The Bruton Tyrosine Kinase (BTK) Inhibitor Acalabrutinib Demonstrates Potent On-Target Effects and Efficacy in Two Mouse Models of Chronic Lymphocytic Leukemia.

Acalabrutinib (ACP-196) is a novel, potent, and highly selective Bruton tyrosine kinase (BTK) inhibitor, which binds covalently to Cys481 in the ATP-binding pocket of BTK. We sought to evaluate the antitumor effects of acalabrutinib treatment in two established mouse models of chronic lymphocytic leukemia (CLL). Two distinct mouse models were used, the TCL1 adoptive transfer model where leukemic cells from Eμ-TCL1 transgenic mice are transplanted into C57BL/6 mice, and the human NSG primary CLL xenograft model.

RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics.

RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1.

Catching up with solid tumor oncology: what is the evidence for a prognostic role of programmed cell death-ligand 1/programmed cell death-1 expression in B-cell lymphomas?

Therapeutic strategies targeting the programmed cell death-ligand 1/programmed cell death-1 pathway have shown significant responses and good tolerability in solid malignancies. Although preclinical studies suggest that inhibiting programmed cell death-ligand 1/programmed cell death-1 interactions might also be highly effective in hematological malignancies, remarkably few clinical trials have been published. Determining patients who will benefit most from programmed cell death-ligand 1/programmed cell death-1-directed immunotherapy and whether programmed cell death-ligand 1/programmed cell death-1 are adequate prognostic markers becomes an increasingly important clinical question, especially as aberrant programmed cell death-ligand 1/programmed cell death-1 expression are key mediators of impaired anti-tumor immune responses in a range of B-cell lymphomas.

Allogeneic Transplantation for Chronic Lymphocytic Leukemia in the Age of Novel Treatment Strategies.

Hematopoietic stem cell transplantation (HSCT) is the only established potentially curative treatment option for chronic lymphocytic leukemia (CLL) to date. However, this approach is associated with high toxicity and significant treatment-related morbidity and mortality; thus, it is suitable for only a minority of high-risk patients, given that most persons with CLL have comorbidities and are of advanced age. Until very recently, international guidelines recommended HSCT for physically fit patients who displayed poor-risk features or had only a short response to immunochemotherapy.

New insights into hematopoietic stem cell transplantation for chronic lymphocytic leukemia: a 2015 perspective.

A considerable body of evidence demonstrates that allogeneic hematopoietic stem cell transplantation (HSCT) offers the only potentially curative treatment option for patients with chronic lymphocytic leukemia (CLL). However, this approach is suitable for only a minority of CLL patients, owing to its significant treatment-related mortality and morbidity. Until recently, internationally accepted guidelines suggested that HSCT should be considered in physically fit CLL patients who carry poor-risk features, such as TP53 abnormalities, or who had a short response to previous immunochemotherapy.

Rituximab maintenance improves survival in male patients with diffuse large B-cell lymphoma. Results of the HD2002 prospective multicentre randomized phase III trial.

In the multicentre prospective randomized HD2002 trial, rituximab maintenance therapy (375 mg/m(2) every 3 months for 2 years) versus observation was evaluated for CD20(+) B-cell lymphoma. Out of 321 patients [161 randomized to the treatment group (TG), 160 to the observation group (OG)], 295 data sets were evaluable for statistical analysis. Estimated 5-year relapse-free survival (RFS) was 81% in the TG and 70% in the OG (logrank test, P = 0·047).

Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Eµ-TCL1 CLL mouse model.

T-cell defects, immune suppression, and poor antitumor immune responses are hallmarks of chronic lymphocytic leukemia (CLL), and PD-1/PD-L1 inhibitory signaling has emerged as a major immunosuppressive mechanism. However, the effect of different microenvironments and the confounding influence of aging are poorly understood. The current study uses the Eμ-TCL1 mouse model, which replicates human T-cell defects, as a preclinical platform to longitudinally examine patterns of T-cell dysfunction alongside developing CLL and in different microenvironments, with a focus on PD-1/PD-L1 interactions.

PD-L1 checkpoint blockade prevents immune dysfunction and leukemia development in a mouse model of chronic lymphocytic leukemia.

Blockade of the programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint augments antitumor immunity and induces durable responses in patients with solid cancers, but data on clinical efficacy in leukemias are sparse. Chronic lymphocytic leukemia (CLL) is associated with a tumor-supportive microenvironment and a dysfunctional immune system, as shown by "exhausted" T cells, defective immunologic synapse formation, and immunosuppressive myeloid cells. These defects involve aberrant expression of PD-L1 and are closely mirrored in the Eµ-TCL1 mouse model for CLL.

Generation of a poor prognostic chronic lymphocytic leukemia-like disease model: PKCα subversion induces up-regulation of PKCβII expression in B lymphocytes.

Overwhelming evidence identifies the microenvironment as a critical factor in the development and progression of chronic lymphocytic leukemia, underlining the importance of developing suitable translational models to study the pathogenesis of the disease. We previously established that stable expression of kinase dead protein kinase C alpha in hematopoietic progenitor cells resulted in the development of a chronic lymphocytic leukemia-like disease in mice. Here we demonstrate that this chronic lymphocytic leukemia model resembles the more aggressive subset of chronic lymphocytic leukemia, expressing predominantly unmutated immunoglobulin heavy chain genes, with upregulated tyrosine kinase ZAP-70 expression and elevated ERK-MAPK-mTor signaling, resulting in enhanced proliferation and increased tumor load in lymphoid organs.

