine cycles. No correlation was found in other parameters such as disease stage at diagnosis, disease status at stimulation or age. The poorly mobilized patients had significantly lower prestimulation blood counts (platelets, WBC and haemoglobin). Our data show that fludarabine does not generally prevent the stem cell mobilization; nevertheless, mechanisms related to the impact of fludarabine on stem cell harvest must be further investigated.

Adult↗

PubMed2001

Absence of clonal chromosomal relationship between concomitant B-CLL and multiple myeloma--a report on two cases.

B-cell chronic lymphocytic leukemia (B-CLL) and multiple myeloma (MM) are chronic B-cell malignancies that represent different stages of B-cell maturation. Occasionally, both diseases are present in the same patient, and this raises the question of clonal associations between the two neoplasms. We here report on two patients with concomitant B-CLL and MM. Clonal chromosomal abnormalities in both lymphocytic cells and plasma cells were studied by interphase fluorescence in situ hybridization (FISH) using a panel of 24 chromosome- and region-specific DNA probes. In the first patient, cytogenetics revealed 47, X, t(Y;22)(p11;q10), +12, dell4(q21q32). By FISH, +12 was present in lymphoid cells, but not in plasma cells. MM cells were characterized by multiple chromosomal gains (1, 11q23) and losses (5q, 10, 13q14, 15, 17p13, Y), which were all undetectable in lymphoid cells. The second patient, in whom no clonal abnormalities were obtained by conventional cytogenetic analysis, had lymphoid cells with loss of 8q24 by FISH. In contrast, evidence for a gain of 8q24 (consistent with amplification of c-myc) was obtained in 13% of plasma cells. Plasma cells were further characterized by gains of chromosomes 1, 3, 11, 18, and Y. We thus conclude that this comprehensive molecular cytogenetic analysis demonstrates the existence of two clonally distinct B-cell malignancies in both patients.

Aged↗

PubMed1995

Potentiation of chlorambucil toxicity in B-CLL lymphocytes using the DNA synthesis inhibitors aphidicolin and 1-beta-D-arabinofuranosylcytosine.

Previous studies in our laboratory have identified enhanced cross-link repair as a primary mechanism of resistance to nitrogen mustards in B-cell chronic lymphocytic leukemia (B-CLL). To evaluate the therapeutic potential for modulation of DNA repair by aphidicolin and 1-beta-D-arabinofuranosylcytosine (ara-C), we examined the interaction between these two agents and chlorambucil in lymphocytes from untreated and treated-resistant B-CLL patients. We found that both aphidicolin and ara-C displayed synergy with chlorambucil over a range of inhibitor concentrations. This synergy was not restricted to the resistant samples. Our results indicate that these combinations can enhance the potency of chlorambucil in a clinically relevant model and should be considered for further preclinical and, eventually, clinical trials.

Aphidicolin↗

PubMed1982

Acetylcholinesterase (AchE) activity of lymphocytes in chronic lymphoid leukemia (CLL).

The specific AchE (EC 3.1.1.7) activity of lymphocytes from the peripheral blood of normal donors was determined. On Leukopak filter the isolated T lymphocytes showed activity, whereas in stepwise Percoll gradient, population TLD displayed enzyme activity. The THD and B cells were inactive. [Szelényi J. G., Bartha E. & Hollán S. R. (1982) Br. J. Haemat. 50, 241]. A mixed cell population derived from CLL patients had significantly lower enzyme activity than normal. With the progress of B-cell proliferation AchE activity decreased in parallel with the number of T cells. The sp. act. of TLD population isolated from CLL patients was the same as that of normal donors whereas their B cells were inactive.

Acetylcholinesterase↗

PubMed1988

Mitogenic stimulation of malignant B cells CLL: diminished in-vitro stimulation with anti-CR1 antibodies.

Peripheral B lymphocytes of five CLL patients were tested in a radioimmunoassay to determine the density of the C3b receptor (CR1) and the cells were assayed for their ability to mature into IgM secreting cells after in-vitro culture with a combination of Pokeweed Mitogen (PWM) and antibodies directed against CR1. Despite the presence of normal amounts of CR1 on the leukemic B cells, crosslinking of these receptors by anti-CR1 antibodies stimulated only a fraction of the leukemic cell population to differentiate into IgM secreting cells. These results add to the partial functional impairment of CLL-B cells.

Antibodies↗

PubMed2005

Protein expression profiling of CLL B cells using replicate off-line strong cation exchange chromatography and LC-MS/MS.

