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PubMed2003

Predictive value of serum thymidine kinase level for Ig-V mutational status in B-CLL.

In B-CLL IgV(H) genes mutational status is a major prognostic factor. Since sequencing of IgV(H) genes is not available in most laboratories, an easily performed surrogate assay is desirable. To identify the best surrogate assay, and to better discriminate prognostic subgroups we analyzed clinical and biological data from 58 typical CLL cases. A higher serum thymidine kinase level (>15 U/l) proved to be a strong predictor of mutational status, and the only independent one among the studied parameters. To further identify prognostic subgroups, cluster analysis was employed on 38 cases on which all data were available, which segregated two groups including 25 and 13 patients, respectively. These two clusters differed by their proliferative potential and appeared to discriminate patients with very different clinical course and outcome. s-TK was strikingly different among these two clusters, suggesting that s-TK level could be used routinely to identify patients at risk of progression.

Aged↗

PubMed2004

Comparative analysis of minimal residual disease detection using four-color flow cytometry, consensus IgH-PCR, and quantitative IgH PCR in CLL after allogeneic and autologous stem cell transplantation.

The clinically most suitable method for minimal residual disease (MRD) detection in chronic lymphocytic leukemia is still controversial. We prospectively compared MRD assessment in 158 blood samples of 74 patients with CLL after stem cell transplantation (SCT) using four-color flow cytometry (MRD flow) in parallel with consensus IgH-PCR and ASO IgH real-time PCR (ASO IgH RQ-PCR). In 25 out of 106 samples (23.6%) with a polyclonal consensus IgH-PCR pattern, MRD flow still detected CLL cells, proving higher sensitivity of flow cytometry over PCR-genescanning with consensus IgH-primers. Of 92 samples, 14 (15.2%) analyzed in parallel by MRD flow and by ASO IgH RQ-PCR were negative by our flow cytometric assay but positive by PCR, thus demonstrating superior sensitivity of RQ-PCR with ASO primers. Quantitative MRD levels measured by both methods correlated well (r=0.93). MRD detection by flow and ASO IgH RQ-PCR were equally suitable to monitor MRD kinetics after allogeneic SCT, but the PCR method detected impending relapses after autologous SCT earlier. An analysis of factors that influence sensitivity and specificity of flow cytometry for MRD detection allowed to devise further improvements of this technique.

Adult↗

PubMed2001

Expansion of CD4+ T cells with a cytotoxic phenotype in patients with B-chronic lymphocytic leukaemia (B-CLL).

Abnormal CD4/CD8 ratios and T-cell function have previously been shown in patients with B-chronic lymphocytic leukaemia (B-CLL). We have demonstrated that CD4+ T cells containing both serine esterase and perforin (PF) are increased in the blood of these patients. Using flow cytometry, we have shown that the CD4+ PF+ cells were CD57+ but lacked expression of CD28, suggesting a mature population. The same phenotype in CD8+ T cells is characteristic of mature cytotoxic T cells. However, in contrast to the CD8+ T cells, the CD4+ T cells were more frequently CD45RO positive than CD45RA positive, indicating prior antigen experience. In contrast, this population lacked expression of either CD69 or HLA-DR, arguing that they were not activated or that they are an abnormal population of T cells. Their constitutive cytokine levels showed them mainly to contain IL4 and not IFNgamma, suggesting a Th2 phenotype. The role of the CD4+ PF+ T-cell population is at present uncertain. However, this potentially cytotoxic T-cell population could contribute both to enhancing survival of the B-CLL tumour cells through production of IL4, and to the immunodeficient state frequently seen in patients with this tumour, independent of drug treatment.

Aged↗

PubMed1995

The DNA and steroid binding domains of the glucocorticoid receptor are not altered in mononuclear cells of treated CLL patients.

The aim of this study was to investigate whether mutations in the glucocorticoid receptor could account for the increasing unresponsiveness of patients with chronic lymphatic leukemia (CLL) to combination chemotherapy. The receptor was tested immunocytochemically, in steroid binding assays, and by a mutation screening (denaturing gradient gel electrophoresis) of the receptor-cDNA. The receptor concentration, as measured by staining and steroid binding test, varied considerably but showed no clear correlation to clinical response. Using a highly sensitive mutation screening assay of the DNA- and the steroid-binding region, none of the treated patients revealed any mutation, suggesting that the glucocorticoid receptor in the CLL patients tested is not altered in these domains. In one individual who had not been treated before analysis a silent mutation was found in one receptor allele. The results suggest that mechanisms other than altered ligand or DNA binding of the receptor may be responsible for the lack of response to chemotherapy. This conclusion is discussed in relation to the mechanism of corticoid resistance in mouse and human lymphoma cells in culture.

