SEARCH · PubMed Health

Results for “CLL”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 379 records · Page 21Linked to original sources

PubMed1999

Exclusion of Leu1 and Leu2 genes as tumor suppressor genes in 13q14.3-deleted B-CLL.

The chromosomal region 13q14.3 is frequently deleted in B cell chronic lymphocytic leukemia (B-CLL) and it is supposed that a tumor suppressor gene, involved in this leukemogenesis, is located in this area. The first exons of two genes, Leu1 and Leu2, mapped in a minimally deleted 13q14.3 region, are systematically lost in B-CLL sharing a 13q14.3 deletion. These two genes have been proposed as strong tumor suppressor gene candidates. However, in a study on 15 13q14.3 deleted B-CLL, we found three patients in which this critical region was not involved. Because of these results and that no mutations were detected on the two genes in a previous study, we think that Leu1 and Leu2 can be excluded as tumor suppressor genes.

CD5 Antigens↗

PubMed2001

Phosphodiesterase type 4 inhibitor suppresses expression of anti-apoptotic members of the Bcl-2 family in B-CLL cells and induces caspase-dependent apoptosis.

B cell chronic lymphocytic leukemia (B-CLL) is an incurable clonal disease which shows initial responsiveness to a number of chemotherapeutic drugs. However, in most patients the disease becomes resistant to treatment. Rolipram, a specific inhibitor of phosphodiesterase (PDE) type 4, the PDE predominantly expressed in B-CLL cells, has been shown to induce cAMP-dependent apoptosis in these cells. In the present study, we demonstrate that the extent of rolipram-induced apoptosis is similar to fludarabine-induced apoptosis in vitro. The combination of rolipram and fludarabine results in an enhancement in the number of apoptotic cells compared to apoptosis induced by either agent alone. Second, rolipram suppresses the expression of anti-apoptotic members of the Bcl-2 family and induces the pro-apoptotic protein Bax, thereby shifting the balance between pro- and anti-apoptotic members of the Bcl-2 family towards a pro-apoptotic direction. Finally rolipram-induced apoptosis is caspase-dependent. PDE 4 inhibitors are currently under investigation for chronic obstructive pulmonary disease and asthma in phase III clinical trials showing promising results with tolerable side-effects. In conclusion, by inducing apoptosis, by enhancing apoptosis induced by fludarabine, by suppressing Bcl-2, Bcl-X and by inducing Bax expression, PDE 4 inhibitors may add a new therapeutic option for patients with B-CLL.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2004

Apoptotic tumor cells are superior to tumor cell lysate, and tumor cell RNA in induction of autologous T cell response in B-CLL.

B cell chronic lymphocytic leukemia (B-CLL) is a chronic leukemia manifested by increased numbers of B cells in circulation. The slow, smouldering nature of the disease in a significant proportion of the cases makes it an ideal target for immunotherapy. Dendritic cell (DC)-based immunotherapy is emerging as an exciting modality with significant clinical potential. In this study, three strategies for delivering antigens to DC, namely apoptotic bodies (Apo-DC), tumor lysates, and tumor RNA were studied in an autologous setting. In all six CLL patients, Apo-DC induced higher HLA-restricted, T cell responses than DC pulsed with tumor lysate or RNA. Real-time PCR confirmed higher expression of genes for IL-2 and IFN-gamma in T cells stimulated with Apo-DC. Concurrently, no IL-10 and low IL-4 responses indicated that the immune response was primarily of the Th1 type. Enzyme-linked immunospot assay revealed high IFN-gamma secretion by T cells when Apo-DC was used to stimulate autologous T cells in all patients. Our data suggest that cellular vaccines with DC loaded with apoptotic bodies may be a suitable approach for immunotherapy of B-CLL.

Aged↗

PubMed2005

Translocation t(1;6)(p35.3;p25.2): a new recurrent aberration in "unmutated" B-CLL.

