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PubMed2001

Progress in CLL, chemotherapy, antibodies and transplantation.

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.

Antibodies, Monoclonal↗

PubMed2002

The CD23b promoter is a target for NF-AT transcription factors in B-CLL cells.

CD23 is atypically highly expressed in various chronic diseases, including B-CLL, lupus erythematodes and rheumatoid arthritis. Its expression can be further enhanced by interleukin 4 (IL-4). We have shown before that in B-CLL cells nuclear factor(s) of activated T cells (NF-ATs) show permanent nuclear localization and therefore constitutive transcriptional activity. Here we identify CD23b promoter as a novel target for NF-AT factors in B-CLL cells. The CD23b promoter contains two NF-AT binding sites to which NF-ATp and NF-ATc factors bind with high affinity. Mutations introduced into these sites abolished NF-AT binding and impaired the promoter activity, as did cyclosporin A (CsA), an inhibitor of nuclear transport of NF-ATs. Furthermore, we show that IL-4-induced transcription factor STAT6 cooperates with NF-ATs in the induction of the CD23b promoter activity. These results show that the CD23b promoter is a target for NF-AT factors and suggest that the cooperation between NF-AT and STAT factors might be one of the molecular mechanisms responsible for high-level expression of CD23 on the surface of B-CLL cells.

Base Sequence↗

PubMed1993

Treatment of chronic lymphocytic leukaemia. French Co-operative Group on CLL.

The variable course of the disease, the advanced age of most patients and the absence of uniform criteria to evaluate treatment have constituted important setbacks in the therapy of CLL. The advent of clinical staging systems, which allow the identification of patients with different risks and the planning of appropriate therapy, constitutes a major advance. Results of trials based on these staging systems have demonstrated that treatment of patients with CLL in early stage is of no benefit and may even be harmful. By contrast, there is general agreement that patients in advanced stage should be treated. Chlorambucil, either daily or intermittently, and given alone or with corticosteroids, remains the most commonly used drug. Other single agents used in CLL include prednisone, busulphan and cyclophosphamide. Results are often comparable with those observed with chlorambucil alone, although sometimes with more toxicity. The benefit in survival terms of all these drugs remains to be proved. New agents, such as fludarabine, 2-deoxycoformycin and 2-chlorodeoxyadenosine, offer promise. However, the superiority of these drugs over chlorambucil needs to be demonstrated in randomized trials. Most combination therapy regimens have failed to show advantage over chlorambucil with or without prednisone when compared in clinical trials. In a previous randomized trial, the French Co-operative Group on CLL showed a beneficial role for low-dose adriamycin given with cyclophosphamide, vincristine and prednisone (mini-CHOP) in patients with stage C disease. However, these results were obtained in a small series of patients and need to be confirmed. Splenectomy can be considered in patients with autoimmune haemolytic anaemia or thrombocytopenia, with splenic destruction. Radiotherapy, administered either as 32P, total body irradiation, extracorporeal irradiation of blood or thymic irradiation, is effective in a few patients, but severe myelosuppression is a frequent sequel. Splenic irradiation has more often been used when splenectomy was difficult in the case of massive splenomegaly or immune cytopenia. New strategies, including the use of biological response modifiers (interferons, interleukins 2 and 4, erythropoietin, cyclosporine and monoclonal antibodies either alone or conjugated with immunotoxins), are presently under study. So far, only transient effects have been observed. Although complete remission in classical terms is frequently observed with these therapies, clonal remission is a very rare event and cure cannot be achieved.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

PubMed1999

Theophylline-induced B-CLL apoptosis is partly dependent on cyclic AMP production but independent of CD38 expression and endogenous IL-10 production.

