Project description:Mechanisms behind carcinogenesis and resistance of tumor cells to treatment regimes remain elusive. The major stress proteins Hsp72, Hsp90, and Hsp27 are credible candidates to provide this resistance, as their overexpression in many cancer types is well documented. In addition to being present inside tumor cells, where they confer resistance to apoptosis, Hsp72, in particular, is presented externally, embedded in the cell membrane of cancer cells. This study aimed to investigate the localization of Hsp72, Hsp90, and Hsp27 in leukocytes from patients with CLL and age-matched control subjects. CLL patients were found to express significantly higher levels of iHsp90 (CLL=2463 MFI; control=748 MFI) and iHsp27 (CLL=2190 MFI; control=1031 MFI) in lymphocytes than that expressed by lymphocytes from control subjects. Furthermore, expression of iHsp90 was shown to be related to stage of disease, and expression of iHsp27 correlated with levels of active caspase-3. Patients were found to express very high levels or very low levels of sHsp72 and iHsp72 in CD5(+)/CD19(+) cells, although surface and intracellular datasets did not correlate. Levels of extracellular Hsp72 circulating in the serum were found to correlate with internal levels of Hsp72 and were also found to be significantly lower in patients receiving corticosteroid treatment than in patients not receiving corticosteroid treatment. Finally, analysis of the number of circulating Tregs revealed significantly elevated numbers in CLL patients compared with control subjects.
Project description:The advent of BTK inhibitors has changed the treatment of patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). The first-in-class BTK inhibitor ibrutinib has shown remarkable therapeutic effects and manageable toxicities in multiple clinical trials. The second-generation BTK inhibitors, including acalabrutinib and zanubrutinib, also show remarkable efficacies. However, using BTK inhibitors as monotherapies requires continuous treatment. Resistance to BTK inhibitors and severe side effects unavoidably occur during BTK inhibitor monotherapy, frequently resulting in treatment failure. The addition of the BCL2 inhibitor venetoclax to BTK inhibitor may improve the therapeutic effects and result in deeper responses, providing a potential fixed-duration treatment, especially for patients with CLL. In this review, by focusing on CLL and MCL, we discussed the rationale for the combinational use and summarized the current data on the combinations of BTK inhibitors and venetoclax in patients with CLL and MCL.
Project description:Although chemo-immunotherapy remains at the forefront of first-line treatment for mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), small molecules, such as ibrutinib, are beginning to play a significant role, particularly in patients with multiply relapsed or chemotherapy-refractory disease and where toxicity is an overriding concern. Ibrutinib is a first-in-class, oral inhibitor of Bruton's tyrosine kinase, which functions by irreversible inhibition of the downstream signaling pathway of the B-cell receptor, which normally promotes cell survival and proliferation. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile even in elderly and multiply pretreated patient cohorts. Although the majority of disease responses tend to be partial, efficacy data have also been encouraging with more than two-thirds of patients with CLL and MCL demonstrating a durable response, even in the high-risk disease setting. Resistance mechanisms are only partially understood and appear to be multifactorial, including the binding site mutation C481S, and escape through other common cell-signaling pathways. This article appraises the currently available data on safety and efficacy from clinical trials of ibrutinib in the management of MCL and CLL, both as a single agent and in combination with other therapies, and considers how this drug is likely to be used in future clinical practice.
Project description:Downregulation of miR26A1 has been reported in various B-cell malignancies; however, the mechanism behind its deregulation remains largely unknown. We investigated miR26A1 methylation and expression levels in a well-characterized series of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). From 450K methylation arrays, we first observed miR26A1 (cg26054057) as uniformly hypermethylated in MCL (n = 24) (all >75%), while CLL (n = 18) showed differential methylation between prognostic subgroups. Extended analysis using pyrosequencing confirmed our findings and real-time quantitative PCR verified low miR26A1 expression in both CLL (n = 70) and MCL (n = 38) compared to normal B-cells. Notably, the level of miR26A1 methylation predicted outcome in CLL, with higher levels seen in poor-prognostic, IGHV-unmutated CLL. Since EZH2 was recently reported as a target for miR26A1, we analyzed the expression levels of both miR26A1 and EZH2 in primary CLL samples and observed an inverse correlation. By overexpression of miR26A1 in CLL and MCL cell lines, reduced EZH2 protein levels were observed using both Western blot and flow cytometry. In contrast, methyl-inhibitor treatment led to upregulated miR26A1 expression with a parallel decrease of EZH2 expression. Finally, increased levels of apoptosis were observed in miR26A1-overexpressing cell lines, further underscoring the functional relevance of miR26A1. In summary, we propose that epigenetic silencing of miR26A1 is required for the maintenance of increased levels of EZH2, which in turn translate into a worse outcome, as shown in CLL, highlighting miR26A1 as a tumor suppressor miRNA.