Although reciprocal chromosomal translocations are not typical for B-cell chronic lymphocytic leukemia (B-CLL), we identified the novel t(1;6)(p35.3;p25.2) in eight patients with this disorder. Interestingly, all cases showed lack of somatically mutated IgV(H). Clinical, morphological, immunologic, and genetic features of these patients are described. Briefly, the age ranged from 33 to 81 years (median: 62.5 years) and the sex ratio was 6M:2F. Most of the patients (6/8) presented with advanced clinical stage. Therapy was required in seven cases. After a median follow-up of 28 months, five patients are alive and three died from disease evolution. Three cases developed transformation into diffuse large B-cell lymphoma. Translocation t(1;6) was found as the primary karyotypic abnormality in three patients. Additional chromosomal aberrations included changes frequently found in unmutated B-CLL, that is, del(11)(q), trisomy 12 and 17p aberrations. Fluorescence in situ hybridization analysis performed in seven cases allowed us to map the t(1;6) breakpoints to the 1p35.3 and 6p25.2 chromosomal bands, respectively. The latter breakpoint was located in the genomic region coding for MUM1/IRF4, one of the key regulators of lymphocyte development and proliferation, suggesting involvement of this gene in the t(1;6). Molecular characterization of the t(1;6)(p35.3;p25.2), exclusively found in unmutated subtype of B-CLL, is in progress.

Chromosomes, Human, Pair 1↗

PubMed2005

CLL family 'Pedigree 14' revisited: 1947-2004.

The notion that inherited predisposition contributes to the development of haematological malignancies is generally thought of as being a relatively new idea. However, Videbaek made a clear enunciation of such a hypothesis in 1947, from a study of tumour incidence in relatives of patients with different leukaemias. To gain further insight into inherited susceptibility to chronic lymphocytic leukaemia (CLL), we followed up the descendants of Videbaek's 'Pedigree 14' series of families. Using the Danish medical and pedigree databases, complete tracing of 222 descendants of the original 57 family members was achieved. To date, 10 family members have been diagnosed with CLL, one with T-cell lymphoma and 17 with nonhaematological cancers, including five with breast cancer. The detailed follow up of this family provides further support for inherited predisposition to CLL and illustrates the value of follow-up studies of previously published family material for genetic analyses.

Aged↗

PubMed2006

Hyperforin inhibits MMP-9 secretion by B-CLL cells and microtubule formation by endothelial cells.

We previously reported that hyperforin (HF), a natural phloroglucinol purified from Saint John's wort, can induce the apoptosis of leukemic cells from patients with B-cell lymphocytic leukemia (B-CLL) ex vivo. We show here that treatment of cultured B-CLL patients' cells with HF results in a marked inhibition of their capacity to secrete matrix metalloproteinase-9, an essential component in neo-angiogenesis through degradation of the extracellular matrix process. The phloroglucinol acts by decreasing the production of the latent 92 kDa pro-enzyme. The inhibitory effect of HF is associated with a decrease in VEGF release by the leukemic cells. Moreover, HF is found to prevent the formation of microtubules by human bone marrow endothelial cells cultured on Matrigel, evidencing its capacity to inhibit vessel formation. Our results show the antiangiogenesis activity of HF and strengthen its potential interest in the therapy of B-CLL.

Adult↗

PubMed2006

ZAP-70 expression, as detected by immunohistochemistry on bone marrow biopsies from early-phase CLL patients, is a strong adverse prognostic factor.

Zeta-associated protein-70 (ZAP-70), mostly assessed by flow-cytometry (FC), recently emerged as reliable prognostic factor in chronic lymphocytic leukaemia (CLL) at presentation. We evaluated ZAP-70 expression in 156 CLL patients by immunohistochemistry (IHC) on formalin-fixed bone marrow (BM) biopsies at diagnosis. At presentation, 117 patients (75%) were with Binet stage A, 27 (17%) stage B and 12 (8%) stage C. Median follow-up was 61 months (range 6-242). ZAP-70 was expressed in neoplastic lymphocytes of 69 patients (44%). Concordance between ZAP-70 by IHC and ZAP-70 by FC, immunoglobulin heavy chain variable genes (IGHV) mutational status and CD38 expression was found in 41/46 (89%), 41/49 (80%) and in 60/88 (68%) tested cases, respectively. ZAP-70 expression significantly correlated with advanced Binet stage (B-C), diffuse BM infiltration, increased lactate dehydrogenase (LDH) and beta2-microglobulin serum levels and lymphocyte doubling time <12 months. ZAP-70 positivity was significantly related to poorer time to progression (median 16 months vs 158 of ZAP-70-negative cases) (P<0.0001) and overall survival (median 106 months vs not reached) (P=0.0002); this correlation was confirmed at multivariate analysis. ZAP-70 expression correlated with poorer outcome also when evaluated only in the 117 stage A patients. In conclusion, immunohistological detection of ZAP-70 on formalin-fixed BM biopsies at diagnosis appears a useful methodological approach to identify patients with poor prognosis in CLL.