Our recent work has shown that theophylline which inhibits intracellular cyclic adenosine monophosphate (cAMP) degradation is able to kill chronic lymphocytic leukemia (CLL) cells in vitro and synergizes in vitro and in vivo with chlorambucil. In order to test the hypothesis that theophylline works through an indirect increase in cAMP, we have investigated the role of several molecules on B-CLL cells from 20 patients. Direct cAMP inducers such as dibutyryl-cAMP (db-cAMP), prostaglandin-E2 (PGE2) and forskolin induced moderate apoptosis but extremely high levels of intracellular cAMP. By contrast theophylline was highly apoptotic but did not synergize with cAMP inducers. Apoptosis was completely reversed by a cAMP antagonist when induced by PGE2 or forskolin, but was only partially antagonized when induced by theophylline. Since CD38+ CLL cells are more sensitive to apoptosis and since CD38 is enhanced by cAMP inducing agents its expression was investigated. In our hands CD38 was not induced by the above pharmacological compounds. Exogenous IL-10 has been shown to induce CLL cell death; however, apoptosis following treatment with theophylline or cAMP inducers could not be ascribed to endogenous production of IL-10. This ruled out the involvement of cytokines or of an activation or differentiation process in apoptosis. Altogether our data show that an increase in intracellular cAMP mediates apoptosis in vitro but accounts only partly for theophylline-mediated apoptosis.

ADP-ribosyl Cyclase↗

PubMed2001

Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes.

Fludarabine is active but not curative in the treatment of chronic lymphocytic leukemia (B-CLL). Nitric oxide (NO) supplied from exogenous, NO-donating pro-drugs can also induce apoptosis and death of acute leukemia cells. This study investigated combinations of fludarabine with NO-donating pro-drugs for their cytotoxicity against freshly isolated B-CLL lymphocytes following a 72 h exposure in vitro. The median IC(50)for fludarabine was 2.2 microM (n = 85). The nitric oxide donors DETA-NO, PAPA-NO, and MAHMA-NO were also cytotoxic, and their effects were inversely related to rates of NO release. Neither DETA-NO depleted of NO nor DETA itself was effective, indicating that NO was required for cytotoxicity. Drug interactions were evaluated by a modified combination index method. Synergy was observed in combinations of fludarabine or nelarabine (506U78) with DETA-NO in 52% and 88% of samples, respectively. Interestingly, the combination of fludarabine and DETA-NO was more cytotoxic in B-CLL cells less sensitive to fludarabine. DETA-NO did not enhance the activity of other DNA anti-metabolites, topoisomerase I and II inhibitors, or alkylating agents. Finally, the anti-leukemic activity of fludarabine alone or in combination with DETA-NO was found to correlate with inhibition of cellular RNA synthesis. These results indicate that NO donors could enhance fludarabine therapy for B-CLL.

Adult↗

PubMed2003

Expansion of natural killer (NK) and natural killer-like T (NKT)-cell populations derived from patients with B-chronic lymphocytic leukemia (B-CLL): a potential source for cellular immunotherapy.

B-cell chronic lymphocytic leukemia (B-CLL) is the most common leukemia in the Western world. It is currently an incurable disease, making new treatment options such as immunotherapy desirable. Monoclonal antibodies (Mabs) to surface antigens of the tumor cell is one option. Administration of cytotoxic cells such as natural killer (NK) and natural killer-like T (NKT) cells expanded in vitro might be a useful treatment modality alone or in combination with MAbs. A limiting step in the development of successful cellular immunotherapy has been the availability of appropriate cytotoxic cells. Here, we report the feasibility of expanding populations of the human killer cells, CD3-CD56+ NK and CD3+CD56+ NKT cells, from peripheral blood mononuclear cells (PBMCs) of B-CLL patients. The influence of tumor B cells on the in vitro expansion of killer cells was assessed by depleting B cells from PBMCs by microbead separation before culture. The 21-day cultures from both B-cell- and non-B-cell-depleted PBMC showed a marked expansion of NK cells, and also of T cells, among which almost half had the NKT phenotype. Depletion of B cells before culture did not change the expansion rates of NK and NKT cells significantly. In patients with progressive B-CLL, NK cell expansion capacity was improved after fludarabine treatment when compared to samples obtained before treatment. Repeated samples of PBMCs from individual untreated patients with both indolent and progressive disease cultured under identical conditions gave similar NK cell expansion rates. Expanded killer cell populations had cytotoxic function against the NK-sensitive target K562 cell line and expressed high levels of Granzyme B. From our studies, we conclude that NK cells as well as NKT cells from the peripheral blood of B-CLL patients can be expanded, and that these cells have cytotoxic capacity.

