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PubMed2005

Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL).

Tumor necrosis factor alpha (TNF-alpha) and vascular endothelial growth factor (VEGF) play an important role in the biology of chronic lymphocytic leukemia (CLL) cells. Thalidomide is a first-generation immuno-modulating agent that down-regulates TNF-alpha and VEGF. We initiated a phase 1/2 clinical trial to determine the safety and efficacy of combining thalidomide with fludarabine in patients with treatment-naïve CLL. Patients received 6 months of continuous daily thalidomide with standard monthly doses of fludarabine. Three dose levels of thalidomide (100, 200, and 300 mg) were studied. Results from the phase 1 part of this study are reported here. Thirteen patients were enrolled in the phase 1 component of the study. Dose-limiting toxicity was not reached. The most common toxicities noted were fatigue, constipation, and peripheral sensory neuropathy. Overall response rate was 100% with 55% of patients achieving complete remissions. At a median follow-up of 15+ months none of the patients have had a relapse and the median time to disease progression has not yet been reached. Responses were noted at all dose levels. Thalidomide given up to 300 mg/day concurrently with fludarabine in patients with previously untreated CLL shows encouraging clinical efficacy and acceptable toxicity. An ongoing phase 2 part of this study will help validate the clinical efficacy of this regimen.

Antineoplastic Agents↗

PubMed2005

How I treat refractory CLL.

Therapy for patients with chronic lymphocytic leukemia (CLL) has greatly changed over the past few years. After years of stagnation, with treatment revolving around the use of rather ineffective drugs such as alkylators, many patients are now being treated with more effective agents such as purine analogs either alone or combined with other drugs and/or monoclonal antibodies. Treatment of patients refractory to these treatments is particularly challenging and should be decided only upon a careful evaluation of the disease, patient characteristics, and prognostic factors. Refractory disease should be clearly separated from relapsing disease. The only curative therapy for patients with CLL, including those with refractory disease, is allogeneic stem cell transplantation. However, the use of allogeneic transplantation is limited because of the advanced age of most patients and the high transplant-related mortality (TRM). Transplants with nonmyeloablative regimens may reduce TRM and allow more patients to receive transplants more safely. For patients in whom an allogeneic transplantation is not feasible or in whom it is deemed inappropriate, participation in phase 2 trials should be encouraged. Finally, to investigate mechanisms to overcome resistance to therapy in CLL and to identify patients that might gain benefit from early, intensive therapies (eg, based on biologic markers) constitute a challenge that needs active investigation.

Antibodies, Monoclonal↗

PubMed2005

Targeting endoplasmic reticulum protein transport: a novel strategy to kill malignant B cells and overcome fludarabine resistance in CLL.

Previous studies showed that chronic lymphocytic leukemia (CLL) cells exhibit certain mitochondrial abnormalities including mtDNA mutations, increased superoxide generation, and aberrant mitochondrial biogenesis, which are associated with impaired apoptosis and reduced sensitivity to fludarabine. Here we report that CLL cells and multiple myeloma cells are highly sensitive to brefeldin A, an inhibitor of endoplasmic reticulum (ER) to Golgi protein transport currently being developed as a novel anticancer agent in a prodrug formulation. Of importance, brefeldin A effectively induced apoptosis in fludarabine-refractory CLL cells. Disruption of protein trafficking by brefeldin A caused the sequestration of the prosurvival factors APRIL and VEGF in the ER, leading to abnormal ER swelling and a decrease in VEGF secretion. Such ER stress and blockage of secretory protein traffic eventually resulted in Golgi collapse, activation of caspases, and cell death. Notably, the cellular sensitivity to this compound appeared to be independent of p53 status. Taken together, these findings suggest that malignant B cells may be highly dependent on ER-Golgi protein transport and that targeting this process may be a promising therapeutic strategy for B-cell malignancies, especially for those that respond poorly to conventional treatments.

Adult↗

PubMed2006

The PANE1 gene encodes a novel human minor histocompatibility antigen that is selectively expressed in B-lymphoid cells and B-CLL.