ADP-ribosyl Cyclase 1↗

PubMed2003

A study of the proteins responsible for stimulating B-CLL-specific T-cell responses by autologous dendritic cells pulsed with tumour cell lysate.

We have previously shown that autologous dendritic cells (DCs) pulsed with tumour cell lysate and cultured with autologous T cells from patients with B-cell chronic lymphocytic leukaemia (B-CLL) stimulate significant increases in proliferation, IFN-gamma secretion and specific HLA class II-restricted cytotoxicity to B-CLL targets. In this study, normal and tumour cell lysates were analysed by reducing SDS-PAGE, and protein bands of interest eluted from the polyacrylamide gel by electroelution. The eluted protein fractions and whole-cell lysate were then pulsed onto autologous DCs and cocultured with autologous T cells. Finally, the stimulatory fractions were sequenced. B-CLL cell lysates revealed protein bands at 65, 42, 35 and 25 kDa, while normal B-cell lysates only showed a single protein band at 65 kDa. Both the 65 kDa band and 42 kDa bands were capable of stimulating comparable amounts of IFN-gamma secretion and specific cytotoxicity as whole lysate, while the other protein bands were not. Sequencing of the 65 kDa fraction showed a dominant peptide that matched human serum albumin, while sequencing the 42 kDa fraction showed three dominant peptides which matched human actin and another unidentified protein. The significance of these findings remains unclear.

Actins↗

PubMed1996

An aggressive subtype of B-CLL is characterized by strong CD44 expression and lack of CD11c.

In a retrospective study based on 107 B-CLL patients, the expression of the adhesion molecules CD44, CD11a, CD11b, CD11c, CD18, CD25 and CD54 was analysed in bone marrow cryostat sections by immunohistochemistry. CD44 expression clearly identified two subgroups of B-CLL patients with different clinical course. In particular, CD44-positive patients presented with advanced disease, more often displayed a diffuse pattern of bone marrow infiltration, and had a worse prognosis. 33/61 patients positive for CD44 died within the observation period compared to 7/46 patients negative for CD44 (P = 0.0012). Multivariate analysis emphasized the independent prognostic value of CD44 expression for overall survival (P = 0.022). In contrast, patients positive for CD11c showed a longer survival, with 9/40 patients dying within the observation period compared to 31/67 negative for CD11c (P = 0.0013). Patients lacking CD11c were in advanced Rai and Binet stage. Multivariate analysis confirmed CD11c as a relevant independent prognostic marker (P = 0.033). Moreover, CD11c was able to separate patients with significantly different prognosis in the subgroup of CD44-positive cases. 4/18 patients positive for CD44 and CD11c died before median survival time was reached. Patients positive for CD44 but negative for CD11c had an adverse prognosis: 29/43 patients died, median survival time was 33.4 months. Our results indicate that CD44 positivity and CD11c negativity are associated with more advanced disease and worse prognosis in B-CLL and suggest CD44-positive/CD11c-negative cases represent a more aggressive form of the disease.

Adult↗

PubMed1997

In vivo 'purging' of residual disease in CLL with Campath-1H.

We assessed the role of human CD52 antibody (Campath-1H) in six patients with chronic lymphocytic leukaemia (CLL) treated to maximal response with purine analogues (fludarabine/deoxycoformycin) in whom persistent leukaemic infiltration of blood and bone marrow had precluded autologous stem cell transplantation. Five patients achieved haematological and histological complete remission following Campath-1H and one had minimal focal residual CLL in a trephine biopsy. Autologous transplantation was performed in two patients without complications and with rapid haemopoietic engraftment. Treatment with Campath-1H may be of value in eradicating residual disease in CLL and may facilitate high-dose therapy in young patients.

Adult↗

PubMed2005

Eradication of minimal residual disease with alemtuzumab in B-cell chronic lymphocytic leukemia (B-CLL) patients: the need for a standard method of detection and the potential impact of bone marrow clearance on disease outcome.