Aged↗

PubMed2006

Thymidine-phosphorothioate oligonucleotides induce activation and apoptosis of CLL cells independently of CpG motifs or BCL-2 gene interference.

We compared antisense phosphorothioate oligonucleotides (PS-ODN) that target BCL-2 such as Genasense (G3139-PS), with other PS-ODN or phosphodiester-ODN (PO-ODN) in their relative capacity to induce apoptosis of chronic lymphocytic leukemia (CLL) B cells in vitro. Surprisingly, we found that thymidine-containing PS-ODN, but not PO-ODN, induced activation and apoptosis of CLL cells independent of BCL-2 antisense sequence or CpG motifs. All tested thimidine-containing PS-ODN, irrespective of their primary sequences, reduced the expression of Bcl-2 protein and increased the levels of the proapoptotic molecules p53, Bid, Bax in CLL cells. Apoptosis induced by thymidine-containing PS-ODN was preceded by cellular activation, could be blocked by the tyrosine-kinase inhibitor imatinib mesylate (Gleevec), and was dependent on ABL kinase. We conclude that thymidine-containing PS-ODN can activate CLL cells and induce apoptosis via a mechanism that is independent of BCL-2 gene interference or CpG motifs.

Amino Acid Chloromethyl Ketones↗

PubMed1996

Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients.

We have analysed the clinical and laboratory features in 544 patients with chronic lymphocytic leukaemia (CLL) with available cytogenetics and fluorescence in-situ hybridization (FISH) analysis for trisomy 12 in half of them, to examine the correlation between chromosome abnormalities and clinical or laboratory parameters. Five chromosome groups were defined: (1) trisomy 12 (18%), detected as the sole abnormality or associated with other changes; (2) del(13)(q12-14) (7%); (3) other abnormal karyotypes (20%); (4) normal karyotype (41%); and (5) no divisions (14%). There were no differences in the age distribution between the five groups. Clinical stages (Binet) were: A (74%), B (12%) and C (14%). Stage A was common in cases with del(13q)(82%), normal (84%) and other abnormal karyotypes (74%), whereas it was less common in trisomy 12 cases (64%) and those with no divisions (48%). Typical CLL morphology was found in 83% of cases; 10% had more than 10% prolymphocytes (CLL/PL) and 7% had other atypical features. CLL with trisomy 12 was the only group with a high frequency of either CLL/PL (31%) or atypical morphology (24%). Atypical morphology and CLL/PL were even more frequent when trisomy 12 was associated with other chromosomal abnormalities (70% v 46%). The incidence of cases with CLL/PL and other atypical morphology was significantly lower in the other chromosome groups (P < 0.001). There were no differences in immunophenotype among the various groups except for a higher frequency of stronger Smlg and FMC7 expression in cases with trisomy 12, particularly those with CLL/PL and other atypical morphology. Our findings confirm that trisomy 12 defines a subgroup of CLL with more frequent atypical morphology, including CLL/PL, stronger SmIg and FMC7 expression, more advanced stages (B and C in 18%) and possibly worse prognosis.

Aged↗

PubMed1997

Interleukin-4 prevents spontaneous in-vitro apoptosis in chronic lymphatic leukaemia but sensitizes B-CLL cells to melphalan cytotoxicity.