Minor histocompatibility antigens (mHAg's) are peptides encoded by polymorphic genes that are presented by major histocompatibility complex (MHC) molecules and recognized by T cells in recipients of allogeneic hematopoietic cell transplants. Here we report that an alternative transcript of the proliferation-associated nuclear element 1 (PANE1) gene encodes a novel human leukocyte antigen (HLA)-A(*)0301-restricted mHAg that is selectively expressed in B-lymphoid cells. The antigenic peptide is entirely encoded within a unique exon not present in other PANE1 transcripts. Sequencing of PANE1 alleles in mHAg-positive and mHAg-negative cells demonstrates that differential T-cell recognition is due to a single nucleotide polymorphism within the variant exon that replaces an arginine codon with a translation termination codon. The PANE1 transcript that encodes the mHAg is expressed at high levels in resting CD19(+) B cells and B-lineage chronic lymphocytic leukemia (B-CLL) cells, and at significantly lower levels in activated B cells. Activation of B-CLL cells through CD40 ligand (CD40L) stimulation decreases expression of the mHAg-encoding PANE1 transcript and reciprocally increases expression of PANE1 transcripts lacking the mHAg-encoding exon. These studies suggest distinct roles for different PANE1 isoforms in resting compared with activated CD19(+) cells, and identify PANE1 as a potential therapeutic target in B-CLL.

Alternative Splicing↗

PubMed1994

Is the CHOP regimen a good treatment for advanced CLL? Results from two randomized clinical trials. French Cooperative Group on Chronic Lymphocytic Leukemia.

Between 1985 and 1990, the French Cooperative Group on Chronic Lymphocytic Leukemia (CLL) randomized 287 stage B patients between intermittent chlorambucil plus prednisone (n = 140) or CHOP (n = 147), and 90 stage C patients between CHOP (n = 44) or CHOP plus methotrexate (n = 46). In stage B, although treatment response was improved with CHOP (p = 0.007, chi-square test), no difference in survival was observed between the two randomized groups (p = 0.33, score test). In stage C, no differences in treatment response and survival were shown, with median survival close to that reported with CHOP in the previous CLL-80 trial. These results associated with those from other groups raise the question whether the CHOP regimen, which has been consistently shown to improve response to therapy, is an effective treatment in advanced CLL patients.

Aged↗

PubMed1995

In vitro sensitivity of B-CLL cells to fludarabine and interferons.

In this study we evaluated the cytotoxicity of Fludarabine (FAMP) both alone and in combination with alpha and beta interferon (IFN) against B-cells from patients affected by chronic lymphocytic leukemia (CLL). We used an in vitro colorimetric assay based on the bioreduction of the tetrazolium salt XTT by viable cells. Fludarabine concentrations ranging from 0.03 to 30 microM were tested on cells collected from 22 B-CLL patients. For each fludarabine concentration, 800 I.U. of either alpha or beta IFN were added. Interferon alone did not exert any cytotoxic effect, while Fludarabine showed a strong cytotoxicity against B-CLL cells. The concentration of Fludarabine required to induce a 50% cytotoxicity (IC50) was below 3 microM (the achievable serum level after standard dose in vivo administration) for 19 out of 22 patients. After IFNs supplementation to Fludarabine, it was possible to identify three groups of samples. The first in which IFNs addition did not produce almost any significant change in Fludarabine cytotoxicity (13/22), the second in which there was an improvement in FAMP IC50 (6/22), and finally the third group in which IFNs worsened it (3/22). Stage of disease was the only identified factor accounting for these different results. The second group included samples from 5 patients at stage A and one at stage B, while in the third group all three samples were from patients at stage C. Interferon-alpha and -beta induced the same degree of FAMP IC50 variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1997

Evaluation of Taxol cytotoxicity on B-CLL cells in vitro.

Taxol is a new antimicrotubule agent that, besides a well known efficacy against solid tumors, has shown activity in non-Hodgkin's lymphomas too. We therefore investigated its in vitro cytotoxic activity against cells from patients affected by chronic lymphocytic leukemia (CLL). Peripheral blood lymphocytes from 46 CLL patients were incubated for four days with Taxol at doses ranging from 0.01 to 10 mM and the cytotoxicity was evaluated by a colorimetric method (XTT). In most samples Taxol was inactive and the IC50 was > 10 mM in 40 out of 46 patients. It is worthwhile noting that four of the six in vitro responsive patients had unfavourable clinical features. In three unresponsive patients we also observed that Taxol was not able to induce apoptosis in vitro. In conclusion, based on in vitro data, it seems that Taxol is not an active drug in standard CLL but we cannot exclude some efficacy in other more rapidly proliferating lymphoproliferative disorders.

