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PubMed2004

[Characteristics and clinical significance of immunophenotype in chronic lymphocytic leukemia].

OBJECTIVE: To investigate the characteristics of immunophenotype of chronic lymphocytic leukemia (CLL) and to evaluate the prognosis of CLL by using the indexs of the characteristics of immunophenotype combined with serum LDH and beta2-MG levels. METHODS: The immunophenotype of 15 CLL, 12 AML, 11 ALL, and 1 FCL (follicular cell lymphoma) patients were analyzed by the indirect immunofluorescent assay. The serum LDH and beta2-MG were detected in 13 CLL patients by the rate nephelometry. RESULTS: The mean age of episode for CLL was 62.9 years and the ratio of male to female was 4:1 in the CLL group. The immune markers (CD5, CD19, and CD20) were positive in the 15 CLL, and negative in the 11 ALL and the 12 AML. The expression of CD23 was positive in 12 of the 15 CLL and negative in the 11 ALL and 12 AML. The expression of CD38 was positive in the 15 CLL. The immunophenotype of 1 FCL was CD10+, CD19+, CD20+, CD5- and CD23-. The serum beta2-MG and LDH levels in 9 CLL patients at Stage Binet C were significantly higher than those in 3 CLL patients at Stage Binet A (P < 0.05). CONCLUSION: CD19+, CD20+ and CD5+ are specific assembly of immunophenotype in B-CLL and contribute to the diagnosis of CLL. The clinical stage of CLL patients of CD23- belongs to Stage Binet C, indicating the poor prognosis. CD23 contributes to differentiate CLL from FCL. CD38+ as a prognostic marker of CLL is not specific. The levels of LDH and beta2-MG are useful indexes for evaluating the prognosis of CLL.

Aged↗

PubMed1996

Drug resistance mechanisms in chronic lymphocytic leukemia.

Peripheral blood samples from 18 patients with chronic lymphocytic leukemias (CLL) who were either untreated but who were later sensitive to chlorambucil (CLL S) or resistant to a combination containing doxorubicin, vincristine, cyclophosphamide and prednisone (CLL R) were studied for glutathione system, P-glycoprotein, PCNA and topoisomerase II expression. P-glycoprotein expression detected by an immunocytochemical technique using MRK 16 antibody was present at the same level in CLL S and CLL R. The percentage of cells positive for P-gp was below 5% in all samples tested. Topoisomerase IIalpha level was quantified by Western blot analysis. None of the 18 CLL samples had detectable topoisomerase IIalpha protein. In addition, 12 CLL were tested for PCNA staining and no samples had more than 1% of positive cells at immunocytochemical detection indicating that CLL cells were not engaged in the cell cycle. Some differences were found between CLL S and CLL R in the glutathione system. Glutathione concentration (GSH) and GST activity was the same in CLL S and CLL R. The glutathione-S-transferase (GST) isoenzyme profile was different in the two CLL groups. The mean GST-pi and GST-alpha quantitation were twice as high as in CLL R compared to CLL S, but this difference did not reach statistical significance because of large variations between CLL samples. A significant correlation was observed between GST-pi expression and GST activity using CDNB as the substrate. GST-mu was detected in only one of seven CLL before therapy and in six of 11 resistant to chemotherapy. No correlation was found between P-glycoprotein expression, GST activity and the different GST isoenzymes studied. These results suggest that the glutathione system could play a role in the resistance of anticancer agents in chronic lymphocytic leukemia. The role of the other drug resistance mechanisms (P-glycoprotein and topoisomerase IIalpha) seems to be of limited importance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Surface antigen expression and correlation with variable heavy-chain gene mutation status in chronic lymphocytic leukemia.

