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Chronic lymphocytic leukemia (CLL) cells are characterized by defective apoptosis which leads to their extended survival. Arsenic trioxide (As2O3) was reported to induce cell death in many malignant cells, but the specific pathway of As2O3-induced apoptosis/necrosis remains controversial. Our aim was to determine if As2O3 kills CLL cells through apoptosis and whether this is accompanied by reduction in Bcl-2 levels. Cells from nine patients with CLL were incubated with increasing concentrations of As2O3 (0.5–2 μm) for 2, 7, or 14 days. Cells viability was measured using Alamar Blue assay and apoptosis using human Annexin V-FITC and propidium iodine (PI) kit (BMS306FI; Bender MedSystems, Vienna, Austria). Intracellular Bcl-2, Bax, and caspase-3 levels were measured by flow cytometry. As2O3 significantly reduced CLL cell viability ( P < 0.01) and induced apoptotic cell death in a time- and dose-dependent manner. After 7 days, CLL cells showed a significant decrease in mean fluorescence intensity (MFI) of Bcl-2 on flow cytometry study. Bax and caspase-3 levels showed significant decrease in MFI only after prolonged incubations (7 and 14 days) and mostly at higher concentrations of As2O3. The mechanism underlying the reduction in viability of CLL cells incubated with As2O3 is mediated by induction of apoptosis maybe through the down-regulation of Bcl-2. Further studies are needed to elucidate the potential therapeutic role of As2O3 in CLL. [ABSTRACT FROM AUTHOR]

Cancer antigen 125 (CA 125) is a glycoprotein expressed in normal tissues originally derived from celomic epithelia and its serum level is elevated in various benign and malignant conditions that involve stimulation of these tissues. Elevated levels have been reported in 40–43% of patients with non-Hodgkin's lymphoma (NHL) at diagnosis and were associated with parameters known to be associated with advanced and disseminated disease, and with event-free and overall survival. No difference in CA 125 level was found between indolent and aggressive lymphomas, and four of six patients with small lymphocytic lymphoma had elevated CA 125 levels. We therefore decided to measure serum CA 125 levels in chronic lymphocytic leukemia (CLL) patients, and evaluated them in 74 consecutive patients. The mean time from diagnosis to test was 74.5 months (range: 0–300). The mean serum CA 125 level was 16.3 U/ml (range: 3.7–133, normal value:<35 U/ml). CA 125 levels were elevated only in two patients (2.7%). To conclude, serum CA 125 levels are rarely elevated in CLL patients. It is possible that serum CA 125 levels can help differentiate between equivocal cases of small lymphocytic lymphoma and CLL. [ABSTRACT FROM AUTHOR]

B-chronic lymphocytic leukemia (B-CLL) cells have a long survival owing to an alteration in the normal pathways of apoptosis. CLL cells have been found to produce and secrete vascular endothelial growth factor (VEGF). In addition to its major role in angiogenesis, VEGF affects cell survival by interfering with apoptosis. The aim of the present study was to investigate the expression of the VEGF receptors VEGFR-1, VEGFR-2, and VEGFR-3 on B-CLL cells, singly and combined. B-CLL cells were isolated from peripheral blood drawn from patients with CLL. Total VEGF receptor, examined in 13 samples by flow cytometery was present in all cases with mean CD19+/VEGF+ expression of 76% (range 52–92%). Specific receptor expression, examined in 27 samples by immunocytochemical methods, was positive for VEGFR-1 in all 27 patients and for VEGFR-2 and VEGFR-3 in 26 (96%). These findings suggest that the VEGF transduction pathway may be very active in CLL cells, and both its paracrine and autocrine pathways may contribute to their enhanced survival. [Copyright &y& Elsevier]

A large proportion of B-chronic lymphocytic leukaemia (B-CLL) cells express the anti-apoptotic protein Bcl-2. Basic fibroblast growth factor (bFGF) has been shown to upregulate the expression of Bcl-2 in B-CLL cell lines. Vascular endothelial growth factor (VEGF) has been shown to enhance the survival of endothelial cells by upregulating the expression of Bcl-2. In the present study, we measured serum and cellular levels of bFGF and VEGF in 85 patients with CLL using a commercial quantitative sandwich enzyme immunoassay technique. Levels of Bcl-2 were also assayed concomitantly using Western blot analysis. The mean serum level of bFGF was 53·4 pg/ml (range 0–589) and that of VEGF 459·2 pg/ml (range 33–1793). The mean cellular level of bFGF was 158·3 pg/2 × 105 cells (range 0·8–841) and VEGF, 42·4 pg/2 × 105 cells (range 0–244). A high correlation was found between serum and cellular bFGF levels (P < 0·001), but not between the corresponding VEGF levels. Twenty-nine of 69 patients (42%) evaluated for Bcl-2 level, expressed it. The Bcl-2 level was positively correlated with the serum bFGF level (P = 0·007). However, surprisingly there was a negative correlation between Bcl-2 expression and intracellular VEGF level (P = 0·003). A positive correlation was also found between serum bFGF and disease follow-up time and log white blood cell count. These findings indicate that in CLL there is a correlation between angiogenesis-related factors and apoptosis-related protein expression, and elevated bFGF levels may account for the elevated Bcl-2 levels. [ABSTRACT FROM AUTHOR]

B‐Chronic lymphocytic leukemia (B‐CLL) is an example of a human malignancy caused by alterations in the pathways of programmed cell death. In this disease the anti‐apoptotic protein, bcl‐2, is overexpressed and may lead to the prolonged survival of a malignant CLL clone. In the present study we examined the expression of bcl‐2 and bax, which has an antagonistic role against the function of bcl‐2, in cells from CLL patients at different stages of the disease, by immunoblot analysis. A direct association between the stage of the disease and the level of bcl‐2 in the patients' cell, was observed. At stages A and B, 33% and 29% of patients, respectively, expressed high levels of bcl‐2, as opposed to 80% of patients at stage C (p=0.019). Bax level was not significantly associated with the stage of the disease, although patients at stage C had higher levels of bax. In this study we found a trend of association between bcl‐2 and bax levels. Analysis including all patients revealed that 65% of the patients who expressed high levels of bcl‐2 had high levels of bax (p=0.058). Of patients in stage C, 45% expressed high levels of both bcl‐2 and bax while 50% and 42% of patients at stages A and B had low levels of both proteins. [ABSTRACT FROM AUTHOR]

Background: Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma.Methods: We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee.Results: The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib.Conclusions: Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.). [ABSTRACT FROM AUTHOR]