In this study we use replicate 2D-LC-MS/MS analyses of crude membranes from B cells derived from a patient with chronic lymphocytic leukemia (CLL) to examine the protein expression profile of CLL B cells. Protein identifications made by replicate 2D-LC-MS/MS analysis of tryptic peptides from detergent solubilized B cell membrane proteins, as well as replicate LC-MS/MS analysis of single off-line strong cation exchange chromatography (SCX) fractions, were analyzed. We show that despite the variance in SCX, capillary LC, and the data-dependent selection of precursor ions, an overlap of 64% between proteins identified in replicate runs was achieved for this system.

Antigens, CD↗

PubMed1988

Human Ia-associated invariant chain gene has multiple transcription initiation sites in CLL cells.

We show a northern transfer experiment revealed two mRNA of Ia-associated invariant chain (In) gene in chronic lymphocytic leukemia (CLL) cells which are approximately 1580 and 1440 nucleotides in length. Primer extension experiment shows that less prominent transcript was found to initiate 140 nucleotides upstream from the major cap site. The newly identified cap site was preceded by CG rich sequence but no typical promotor sequence. Southern hybridization analysis with In cDNA probe indicates no recombination or amplification of In gene in the CLL cells. This is the first documented example of such a mode of expression in malignant cells in vivo.

Base Sequence↗

PubMed1996

Autologous bone marrow transplantation in chronic lymphocytic leukemia (CLL).

Chronic lymphocytic leukemia (CLL) is an indolent disease characterized by an abnormal proliferation of monoclonal lymphocytes in the bone marrow and lymphoid tissues. Most of the cases (> 90%) belong to the B-lymphocyte lineage and the course of the disease is variable depending on the presence of poor prognostic factors at diagnosis. Therefore optimal treatment is still questioned; presently there are no proven cures for CLL, but the natural history of the disease and the advanced age of the majority of patients makes prolongation of survival a reasonable therapeutic goal in most cases. The traditional therapeutic approach has been based on the activity of alkylating agents and corticosteroid, while patients resistant have been treated with nucleoside analogs. However, patients ultimately relapse and the choice of salvage therapy by conventional methods does not offer many chances. Particularly in younger patients, with poor prognostic factors, the therapeutic options may substantially change in the near future, based on alternative and innovative approaches aimed at achieving cure or long disease-free-survival. The results of high-dose therapy followed by reinfusion of hematopoietic stem cells, either from bone marrow or peripheral blood, will be presented and discussed.

Bone Marrow Transplantation↗

PubMed1998

Comparative expression of major histocompatibility complex (MHC) antigens on CD5+ and CD5- B cells in patients with chronic lymphocytic leukaemia (CLL)

The aim of this study was to investigate the expression of major histocompatibility complex (MHC) antigens on CD5+ and CD5- B cells of 13 patients with chronic lymphocytic leukaemia (CLL). This was carried out using a series of monoclonal antibodies (MAbs) against polymorphic and monomorphic class I and class II antigens, as well as to the transferrin receptor and assessed by flow cytometry and direct and indirect immunofluorescence. The expression of these molecules was assessed as mean fluorescent intensity (MFI). The results showed that cells from all 13 individuals expressed monomorphic class I antigens. The number of cases expressing polymorphic HLA-Bw6, -Bw4, -B7, -B27 and -A2 class I antigens on CD5- B cells was 11 (85%), 6(46%), 2(15%), 1(8%), 3 (23%), respectively, which was consistent with the expected population frequency distributions of these antigens. For each of the class I antigens on CD5+ and CD5- B cells, the ratio of the MFI was greater than 1 in 12 of 13 cases. For the transferrin receptor (CD71), this ratio was also almost always greater than 1. These results indicate that, unlike solid tumours where the loss or abnormal expression of class I and II antigens is a frequent event, the expression of class I antigens in CLL patients seems to be normal. This indicates that the loss of these antigens cannot provide the leukaemic cells with a selective advantage to escape immunological detection.

Antigens, Neoplasm↗

PubMed1997

Autologous blood cell transplantation in B-CLL: response to chemotherapy prior to mobilization predicts the stem cell yield.

Successful stem cell mobilization and collection is possible in B-CLL after a favorable response to preceding chemotherapy, and also after treatment with the new nucleoside analogues fludarabine and cladribine. A poor response, on the other hand, seemed to predict a mobilization failure. CD34+ cell selection resulted in a 2- to 3-log reduction of the CLL cells in the harvests. Engraftment with both unselected and selected progenitor cells was rapid, and need for hospitalization was short. High-dose therapy with stem cell rescue appears to be capable of inducing CRs of high quality, but so far the follow-up is too short to define whether this will be translated into prolonged disease-free survival.

Antineoplastic Combined Chemotherapy Protocols↗