Animals↗

PubMed2004

Maintenance therapy with a monthly injection of alemtuzumab prolongs response duration in patients with refractory B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL).

Alemtuzumab, the monoclonal anti-CD52 antibody, has clinical activity in B-cell and T-cell malignancies at the dose of 30 mg three times weekly for 9-12 weeks. This standard regimen induced responses usually shorter than 6 months. To prolong time to progression, we initialized a phase II study with an identical initial scheme until partial response, followed by a maintenance therapy lasting at least 4 months. Eleven heavily pretreated patients (8 with B-chronic lymhocytic leukemia (B-CLL) and 3 with small lymphoctyic lymphoma (SLL)) have been treated with this maintenance regimen (MR patients) and were retrospectively compared to 5 patients (3 B-CLL and 2 SLL) treated with the standard regimen (SR patients). Patients characteristics before treatment were identical in both groups. Objective response was reached by 9 (82%) MR patients and 3 (60%) SR patients (p NS). After the treatment, 8 (73%) MR patients and all SR patients progressed with a median time at 12.2 months and 3 months respectively. Survival time from alemtuzumab was significatively different (P < 0.005). None of the patients died in the MR group with a median follow-up at 16 months. In the SR group, the median survival from alemtuzumab was 5.9 months. We did not observe any differences in terms of hematological toxicites and infections between the two groups. In conclusion, maintenance alemtuzumab therapy seems to increase the time to progression and the survival, without adding hematological toxicities and infectious complications. More patients are needed to confirm this observation.

Aged↗

PubMed2004

Quantification of CD38 expression in B-cell chronic lymphocytic leukemia (B-CLL): a comparison between antibody binding capacity (ABC) and relative median fluorescence (RMF).

We have previously shown that quantification of CD38 expression using microbeads of specific antibody binding capacity (ABC) improves the prognostic value of CD38 expression in B-cell chronic lymphocytic leukemia, particularly for Binet Stage A patients. Quantification of CD38 expression using beads is expensive, time consuming and could be difficult to implement in a routine clinical laboratory. The calculation of relative median fluorescence (RMF) using the median fluorescence intensities of the test and control samples, is even more simply and cheaply obtained by flow cytometry and could be used as an alternative way of quantifying antigen expression. The present study demonstrates that RMF is an effective prognostic indicator in B-CLL that correlates closely with ABC in predicting disease-specific survival and time to progression for all patients. RMF predicted overall survival and time to progression in all patients (P < 0.0001 for both), in Binet Stage A patients (P < 0.0001 for both) and in Stage A patients under 60 years (P = 0.0299 and P = 0.0143, respectively). ABC predicted overall survival and time to progression in all patients (P < 0.0001 for both) in Stage A patients (P = 0.0024 and P < 0.0001, respectively) and in Stage A patients under 60 (P = 0.0379 and P = 0.0032, respectively). RMF is more effective than percentage CD38 positivity > 30% or > 20% in predicting disease-specific survival in Stage A patients of all ages (CD38 < > 30%: P = 0.0853, CD38 < > 20%: P = 0.0894) and in those under 60 years old (CD38 < > 30%: P = 0.5438, CD38 < > 20%: P = 0.2872). Also, RMF is more effective in predicting time to progression of Binet Stage A patients less than 60 years (P = 0.0143), while percentage CD38 positivity of 30%, 20% or 7% did not achieve statistical significance (P = 0.1103, = 0.0547, = 0.3399, respectively). We suggest that CD38 RMF could be used clinically as an alternative to ABC to identify patients with B-CLL that are likely to progress and require early treatment.

ADP-ribosyl Cyclase↗

PubMed2005

TNF family molecules in the serum of patients with B-cell chronic lymphocytic leukemia (B-CLL).