Antineoplastic Agents, Phytogenic↗

PubMed2004

Expression analysis of the epigenetic methyltransferases and methyl-CpG binding protein families in the normal B-cell and B-cell chronic lymphocytic leukemia (CLL).

The importance of epigenetic modifications in carcinogenesis has been a source of controversy for some time. There is little doubt that changes in genomic hypermethylation contribute to the silencing of tumor suppressor genes. Furthermore, recent studies have also identified the significance of genomic hypomethylation associated with chromosomal instability and tumorigenesis. One of the most perplexing questions regarding epigenetic modifications and leukemogenesis is the relationship with DNA methyltransferases (DNMT's). The primary function of the DNMT enzymes is to methylate genomic DNA, whereas the methyl-CpG binding domain proteins (MBD) interpret this methylation signal and regulate gene expression and chromatin behavior. In this study we analyse these gene families by quantitative real-time PCR to investigate whether expression levels and the B-cell chronic lymphocytic leukemia (B-CLL) phenotype are associated. Furthermore, given the epigenetic crosstalk between genome stability and the histone chromatin code we have analysed eukaryotic histone methyltransferase (Eu-HMTaseI). Surprisingly, we did not observe significant changes in DNMT1 expression in B-CLL cases when compared to normal lymphocytes, regardless of whether we normalise against GAPDH or PCNA as reference standards. Indeed, expression of the maintenance and de novo methylases were independently regulated. Of particular note was the significant down regulation of DNMT3b. Furthermore, we observed a positive correlation between HMTaseI expression levels and stage of leukemia suggesting that changes in the methylation patterns in B-CLL may represent deregulation of the epigenetic repertoire that also include the methylation dependent binding proteins, MBD2 and MeCP2. We envisage changes in the epigenetic program are multifactorial in nature and postulate that the prevalent genomic methylases just one component of a larger epigenetic repertoire.

B-Lymphocytes↗

PubMed1975

Impaired T-cell transformation in chronic lymphocytic leukemia (CLL): Demonstration of a blastogenesis inhibitory factor.

A noncytotoxic serum factor was found in CLL serum which interfered with the response of normal lymphocytes to phytohemagglutinin (PHA) and pokeweed mitogen (PWM). This factor was not produced by B-lymphocytes during short-term culture. This factor may contribute to the impaired lymphocyte responsiveness in CLL. In five of six patients, T-lymphocytes which were purified by passage over nylon wool columns exhibited an impaired response to both PHA and PWM, suggesting that a dilutional effect alone does not fully explain the impaired lymphocyte transformation in CLL.

Adult↗

PubMed2001

Characterization of the 13q14 tumor suppressor locus in CLL: identification of ALT1, an alternative splice variant of the LEU2 gene.

Chromosome 13q14 deletions constitute the most common genetic abnormality in chronic lymphocytic leukemia (CLL). To identify the putative tumor suppressor gene targeted by 13q14 genomic loss, we completely sequenced and characterized a segment of 790 kb at 13q14 spanning the minimal region of loss in CLL. Transcribed sequences in the region were identified through database homology searches and exon-prediction analysis. Two-hundred kb at the centromeric end of the sequence contain five CpG islands, three previously identified genes LEU5/RFP2, LEU2, and LEU1, seven of seven EST clusters composed of >10 ESTs, and a large number of predicted exons. Homology searches against the mouse EST database have allowed us to identify a highly conserved alternative first exon of the LEU2 gene, giving rise to a novel transcript, ALT1 (GenBank accession no. AF380424), which originates within a G+C region in the vicinity of the D13S272 marker. Two novel 3' exons of LEU2 were also identified and are present in both LEU2 and ALT1 transcripts. However, we have not identified any mutations in leukemia cases, or alterations in expression of mRNAs in the region, that might directly implicate these mRNAs in the pathology of CLL. The centromeric end of the sequence, where all reported genes are located, contains twice the expected amount of ALU repeats, whereas the telomeric end is LINE1 rich and contains four LINE1 elements longer than 4 kb, including two full-length LINE1 sequences. This feature of the sequence may favor the occurrence of chromosomal rearrangements and may confer instability to the region, resulting in deletions that may inactivate an as yet unidentified tumor suppressor.

Alternative Splicing↗

PubMed1992

Expression of p53 gene in B-CLL peripheral lymphocytes.

