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Cold Spring Harbor Perspectives in... Feb 2021Patients with chronic lymphocytic leukemia can be divided into three categories: those who are minimally affected by the problem, often never requiring therapy; those... (Review)
Review
Patients with chronic lymphocytic leukemia can be divided into three categories: those who are minimally affected by the problem, often never requiring therapy; those that initially follow an indolent course but subsequently progress and require therapy; and those that from the point of diagnosis exhibit an aggressive disease necessitating treatment. Likewise, such patients pass through three phases: development of the disease, diagnosis, and need for therapy. Finally, the leukemic clones of all patients appear to require continuous input from the exterior, most often through membrane receptors, to allow them to survive and grow. This review is presented according to the temporal course that the disease follows, focusing on those external influences from the tissue microenvironment (TME) that support the time lines as well as those internal influences that are inherited or develop as genetic and epigenetic changes occurring over the time line. Regarding the former, special emphasis is placed on the input provided via the B-cell receptor for antigen and the C-X-C-motif chemokine receptor-4 and the therapeutic agents that block these inputs. Regarding the latter, prominence is laid upon inherited susceptibility genes and the genetic and epigenetic abnormalities that lead to the developmental and progression of the disease.
Topics: Disease Progression; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; PAX5 Transcription Factor; Receptors, Antigen, B-Cell; Signal Transduction; Tumor Microenvironment
PubMed: 32229611
DOI: 10.1101/cshperspect.a035220 -
Frontiers in Immunology 2021Targeting the B-cell receptor signaling pathway through BTK inhibition proved to be effective for the treatment of chronic lymphocytic leukemia (CLL) and other B-cell... (Review)
Review
Targeting the B-cell receptor signaling pathway through BTK inhibition proved to be effective for the treatment of chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Covalent BTK inhibitors (BTKis) led to an unprecedented improvement in outcome in CLL, in particular for high-risk subgroups with aberration and unmutated immunoglobulin heavy-chain variable-region gene (IGHV). Ibrutinib and acalabrutinib are approved by the US Food and Drug Administration for the treatment of CLL and other B-cell lymphomas, and zanubrutinib, for patients with mantle cell lymphoma. Distinct target selectivity of individual BTKis confer differences in target-mediated as well as off-target adverse effects. Disease progression on covalent BTKis, driven by histologic transformation or selective expansion of and mutated CLL clones, remains a major challenge in the field. Fixed duration combination regimens and reversible BTKis with non-covalent binding chemistry hold promise for the prevention and treatment of BTKi-resistant disease.
Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Animals; Antineoplastic Agents; Benzamides; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Mutation; Piperidines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Signal Transduction; Treatment Outcome
PubMed: 34248972
DOI: 10.3389/fimmu.2021.687458 -
Blood Mar 2017Large granular lymphocyte (LGL) leukemia has been recognized by the World Health Organization classifications amongst mature T-cell and natural killer (NK) cell... (Review)
Review
Large granular lymphocyte (LGL) leukemia has been recognized by the World Health Organization classifications amongst mature T-cell and natural killer (NK) cell neoplasms. There are 3 categories: chronic T-cell leukemia and NK-cell lymphocytosis, which are similarly indolent diseases characterized by cytopenias and autoimmune conditions as opposed to aggressive NK-cell LGL leukemia. Clonal LGL expansion arise from chronic antigenic stimulation, which promotes dysregulation of apoptosis, mainly due to constitutive activation of survival pathways including Jak/Stat, MapK, phosphatidylinositol 3-kinase-Akt, Ras-Raf-1, MEK1/extracellular signal-regulated kinase, sphingolipid, and nuclear factor-κB. Socs3 downregulation may also contribute to Stat3 activation. Interleukin 15 plays a key role in activation of leukemic LGL. Several somatic mutations including Stat3, Stat5b, and tumor necrosis factor alpha-induced protein 3 have been demonstrated recently in LGL leukemia. Because these mutations are present in less than half of the patients, they cannot completely explain LGL leukemogenesis. A better mechanistic understanding of leukemic LGL survival will allow future consideration of a more targeted therapeutic approach than the current practice of immunosuppressive therapy.
Topics: Humans; Leukemia, Large Granular Lymphocytic
PubMed: 28115367
DOI: 10.1182/blood-2016-08-692590 -
Journal of Clinical and Experimental... Dec 2020Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and is characterized by the clonal expansion of mature CD5 B cells. There have... (Review)
Review
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and is characterized by the clonal expansion of mature CD5 B cells. There have been substantial advances in the field of CLL research in the last decade, including the identification of recurrent mutations, and clarification of clonal architectures, signaling molecules, and the multistep leukemogenic process, providing a comprehensive understanding of CLL pathogenesis. Furthermore, the development of therapeutic approaches, especially that of molecular target therapies against CLL, has markedly improved the standard of care for CLL. This review focuses on the recent insights made in CLL leukemogenesis and the development of novel therapeutic strategies.