Recent studies have demonstrated that B-cell chronic lymphocytic leukemia (CLL) consists of two clinical entities with either somatically hypermutated (M-CLL) or unmutated (UM-CLL) immunoglobulin variable heavy-chain (VH) regions. In view of the fact that the cellular biology of these two subsets of disease is currently unexplored, we performed an extensive analysis of the surface antigen expression and correlated this with the VH gene mutation status in a cohort of 32 CLL patients. Using polymerase chain reaction amplification and nucleotide sequencing, the VH genes were shown to be mutated in 10 cases (31%) and unmutated in 22 (69%). The expression of 27 surface membrane antigens in peripheral blood leukemic cells was analyzed by flow cytometry, measuring both the percentage of positive cells as well as the geometric mean fluorescence intensity (GMF). Most of the surface membrane antigens (CD5, CD11c, CD19, CD20, CD21, CD22, CD23, CD25, CD40, CD45, VD79b, CD80, CD95, CD122, CD124, CD126, CD130, CD154, IgM, and IgD) showed a similar expression pattern in both UM-CLL and M-CLL patients. The similarity of M-CLL and UM-CLL, as demonstrated here for the first time with many protein markers, indicates a considerably homogeneous phenotype in both subsets. Furthermore, CD27 was strongly expressed in all cases, which may suggest a memory cell phenotype for both M-CLL and UM-CLL. More positive cells in the UM-CLL group were observed regarding CD38, but CD38 was not a good predictor of VH gene mutation status. Seventy percent of the M-CLL cases, but only 36% of UM-CLL cases, were Ig-lambda+. The most striking differential expression, however, was observed in the two slicing variants of the common leukocyte antigen CD45, namely CD45RO and CD45RA. CD45RO expression was significantly associated with M-CLL, whereas the GMF intensity of CD45RA tended to be associated with UM-CLL. The role of these CD45 splicing variants in the pathogenesis of CLL deserves further investigation.

Antigens, Surface↗

PubMed2003

Biology and treatment of chronic lymphocytic leukemia.

Major advances have occurred in our understanding of the biology, immunology, and opportunities for treatment of chronic lymphocytic leukemia (CLL) in recent times. Surface antigen analysis has helped us define classical CLL and differentiate it from variants such as marginal zone leukemia, mantle cell leukemia, and prolymphocytic leukemia. An important observation has been that the B-cells in indolent types of CLL, which do not require therapy, have undergone somatic hypermutation and function as memory B-lymphocytes whereas those more likely to progress have not undergone this process. Section I by Dr. Nicholas Chiorazzi encompasses emerging elements of the new biology of CLL and will address the types of somatic hypermutation that occur in CLL cells and their correlation with other parameters such as telomere length and ZAP70 status. In addition he addresses the concept of which cells are proliferating in CLL and how we can quantitate the proliferative thrust using novel methods. The interaction between these parameters is also explored. Section II by Dr. Thomas Kipps focuses on immune biology and immunotherapy of CLL and discusses new animal models in CLL, which can be exploited to increase understanding of the disease and create new opportunities for testing the interaction of the CLL cells with a variety of elements of the immune system. It is obvious that immunotherapy is emerging as a major therapeutic modality in chronic lymphocytic leukemia. Dr. Kipps addresses the present understanding of the immune status of CLL and the role of passive immunotherapy with monoclonal antibodies such as rituximab, alemtuzumab, and emerging new antibodies. In addition the interaction between the CLL cells and the immune system, which has been exploited in gene therapy with transfection of CLL cells by CD40 ligand, is discussed. In Section III, Dr. Michael Keating examines the question "Do we have the tools to cure CLL?" and focuses on the fact that we now have three distinct modalities, which are able to achieve high quality remissions with polymerase chain reaction (PCR) negativity for the immunoglobulin heavy chain in CLL. These modalities include initial chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, the use of alemtuzumab for marrow cytoreduction in minimal residual disease and allogeneic bone marrow transplants. The emergence of non-ablative marrow transplants in CLL has led to the broadening of the range of opportunities to treat older patients. The addition of rituximab to the chemotherapy preparative regimens appears to be a significant advance. The combination of our increased understanding of the biology, immune status, and therapy of CLL provides for the first time the opportunity for curative strategies.