Tumor necrosis factor (TNF) superfamily, involving membrane receptors and ligands are important for the growth and survival of leukemic B cells. In the present study levels of TNF-alpha, sTNFRp55, sTNFRp75 and sCD40 and sCD40L in the serum of patients with B-CLL before and after treatment were measured. In sera of patients before treatment increased concentrations of sCD40 and decreased concentrations of sCD40L were shown. Increased concentrations of TNF-alpha and sTNFRp75 and lack of changes in sTNFRp55 concentrations were also found. Results obtained suggest that the relationships between examined soluble form of TNF family proteins may influence the development of B-cell chronic lymphocytic leukemia. The used therapy with 2CdA and CMC led to a favorable effect for host through changes in the relations between sCD40 and sCD40L. It was also found that sCD40 and sCD40L serum concentrations, which are dependent on the clinical stage and used therapy, are more sensitive tumor markers than TNF-alpha and its soluble receptor in patients with B-CLL treated with 2CdA and CMC.

CD40 Antigens↗

PubMed1988

Heterogeneity of CLL: high CD23 antigen and alpha IFN receptor expression are features of favourable disease and of cell activation.

The relationship between alpha-interferon receptor (alpha IFNR) numbers, B-cell-antigen expression and clinical stage was determined in 35 cases of typical chronic lymphocytic leukaemia (CLL). alpha IFNR numbers were shown to be low in patients with advanced disease and high in those with a more favourable prognosis. The B-cell activation antigen CD 23 was similarly related to stage, being high in more favourable disease. Also, alpha IFNR expression was directly related to CD 23 positivity, but alpha IFN binding was not inhibited by CD 23 monoclonal antibody. There was no correlation between CD 19, 20, 22 and 24 antigen expression and either alpha IFNR numbers or clinical stage. Since CD23 antigen expression is a feature of B-cell activation, we suggest that high CD23 and alpha IFNR positivity are manifestations of an activated cell phenotype and that cell activation in CLL is a feature of favourable disease.

Antigens, Differentiation, B-Lymphocyte↗

PubMed1993

An HTLV-I carrier who developed CD4+ T-CLL expressed the IL-2 receptor beta chain alone without expressing the alpha chain.

We describe a case of T-chronic lymphocytic leukaemia (T-CLL) with monoclonal proliferation of CD3+4+8- T cell expressing the interleukin 2 receptor (IL-2R) beta chain without expressing the alpha chain. Southern blot analysis of T-cell receptor beta chain gene revealed rearranged bands. The serum antibody was positive against human T-cell lymphotropic virus type I (HTLV-1)-associated antigens, but monoclonal integration of proviral DNA was not detected in the leukaemic cells. In accordance with the expression of IL-2R beta chain, the leukaemic cells proliferated in response to exogenous IL-2 without prior stimulation. However, culture supernatants of these cells did not show IL-2 activity. Since the role of the IL-2R beta chain in freshly isolated cells from T-CLL patients is not well understood, detailed analysis of this case would give us valuable information on the role of IL-2/IL-2R system in the proliferation of the leukaemic T cells.

Aged↗

PubMed1979

Mitogen-induced differentiation of human CLL lymphocytes to antibody-secreting cells.

Peripheral blood lymphocytes from nine patients with chronic lymphatic leukaemia (CLL) have been stimulated by photohaemagglutinin, pokeweed mitogen and Epstein-Barr virus. Our results provide proof that the leukaemic B cells in CLL are capable of responding to mitogenic signals by producing and secreting antibodies, transforming into blast cells, and, probably, increasing their rate of DNA synthesis.

Antibody Specificity↗

PubMed1993

Interleukin-4 (IL-4) enhances homotypic adhesion of activated B-chronic lymphocytic leukaemia (B-CLL) cells via a selective up-regulation of CD54.

It is well established that cell-to-cell contact modifies cytokine signalling but little is known on the role of homotypic cell adhesion for proliferation and differentiation of B cells. Homotypic adhesion involves mainly the interaction between the adhesion molecules Leukocyte Function Antigen-1 (LFA-1) and its ligand CD54 (ICAM-1). A well-characterized B-chronic lymphocytic leukaemia (B-CLL) clone (I-83) was used as a source of monoclonal B cells inducible to DNA synthesis and differentiation by using 12-O-tetradecanoyl-phorbol-13-acetate (TPA) in combination with interleukin-4 (IL-4) and thioredoxin (Trx)-containing supernatant from a T-cell hybridoma (BSF-MP6). This paper shows that IL-4 alone was able to induce aggregation of B-CLL cells and to strongly enhance TPA+BSF-MP6-induced aggregation. The results from studying the expression of CD11a and CD18, the two subunits of LFA-1, and CD54 during stimulated DNA synthesis and differentiation suggest that IL-4-induced, or enhanced, aggregation was mainly mediated by a selective up-regulation of CD54. It was further demonstrated by antibody blockade to either CD11a, CD18 or CD54 that aggregation could be inhibited without affecting induced DNA synthesis or differentiation.

