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Nature Reviews. Disease Primers Jan 2017Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5 B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow... (Review)
Review
Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5 B cells that is characterized by the accumulation of small, mature-appearing lymphocytes in the blood, marrow and lymphoid tissues. Signalling via surface immunoglobulin, which constitutes the major part of the B cell receptor, and several genetic alterations play a part in CLL pathogenesis, in addition to interactions between CLL cells and other cell types, such as stromal cells, T cells and nurse-like cells in the lymph nodes. The clinical progression of CLL is heterogeneous and ranges from patients who require treatment soon after diagnosis to others who do not require therapy for many years, if at all. Several factors, including the immunoglobulin heavy-chain variable region gene (IGHV) mutational status, genomic changes, patient age and the presence of comorbidities, should be considered when defining the optimal management strategies, which include chemotherapy, chemoimmunotherapy and/or drugs targeting B cell receptor signalling or inhibitors of apoptosis, such as BCL-2. Research on the biology of CLL has profoundly enhanced our ability to identify patients who are at higher risk for disease progression and our capacity to treat patients with drugs that selectively target distinctive phenotypic or physiological features of CLL. How these and other advances have shaped our current understanding and treatment of patients with CLL is the subject of this Primer.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell
PubMed: 28102226
DOI: 10.1038/nrdp.2016.96 -
Annals of Oncology : Official Journal... Jan 2021
Topics: Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell
PubMed: 33091559
DOI: 10.1016/j.annonc.2020.09.019 -
The New England Journal of Medicine Aug 2011We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T...
We designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with CD137 (a costimulatory receptor in T cells [4-1BB]) and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. A low dose (approximately 1.5×10(5) cells per kilogram of body weight) of autologous chimeric antigen receptor-modified T cells reinfused into a patient with refractory chronic lymphocytic leukemia (CLL) expanded to a level that was more than 1000 times as high as the initial engraftment level in vivo, with delayed development of the tumor lysis syndrome and with complete remission. Apart from the tumor lysis syndrome, the only other grade 3/4 toxic effect related to chimeric antigen receptor T cells was lymphopenia. Engineered cells persisted at high levels for 6 months in the blood and bone marrow and continued to express the chimeric antigen receptor. A specific immune response was detected in the bone marrow, accompanied by loss of normal B cells and leukemia cells that express CD19. Remission was ongoing 10 months after treatment. Hypogammaglobulinemia was an expected chronic toxic effect.
Topics: Agammaglobulinemia; Antigens, CD19; B-Lymphocytes; Bone Marrow; Chimera; Cytokines; Humans; Immunotherapy; Lentivirus; Leukemia, Lymphoid; Male; Receptors, Antigen, T-Cell; Remission Induction; T-Lymphocytes; Tumor Lysis Syndrome
PubMed: 21830940
DOI: 10.1056/NEJMoa1103849 -
Haematologica Jun 2014In the last decade, the management of chronic lymphocytic leukemia has undergone profound changes that have been driven by an improved understanding of the biology of... (Review)
Review
In the last decade, the management of chronic lymphocytic leukemia has undergone profound changes that have been driven by an improved understanding of the biology of the disease and the approval of several new drugs. Moreover, many novel drugs are currently under evaluation for rapid approval or have been approved by regulatory agencies, further broadening the available therapeutic armamentarium for patients with chronic lymphocytic leukemia. The use of novel biological and genetic parameters combined with a careful clinical evaluation allows us to dissect some of the heterogeneity of the disease and to distinguish patients with a very mild onset and course, who often will not need any treatment, from those with an intermediate prognosis and a third group with a very aggressive course (high-risk leukemia). On this background, it becomes increasingly challenging to select the right treatment strategy. In this paper, we describe our own approach to the management of different patients with chronic lymphocytic leukemia.