The p53 tumor suppressor gene expression has been studied in 23 B-CLL cases at different clinical stages. The analysis failed to show a direct correlation with each stage, but the significantly lower frequency of a BglII RFLP in the pathologic population suggests a role of this gene in B-CLL. Northern Blot analysis showed the expression of p53 mRNA in all the B-CLL cases. A protocol for the RT-PCR methods was set up to study a very small amount of materials which should be better used for sequence analysis.

DNA, Neoplasm↗

PubMed2005

Staging for CLL-type non-Hodgkin's lymphoma reveals a gastrointestinal stromal tumour.

We report a 73-year-old man presenting with fatigue, lymphadenopathy and weight loss. He had no abdominal pain, fever or night sweats. Physical examination revealed a palpable 1.4-cm hard nontender lymph node behind the left sternocleidomastoid muscle and a palpable 2-cm lymph node in the left axilla. Bone marrow examination and excisional biopsy of the lymph node behind the left sterno-cleidomastoid muscle showed a CLL-type non-Hodgkin's lymphoma (CLL-type NHL). Staging by CT scanning revealed, besides axillary and mediastinal adenopathy, an unexpected mass in the stomach. Gastroscopy and pathological evaluation showed a gastrointestinal stromal tumour (GIST) with immunohistochemical staining for CD 34 and CD 117. The patient was treated with imatinib. CLL-type NHL and GIST both tend to occur in middle-aged and older patients. A double-tumour consisting of both these tumours is rare: the incidence is estimated to be 3 per 10 billion people.

Aged↗

PubMedDate not supplied

Chronic lymphocytic leukaemia (CLL) in Central Africans.

OBJECTIVE: To document the clinical and haematological features of chronic lymphocytic leukaemia (CLL) in Central Africans. DESIGN: Prospective descriptive analysis. SETTING: Tertiary referral teaching hospitals. SUBJECTS: 48 Zimbabweans and 27 Malawians formed the basis of this analysis. RESULTS: There were 75 patients (40 males and 35 females) studied and their ages ranged from 32 to 78 years with a mean +/- s.d. of 56.8 +/- 10.1 years. The peak age incidence of 26.7% occurred between 60 to 64 year old and 21.3% were below 50 years. The major clinical findings included: splenomegaly (68%); hepatomegaly (37.3%); anaemia (34.7%); lymphadenopathy (33.3%) and nine (12%) patients were diagnosed incidentally. The majority of patients (78.7%) had Rai stage III and IV and only seven (9.3%) patients were in stage 0. Of the 32 patients treated with chemotherapy, 25.9% and 59.3% achieved complete or partial remissions respectively. Six patients were still alive after a follow up period of a mean +/- s.d of 39.3 +/- 24.4 months; five were lost to follow up after a mean +/- s.d period of 28.6 +/- 18.8 months and 16 were dead after a mean +/- s.d. period of 25.7 +/- 19.1 months. The main causes of death in the treated group were septicaemia in six, pneumonia in four and tuberculosis in three. In the untreated group of 43 patients, two refused therapy, four died shortly after diagnosis and 37 were lost to follow up. CONCLUSIONS AND RECOMMENDATIONS: Although the study has disclosed that CLL is not rare in central Africans and its presentations are similar to cases reported in the literature, the majority of patients seek medical treatment late. Optimal therapy is impossible due to lack of chemotherapy and supportive services..Therefore, it is recommended that tertiary referral centers in African health systems should be equipped for better management of CLL patients.

Adult↗

PubMed1986

Differentiation between chronic lymphocytic leukaemia (B-CLL) and non-Hodgkin lymphomas in the leukaemic phase by the mouse red blood cell rosette assay.

A distinction between B-CLL and other malignant B-cell lymphomas in the leukaemic phase may be difficult. Mouse red blood cell rosette formation of lymphocytes from 97 patients with B-CLL and 19 patients suffering from other B-cell lymphoproliferative disorders was examined together with lymphocyte rosette formation of healthy controls. The majority of circulating lymphocytes of B-CLL patients formed rosettes with mouse red cells, whereas there was no relationship between the number of peripheral neoplastic B-cells and that of rosette forming cells in other lymphoproliferative diseases. The relatively simple mouse red blood cell rosette assay proved to be of value in the differentiation of otherwise nearly related conditions.

Adult↗

PubMed1987

Investigation of prostaglandins into the culture supernatant of chronic lymphocytic leukaemia (CLL) cells.