The effect of IL4 on cell viability, cell growth, apoptotic fraction, melphalan-induced cytotoxicity and the degree of interstrand DNA cross-linking after alkylating agent exposure was investigated in peripheral blood B-cell chronic lymphocytic leukaemia (B-CLL) cells obtained from 10 patients suffering from chronic lymphocytic leukaemia and in B lymphocytes from five normal individuals. The addition of IL4 to culture medium maintained in-vitro viability and decreased spontaneous in-vitro apoptosis in both B-CLL cells and normal peripheral blood B lymphocytes. IL4 did not, however, stimulate proliferation of either cell type. IL4 sensitized alkylator-resistant B-CLL cells to the cytotoxic effects of melphalan (L-phenylalanine mustard) but had no influence on melphalan-induced cytotoxicity against normal B lymphocytes. The enhanced cytotoxicity against B-CLL cells was accompanied by an increase in the amount of interstrand-DNA cross-linking in these cells following short-term exposure to melphalan.

Aged↗

PubMed2001

CLL cells in a brain metastasis of bronchial adenocarcinoma in a patient with three different neoplasms - case report.

OBJECTIVE: We report the case of a patient with three different malignancies who had a brain metastasis of bronchial adenocarcinoma with infiltrates of CLL lymphocytes and who had been operated for prostate cancer years before. - PATIENT AND RESULTS: A 72-year-old man was admitted to our department after a Jacksonian seizure. The MRI showed a left temporal mass lesion. The patient was suffering from chronic lymphocytic leukemia (CLL) for ten years, he had had surgery for prostate cancer eight years ago and the diagnosis of bronchial carcinoma was made during preoperative routine diagnostics. After neurosurgical intervention the histologic examination of the cerebral mass lesion disclosed metastasis of a PSA-negative adenocarcinoma with perivasal infiltrates of lymphocytic leukemic cells. - DISCUSSION: There are few reports about patients with three primary malignancies. CLL may play a role in enabling tumor cells to escape the immune response and could facilitate development of the prostate cancer and of a bronchial adenocarcinoma as secondary cancers in this patient. The combined occurrence of adenocarcinoma cells and CLL lymphocytes in the brain metastasis can be explained by impairment of the blood-brain-barrier in the carcinoma metastasis enabling extravasation of circulating leukemic cells.

Adenocarcinoma↗

PubMed2005

Recent advances in immunotherapy of B-CLL using ex vivo modified dendritic cells.

Chronic lymphocytic leukemia (CLL) results from the relentless accumulation of small mature, slowly dividing, monoclonal B-lymphocytes. The clinical course is heterogeneous, some patients with aggressive form of the disease progressing rapidly with early death while others exhibit a more stable, possibly, non-progressing indolent type of the disease lasting many years. Despite progress in modern treatment modalities, relapse invariably occurs and disease still remains incurable. The clinical management of CLL is therefore challenging and considerable effort has been directed towards novel therapeutic strategies aimed at reducing minimal residual disease which can increase remission duration. Recent insight into the role of dendritic cells (DCs) as pivotal antigen presenting cells that initiate immune responses may provide the basis for generating more specific and effective immune responses. Ex-vivo modified and monocyte-derived DCs represents a promising approach within the context of CLL. However, understanding the relationship between DCs and the cellular immune response is crucial in devising strategies for manipulating immune responses. After a brief survey of general properties of DCs, this review focuses on the different approaches exploiting monocyte-derived DCs in CLL, which may help to design novel strategies for phase-I clinical trials.

Cells, Cultured↗

PubMed2003

IL-4 biology: impact on normal and leukemic CLL B cells.

This review provides a perspective on the role of IL-4 in relation to both normal and leukemic CLL B cells. IL-4 is a well-characterized cytokine known to be produced by normal T cells and have impact on normal B cell differentiation and proliferation. This cytokine and its receptor are now known to exist on CLL B cells. An autocrine pathway for CLL B cells is strongly supported by signaling events, alteration of apoptotic proteins and changes in apoptosis resistance. Based on the increasing knowledge regarding the IL-4 pathway unique opportunities for therapy are now available in B-CLL.