Project description:We conducted two indirect comparisons to estimate the efficacy of zanubrutinib versus orelabrutinib in Chinese patients with relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or R/R mantle cell lymphoma (MCL). An unanchored matching-adjusted indirect comparison (MAIC) was performed in R/R CLL/SLL patients. Individual patient data from zanubrutinib trial (BGB-3111-205) were adjusted to match the aggregated data from the orelabrutinib trial (ICP-CL-00103). A naïve comparison was performed in R/R MCL for the different response assessment methodology and efficacy analysis set between the zanubrutinib (BGB-3111-206) and orelabrutinib (ICP-CL-00102) trials. Efficacy outcomes included ORR and PFS. In R/R CLL/SLL patients, after matching, IRC-assessed ORR was comparable (86.6% vs. 92.5%; risk difference, -5.9% [95% CI: -15.8%-3.8%]); IRC-assessed PFS was similar with a favorable trend in zanubrutinib over orelabrutinib (HR, 0.74 [95% CI: 0.37-1.47]) and the 18-month PFS rate was numerically higher in zanubrutinib (82.9% vs. 78.7%). In R/R MCL patients, naïve comparison showed investigator-assessed ORR was similar (83.7% vs. 87.9%; risk difference, -4.2% [95% CI: -14.8%-6.0%]), and CR rate was significantly higher in zanubrutinib over orelabrutinib (77.9% vs. 42.9%; risk difference, 35.0% [95% CI: 14.5%, 53.7%]). Investigator-assessed PFS was similar with a favorable trend (HR, 0.77 [95% CI: 0.45-1.32]) in zanubrutinib over orelabrutinib and the 12-month PFS rate was numerically higher in zanubrutinib (77.5% vs. 70.8%). MAIC result showed zanubrutinib demonstrated favorable PFS over orelabrutinib for R/R CLL/SLL patients. The naïve comparison showed zanubrutinib had favorable PFS and higher CR rate than orelabrutinib for R/R MCL patients.
Project description:The BCL-2 protein family members inhibit cellular apoptosis, and their overexpression represents a common survival adaption in cancer. Recently, a selective BCL-2 inhibitor ABT-199, venetoclax, has demonstrated remarkable activity in relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), both as a single agent and in combination with anti-CD20 immunotherapies, such as rituximab. In this article, we review the development and latest clinical data that have led to the expanded approval of venetoclax with rituximab in relapsed/refractory CLL/SLL. We also discuss ongoing and future clinical trials designed to evaluate the efficacy of venetoclax in previously untreated patients and to investigate venetoclax combinations with inhibitors of B-cell receptor signaling pathway. These studies hope to offer an expanded list of chemotherapy-free regimens for patients with CLL/SLL.
Project description:The two B-cell non-Hodgkin lymphoma (NHL) entities chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) show recurrent chromosomal gains of 3q25 q29, 12q13 q14 and 18q21-q22. The pathomechanisms affected by these aberrations are not understood. The aim of this study was to identify genes, located within these gained regions, which control cell death and cell survival of MCL and CLL cancer cells. Blood samples from 24 CLL and 6 MCL patients as well as 6 cell lines representing both malignancies were analyzed by gene expression profiling. By comparison of genomic DNA and gene expression, 72 candidate genes were identified. We performed a limited RNAi screen with these candidates in order to identify genes affecting cell survival. CCDC50, SERPINI2 and SMARCC2 mediated a reduction of cell viability in primary CLL cells as well as in cell lines. Gene knock down and a NFkB reporter gene assay revealed that CCDC50 is required for survival in MCL and CLL cells and controls NFkB signaling. This SuperSeries is composed of the SubSeries listed below.
Project description:This study investigated the impact of comorbidity in 555 patients with chronic lymphocytic leukemia enrolled in two trials of the German Chronic Lymphocytic Leukemia Study Group on first-line treatment with fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Patients with two or more comorbidities and patients with less than two comorbidities differed in overall survival (71.7 versus 90.2 months; P<0.001) and progression-free survival (21.0 versus 31.5 months; P<0.01). After adjustment for other prognostic factors and treatment, comorbidity maintained its independent prognostic value in a multivariate Cox regression analysis. Chronic lymphocytic leukemia was the major cause of death in patients with two or more comorbidities. Disease control in patients with two or more comorbidities was better with fludarabine plus cyclophosphamide than with fludarabine treatment, but not with fludarabine compared to chlorambucil treatment. These results give insight into interactions between comorbidity and therapy of chronic lymphocytic leukemia and suggest that durable control of the hematologic disease is most critical to improve overall outcome of patients with increased comorbidity. The registration numbers of the trials reported are NCT00276848 and NCT00262795.