The introduction of new therapeutic agents, such as fludarabine phosphate (Fludara) and alemtuzumab (MabCampath, Campath), has made it possible to treat B-cell chronic lymphocytic leukemia (B-CLL) more effectively, compared with alkylating agents. However, although an increasing number of patients are able to achieve complete remission (CR), relapse is almost inevitable, because of the re-emergence of the malignant clone from small numbers of residual malignant cells. This phenomenon has introduced a need for a more sensitive assessment of low-level disease which, in turn, has encouraged the development of therapies aimed at the eradication of all residual disease in CR patients. The eradication of residual disease is associated with improved remission durability and has great potential in offering the possibility of cure. Alemtuzumab is the foundation of many eradication-based treatment approaches because of its ability to achieve clinical remissions and to successfully purge minimal residual disease (MRD) from both blood and bone marrow in B-CLL patients. This article describes and compares polymerase chain reaction (PCR) and flow cytometric methodologies for the assessment of MRD, and presents data demonstrating that alemtuzumab can eliminate residual malignant cells from blood and bone marrow (whether assessed by PCR or flow cytometry) at the highest levels of sensitivity currently available. The ability to clear MRD from bone marrow in patients achieving clinical CR using alemtuzumab is a significant step forward in the treatment of B-CLL, and supports treatment strategies in which alemtuzumab is used in combination with other agents. Purging of MRD from both blood and bone marrow also enables patients to proceed to autologous hematopoietic stem cell transplantation, a strategy that is able to achieve long-term remission.

Alemtuzumab↗

PubMedDate not supplied

Fatal thrombocytopaenia temporally related to the administration of alemtuzumab (MabCampath) for refractory CLL despite early discontinuation of therapy.

Alemtuzumab (Campath 1H -MabCampath), initially used for prophylaxis of graft versus host disease in allogenic transplantaion, is now increasingly used for refractory chronic lymphatic leukaemia (CLL). Its efficacy has been well documented in this--the commonest form of leukaemia. Alemtuzumab is associated with severe immunosuppression, allergic reactions and thrombocytopenia. Data sheet and information supplied by the manufacturer confirm the rare occurrence of serious immune thrombocytopenia, recommending discontinuation of therapy when platelet counts fall below 50x10(9)/l. We report a patient with refractory CLL in which relentless progressive cytopenia occurred despite the discontinuation of alemtuzumab therapy while the platelet count was over 97x10(9)/l. Marrow biopsy showed increased megakaryocytes, the patient bleed uncontrollably and died of cerebral haemorrhage with a platelet count <10x10(9)/l. Data on the predictive factors underlying this complication are few and deserve further study as this drug is increasingly used the treatment of CLL.

Alemtuzumab↗

PubMed2005

CD38 as a prognostic marker in CLL.

Cell-surface expression of CD38 in CLL has been recognised recently as a marker of progressive disease and poor outcome. In contrast to traditional staging systems, CD38 is able to identify progressive cases at an early stage. Measurement of CD38, in conjunction with other novel prognostic factors such as p53 and ZAP-70 helps to identify patients who might benefit from early and more intensive therapy. In addition, CD38 positivity can predict unmutated IgVH gene mutation status in most cases. These features, together with its easy applicability, render CD38 a valuable tool in the routine diagnostics of CLL. Questions remaining to be clarified about CD38 include the incidence and significance of its variations during the course of the disease, the optimal method to define CD38 positivity and the impact of different methodologies on results. Only after these issues are resolved can the definitive place of CD38 be defined in the diagnostics of CLL.

ADP-ribosyl Cyclase↗

PubMed2004

Efficacy and safety of fludarabine and cyclophosphamide combined therapy in patients with refractory/recurrent B-cell chronic lymphocytic leukaemia (B-CLL)-Polish multicentre study.

The aim of this study was to investigate the efficacy of a combination of fludarabine (F) and cyclophosphamide (C) in the treatment of patients with refractory/recurrent B-cell chronic lymphocytic leukaemia (B-CLL). Between November 1999 and December 2001, 63 patients with B-CLL (median age 60 years) received a regimen that consisted of F 25 mg/m2 and C 250 mg/m2, days 1-3, intravenously, every 4 weeks, for a maximum of 6 courses, Response and toxicity were assessed according to current criteria (NCI-WG and WHO). Complete and partial remissions were achieved in 17.5% and 55.6% of patients, respectively; 19% of patients had stable disease and 7.9% of patients showed disease progression. The median follow-up was 16.5 (range 1.5-32) months. The median duration of progression-free survival (PFS) has not been reached among patients treated with FC regimen as second-line therapy. The median PFS was 13 (range 8-26) months in the 19 responding patients treated with FC regimen as third-line therapy. The most frequent side-effects were neutropenia (45%), thrombocytopenia (42%) and infections (57%). We conclude that the combination of fludarabine and cyclophosphamide demonstrated significant efficacy in pretreated, advanced B-CLL patients, with tolerable toxicity.