B-Lymphocytes↗

PubMed2003

Relative importance of CD38 expression over myeloid-associated markers expression in predicting the clinical course of B-CLL patients.

Expression of CD38 or myeloid-associated markers has been reported to be important in predicting prognosis in B-cell chronic lymphocytic leukemia (B-CLL) in separate studies but the impact of combining these markers on prognosis has not been examined. The current study aimed to evaluate the relative contribution of expression of CD38 and/or myeloid-associated markers (CD11b, CD13, CD15 and CD33) by flow cytometry (FCM) on the clinical course of 24 B-CLL patients. B-CLL patients with high levels of CD38 expression, defined as greater than or equal to 30% of neoplastic lymphocytes expressing CD38, had a significantly poorer OS than those with low levels of CD38 expression (54% cumulative survival: 51 months vs. 103 months, Kaplan-Meier survival analysis, p < 0.005, Logrank test). High levels of expression of myeloid-associated markers showed no statistically significant impact on OS in these patients. Ten of 11 patients (91%) with high levels of CD38 expression required chemotherapy. In contrast, only 5 of 13 patients (38%) with low levels of CD38 expression required chemotherapy (p < 0.009, Chi Square). There was no significant difference in the requirement for chemotherapy between patients with high levels of expression of myeloid-associated marker and those without (5/8 or 63% vs. 10/16 or 63%). Thus, our results suggest that CD38 is superior to myeloid-associated markers in predicting the prognosis of patients with B-CLL. Further studies with a larger sample size are indicated to confirm our observation.

ADP-ribosyl Cyclase↗

PubMed2006

New molecular markers in resistant B-CLL.

B-chronic lymphocytic leukemia (B-CLL) is characterized by a highly variable clinical course which has long remained a stumbling block for clinicians. This variability appears to arise from complex molecular alterations identified in malignant cells from patient subsets. Recent studies have focused in particular on identifying new molecular markers to help predict the most effective and adapted treatments. In addition to the mutation status of immunoglobulin variable heavy-chain region (IgVH) genes, which is a well-established predictive factor in B-CLL, these new markers include defects of cell factors involved in the maintenance of genome stability, such as telomere function, DNA repair, ATM and p53. Other predictive factors, such as tyrosine kinase Zap-70 and soluble factors found in patient sera, may be associated with B-cell receptor signal transduction. Interestingly, an alteration of these factors fits closely, though not strikingly, with the absence of somatic mutations in IgVH genes, suggesting that the latter may be due either to epigenetic events leading to an unstable genome or to an inherited defect in the immune response of malignant B-cells. Recent lessons from Zap-70 expression/phosphorylation suggest that some of these markers may reflect the defective pathways in B-CLL cells rather than being markers of cell malignancy per se. Furthermore, specific subsets of markers are found in patient cells resistant to treatment. Current studies on gene expression profiling and proteomic analyses should soon lead to a better understanding of how these pathways are affected, especially in multi-drug resistant B-CLL.

Biomarkers↗

PubMed2004

CD40 activation: potential for specific immunotherapy in B-CLL.

Despite encouraging scientific and therapeutic advances, chronic lymphocytic leukemia (CLL) principally remains an incurable disease. Allogeneic transplantation represents the only curative approach, but is marked by high mortality. Novel and less toxic treatment modalities are needed. Immunotherapeutic approaches have clearly demonstrated potential effectiveness in CLL and other B-cell malignancies. To successfully direct immunity against CLL, highly immunogenic tumor cells or tumor-antigen-loaded antigen-presenting cells are necessary. The CD40-CD40L interaction has been shown to significantly increase antigen presentation in normal and malignant B-cells. Here we discuss biology and potential therapeutic applications of the CD40-system in CLL.

Antigen Presentation↗

PubMed1997

Specific inhibition of lymphocyte proliferation and induction of apoptosis by CLL-I, a beta-galactoside-binding lectin.