Animals↗

PubMed2003

New directions in the diagnosis and treatment of chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia of adults in Western countries. It is a systemic haematological malignancy that originates from B cells (B-CLL) in 95% of patients, while only a minority are derived through malignant transformation of T cells (T-CLL). Although B-CLL is classified as a non-Hodgkin's lymphoma, several issues make this leukaemia a unique entity among malignant lymphoma. Inhibition of the programmed cell death (apoptosis) and upregulation of the anti-apoptotic protein Bcl-2 are key elements of the pathophysiology of B-CLL cells and define clinical prognosis. Furthermore, B-CLL cells are arrested in G0/G1 phase of the cell cycle. Dysfunctional apoptosis and cell cycle are the main reasons for the clinical enigma, that CLL can not yet be cured with conventional chemotherapy. However, the molecular pathways that are responsible for this characteristic feature of the B-CLL cells still need further definition.Recently, considerable progress has been made in defining the molecular basis for the pathogenesis of CLL and in finding new therapeutic options. Recent studies indicate that B-CLL cells may be delineated from two main groups of normal B cells, i.e. pre- and postgerminal B cells, and can be distinguished through lack of or existence of mutations of the V heavy chain gene. This differential mutational status of the Ig V gene has significant impact on patient survival. Modern cytogenetic methods such as fluorescence in situ hybridisation (FISH) have opened a new era in the molecular analysis of CLL cells. Determining the chromosomal aberration of the leukaemic cells has become a standard scientific programme for each clinical trial. The cytogenetic profile may soon help to define a clinical risk profile and guide the various treatment strategies. Further progress has been made in the therapy of CLL. Purine analogues such as fludarabine were able to induce significant improvement in remission rates; however, they did not lead to improved survival. Chimera of murine or rat monoclonal antibodies and human antibodies were designed to treat CLL. Antibodies such as rituximab and alemtuzumab (Campath-1H), directed against CD20 and CD52, respectively, appear as attractive alternatives to conventional chemotherapy because of their lack of significant myelotoxicity. Studies using myeloablative chemotherapy followed by autologous or allogeneic stem cell transplantation were initiated with the hope of finding a cure for CLL. In contrast to autologous stem cell transplantation, allogeneic transplants appear to display a plateau of relapse rates. In conclusion, for many years CLL was considered as a chronic haematological malignancy that required only few diagnostic tools and for whom no hope of cure could be offered. The current review focuses on recent improvements in diagnosis and treatment of CLL that have opened a new era in the management of patients with this systemic malignancy.

Alemtuzumab↗

PubMed1985

The relationship between membrane characteristics, functional reactivity of T-lymphocytes, and the progression rate of B-cell chronic lymphocytic leukemia.

Study performed on 192 patients has demonstrated that the progression rate of chronic lymphocytic leukemia (CLL) is associated with the existence of T-cell defect(s). A dynamic classification system based on evaluation of tumor mass growth rate, response to therapy, and myelopoietic failure (MF) has been devised for evaluation of progression rate of CLL. Besides four basic groups (Group 1: CLL without therapy; Group 2: CLL on therapy, without remission; Group 3: CLL on therapy, partial remission; Group 4: CLL on therapy, complete remission) patients were further classified into phase (type) A (stable, indolent CLL) or phase (type) B (active, progressive CLL). The major criteria for phase A were: total tumor mass (TTM) doubling time (DT) longer than 12 months, no MF, and/or good response to therapy. The major criteria for phase B were: TTM DT less than 12 months and/or accompanying MF and/or no response to therapy. The following major findings have been demonstrated: (1) altered quantitative relationship between active and nonactive parts of T-cell compartment (E/A ratio) in the progressive phase of CLL; (2) altered B/T gamma ratio in the progressive phase of CLL; (3) more than 50% increased percentage of T gamma cells in the stable phase of CLL; (4) very low stable and absent seeding efficiency of T-cells in the progressive phase of CLL; (5) altered (delayed) DNA synthesis pattern in the progressive phase of CLL; and (6) negative local xenogeneic graft versus host reaction in the progressive phase of CLL. Based on reported results, a hypothesis regarding the possible role of T-cells in the pathogenesis of CLL was suggested.

Animals↗

PubMed1992

Immunophenotyping of subtypes of B-chronic (mature) lymphoid leukemia. A study of 242 cases.

BACKGROUND: The French-American-British group's proposal for the classification of chronic lymphoid leukemias is unique at this time. Testing, expanding, and adding to the theory by immunophenotyping will help to additionally characterize this group of diseases. METHODS: Peripheral blood samples from 242 patients with chronic lymphoid leukemias were analyzed for immunologic evaluation of the following subtypes: typical chronic lymphocytic leukemia (CLL), 189; CLL with pleomorphic lymphocytes (CLL-pleo), 19; CLL of mixed cell type (CLL/PL), 20; prolymphocytic leukemia (PLL), 22; hairy cell leukemia (HCL), 10; HCL-variant, 1; and splenic lymphoma with villous lymphocytes, 1. RESULTS: The phenotype of CLL and CLL-pleo was weak surface immunoglobulin (SIg) with positive results of mouse rosettes (MR+), CD5+, and CD22-. Of PLL and HCL, it was strong SIg, MR-, CD5-, and CD22+. By analyzing the four markers and accepting the relevant results of two or more as sufficient for diagnosis, all cases (100%) of CLL, CLL-pleo, PLL, and HCL were diagnosed. CLL/PL showed the phenotype of CLL in 66.67% and of PLL in 33.33% of patients. The frequency of cases with weak fluorescence in decreasing order was CLL, CLL-pleo, CLL/PL, and PLL and HCL. The same sequence applied to the mean percentage of mouse rosette-forming cells and CD5 cells, but the sequence was reversed for CD22 cells. CONCLUSIONS: SIg intensity, MR, CD5, and CD22 constitute the minimum number of immune markers for the differential diagnosis of the subtypes of chronic lymphoid leukemia. The frequency of the four markers among the subtypes suggested that CLL and CLL-pleo have identical phenotypes and that the five subtypes follow a continuous range of B-cell differentiation from early mature (CLL and CLL-pleo) to late mature pre-plasma cell stages (PLL followed by HCL), with CLL/PL of intermediate maturity.