Topics: Disease Management; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Staging; Prognosis
PubMed: 24881042
DOI: 10.3324/haematol.2013.096107 -
Physiological Research Jul 2018Elevated levels of eukaryotic initiation factor 4E (eIF4E) are implicated in neoplasia, with cumulative evidence pointing to its role in the etiopathogenesis of... (Review)
Review
Elevated levels of eukaryotic initiation factor 4E (eIF4E) are implicated in neoplasia, with cumulative evidence pointing to its role in the etiopathogenesis of hematological diseases. As a node of convergence for several oncogenic signaling pathways, eIF4E has attracted a great deal of interest from biologists and clinicians whose efforts have been targeting this translation factor and its biological circuits in the battle against leukemia. The role of eIF4E in myeloid leukemia has been ascertained and drugs targeting its functions have found their place in clinical trials. Little is known, however, about the pertinence of eIF4E to the biology of lymphocytic leukemia and a paucity of literature is available in this regard that prospectively evaluates the topic to guide practice in hematological cancer. A comprehensive analysis on the significance of eIF4E translation factor in the clinical picture of leukemia arises, therefore, as a compelling need. This review presents aspects of eIF4E involvement in the realm of the lymphoblastic leukemia status; translational control of immunological function via eIF4E and the state-of-the-art in drugs will also be outlined.
Topics: Antineoplastic Agents; Eukaryotic Initiation Factor-4E; Gene Expression Regulation, Leukemic; Humans; Leukemia, Lymphoid
PubMed: 29527921
DOI: 10.33549/physiolres.933696 -
Ugeskrift For Laeger Oct 2021Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the world with approximately 450 new cases yearly in Denmark. The disease is highly heterogeneous,... (Review)
Review
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the world with approximately 450 new cases yearly in Denmark. The disease is highly heterogeneous, and half of the patients will never require treatment. The standard treatment is chemoimmunotherapy, but highly effective targeted therapies are approved for patients with high-risk disease or relapse as summarised in this review. The Danish CLL guidelines are continuously updated based on results from ongoing clinical trials and international guidelines.
Topics: Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Recurrence, Local
PubMed: 34709154
DOI: No ID Found -
Virchows Archiv : An International... Jan 2023The International Clinical Advisory Committee reviewed advances in our understanding of the clinicopathologic and biologic features of chronic lymphocytic... (Review)
Review
The International Clinical Advisory Committee reviewed advances in our understanding of the clinicopathologic and biologic features of chronic lymphocytic leukaemia/small lymphocytic lymphoma, B-cell prolymphocytic leukaemia, and mantle cell lymphoma since the revised 4th edition of the WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues. Discussions amongst pathologists, clinicians, and molecular geneticists around these diseases focussed on incorporating new knowledge into the next classification system. In this manuscript, we review these disease entities and incorporate results of these deliberations, including advances in our understanding of early lesions and transformation.
Topics: Adult; Humans; Lymphoma, Mantle-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell
PubMed: 36454275
DOI: 10.1007/s00428-022-03460-y -
Annual Review of Pathology 2014Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of CD5(+)CD23(+) B cells in blood, marrow, and second lymphoid tissues. Gene-expression... (Review)
Review
Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of CD5(+)CD23(+) B cells in blood, marrow, and second lymphoid tissues. Gene-expression profiling and phenotypic studies suggest that CLL is probably derived from CD5(+) B cells similar to those found in the blood of healthy adults. Next-generation sequencing has revealed recurrent genetic lesions that are implicated in CLL pathogenesis and/or disease progression. The biology of CLL is entwined with its microenvironment, in which accessory cells can promote leukemia cell growth and/or survival. Recently, much attention has been focused on the CLL B cell receptor (BCR) and on chemokine receptors that enable CLL cells to home to lymphoid tissues and to establish the leukemia microenvironment. Agents that can interfere with BCR signaling or chemokine-receptor signaling, or that target surface antigens selectively expressed on CLL cells, promise to have significant therapeutic benefit in patients with this disease.
