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Apoptosis inhibition in chronic lymphocytic leukemia (CLL) is one of the most important mechanism in the disease onset, progression and therapy response and is dependent of interaction with different microenvironments. Aim of our paper is to determine expression of antiapoptoic proteins mcl-1 and bcl-2 in CLL cells isolated from two different compartments (peripheral blood and bone marrow) and its relation to percent of apoptotic cells and concentration of growth factors (FGF and VEGF). Our results showed that peripheral blood CLL lymphocytes have lower apoptotic rate then those isolated from bone marrow, though bone marrow CLL lymphocytes express higher levels of antipoptotic proteins bcl-2 and mcl-1. In bone marrow FGF concentration is 10-fold higher then in patients plasma but has an limited impact on mcl-1 expression. In contrary, VEGF concentration is higher in peripheral blood and corelate with percent of apoptotic cells and mcl-1 expression in this compartment. CLL cells derived from two different microenvironmets acts differently when tested for apoptosis „ex vivo". In peripheral blood apoptosis is strongly connected with expression of antiapoptoic proteins (mcl-1 and bcl-2) and growth factors, but not in bone marrow. [ABSTRACT FROM AUTHOR]

Introduction: Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase, has altered the treatment perspective of chronic lymphocytic leukemia and showed modest activity against several types of non-Hodgkin's lymphomas. According to phase studies and real-world data, reported serious adverse effects included atrial fibrillation, diarrhea, and bleeding diathesis. However, heart failure was not reported to be a probable adverse effect linked with ibrutinib. Case report: In this paper, we present a 66-year-old female chronic lymphocytic leukemia patient who developed significant and symptomatic left ventricular dysfunction at the 13th month of ibrutinib treatment. Management and outcome: Following cessation of ibrutinib, ejection fraction and clinical findings of the left ventricular dysfunction alleviated. Discussion: Although the use of ibrutinib is generally well tolerated, cardiac functions should be monitored occasionally in all patients. [ABSTRACT FROM AUTHOR]

Patients with chronic lymphocytic leukaemia (CLL) are generally older, with many considered 'unfit' for fludarabine-cyclophosphamide-rituximab therapy. In these patients, the combination of obinutuzumab-chlorambucil may be an appropriate therapeutic choice. Obinutuzumab-chlorambucil has been demonstrated to improve overall survival rates compared to chlorambucil alone and to improve progression-free survival and overall response rates compared to rituximab-chlorambucil. This combination can lead to certain toxicities that need to be addressed through appropriate patient selection, pre-medication and management. In this paper, we discuss evidence-based and author-recommended practical management of first-line CLL patients receiving obinutuzumab-chlorambucil. [ABSTRACT FROM AUTHOR]

Background: Somatic Hypermutation (SHM) refers to the introduction of mutations within rearranged V(D)J genes, a process that increases the diversity of Immunoglobulins (IGs). The analysis of SHM has offered critical insight into the physiology and pathology of B cells, leading to strong prognostication markers for clinical outcome in chronic lymphocytic leukaemia (CLL), the most frequent adult B-cell malignancy. In this paper we present a methodology for integrating multiple immunogenetic and clinocobiological data sources in order to extract features and create high quality datasets for SHM analysis in IG receptors of CLL patients. This dataset is used as the basis for a higher level integration procedure, inspired form social choice theory. This is applied in the Towards Analysis, our attempt to investigate the potential ontogenetic transformation of genes belonging to specific stereotyped CLL subsets towards other genes or gene families, through SHM. Results: The data integration process, followed by feature extraction, resulted in the generation of a dataset containing information about mutations occurring through SHM. The Towards analysis performed on the integrated dataset applying voting techniques, revealed the distinct behaviour of subset #201 compared to other subsets, as regards SHM related movements among gene clans, both in allele-conserved and non-conserved gene areas. With respect to movement between genes, a high percentage movement towards pseudo genes was found in all CLL subsets. Conclusions: This data integration and feature extraction process can set the basis for exploratory analysis or a fully automated computational data mining approach on many as yet unanswered, clinically relevant biological questions. [ABSTRACT FROM AUTHOR]

Immunoglobulins (Ig) are produced by B lymphocytes as secreted antibodies or as part of the B-cell receptor. There is tremendous diversity of potential Ig transcripts (>1 × 1012) as a result of hundreds of germ-line gene segments, random nucleotide incorporation during joining of gene segments into a complete transcript, and the process of somatic hypermutation at individual nucleotides. This recombination and mutation process takes place in the maturing B cell and is responsible for the diversity of potential epitope recognition. Cancers arising from mature B cells are characterized by clonal production of Ig heavy (IGH@) and light chain transcripts, although whether the sequence has undergone somatic hypermutation is dependent on the maturation stage at which the neoplastic clone arose. Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and arises from a mature B cell with either mutated or unmutated IGH@ transcripts, the latter having worse prognosis and the assessment of which is routinely performed in the clinic. Currently, IGHV mutation status is assessed by Sanger sequencing and comparing the transcript to known germ-line genes. In this paper, we demonstrate that complete IGH@ V-D-J sequences can be computed from unselected RNA-seq reads with results equal or superior to the clinical procedure: in the only discordant case, the clinical transcript was out-of-frame. Therefore, a single RNA-seq assay can simultaneously yield gene expression profile, SNP and mutation information, as well as IGHV mutation status, and may one day be performed as a general test to capture multidimensional clinically relevant data in CLL. [ABSTRACT FROM AUTHOR]