Adult↗

PubMed1993

Chronic lymphocytic leukemia with low lymphocyte count.

BACKGROUND: A peripheral blood absolute lymphocyte count (ALC) of greater than 5 x 10(9)/l is considered the required minimum for diagnosis of chronic lymphocytic leukemia (CLL). Cases with low ALC (CLL-LLC), less than 5 x 10(9)/l, have not been included in the current staging systems, and would not be suspected of having CLL, or investigated for the disease, especially in the absence of clinical manifestations. On the other hand, the diagnostic value of the differential lymphocyte counts have not been emphasized. METHODS: Cell suspensions from peripheral blood of previously untreated cases of CLL-LLC (n = 12) and typical CLL (n = 189) were analyzed for immunologic evaluation of surface immunoglobulin (SIg), mouse erythrocyte rosettes, CD5, CD19, CD20, CD22, and CD2, as well as cytochemical evaluation of tartrate-resistant acid phosphatase (TRAP). The results in CLL-LLC were compared statistically with typical CLL. RESULTS: The ages of the 12 patients with CLL-LLC ranged from 47 to 84 years. The absolute lymphocyte counts ranged from 1.5 x 10(9)/l to 4.9 x 10(9)/l, and the percentage of lymphocytes in the differential leukocyte counts ranged from 52% to 93%. None of the patients had signs and symptoms of CLL or other conditions that may cause reactive lymphocytosis. CLL-LLC demonstrated similar characteristics to typical CLL, i.e., weak expression of monoclonal SIg, mouse rosette formation, positive CD5, high CD19 and CD20, negative CD22 and TRAP. No statistical differences existed between the immunologic markers or between SIg isotype distribution in the two groups. CONCLUSIONS: Cases of CLL-LLC constituted 6% of B-CLL and would have been missed if immunologic investigation was not carried out because of the absence of absolute lymphocytosis and clinical manifestations of CLL. Persistent relative lymphocytosis of > or = 50% of the differential leukocyte count in older individuals (older than 50 years of age), is an indication for further investigation of CLL by immunophenotyping of peripheral blood lymphocytes and examination of bone marrow.

Aged↗

PubMed2000

Morphological and immunophenotypic features of chronic lymphocytic leukemia.

In this review, we summarize the morphological features and immunophenotypic profile of chronic lymphocytic leukemia (CLL) cells, discuss the value of these investigations as front line diagnostic tests, and emphasize their correlation with the clinical features, disease progression, molecular genetics and pathogenesis of CLL. In CLL, the morphology of the circulating cells is characteristic and typical in the majority of cases. However, 15% of patients, either at diagnosis or during the course of the disease, show atypical morphology reflected by either (1) an increased (> 10%) number of circulating prolymphocytes, designated CLL/PL, or (2) an increased (> 15%) number of circulating lymphoplasmacytic and cleaved cells, designated 'atypical' CLL. There is strong evidence of a close association between atypical morphology (CLL/PL) and atypical (CLL) and clinical features, e.g. disease progression, advanced stage and survival, molecular genetics, particularly trisomy 12, but also the rare cases with t(11;14) or t(14;19), p53 abnormalities, unmutated immunoglobulin (Ig) VH genes and origin of the cell (naive, pregerminal center cell). CLL cells have a distinct immunological repertoire different from that of other lymphoproliferative disorders. The typical CLL phenotype is CD5+, CD23+, FMC7-, weak expression of surface Ig (sIg) and weak or absent expression of membrane CD22 and CD79b. The latter marker identifies an extracellular epitope of the B-cell receptor (BCR) beta chain and its weak or absent expression in CLL may derive from the expression of a truncated form. This, together with the low expression of CD22, might explain the abnormal signal transduction of CLL cells similar to that of anergic B lymphocytes. Because no single marker is specific for CLL, a composite phenotype considering this set of 5 or 6 markers compounded into a scoring system helps to distinguish CLL from the other B-cell malignancies. Immunophenotypic analysis has also been shown to be useful for minimal residual disease detection and adds valuable prognostic information because the expression of certain markers, such as FMC7 or CD38, seems to be associated with a poor outcome. In addition, CLL cells express a variety of Bcl-2 family proteins with a profile that favors inhibition of apoptosis which, together with the interaction with microenvironmental (e.g. stromal) cells and the release of cytokines, explains the long life span and subsequent accumulation of CLL cells in various organs. Despite controversies relating to the expression of adhesion molecules (selectins and integrins) in CLL cells, it appears that some of these molecules do play a role in the pathogenesis, biology and clinical patterns of the disease. In conclusion, morphology and immunophenotype are the two essential investigations, which must be carried out in all cases of CLL. Both provide relevant information in terms of diagnosis, course of the disease, prognosis and pathogenesis.