Adult↗

PubMed2004

Routine analysis of IgVH mutational status in CLL patients using BIOMED-2 standardized primers and protocols.

Current methods for the detection of IgVH mutational status in chronic lymphocytic leukemia (CLL), which identifies 2 subgroups of patients with significantly different outcomes, are laborious, expensive and do not lend themselves to a routine diagnostic setting. With the introduction of BIOMED-2 primers, a rapid protocol is now available. This study evaluated the protocol by examining DNA from 100 CLL patients. Conventional methods using RNA, and fluorescence in-situ hybridization (FISH) analysis for recurring chromosomal abnormalities, were carried out on 30 and 60 of these patients, respectively. There was complete concordance between the BIOMED-2 protocol and the RNA based method, both in mutational status and gene usage, whilst unmutated IgVH genes showed association with 17p13 and 11q23 deletions, and trisomy 12, associated with poor and intermediate outcomes, respectively. This study demonstrates that it is feasible to use the BIOMED-2 protocol in the diagnostic profile of CLL patients, obviating the need for inclusion of surrogate markers such as ZAP-70.

Adult↗

PubMed2002

Interleukin-12 inhibits apoptosis in chronic lymphatic leukemia (CLL) B cells.

The purpose of the present study was to investigate the effect of interleukin-12 on apoptosis of chronic lymphatic leukemia (CLL) B cells. Apoptotic indices were determined in highly purified CD5(+) B lymphocytes isolated from peripheral blood of seven patients with histologically confirmed CLL. Interleukin-4 as a known inhibitor of apoptosis was used as control. Quantitative analysis of apoptosis was determined by cell death detection ELISA. Our findings indicate that interleukin-12 inhibits ex vivo apoptosis in a large proportion of B-CLL patients and may be closely involved in the pathogenesis of disease. Therefore, our results may help identify potential new therapeutic targets in this malignancy.

Adult↗

PubMed1987

New aggressive variant of suppressor/cytotoxic T-CLL.

Three cases of CD8+ CLL are reported. The patients are young (28, 18, 27 years old). The leukemia cells are predominantly small lymphocytes with irregular nuclei bearing notches and lobations. Cytoplasmic azurophilic granules are absent. Cytochemistry shows periodic acid-Schiff granular, alpha-naphthylacetate esterase focal, and acid phosphatase focal/granular positivities. Immunophenotypically cells are CD2+, CD3+, and CD8+ and lack CD4 as well as B-cell and NK cell antigens. All patients died within 20, 16, and 9 months, respectively. The clinicopathologic features of these cases differ clearly from those of the CD8+ CLL with azurophilic granules. These three cases represent a morphologically distinctive and more aggressive variant of CD8+ CLL.

Adolescent↗

PubMed2001

B-cell neoplasia associated gene with multiple splicing (BCMS): the candidate B-CLL gene on 13q14 comprises more than 560 kb covering all critical regions.

Deletions in chromosomal band 13q14.3 occur in >50% of B-cell chronic lymphocytic leukemias (B-CLL) and mantle cell lymphoma, indicating the localization of a tumor suppressor gene involved in the pathomechanism of these diseases. Within a 400 kb recurrently deleted segment at least two minimally deleted subregions had been reported. For the two genes residing in the proximal subregion, initially named LEU1 and LEU2, a pathogenic role has not yet been established. We report here that LEU1 is only a small portion of a large gene, which spans all previously reported critical subregions including the distal subregion. This gene, designated B-cell neoplasia-associated gene with multiple splicing (BCMS), is composed of at least 50 exons spanning >or=560 kb of genomic DNA and is expressed in more than 20 RNA splicing variants. While tissue-specific expression of RNA variants was observed, there was no evidence for the expression of a variant specific for B-CLL. Sequence analysis of the RNA variants suggests that BCMS transcripts belong to the group of non-coding RNAs. The alignment of the gene with all critical subregions provides a strong argument for BCMS being the most likely candidate for the tumor suppressor gene in 13q14 involved in the leukemogenesis of B-CLL. Due to the limited understanding of functional RNAs, however, it remains difficult to prove the pathogenic role of BCMS.

Alternative Splicing↗