New lessons learned in T-PLL: results from a prospective phase-II trial with fludarabine-mitoxantrone-cyclophosphamide-alemtuzumab induction followed by alemtuzumab maintenance.

Clinical trials in T-cell prolymphocytic leukemia (T-PLL) are scarce. Based on a precursor study testing fludarabine, mitoxantrone, and cyclophosphamide followed by alemtuzumab (FMC-A), we aimed to improve this regimen by upfront combining subcutaneous (s.c.

Bendamustine followed by obinutuzumab and venetoclax in chronic lymphocytic leukaemia (CLL2-BAG): primary endpoint analysis of a multicentre, open-label, phase 2 trial.

Background: Targeted agents such as the type II anti-CD20 antibody obinutuzumab and the B-cell lymphoma-2 antagonist venetoclax have shown impressive therapeutic activity in chronic lymphocytic leukaemia. The CLL2-BAG trial was initiated to investigate the combination of these two agents in patients with chronic lymphocytic leukaemia.

Methods: In this ongoing multicentre, open-label, investigator-initiated phase 2 trial, patients (aged ≥18 years) with chronic lymphocytic leukaemia requiring treatment according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 16 sites in Germany.

Oral Bruton tyrosine kinase inhibitors selectively block atherosclerotic plaque-triggered thrombus formation in humans.

Interaction of von Willebrand factor (VWF) with platelet glycoprotein Ib (GPIb) and interaction of collagen with GPVI are essential for thrombus formation on ruptured or eroded atherosclerotic plaques (atherothrombosis). GPIb and GPVI signal through Bruton tyrosine kinase (Btk), which can be blocked irreversibly by oral application of ibrutinib, an established therapy for chronic lymphocytic leukemia (CLL) with long-term safety. We found that ibrutinib and the novel Btk inhibitors acalabrutinib and ONO/GS-4059 block GPVI-dependent static platelet aggregation in blood exposed to human plaque homogenate and collagen but not to ADP or arachidonic acid.

The Emerging Role of PI3K Inhibitors in the Treatment of Hematological Malignancies: Preclinical Data and Clinical Progress to Date.

The phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is implicated in the pathogenesis of lymphoma. Deeper understanding of the diversity and biological impact of this pathway has led to the development of specific inhibitors to this pathway. Preclinical data in cell lines, patient samples and disease models have broadened our understanding of PI3K inhibition.

Progranulin is a novel independent predictor of disease progression and overall survival in chronic lymphocytic leukemia.

Progranulin (Pgrn) is a 88 kDa secreted protein with pleiotropic functions including regulation of cell cycle progression, cell motility, wound repair and tumorigenesis. Using microarray based gene expression profiling we have recently demonstrated that the gene for Pgrn, granulin (GRN), is significantly higher expressed in aggressive CD38(+)ZAP-70(+) as compared to indolent CD38(-)ZAP-70(-) chronic lymphocytic leukemia (CLL) cases. Here, we measured Pgrn plasma concentrations by enzyme-linked immunosorbent assay (ELISA) in the Essen CLL cohort of 131 patients and examined Pgrn for association with established prognostic markers and clinical outcome.

High expression of MZB1 predicts adverse prognosis in chronic lymphocytic leukemia, follicular lymphoma and diffuse large B-cell lymphoma and is associated with a unique gene expression signature.

Abstract We recently identified the marginal zone B and B1 cell-specific protein (MZB1) as part of a gene expression signature associated with outcomes in chronic lymphocytic leukemia (CLL). MZB1 is important for B cell function as a key regulator of antibody secretion, calcium homeostasis and adhesion. Therefore, we analyzed the role of MZB1 expression levels in 139 patients with CLL using quantitative real-time polymerase chain reaction (qRT-PCR) and microarray data sets in CLL, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), multiple myeloma (MM) and acute myeloid leukemia (AML).

Advances in the management of follicular lymphoma.

Purpose Of Review: Antibody-based therapy has revolutionized treatment strategies in follicular lymphoma. This review focuses on current standards and recent innovations in the management of the disease.

Recent Findings: Understanding the mechanism of action of antibodies led to the development of next generation CD20 antibodies, antibodies targeting other molecules and bispecific antibodies.