Antibodies↗

PubMed1978

Effects of prednisolone in 6 cases of glucocorticoid receptor-positive CLL.

The effect of treatment with prednisolone on clinical and laboratory variables was studied in 6 patients with chronic lymphocytic leukaemia (CLL). The laboratory variables analyzed on the leukaemic cells were surface immunoglobulin (S-Ig), sheep red blood cell receptors (SRBC), proliferative activity (PI) and glucocorticoid receptor (GR). In all cases the CLL was of B-cell type and the leukaemic cells contained a significant amount of GR. 4 out of 6 patients had a progressive disease with increased PI. On treatment they went into clinical remission, which was paralleled by a reduction in the leukaemic B-cell number and in PI. The amount of GR was unaffected. In 2 patients with nonprogressive disease, prednisolone produced no clearcut effect on clinical or laboratory variables.

Complement System Proteins↗

PubMed1988

Expression of tartrate-resistant acid phosphatase in B-CLL treated with phorbol ester or phorbol ester plus calcium ionophore.

Cells from 3 patients with B-chronic lymphocytic leukaemia (B-CLL) and 1 with B-prolymphocytic leukaemia (B-PLL) were treated in vitro with the phorbol ester 12-0-tetradecanoylphorbol (TPA), the calcium ionophore A23187, or a combination of TPA and A23187. TPA induced the cells to adhere to the culture flask or to clump in dense clusters; single cells became enlarged, often with cytoplasmic elongations. Cells treated with TPA plus A23187 acquired a plasmacytoid morphology and formed regular aggregates in culture. Only TPA alone induced the expression of tartrate-resistant acid phosphatase (TRAP) as documented by isoelectric focusing on horizontal thin-layer gels. The TRAP isoenzyme was first detected after 24 h of TPA treatment; its intensity increased during further TPA exposure, being maximally expressed at 72/96 h. The results suggest that, while TPA triggers B-CLL cells to convert to hairy cell leukaemia (HCL)-type cells, the double stimulus which more closely imitates physiological activation initiates a 'normal' differentiation programme which leads to plasma cells.

Acid Phosphatase↗

PubMed1996

The bone-marrow infiltration pattern in B-cell chronic lymphocytic leukemia is not an important prognostic factor. Danish CLL Study Group.

In a multicentre study of 635 consecutive newly diagnosed patients with B-CLL, the histological bone marrow (BM) specimens were reviewed independently by each of 3 pathologists and found evaluable for BM infiltration pattern in 575 patients, 404 of whom had a CD5+, mainly FMC7-, faint surface-membrane immunoglobulin (SIg) fluorescence-intensity ppenotype. In these 404 patients the following BM infiltration patterns were found: mixed nodular-interstitial (30%), moderate interstitial (44%), heavy interstitial (20%) and diffuse packed (6%). In univariate survival analysis, significant differences were found according to BM pattern (p < 0.05), the presence of nodules being a favorable prognostic sign. In multivariate survival analysis in a model including age, clinical stage, BM pattern, BM lymphocytosis, WBC and sex, only age and stage but not BM pattern or BM lymphocytosis had independent prognostic significance. In stage A, progression-free survival was significantly longer in patients with nodular than in patients with non-nodular bone-marrow pattern. The overall survival of these patients, however, did not differ, possibly owing to the prompt and prolonged treatment given to most patients at the time of progression to stage B or C. We conclude that in CD5+, SIg(faint), mainly FMC7-B-CLL, bone-marrow histology may predict unstable disease in early clinical stage but is not important for treatment decisions, when these are based on clinical stage.

Age Factors↗

PubMed2006

Serum TK levels in CLL identify Binet stage A patients within biologically defined prognostic subgroups most likely to undergo disease progression.