Bone Marrow↗

PubMed1994

Transforming growth factor beta as endogenous growth inhibitor of chronic lymphocytic leukemia B cells.

Chronic lymphocytic leukemia (CLL) B cells are hyporesponsive or refractory to mitogens and growth factors in vitro. This study examined whether transforming growth factor beta (TGF-beta), a potent inhibitor of lymphocyte proliferation may play a role in the growth regulation of CLL B cells. CLL B cells from all donors treated expressed detectable TGF-beta 1 mRNA. In vitro release of TGF-beta by unstimulated cultures, or cultures stimulated by antibody to cell surface immunoglobulin (anti-mu) plus phorbol 12-myristate 13-acetate (PMA) was higher in CLL than in normal B cells. High levels of TGF-beta activity were also detected in plasma samples of CLL patients. The role of TGF-beta in growth regulation of CLL B cells was tested in assays using different B cell activators. Purified neoplastic B cells from most CLL patients proliferated in response to anti-mu, or the combination of anti-mu plus PMA. Levels of CLL B cell proliferation were lower than observed in normal B cells. Some CLL were refractory to these stimuli. Antibody to CD40 induced proliferation of CLL B cells from all donors tested when presented on Fc gamma RII (CDw32)-expressing L cells. Neutralizing antibodies to TGF-beta increased CLL B cell proliferation in the absence or presence of additional stimuli. These effects were dose dependent and specific. Exogenous TGF-beta completely inhibited CLL B cell proliferation induced by anti-mu, PMA, and anti-TGF-beta. CLL B cell proliferation induced by anti-CD40 was reduced by exogenous TGF-beta. However, even at high doses, TGF-beta did not completely inhibit the anti-CD40 effect. In summary, TGF-beta is overexpressed in CLL. CLL B cells are sensitive to TGF-beta and this cytokine functions as an autocrine growth inhibitor accounting at least in part for reduced proliferative responses of these leukemic cells and for the slow progression of the malignant process in vivo.

Aged↗

PubMed1999

CD40-activated B-cell chronic lymphocytic leukemia cells for tumor immunotherapy: stimulation of allogeneic versus autologous T cells generates different types of effector cells.

Although spontaneous remissions may rarely occur in B-cell chronic lymphocytic leukemia (B-CLL), T cells do generally not develop a clinically significant response against B-CLL cells. Because this T-cell anergy against B-CLL cells may be caused by the inability of B-CLL cells to present tumor-antigens efficiently, we examined the possibility of upregulating critical costimulatory (B7-1 and B7-2) and adhesion molecules (ICAM-1 and LFA-3) on B-CLL cells to improve antigen presentation. The stimulation of B-CLL cells via CD40 by culture on CD40L expressing feeder cells induced a strong upregulation of costimulatory and adhesion molecules and turned the B-CLL cells into efficient antigen-presenting cells (APCs). CD40-activated B-CLL (CD40-CLL) cells stimulated the proliferation of both CD4(+) and CD8(+) T cells. Interestingly, stimulation of allogeneic versus autologous T cells resulted in the expansion of different effector populations. Allogeneic CD40-CLL cells allowed for the expansion of specific CD8(+) cytolytic T cells (CTL). In marked contrast, autologous CD40-CLL cells did not induce a relevant CTL response, but rather stimulated a CD4(+), Th1-like T-cell population that expressed high levels of CD40L and released interferon-gamma in response to stimulation by CD40-CLL cells. Together, these results support the view that CD40 activation of B-CLL cells might reverse T-cell anergy against the neoplastic cell clone, although the character of the immune response depends on the major histocompatibility complex (MHC) background on which the CLL or tumor antigens are presented. These findings may have important implications for the design of cellular immunotherapies for B-CLL.

