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American Journal of Hematology Dec 2021Chronic lymphocytic leukemia (CLL) is one of the most frequent types of leukemia. It typically occurs in elderly patients and has a highly variable clinical course.... (Review)
Review
DISEASE OVERVIEW
Chronic lymphocytic leukemia (CLL) is one of the most frequent types of leukemia. It typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that interfere with the regulation of proliferation and of apoptosis in clonal B-cells.
DIAGNOSIS
The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen as well as typical B-cell markers.
PROGNOSIS AND STAGING
The clinical staging systems provide prognostic information by using the results of physical examination and blood counts. Various biological and genetic markers provide additional prognostic information. Deletions of the short arm of chromosome 17 (del[17p]) and/or mutations of the TP53 gene predict resistance to chemoimmunotherapy and a shorter time to progression with most targeted therapies. The CLL international prognostic index integrates genetic, biological, and clinical variables to identify distinct risk groups of patients with CLL.
THERAPY
Only patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. When treatment is indicated, several therapeutic options exist: a combination of the B-cell lymphoma 2 (BCL2) inhibitor venetoclax with obinutuzumab, monotherapy with inhibitors of Bruton tyrosine kinase (BTK) such as ibrutinib and acalabrutinib, or chemoimmunotherapy. At relapse, the initial treatment may be repeated, if the treatment-free interval exceeds 3 years. If the disease relapses earlier, therapy should be changed using an alternative regimen. Patients with a del(17p) or TP53 mutation are usually resistant to chemotherapy and should, therefore, be treated with targeted agents.
FUTURE CHALLENGES
Combinations of targeted agents are now being investigated to create efficient, potentially curative therapies of CLL with fixed duration. One of the most relevant questions currently addressed in clinical trials is the comparison of monotherapies with BTK inhibitors with fixed duration combination therapies. Moreover, the optimal sequencing of targeted therapies remains to be determined. Alternative therapies are needed for patients with BTK and BCL2 inhibitor double-refractory disease.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Combined Modality Therapy; Disease Management; Humans; Immunotherapy, Adoptive; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Staging; Prognosis
PubMed: 34625994
DOI: 10.1002/ajh.26367 -
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 -
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 -
American Journal of Hematology Nov 2019Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical... (Review)
Review
DISEASE OVERVIEW
Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B-cells.
DIAGNOSIS
The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen, as well as typical B-cell markers.
PROGNOSIS
The two similar clinical staging systems, Rai and Binet, create prognostic information by using results of physical examination and blood counts. Various biological and genetic markers also have prognostic value. Deletions of the short arm of chromosome 17 (del [17p]) and/or mutations of the TP53 gene, predict resistance to chemoimmunotherapy and a shorter time to progression, with most targeted therapies. A comprehensive, international prognostic score (CLL-IPI) integrates genetic, biological and clinical variables to identify distinct risk groups of CLL patients.
THERAPY
Only patients with active or symptomatic disease, or with advanced Binet or Rai stages require therapy. When treatment is indicated, several options exist for most CLL patients: a combination of venetoclax with obinutuzumab, ibrutinib monotherapy, or chemoimmunotherapy. For physically fit patients younger than 65 (in particular when presenting with a mutated IGVH gene), chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab remains a standard therapy, since it may have curative potential. At relapse, the initial treatment may be repeated, if the treatment-free interval exceeds 3 years. If the disease relapses earlier, therapy should be changed using an alternative regimen. Patients with a del (17p) or TP53 mutation are a different, high-risk category and should be treated with targeted agents. An allogeneic SCT may be considered in relapsing patients with TP53 mutations or del (17p), or patients that are refractory to inhibitor therapy.