Transplantation in chronic lymphocytic leukemia: does it still matter in the era of novel targeted therapies?

Allogeneic stem cell transplantation (HSCT) offers the only potentially curative approach in chronic lymphocytic leukemia (CLL). However, this applies only to a minority of patients, and is associated with significant treatment-related mortality and morbidity. HSCT must therefore always be considered in view of other, potentially less toxic therapies.

Trisomy 12 chronic lymphocytic leukemia cells exhibit upregulation of integrin signaling that is modulated by NOTCH1 mutations.

The leukocyte adhesion cascade is important in chronic lymphocytic leukemia (CLL), as it controls migration of malignant cells into the pro-survival lymph node microenvironment. Circulating trisomy 12 CLL cells have increased expression of the integrins CD11a and CD49d, as well as CD38, but the tissue expression of these and other molecules, and the functional and clinical sequelae of these changes have not been described. Here, we demonstrate that circulating trisomy 12 CLL cells also have increased expression of the integrins CD11b, CD18, CD29, and ITGB7, and the adhesion molecule CD323.

T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production.

T-cell exhaustion, originally described in chronic viral infections, was recently reported in solid and hematologic cancers. It is not defined whether exhaustion contributes to T-cell dysfunction observed in chronic lymphocytic leukemia (CLL). We investigated the phenotype and function of T cells from CLL patients and age-matched controls.

Autologous Stem Cell Transplantation for Chronic Lymphocytic Leukemia - Still a Valid Treatment Option, or is the Game Over?

Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has been established as the current standard of care for young and fit patients with chronic lymphocytic leukemia (CLL). In the early nineties of the last century, long before the advent of fludarabine or antibody-based strategies, there was realistic hope that myeloablative therapy followed by autologous stem cell transplantation (autoSCT) might be an effective and potentially curative front-line treatment option for suitable patients with CLL. Since then, several prospective trials have disenthralled this hope: although autoSCT can prolong event and progression-free survival if used as part of early front-line treatment, it does not improve overall survival, while it is associated with an increased risk of late adverse events such as secondary malignancies.

Prognostic value of the Follicular Lymphoma International Prognostic Index score in marginal zone lymphoma: an analysis of clinical presentation and outcome in 144 patients.

Background: In marginal zone lymphoma (MZL), clinical and follow-up data on large cohorts of patients are difficult to obtain. The objective of this single-center, retrospective analysis of a large cohort of 144 patients with MZL was to elucidate the role of prognostic markers, treatments, and outcomes in this disease.

Methods: In total, 144 patients were identified who were diagnosed with MZL at the authors' institution between 2003 and 2010.

Early autologous stem cell transplantation for chronic lymphocytic leukemia: long-term follow-up of the German CLL Study Group CLL3 trial.

The CLL3 trial was designed to study intensive treatment including autologous stem cell transplantation (autoSCT) as part of first-line therapy in patients with chronic lymphocytic leukemia (CLL). Here, we present the long-term outcome of the trial with particular focus on the impact of genomic risk factors, and we provide a retrospective comparison with patients from the fludarabine-cyclophosphamide-rituximab (FCR) arm of the German CLL Study Group (GCLLSG) CLL8 trial. After a median observation time of 8.

Diffusion-weighted imaging for non-invasive and quantitative monitoring of bone marrow infiltration in patients with monoclonal plasma cell disease: a comparative study with histology.

Bone marrow plasma cell infiltration is a crucial parameter of disease activity in monoclonal plasma cell disorders. Until now, the only way to quantify such infiltration was bone marrow biopsy or aspiration. Diffusion-weighted imaging (DWI) is a magnetic resonance imaging-technique that may mirror tissue cellularity by measuring random movements of water molecules.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging of bone marrow in healthy individuals.

Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) displays microcirculation and permeability by application of contrast-media and diffusion-weighted imaging (DWI) is a tool for quantification of cellularity in the investigated area. Recently published examples cover breast cancer, CNS tumors, head and neck cancer, gastrointestinal cancer, prostate cancer as well as hematologic malignancies.

Purpose: To investigated the influence of age, sex, and localization of the investigated region on findings of DCE-MRI and DWI.

Clinical outcome of patients with follicular lymphoma and bulky disease after rituximab-CHOP immunochemotherapy with and without consolidating radiotherapy.

Background: The strategy to apply involved-field radiotherapy (IF-RT) after immunochemotherapy in patients with bulky follicular lymphoma (FL) remains controversial.

Patients And Methods: To evaluate the benefit of consolidating IF-RT, we retrospectively analysed relapse patterns and survival of patients with bulky FL. All patients were treated within a multicenter prospective randomized trial on 126 patients with one, three or six cycles Rituximab and six cycles CHOP.

Long-term population-based risks of breast cancer after childhood cancer.

Previous studies have reported substantially increased risks of breast cancer among survivors of childhood cancer at 10-20 years posttreatment. Whether these excess risks are sustained beyond 40 years of age when general population incidence of breast cancer begins its steep increase is largely unknown. We quantified the risk of breast cancer in adult female survivors with considerably more survivors followed-up beyond 40 years of age than previously available.