Aged↗

PubMed1992

Variable region gene analysis of an isotype-switched (IgA) variant of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia of B-cell origin (B-CLL) is generally thought to arise by neoplastic transformation of B lymphocytes, which express CD5 and have features of an early stage of B-cell differentiation. To study isotype-switched B-CLL as a potentially more differentiated variant, we performed genetic and functional immunoglobulin (Ig) gene analysis in two cases of CD5+ B-CLL in which the peripheral blood mononuclear cells (PBMC) secreted predominantly IgA (CLL-249) or IgG (CLL-412) when stimulated with pokeweed mitogen in vitro. By cDNA sequencing and by studies of CLL-heterohybridomas, CLL-249 expresses the heavy chain constant region C alpha as anticipated, while CLL-412 expresses C mu, not C gamma. In CLL-249, the expressed VH gene is 98% homologous to VH26, a germline VH3 gene that occurs frequently in the fetal repertoire, and which has been associated with anti-DNA specificity. The VL gene of CLL-249 is a lambda VL gene for which the germline sequence is not known. In CLL-412, the VH gene is 100% homologous to the VH1 gene of a published anti-DNA antibody (21/28), and is probably a germline gene sequence; the VL gene is 100% homologous to 15AVKI, also a germline gene. The supernatant antibody of the CLL-412 heterohybridoma is an IgM-kappa, which reacts with ssDNA and cardiolipin. The CLL-249 heterohybridoma secreted IgA-lambda, which bound none of the antigens tested, a finding that may be related to amino acid differences from the probable germline V genes. The demonstration of an in vivo isotype-switched variant, such as CLL-249, suggests that B-CLL may be a heterogeneous group of clonal disorders, of which less common variants may have features of more differentiated B-cell stages, such as isotype switching.

Amino Acid Sequence↗

PubMed1997

Morphological variants of leukemic cells in B chronic lymphocytic leukemia are associated with different T cell and NK cell abnormalities.

B chronic lymphocytic leukemia (B-CLL) is a heterogeneous disease. The different morphological variants of leukemic B cells appear to define different clinical groups of patients. Several abnormalities have been found in T lymphocytes and natural killer (NK) cells from B-CLL patients. We have investigated the phenotypic and functional characteristics of purified CD2+ cells from B-CLL patients at Binet's stage A and classified according to the neoplastic B lymphocyte morphology criteria: 32 patients with typical B-CLL and 12 patients with atypical B-CLL. Forty-three age and sex matched healthy controls were also studied. In fresh purified CD2+ cells from typical B-CLL patients, percentages of CD4+, CD4+CD45RA+, CD8+CD45RA+ T lymphocytes and CD3-CD56+ (NK) cells were significantly higher than those found in atypical B-CLL patients. However, in DC2+ cells from typical B-CLL patients, percentages of CD3+, CD3+DR+, CD8+, CD4+CD45RO+, and CD3+CD56+ cells were significantly lower than those found in atypical B-CLL patients. Increased percentage of NK cells was only found in typical B-CLL patients. The proliferative response and the production of interleukin (IL)-2 and IL-4 by phytohemagglutinin (PHA) stimulated CD2+ cells were significantly higher in typical B-CLL patients than in atypical B-CLL patients. We concluded that different patterns of phenotypic and functional alterations in the T lymphocytes and NK cells of B-CLL patients are found in patients with typical or atypical B-CLL defined according to the morphology of the leukemic cells.

Adult↗

PubMed2001

Chronic lymphocytic leukemia incidence is substantially higher than estimated from tumor registry data.