Backgrounds: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults and is characterized by a clonal accumulation of mature apoptosis-resistant neoplastic cells. It is also a heterogeneous disease with a variable clinical outcome. Here, we present a review of currently known (epi)genetic alterations that are related to the etiology, progression and chemo-refractoriness of CLL. Relevant literature was identified through a PubMed search (1994-2014) of English-language papers using the terms CLL, signaling pathway, cytogenetic abnormality, somatic mutation, epigenetic alteration and micro-RNA. Results: CLL is characterized by the presence of gross chromosomal abnormalities, epigenetic alterations, micro-RNA expression alterations, immunoglobulin heavy chain gene mutations and other genetic lesions. The expression of unmutated immunoglobulin heavy chain variable region (IGHV) genes, ZAP-70 and CD38 proteins, the occurrence of chromosomal abnormalities such as 17p and 11q deletions and mutations of the NOTCH1, SF3B1 and BIRC3 genes have been associated with a poor prognosis. In addition, mutations in tumor suppressor genes, such as TP53 and ATM, have been associated with refractoriness to conventional chemotherapeutic agents. Micro-RNA expression alterations and aberrant methylation patterns in genes that are specifically deregulated in CLL, including the BCL-2, TCL1 and ZAP-70 genes, have also been encountered and linked to distinct clinical parameters. Conclusions: Specific chromosomal abnormalities and gene mutations may serve as diagnostic and prognostic indicators for disease progression and survival. The identification of these anomalies by state-of-the-art molecular (cyto)genetic techniques such as fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), single nucleotide polymorphism (SNP) microarray-based genomic profiling and next-generation sequencing (NGS) can be of paramount help for the clinical management of these patients, including optimal treatment design. The efficacy of novel therapeutics should to be tested according to the presence of these molecular lesions in CLL patients. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia among adults. It is the clonal expansion of B cells expressing CD19 and CD5. Despite significant progress in treatment, CLL is still incurable. γδ T cells comprise an important subset of the cytotoxic T cells. Although γδ T cells in CLL are dysfunctional, they still can possibly be used for immunotherapy. The current paper reviews our understanding of γδ T lymphocytes in CLL. [ABSTRACT FROM AUTHOR]

Simple Summary: This review analyzes the occurrence, clinical characteristics, and prognostic impact and treatment of autoimmune hemolytic anemia (AIHA) in chronic lymphocytic leukemia (CLL). Autoimmune hemolytic anemia is observed in about 10% of CLL. Pathogenesis is multifactorial involving humoral, cellular, and innate immunity, so the different mechanisms are well described in this review which also focuses on drugs associated to CLL-AIHA and on difficulties to diagnose it. There is a comprehensive revision of the main published casistics and then of the treatments; in particular the paper analyzes the main chemo-immunotherapeutic agents used in this setting. Since the therapy depends on the presence and severity of clinical symptoms, disease status, and comorbidities, treatment is nowadays more individualized in CLL and also in CLL-AIHA. Patients not responding to corticosteroids and rituximab are treated with CLL-specific drugs as per current guidelines according to age and comorbidities and new targeted agents against BCR and BCL-2 which can be given orally and have few side effects, are very effective both in progressive CLL and in situations such as AIHA. Chronic lymphocytic leukemia (CLL) patients have a greater predisposition to develop autoimmune complications. The most common of them is autoimmune hemolytic anemia (AIHA) with a frequency of 7–10% of cases. Pathogenesis is multifactorial involving humoral, cellular, and innate immunity. CLL B-cells have damaged apoptosis, produce less immunoglobulins, and could be responsible for antigen presentation and releasing inflammatory cytokines. CLL B-cells can act similar to antigen-presenting cells activating self-reactive T helper cells and may induce T-cell subsets imbalance, favoring autoreactive B-cells which produce anti-red blood cells autoantibodies. Treatment is individualized and it depends on the presence and severity of clinical symptoms, disease status, and comorbidities. Corticosteroids are the standardized first-line treatment; second-line treatment comprises rituximab. Patients not responding to corticosteroids and rituximab should be treated with CLL-specific drugs as per current guidelines according to age and comorbidities. New targeted drugs (BTK inhibitors and anti BCL2) are recently used after or together with steroids to manage AIHA. In the case of cold agglutinin disease, rituximab is preferred, because steroids are ineffective. Management must combine supportive therapies, including vitamins; antibiotics and heparin prophylaxis are indicated in order to minimize infectious and thrombotic risk. [ABSTRACT FROM AUTHOR]