OBJECTIVE: Serum thymidine kinase (TK) levels have been shown to be correlated with survival in many malignancies, including chronic lymphocytic leukaemia (CLL). This study was designed to investigate associations between TK levels and other prognostic markers, in newly and previously diagnosed Binet stage A patients. Furthermore, the use of serum TK measurement to identify subcategories of disease within those defined by IgV(H) mutational status, gene usage and chromosomal aberrations was investigated. METHODS: Ninety-one CLL patients were enrolled. Serum TK levels were measured using a radioenzyme assay. IgV(H) mutational status and V(H) gene usage were determined using BIOMED-2 primers and protocol. Recurring chromosomal abnormalities were detected by interphase fluorescent in situ hybridisation (FISH). Flow cytometry and reverse transcriptase polymerase chain reaction (RT-PCR) determined CD38 and Zap-70 expression, respectively. RESULTS: Significantly higher serum TK levels were found in IgV(H) unmutated, compared with IgV(H) mutated, patients (P < 0.001). Elevated TK levels were also found in patients with CD38 and Zap-70 positivity (P = 0.004, P < 0.001, respectively), short lymphocyte doubling time (LDT) (P = 0.044) and poor or intermediate prognosis chromosomal aberrations (P < 0.001). CONCLUSION: A TK level of >8.5 U/L best identified patients with progressive disease. Elevated TK levels could identify patients categorised, at diagnosis, into good prognosis subgroups by the various biological markers (mutated IgV(H), good prognosis chromosomal aberrations, Zap-70(-) and CD38(-)) who subsequently showed disease progression. Additionally, patients with V(H)3-21 gene usage showed high TK levels, irrespective of mutational status, and serum TK measurement retained predictive power as disease progressed in all subcategories studied.

ADP-ribosyl Cyclase 1↗

PubMed1985

Predominant T cells in pleural effusion of a patient with B-cell CLL.

Pleural effusion is a relatively rare complication of chronic lymphatic leukemia (CLL). It can be the result of primary pleural involvement, central lymphatic blockage, infection or changes induced by previous irradiation or chemotherapy. When the effusion is caused by leukemic pleural infiltration, the lymphocytes are identical to those in the peripheral blood. We have recently treated a splenectomized patient with B-cell CLL who developed pleural effusion with predominant T cells. It is suggested that this might be due to a redistribution of the T cells in the recirculating lymphocytic pool in a patient who had undergone splenectomy in the past. The possible source of these cells in the pleural effusion is discussed.

B-Lymphocytes↗

PubMed1983

Spontaneous complete remission of CLL. Report of a case studied with monoclonal antibodies.

A case of complete spontaneous remission of CLL in a 76-year-old woman is reported. Despite the complete remission, the study of the peripheral blood T lymphocytic subsets by the aid of monoclonal antibodies has showed, however, that the ratio between helper-induced and suppressor cytotoxic T cells is still impaired (0.81) as we can see in overt B-CLL. The cause of the remission and its possible connection with the imbalanced distribution of the T lymphocytic subsets is discussed.

Aged↗

PubMed1986

A case of classical Kaposi's sarcoma in B-cell chronic lymphocytic leukemia (B-CLL).

We report a case of classical Kaposi's sarcoma (KS) in a patient affected by B-cell chronic lymphocytic leukemia for 2 years and who had not received any antiblastic treatment. At the ultrastructural analysis the leukemic cell showed rather immature features, and the immunologic phenotype (absence of detectable cytoplasmic Ig, and expression only of the DR, B2 and IgD lambda molecules on the surface membrane) proved its intermediate level of maturity, its monoclonality and relative rarity. The patient presented a complex immunologic deficiency, revealed not only by the monoclonality of the B lymphocytes and their low degree of maturity, but also by the almost total absence of T helper lymphocytes, by the high reduction in NK activity, by the very scarce proliferative response to the polyclonal mitogens PHA, ConA and PWM, and by a complete anergy to the skin test of delayed reactivity. The search for antibodies against the viruses EBV, CMV, HTLV-I and HTLV-III in the serum was negative. At the HLA typing, the patient was DR5, as are most classical KS and/or B-CLL patients. The data are discussed in relation to documented non-casual association between B-CLL and KS. We stress that immunosuppression may play an important role in the pathogenesis of both diseases and the possibility of their being conditioned by common genetic HLA-associated factors of predisposition.

Aged↗