BACKGROUND: Although chronic lymphocytic leukemia (CLL) often is described as the most common leukemia in the U.S. and Western Europe, to the authors' knowledge the true incidence of CLL in the U.S. is unknown. CLL incidence is estimated from tumor registry reports based on tissue pathology and cancer treatment data. Tumor registry data may underestimate the incidence of CLL substantially because CLL can be diagnosed by flow cytometric analysis of peripheral blood cells, and the majority of patients do not require treatment at the time of diagnosis. METHODS: To test the hypothesis that CLL has a higher incidence than estimated from tumor registry data, the authors compared the actual and reported incidence of CLL for a 10-year interval at the Central Arkansas Veterans Healthcare System (CAVHS). The accuracy of surveillance methods for new diagnoses of CLL was confirmed by reviewing the lymphocyte counts in 45,009 CAVHS patients over a 4-year period. RESULTS: The tumor registry correctly reported 58 of 93 patients with CLL (62.4%) who were diagnosed between January 1, 1990 and December 31, 1999. The tumor registry correctly reported 100% of patients with CLL diagnosed between 1990-1991 but reported only 34.5% of patients with CLL diagnosed between 1998-1999. CONCLUSIONS: The incidence of CLL in the CAVHS was 37.6% higher than estimated from tumor registry data due to an increase in the use of peripheral blood immunophenotype as the only diagnostic test for CLL over the time period of the study. These data suggest that the true incidence of CLL may be substantially higher than estimated from tumor registry data.

Humans↗

PubMed2000

Selective toxicity of vincristine against chronic lymphocytic leukemia cells in vitro.

The cytotoxicity of vincristine in vitro was investigated in B chronic lymphocytic leukemia (CLL) cells and in normal peripheral blood mononuclear cells. An approximately 25-fold selectivity towards leukemic vs. normal lymphocytes was demonstrated. Cells from patients having a mature subtype (CLL or CLL/mix) or a slowly progressing form of CLL were significantly more sensitive to vincristine in vitro than the cases with a CLL/PL phenotype or faster-progressing disease. Depending on the vincristine dose, the number of dead CLL cells accumulated slowly during the 4-d observation period. Our data indicate a marked individual variation in vincristine susceptibility among individual CLL cells. Vincristine induced annexin positivity, nuclear blebbing and DNA fragmentation in CLL cells. These indicate an "apoptosis-like" cell death. Since CLL cells are in the G0/G1 phase of the cell cycle, the only known mode of anticancer action of vinca alkaloids, i.e. anti-mitotic action, cannot explain the death of CLL cells. Furthermore, similar cellular uptake and efflux of vincristine by normal and CLL cells excluded pharmacokinetic differences as a cause of selectivity of vincristine towards leukemic lymphocytes. Immunostaining of filamentous structures of CLL cells revealed that vincristine brings about selective changes in alpha-tubulin but not in beta-actin or vimentin. Although the antitubulin action of vinca alkaloids in the biochemical sense is well demonstrated, this kind of anticancer effect has not previously been shown. Vincristine is used in several regimens for CLL, but its efficacy in CLL has never been demonstrated in a clinical context and its value in routine CLL chemotherapy has been questioned. The present data strongly support the need for further evaluation of the role and mode of action of vincristine in chemotherapy of CLL and other cancers as well.

Aged↗

PubMedDate not supplied

Chronic lymphocytic leukemia: economic burden and quality of life: literature review.

The purpose of this review was answer 2 main questions: what is the impact of chronic lymphocytic leukemia (CLL) on the patient's quality of life and how great is the economic burden of this disease on the health care payers and providers. Patients with CLL typically do not receive any treatment soon after the initial diagnosis. Although there is no known cure for CLL yet, when treated, the patients receive aggressive and expensive therapies (eg, chemotherapy or bone marrow transplantation). A rigorous and systematic literature review was performed of English-language articles published in 1990-2002. It was supplemented with additional articles published before 1990 for completeness and additional references to fill the gaps identified in the published medical literature. The literature on the quality of life (QOL) of CLL patients is very limited. We identified only 8 articles, and none of them analyzed the QOL in untreated CLL patients. Because CLL is a disease affecting adults, especially the elderly, all 8 studies measured the QOL in the adult population. QOL difficulties include fear of death and disability, problems gaining employment or health insurance, and fatigue. No specific leukemia or CLL instruments but general QOL instruments (eg, I-HRQL) were identified and some cancer-specific ones (eg, EORTC QLQ-C30, FACT-G, FACT Anemia, FACT-Fatigue). Interestingly, a FACT-Bone Marrow Transplant instrument exists, although we found no study on CLL that used it. Even the literature on the economic burden of CLL is very limited. We identified 13 studies on the cost of CLL: Most of them were cost-identification or cost-comparison studies, and 5 dealt with the cost-effectiveness of medical interventions to treat CLL. Cost drivers identified for CLL were the chemotherapy costs, intravenous immunoglobulin costs, transplantation costs, and costs associated with the differential staining cytotoxicity assay. We identified very few articles on the QOL of CLL patients and therefore cannot draw strong conclusions about the key QOL predictors. Nevertheless, patients with anemia were found to have a better QOL if they had higher hemoglobin counts and good response to erythropoietin treatment. The articles published seem to demonstrate that the older the age of the patient was, the poorer the QOL. The main cost drivers identified for CLL were related to the treatment chosen (eg, chemotherapy, bone marrow transplantation). There are hints that higher costs often result from the delivery of non-optimal therapy that leads to adverse events, infections, and drug resistance. In summary, the impact of this disease on the health care budget of the different health care providers and payers as well as on the patient's QOL is substantially unknown, calling for appropriate economic and QOL studies.