Beta-galactoside-binding lectins or galectins are a family of closely related carbohydrate-binding proteins which functions still remain to be elucidated. Several evidence suggest they could play a role in different biological processes, such as cell growth regulation and immunomodulation. In the present study we report that affinity-purified CLL-I (chicken lactose lectin-I), an acidic 16-kDa galectin exhibits specific growth regulatory properties. Con A-stimulated rat spleen mononuclear cells showed a marked dose-dependent growth inhibition upon incubation with the galectin protein. Cell growth arrest was highly prevented by galectin-specific sugars. In addition, biochemical, cytofluorometrical, and morphological evidence are also provided to show that these inhibitory properties are related to a positive control in the apoptotic threshold of spleen mononuclear cells. Flow cytometric analysis showed a dose- and time-dependent increase of cells with hypodiploid DNA content upon exposure to CLL-I. Moreover, cells treated with CLL-I displayed the typical ultrastructural changes compatible with apoptosis, mainly chromatin condensation and margination along the inner surface of the nuclear envelope. Finally, the highly characteristic "ladder" pattern of DNA fragmentation into oligonucleosome-length fragments of approximately 180-200 bp could be found within 6 h of cell culture with CLL-I, mainly in the T cell-enriched population. Induction of apoptosis by a beta-galactoside-binding protein highlights a potentially novel mechanism for regulating the immune response and points to a rational basis for the postulated immunomodulatory properties of this protein family.

Animals↗

PubMed2001

Concurrent chronic lymphocytic leukemia cutis and acute myelogenous leukemia cutis in a patient with untreated CLL.

Patients who have chronic lymphocytic leukemia (CLL) are known to have a high frequency of second malignant neoplasms. However, acute myelogenous leukemia (AML) occurring concurrent with or after a diagnosis of CLL is extremely rare. In this article we report a case of AML developing in a 55-year-old male with a 6-year history of untreated CLL. The diagnosis was facilitated by touch preparation of a skin punch biopsy specimen. The patient presented with a two-week history of fever, weakness, anasarca, and a skin rash. Physical examination revealed pink to skin-colored firm papules, which coalesced into indurated plaques on his trunk, upper extremities, and face. The lesions, in combination with generalized edema, produced a leonine facies. Touch prep of the biopsy showed medium to large blasts, large monocytoid cells, and numerous small mature lymphocytes, providing the preliminary diagnosis of a second, previously undiagnosed myelomonocytic malignancy in this patient. The initial diagnosis was subsequently confirmed by histologic, cytochemical, immunohistochemical and flow cytometry studies. This is the first reported case of CLL with concurrent AML in which rapid touch prep of a skin punch biopsy facilitated diagnosis.

Humans↗

PubMed1982

B-CLL cells express true endogenous E receptor after culture with T-cells and mitogens.

Culture studies of peripheral blood mononuclear cells from seven typical cases of B-cell chronic lymphatic leukaemia (CLL) showed that, in the presence of PHA or Con A and greater than or equal to 20% autologous or allogeneic T-cells, CLL cells express true sheep erythrocyte (E) receptor after 2-5 d, but fail to stain with a panel of anti-T-cell sera. In contrast to similarly cultured hairy cells (HCs), the cultured CLL cells continue to express light-chain-restricted surface immunoglobulin (SIg) and show no change in their morphology. The continued SIg positivity and staining with a panel of monoclonal antibodies indicated that the high proportion of E+ cells could not be attributed to the outgrowth of normal T-cells or to mitogen-induced non-specific stickiness. Repeated addition of supernatants from cultured T-cells caused no phenotypic changes and therefore excluded the possibility of shedding and passive acquisition of E receptor. The points of similarity and difference between the responses of CLL cells and HCs cultured in a like manner are briefly considered in relation to the possible lineages of these two cell types.

B-Lymphocytes↗