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American Journal of Hematology Mar 2016The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the... (Review)
Review
The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the years, the prognostication in CLL has expanded with the addition in late 90s of mutational status of variable region of immunoglobulin heavy chain (IGHV), and chromosomal analyses using fluorescent in situ hybridization (FISH). More recently, stereotypy of BCR (B cell receptor) and whole exome sequencing (WES) based discovery of specific mutations such as NOTCH1, TP53, SF3B1, XPO-1, BIRC3, ATM, and RPS15 further refined the current prognostication system in CLL. In therapy, the field of CLL has seen major changes from oral chlorambucil and steroids prior to 1980s, to chemo-immunotherapy (CIT) with fludarabine, cyclophosphamide, rituximab (FCR) to the orally administered targeted therapeutic agents inhibiting kinases in the B cell receptor (BCR) signaling pathway such as Ibrutinib (BTK inhibitor) and Idelalisib (p110 PI3Kδ inhibitor) and novel anti-CD20 mAb's (monoclonal antibodies) such as obinutuzumab. This progress is continuing and other targeted therapeutics such as Bcl2 antagonists (Venetoclax or ABT-199) and finally chimeric antigen receptor against T cells (CART) are in the process of being developed. This review is an attempt to summarize the major benchmarks in the prognostication and in the therapy of CLL. The topic allocated to us by Dr Ayalew Tefferi and Dr Carlo Brugnara is very appropriate to reminisce what our understanding of chronic lymphocytic leukemia (CLL) was in 1976 and how rapidly have the advances occurring in this field affected the patients with CLL.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Prognosis
PubMed: 26690614
DOI: 10.1002/ajh.24282 -
Blood Cancer Journal Nov 2022The treatment landscape for patients with chronic lymphocytic leukemia (CLL) has changed considerably with the introduction of very effective oral targeted therapies... (Review)
Review
The treatment landscape for patients with chronic lymphocytic leukemia (CLL) has changed considerably with the introduction of very effective oral targeted therapies (such as Bruton tyrosine kinase inhibitors and venetoclax) and next-generation anti-CD20 monoclonal antibodies (such as obinutuzumab). These agents lead to improved outcomes in patients with CLL, even among those with high-risk features, such as del17p13 or TP53 mutation and unmutated immunoglobulin heavy chain (IGHV) genes. Selecting the right treatment for the right patient requires consideration of disease characteristics and prior treatment sequence, as well as patient preferences and comorbidities. The CLL-International Prognostic Index (CLL-IPI) remains the best-validated tool in predicting the time to first therapy among previously untreated patients, which guides selection for early intervention efforts. This review summarizes our current approach to the management of CLL, right from the time of diagnosis through relapsed disease.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Algorithms; Antibodies, Monoclonal; Mutation
PubMed: 36446777
DOI: 10.1038/s41408-022-00756-9 -
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 -
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 -
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 -
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 -
Oncology Research and Treatment 2016
Topics: Antineoplastic Agents; Evidence-Based Medicine; Genetic Predisposition to Disease; Genetic Testing; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Molecular Targeted Therapy; Physical Examination; Treatment Outcome
PubMed: 26889878
DOI: 10.1159/000443821 -
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 -
Missouri Medicine 2017In recent years, the choice of therapies for symptomatic Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) have grown exponentially, with no single... (Review)
Review
In recent years, the choice of therapies for symptomatic Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) have grown exponentially, with no single agreed upon standard first-line therapy. The choice of therapy is often dictated by goals of care, patient characteristics and tumor genetic abnormalities. The goal of this article is to familiarize the primary care provider with some of the most commonly used therapeutic modalities with attention to the side effect profile of these regimens.
Topics: Antineoplastic Agents; Combined Modality Therapy; Cytogenetics; Diagnosis, Differential; Humans; Karnofsky Performance Status; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphadenopathy; Lymphocytosis; Primary Health Care; Survival Analysis
PubMed: 30228579
DOI: No ID Found -
Cancer Control : Journal of the Moffitt... Jan 2012The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous, with some patients experiencing rapid disease progression and others living for... (Review)
Review
BACKGROUND
The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous, with some patients experiencing rapid disease progression and others living for decades without requiring treatment. The Rai and Binet clinical staging systems are used to define disease extent and predict survival. The pathology laboratory also provides important prognostic information.
METHODS
A review of the literature was performed on the subject of staging in CLL from clinical and pathologic standpoints. This article also reviews currently available diagnostic approaches related to disease prognosis and to timing of treatment and follow-up in patients with CLL.
RESULTS
Novel biological and cytogenetic features such as immunoglobulin heavy-chain variable gene segment [IgVH], genomic aberrations including del(17p13), del(11q23), del(13q14), and trisomy 12, serum markers (thymidine kinase and beta-2 microglobulin), and cellular markers (CD38 and ZAP70) have become increasingly important in predicting prognosis at the time of diagnosis.
CONCLUSIONS
Current prognostic factors directly or indirectly influence the management of patients with CLL and help to predict treatment-free and overall survival.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Staging; Prognosis; Survival Analysis
PubMed: 22143059
DOI: 10.1177/107327481201900103