Adult↗

PubMed2005

Mitogen induced activation, proliferation and surface antigen expression patterns in unmutated and hypermutated chronic lymphocytic leukemia cells.

OBJECTIVES: To determine whether the immunoglobulin V(H) gene mutational status has an effect on the activation, proliferation and surface antigen expression of chronic lymphocytic leukemia (CLL) cells when stimulated in vitro. METHODS: The proliferation and activation responses of CLL cells were studied in 22-immunoglobulin gene V(H) unmutated (UM-CLL) and 12 hypermutated (M-CLL) CLL cases in 4-day cultures. As the mitogen responses have been previously shown to be diverse in CLL, a case-specific strategy based on optimized mitogen combinations (OMCs) of interleukin-2 (IL-2), 12-O-tetradecanoylphorbol 13-acetate (TPA), Staphylococcus aureus Cowan 1 (SAC), and human recombinant tumor necrosis factor alpha (TNF) was applied in cell stimulation. The expression of 23 surface membrane antigens (CD5, CD11c, CD19, CD20, CD21, CD22, CD23, CD25, CD27, CD38, CD40, CD45, CD45RA, CD45RO, CD79b, CD80, CD95, CD124, CD126, CD130, FMC7, IgD, and IgM) was studied by flow cytometry at days 0 and 4. RESULTS: The proliferation and activation responses were similar in UM-CLL and M-CLL when OMCs contained IL-2, TPA or TNF. SAC induced faster proliferation in UM-CLL than in M-CLL. OMC stimulation induced preferential down-regulation of growth- promoting cell surface receptors CD5, CD21, and CD124 and preferential up-regulation of growth-inhibiting antigen CD80 in M-CLL. CONCLUSIONS: Difference in immunophenotypic evolution of UM-CLL and M-CLL can be demonstrated if appropriate matrix signals are provided. The pathways for CD5, CD21, CD124 (IL4R), and CD80 (B7-1) regulation should be further explored in relation with somatic hypermutation and outcome of CLL.

Antigens, CD↗

PubMed1985

Lung surfactant replacement in premature lambs with extracted lipids from bovine lung lavage: effects of dose, dispersion technique, and gestational age.

Extracted bovine calf lung lipids (CLL) with minimal protein (approximately 1%) were instilled prior to ventilation in groups of premature lambs of average gestational ages of 127 and 133 days. Aqueous dispersions of CLL were prepared by two techniques prior to instillation: sonication in an ice bath (S) and mechanical vortexing at room temperature (V). A low surfactant dose (15 mg CLL/kg animal weight) and a high dose (100 mg/kg) were investigated for each dispersion technique. Following tracheal instillation of surfactant, lambs were ventilated with 100% oxygen for 2 h with umbilical circulation intact, and for up to an additional 10 h after separation. A clear improvement in blood oxygenation and lung compliance was found over controls for lambs given 15 mg/kg and 100 mg/kg CLL(V), and 100 mg/kg CLL(S). Lambs treated with 15 mg/kg CLL(S) failed to improve over controls. Experimental groups treated with equal doses of CLL(V) and CLL(S) had similar amounts of lung lavage phospholipid, with values progressively declining during ventilation. Analyses of in vitro surface properties showed that both vortexed and sonicated CLL dispersions adsorbed to equilibrium surface pressures of 45-47 dynes/cm in seconds at concentrations greater than or equal to 0.25 mg CLL/ml. Both dispersions also lowered surface tension to less than 1 dyne/cm under dynamic compression at 37 degrees C in 100% humidity, although CLL(V) showed some enhancement over CLL(S) in dynamic surface activity at low subphase concentration (0.5 mg/ml). Moreover, CLL(V) and CLL(S) differed markedly in their effects on pressure-volume mechanics in a surfactant-deficient excised rat lung model. Instilled CLL(V) dispersions improved excised lung pressure-volume mechanics at significantly lower concentrations than CLL(S) dispersions.

Animals↗