Topics: Adult; Carcinogenesis; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Mutation
PubMed: 33148933
DOI: 10.3960/jslrt.20036 -
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 -
Journal of Clinical and Experimental... Dec 2020Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) accounts for approximately 1% of all lymphomas in our department. In this article, we describe the... (Review)
Review
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) accounts for approximately 1% of all lymphomas in our department. In this article, we describe the differential diagnosis of CLL/SLL from other indolent lymphomas, with special reference to follicular lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and mantle cell lymphoma, although the latter is considered to be aggressive. CLL/SLL often exhibits proliferation centers, similar to follicular lymphoma. Immunohistological examination can easily distinguish these two lymphomas. The most important characteristic of CLL/SLL is CD5 and CD23 positivity. Mantle cell lymphoma is also CD5-positive and there are some CD23-positive cases. Such cases should be carefully distinguished from CLL/SLL. Some marginal zone lymphomas are also positive for CD5 and such cases are often disseminated. Lymphoplasmacytic lymphoma should also be a differential diagnosis for CLL/SLL. It frequently demonstrates MYD88 L265P, which is a key differential finding. By immunohistological examination, the expression of lymphoid enhancer-binding factor 1 is specific for CLL/SLL and can be a good marker in the differential diagnosis.
Topics: Biomarkers, Tumor; CD5 Antigens; Diagnosis, Differential; Humans; Immunophenotyping; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Neoplasm Proteins; Receptors, IgE
PubMed: 32249238
DOI: 10.3960/jslrt.19041 -
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 -
Clinical Cancer Research : An Official... Jul 2023In an exploratory analysis of the phase II CAPTIVATE study, previously untreated patients with chronic lymphocytic leukemia with a higher-risk feature of immune globulin...
In an exploratory analysis of the phase II CAPTIVATE study, previously untreated patients with chronic lymphocytic leukemia with a higher-risk feature of immune globulin heavy chain variable (IGHV) unmutated status, del(17p), and/or TP53 mutation had similar efficacy and safety outcomes compared with patients without a higher-risk feature when treated with fixed-duration ibrutinib and venetoclax. See related article by Allan et al., p. 2593.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Bridged Bicyclo Compounds, Heterocyclic; Mutation
PubMed: 37289004
DOI: 10.1158/1078-0432.CCR-23-0807 -
Nature May 2019Genetic and epigenetic intra-tumoral heterogeneity cooperate to shape the evolutionary course of cancer. Chronic lymphocytic leukaemia (CLL) is a highly informative...
Genetic and epigenetic intra-tumoral heterogeneity cooperate to shape the evolutionary course of cancer. Chronic lymphocytic leukaemia (CLL) is a highly informative model for cancer evolution as it undergoes substantial genetic diversification and evolution after therapy. The CLL epigenome is also an important disease-defining feature, and growing populations of cells in CLL diversify by stochastic changes in DNA methylation known as epimutations. However, previous studies using bulk sequencing methods to analyse the patterns of DNA methylation were unable to determine whether epimutations affect CLL populations homogeneously. Here, to measure the epimutation rate at single-cell resolution, we applied multiplexed single-cell reduced-representation bisulfite sequencing to B cells from healthy donors and patients with CLL. We observed that the common clonal origin of CLL results in a consistently increased epimutation rate, with low variability in the cell-to-cell epimutation rate. By contrast, variable epimutation rates across healthy B cells reflect diverse evolutionary ages across the trajectory of B cell differentiation, consistent with epimutations serving as a molecular clock. Heritable epimutation information allowed us to reconstruct lineages at high-resolution with single-cell data, and to apply this directly to patient samples. The CLL lineage tree shape revealed earlier branching and longer branch lengths than in normal B cells, reflecting rapid drift after the initial malignant transformation and a greater proliferative history. Integration of single-cell bisulfite sequencing analysis with single-cell transcriptomes and genotyping confirmed that genetic subclones mapped to distinct clades, as inferred solely on the basis of epimutation information. Finally, to examine potential lineage biases during therapy, we profiled serial samples during ibrutinib-associated lymphocytosis, and identified clades of cells that were preferentially expelled from the lymph node after treatment, marked by distinct transcriptional profiles. The single-cell integration of genetic, epigenetic and transcriptional information thus charts the lineage history of CLL and its evolution with therapy.
Topics: Base Sequence; Biological Clocks; Cell Lineage; DNA Methylation; Epigenesis, Genetic; Epigenome; Evolution, Molecular; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation Rate; Sequence Analysis, RNA; Single-Cell Analysis; Transcription, Genetic
PubMed: 31092926
DOI: 10.1038/s41586-019-1198-z -
The New England Journal of Medicine Jul 2014In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome.
METHODS
In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points.
RESULTS
At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group.
CONCLUSIONS
Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.).
Topics: Adenine; Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cough; Diarrhea; Disease-Free Survival; Fatigue; Female; Follow-Up Studies; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Recurrence; Survival Rate
PubMed: 24881631
DOI: 10.1056/NEJMoa1400376