Topics: B-Lymphocytes; Cell Proliferation; Cellular Microenvironment; Disease Progression; Gene Expression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Signal Transduction
PubMed: 23987584
DOI: 10.1146/annurev-pathol-020712-163955 -
American Journal of Clinical Pathology Jun 2023Session 3 of the 2021 Workshop of the Society for Hematopathology/European Association for Haematopathology examined progression and transformation of chronic...
OBJECTIVES
Session 3 of the 2021 Workshop of the Society for Hematopathology/European Association for Haematopathology examined progression and transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and B-cell prolymphocytic leukemia (B-PLL).
METHODS
Thirty-one cases were reviewed by the panel. Additional studies such as immunohistochemistry and molecular genetic testing, including whole-exome sequencing and expression profiling, were performed in select cases.
RESULTS
Session 3 included 27 CLL/SLL cases and miscellaneous associated proliferations, 3 cases of B-PLL, and 1 case of small B-cell lymphoma. The criteria for -accelerated CLL/SLL are established for lymph nodes, but extranodal disease can be diagnostically challenging. Richter transformation (RT) is a broad term and includes true transformation from original CLL/SLL clone(s) and clonally unrelated neoplasms. The morphologic, immunophenotypic, and genetic spectrum is diverse with classical and highly unusual examples. T-cell proliferations can also be encountered in CLL/SLL. B-cell prolymphocytic leukemia is a rare, diagnostically challenging disease due to its overlaps with other lymphoid neoplasms.
CONCLUSIONS
The workshop highlighted complexity of progression and transformation in CLL/SLL and B-PLL, as well as diagnostic caveats accompanying heterogeneous presentations of RT and other manifestations of disease progression. Molecular genetic studies are pivotal for diagnosis and determination of clonal relationship, and to predict response to treatment and identify resistance to targeted therapy.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Prolymphocytic, B-Cell; Lymphoma, B-Cell; Cell Transformation, Neoplastic
PubMed: 37052539
DOI: 10.1093/ajcp/aqad027 -
Leukemia Aug 2020Chronic lymphocytic leukemia (CLL) is a B-cell malignancy, which is associated with profound alterations and defects in the immune system and a prevalent dependency on... (Review)
Review
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy, which is associated with profound alterations and defects in the immune system and a prevalent dependency on the microenvironmental niche. An abnormal T-cell compartment in the blood of CLL patients was already reported 40 years ago. Since then, our knowledge of T-cell characteristics in CLL has grown steadily, but the question of whether T-cells act as pro-tumoral bystander cells or possess anti-tumoral activity is still under debate. Increased numbers of CD4 T-helper cell subsets are present in the blood of CLL patients, and T-helper cell cytokines have been shown to stimulate CLL cell survival and proliferation in vitro. In line with this, survival and growth of CLL cells in murine xenograft models have been shown to rely on activated CD4 T-cells. This led to the hypothesis that T-cells are tumor-supportive in CLL. In recent years, evidence for an enrichment of antigen-experienced CD8 T-cells in CLL has accumulated, and these cells have been shown to control leukemia in a CLL mouse model. Based on this, it was suggested that CD8 T-cells recognize CLL-specific antigens and exert an anti-leukemia function. As described for other cancer entities, T-cells in CLL express multiple inhibitory receptors, such as PD-1, and lose their functional capacity, leading to an exhaustion phenotype which has been shown to be more severe in T-cells from secondary lymphoid organs compared with peripheral blood. This exhausted phenotype has been suggested to be causative for the poor response of CLL patients to CAR T-cell therapies. In addition, T-cells have been shown to be affected by drugs that are used to treat CLL, which likely impacts therapy response. This review provides an overview of the current knowledge about alterations of T-cells in CLL, including their distribution, function, and exhaustion state in blood and lymphoid organs, and touches also on the topic of how CLL drugs impact on the T-cell compartment and recent results of T-cell-based immunotherapy. We will discuss potential pathological roles of T-cell subsets in CLL and address the question of whether they foster progression or control of disease.
Topics: Animals; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocyte Activation; T-Lymphocytes
PubMed: 32457353
DOI: 10.1038/s41375-020-0873-2