FUTURE CHALLENGES
Targeted agents (ibrutinib, idelalisib, venetoclax, obinutuzumab) will be increasingly used in combination to allow for short, but potentially definitive therapies of CLL. It remains to be proven that they generate a superior outcome when compared to monotherapies with inhibitors of Bruton tyrosine kinase, which can also yield long-lasting remissions. Moreover, the optimal sequencing of drug combinations is unknown. Therefore, CLL patients should be treated in clinical trials whenever possible.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Biomarkers, Tumor; Blood Cell Count; Chromosome Deletion; Combined Modality Therapy; Female; Forecasting; Hematopoietic Stem Cell Transplantation; Humans; Immunophenotyping; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Molecular Targeted Therapy; Mutation; Neoplasm Staging; Prognosis; Risk Assessment
PubMed: 31364186
DOI: 10.1002/ajh.25595 -
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 Genetics Nov 2022Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each...
Recent advances in cancer characterization have consistently revealed marked heterogeneity, impeding the completion of integrated molecular and clinical maps for each malignancy. Here, we focus on chronic lymphocytic leukemia (CLL), a B cell neoplasm with variable natural history that is conventionally categorized into two subtypes distinguished by extent of somatic mutations in the heavy-chain variable region of immunoglobulin genes (IGHV). To build the 'CLL map,' we integrated genomic, transcriptomic and epigenomic data from 1,148 patients. We identified 202 candidate genetic drivers of CLL (109 new) and refined the characterization of IGHV subtypes, which revealed distinct genomic landscapes and leukemogenic trajectories. Discovery of new gene expression subtypes further subcategorized this neoplasm and proved to be independent prognostic factors. Clinical outcomes were associated with a combination of genetic, epigenetic and gene expression features, further advancing our prognostic paradigm. Overall, this work reveals fresh insights into CLL oncogenesis and prognostication.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Immunoglobulin Variable Region; Mutation; Prognosis; Genomics
PubMed: 35927489
DOI: 10.1038/s41588-022-01140-w -
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 -
Current Hematologic Malignancy Reports Oct 2023There have been significant advances in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) over the past two decades. However, the intention of... (Review)
Review
PURPOSE OF REVIEW
There have been significant advances in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) over the past two decades. However, the intention of treatment remains control of the disease and delay of progression rather than a cure which remains largely elusive. Considering that CLL is mostly seen in older patients, there are multiple factors that play a role in the selection of CLL beyond the frontline treatment. Here, we review the concept of relapsed CLL, factors that predispose to relapse, and therapeutic options available to this patient population. We also review investigational therapies and provide a framework for selection of therapies in this setting.
RECENT FINDINGS
Targeted therapies with continuous BTK inhibitors (BTKi) or fixed duration venetoclax plus anti-CD20 monoclonal antibody therapy have established superiority over chemoimmunotherapy in relapsed CLL and have become the preferred standard of care treatment. The second-generation more selective BTK inhibitors (acalabrutinib and zanubrutinib) have shown improved safety profile compared to ibrutinib. However, resistance to the covalent BTK inhibitors may emerge and is commonly associated with mutations in BTK or other downstream enzymes. The novel non-covalent BTK inhibitors such as pirtobrutinib (Loxo-305) and nemtabrutinib (ARQ 531) are showing promising activities for relapsed CLL refractory to prior covalent BTKi. Other novel therapies such as chimeric antigen receptor (CAR) T cell therapy have also shown significant activities for relapsed and refractory CLL. Measurable residual disease (MRD) assessment has a growing importance in venetoclax-based limited-duration therapy and there is mounting evidence that MRD negativity improves outcomes. However, it remains to be seen if this will become an established clinically significant endpoint. Further, the optimal sequence of various treatment options remains to be determined. Patients with relapsed CLL now have more options for the treatment of the disease. The choice of therapy is best individualized especially in the absence of direct comparisons of targeted therapies, and the coming years will bring more data on the best sequence of use of the therapeutic agents.
Topics: Humans; Aged; Leukemia, Lymphocytic, Chronic, B-Cell; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents
PubMed: 37278884
DOI: 10.1007/s11899-023-00700-z -
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