Expression analysis of genes located in the minimally deleted regions of 13q14 and 11q22-23 in chronic lymphocytic leukemia-unexpected expression pattern of the RHO GTPase activator ARHGAP20.

In chronic lymphocytic leukemia (CLL), 13q14 and 11q22-23 deletions are found in 2/3 of the cases. 11q22-23 deletions are associated with poor survival, whereas 13q14 deletions as single abnormality are often found in indolent disease forms. The molecular basis for this difference in prognosis is not known.

Optimal application of antibodies in the treatment of follicular lymphoma: current standards and future strategies.

Advanced-stage follicular lymphoma has previously been described as an incurable disease. However, the introduction of monoclonal antibodies such as rituximab has considerably changed the management of the disease in the last decade with a significant subset of patients remaining in remission for a decade or longer. Rituximab, a CD20-targeting antibody, is approved for treatment both upfront and in the relapse setting.

Characterization of structurally defined epitopes recognized by monoclonal antibodies produced by chronic lymphocytic leukemia B cells.

Despite a wealth of information about the structure of surface membrane immunoglobulin (smIg) on chronic lymphocytic leukemia (CLL) cells, little is known about epitopes reacting with their binding sites. Probing phage-displayed peptide libraries, we identified and characterized mimetopes for Igs of 4 patients with IGHV mutated CLL (M-CLL) and 4 with IGHV unmutated CLL (U-CLL). Six of these mAbs were representatives of stereotyped B-cell receptors characteristic of CLL.

Chronic lymphocytic leukemia cells recognize conserved epitopes associated with apoptosis and oxidation.

Chronic lymphocytic leukemia (CLL) represents the outgrowth of a CD5(+) B cell. Its etiology is unknown. The structure of membrane Ig on CLL cells of unrelated patients can be remarkably similar.

Risk stratification in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) follows an extremely variable clinical course with survival ranging from months to decades. Available treatments can often induce remissions, but eventually all patients relapse. Recently, there has been major progress in the identification of molecular and cellular markers that may predict the tendency for disease progression in patients with CLL.

Additional genetic high-risk features such as 11q deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and VH mutation status in chronic lymphocytic leukemia.

Purpose: Immunoglobulin heavy chain variable-region (VH) gene mutation status and zeta-associated protein 70 (ZAP-70) expression are correlated in chronic lymphocytic leukemia (CLL), but their concordance is variable. The goal of this study was to elucidate additional factors potentially characterizing their discordance.

Patients And Methods: We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic aberrations by fluorescence in situ hybridization in 148 CLL patients.

Distinct gene expression patterns in chronic lymphocytic leukemia defined by usage of specific VH genes.

The mutation status and usage of specific VH genes such as V3-21 and V1-69 are potentially independent pathogenic and prognostic factors in chronic lymphocytic leukemia (CLL). To investigate the role of antigenic stimulation, we analyzed the expression of genes involved in B-cell receptor (BCR) signaling/activation, cell cycle, and apoptosis control in CLL using these specific VH genes compared to VH mutated (VH-MUT) and VH unmutated (VH-UM) CLL not using these VH genes. V3-21 cases showed characteristic expression differences compared to VH-MUT (up: ZAP70 [or ZAP-70]; down: CCND2, P27) and VH-UM (down: PI3K, CCND2, P27, CDK4, BAX) involving several BCR-related genes.

V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL), biologic risk factors such as immunoglobulin variable heavy chain gene (V(H)) mutation status, CD38 expression level, and genomic aberrations have recently been identified, but the relative prognostic impact of the individual parameters is unknown. In the current study, we analyzed V(H) mutation status by polymerase chain reaction and sequencing (n = 300), genomic aberrations by fluorescence in situ hybridization (+3q, 6q-, +8q, 11q-, +12q, 13q-, t(14q), 17p-) (n = 300), and CD38 expression by triple-color FACS (CD5, CD19, CD38) (n = 157) in a unicentric CLL cohort. The prognostic influence of V(H) mutation rate and CD38 expression level was tested by maximally selected log-rank statistics.