Prostaglandins have been proposed as intercellular humoral mediators in the immune response and characterised as regulatory agents in the control of intracellular metabolism. The aim of this work was to determine PGE and PGF2 alpha concentrations in the blood plasma and in the supernatant of 96 hour PHA stimulated and unstimulated leukaemic cell cultures of CLL patients. 62 patients with CLL classified in the 1st or 4th stage according to RAI and 23 healthy individuals were investigated. The proliferation degree of the culture cells was tested by incorporating tritiated thymidine. The prostaglandin concentrations was estimated by the isotopic method using RIA-kit. In the 4th stage of CLL a low value of blastogenic transformation was observed, whereas in the 1st stage the value were similar to those of the control group. It was shown that in the 4th stage of the disease an increase in the PGE concentrations occurs in the blood plasma and the culture supernatant without PHA together with a significant decrease in the PGF2 alpha in the culture supernatant, whereas in the 1st stage a significant decrease in the PGE in the culture supernatant with PHA as compared with those of the control group is noted. These results may indicate on antagonistic action of PGE and PGF2 alpha in leukaemic cell proliferation.

Adult↗

PubMed1989

[Red cell hypoplasia following autoimmune hemolytic anemia associated with T-CLL: report of a case and review of the literature].

A 78-year-old woman, who had axillary lymphadenopathy but no hepatosplenomegaly, was admitted because of lymphocytosis. The leukocyte count was 18.1 x 10(9)/l with 72% abnormal cells. Neither anemia nor thrombocytopenia was present. Many abnormal cells and erythroblasts were seen in the bone marrow. These abnormal cells had irregular nuclei but no granules in the cytoplasm. The surface markers of these cells were positive for E-rosette, CD 2, CD 3, and Leu 7 but negative for CD 4, CD 8, CD 11 (OKM 1), CD 16 (Leu 11), and HLA-DR. The DNA analysis revealed the rearrangement of T-cell receptor beta-chain genes. Direct Coombs test was positive and red-cell life-span (51Cr) was T 1/2 = 19.5 days. The patient was diagnosed as having T-CLL with mild autoimmune hemolysis and was followed without treatment. Seven months later, the leukemia cells of peripheral blood increased to 62.6 X 10(9)/l and the frank autoimmune hemolytic anemia developed. After prednisolone, vincristine and cyclophosphamide were administered, leukemia cells of blood decreased. Anemia with reticulocytopenia, however, persisted and direct Coombs test became negative. In the bone marrow at that time, many neutrophils and megakaryocytes besides leukemia cells were preserved, but erythroblasts were hardly seen, namely a pattern of red cell hypoplasia was observed. The patient deteriorated rapidly and died 26 months after initial recognition of lymphocytosis. When complement was added, the patient's serum obtained during red cell hypoplasia but not during autoimmune hemolysis inhibited BFU-E and CFU-GM in in vitro colony assays. This case indicates that not only B-CLL but also T-CLL is accompanied by immune hematocytopenia.

Aged↗

PubMed1988

In vitro effects of B cell growth and maturation factor on B-CLL lymphocytes.

In the presence of anti-mu Ab, B-CLL lymphocytes are able to respond to cytokines such as IL2, BCGF and IFN-alpha. IL2 is most frequently an active factor. According to the B-CLL lymphocytes population, IL2 alone can induce growth or maturation of B cells. IFN-gamma and IL2 are inefficient on B-CLL lymphocyte proliferation, but they can profoundly modulate the response to IL2. IFN-gamma can synergize with IL2. In contrast IL4 profoundly and constantly inhibits the response to IL2.

B-Lymphocytes↗

PubMed1988

Critical factors in new therapeutic approaches in chronic lymphocytic leukaemia (CLL).

Three critical questions in new therapeutic approaches for CLL are analyzed: balance between risks and benefits; impact of therapy on survival; and can CLL be cured? New treatments should take into account a balance between risks and benefits. Relatively risky therapies can be tried only in those subsets of patients in whom the survival is shortened as compared to the control population. The impact of new therapies on survival is best demonstrated by prospective randomized trials. Two errors are common when the response to treatment is analyzed. Frequently unsuitable statistical methods, biased in favour of responders, are employed. In addition, it is often incorrectly implied that response causes longer survival. To investigate whether CLL can be cured, more research should be directed to the characteristics of complete clonal remissions. The use of non-risky biologic response modifiers in early stages may contribute to these efforts.

Humans↗