Seminars in hematology最新文献

{"title":"Targeting the B cell receptor signaling pathway in chronic lymphocytic leukemia","authors":"John T. Patton,&nbsp;Jennifer A. Woyach","doi":"10.1053/j.seminhematol.2024.04.002","DOIUrl":"10.1053/j.seminhematol.2024.04.002","url":null,"abstract":"<div><p>Aberrant signal transduction through the B cell receptor (BCR) plays a critical role in the pathogenesis of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). BCR-dependent signaling is necessary for the growth and survival of neoplastic cells, making inhibition of down-stream pathways a logical therapeutic strategy. Indeed, selective inhibitors against Bruton's tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K) have been shown to induce high rates of response in CLL and other B cell lymphomas. In particular, the development of BTK inhibitors revolutionized the treatment approach to CLL, demonstrating long-term efficacy. While BTK inhibitors are widely used for multiple lines of treatment, PI3K inhibitors are much less commonly utilized, mainly due to toxicities. CLL remains an incurable disease and effective treatment options after relapse or development of TKI resistance are greatly needed. This review provides an overview of BCR signaling, a summary of the current therapeutic landscape, and a discussion of the ongoing trials targeting BCR-associated kinases.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 100-108"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140765969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"outside front cover, PMS 8883 metallic AND 4/C","authors":"","doi":"10.1053/S0037-1963(24)00062-3","DOIUrl":"https://doi.org/10.1053/S0037-1963(24)00062-3","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Page CO1"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141250459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vaccinations in patients with chronic lymphocytic leukemia","authors":"Elizabeth R. Francis ,&nbsp;Jennifer Vu ,&nbsp;Catherine Ostos Perez ,&nbsp;Clare Sun","doi":"10.1053/j.seminhematol.2024.01.003","DOIUrl":"10.1053/j.seminhematol.2024.01.003","url":null,"abstract":"<div><p><span><span>Chronic lymphocytic leukemia (CLL) is characterized by immune dysfunction resulting in heightened susceptibility to infections and elevated rates of morbidity and mortality. A key strategy to mitigate infection-related complications has been immunization against common </span>pathogens. However, the immunocompromised status of CLL patients poses challenges in eliciting an adequate humoral and </span>cellular immune response<span><span> to vaccination. Most CLL-directed therapy disproportionately impairs humoral immunity. Vaccine responsiveness also depends on the phase and type of immune response triggered by immunization. In this review, we discuss the immune dysfunction, vaccine responsiveness, and considerations for optimizing vaccine response </span>in patients with CLL.</span></p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 131-138"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139376220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic targeting of apoptosis in chronic lymphocytic leukemia","authors":"Inhye E. Ahn,&nbsp;Matthew S. Davids","doi":"10.1053/j.seminhematol.2024.01.015","DOIUrl":"10.1053/j.seminhematol.2024.01.015","url":null,"abstract":"<div><p>Therapeutic targeting of apoptosis with small molecule B-cell lymphoma 2 (BCL-2) inhibition with venetoclax is highly efficacious in CLL, leading to sustained deep responses, particularly among patients with treatment-naïve disease with favorable prognostic markers. Patients with unfavorable genetic characteristics such as <em>TP53</em> aberration and unmutated IGHV may also derive durable benefits, but their remission duration after time-limited venetoclax-containing combination therapy is shorter, particularly in patients with relapsed/refractory disease. Emerging data indicate that the context of disease progression after initial treatment with venetoclax may define the success of re-treatment with venetoclax. Specifically, continuous venetoclax exposure may select for resistant disease due to genetic mechanisms such as <em>BCL2</em> mutations and functional resistance mechanisms such as hyperphosphorylation of BCL-2 family proteins, which decrease the affinity of venetoclax binding to the target or lead to increased MCL-1 dependence and concomitant decrease in BCL-2 dependence. These patients may be best served by switching to a different class of targeted agents at the time of progression. In contrast, relapsed CLL that arises while being off therapy after a period of time-limited venetoclax-based regimens maintains sensitivity to re-treatment with venetoclax for the majority of patients. Novel strategies related to therapeutic targeting of apoptosis include next-generation BCL-2 inhibitors with improved potency and pharmacokinetic profiles, direct targeting of anti-apoptotic BH3 family proteins beyond BCL-2 such as MCL-1, and indirect targeting of MCL-1 through mechanisms such as small molecule cyclin-dependent kinase 9 inhibitors.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 109-118"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139831525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostication in chronic lymphocytic leukemia","authors":"Riccardo Moia,&nbsp;Gianluca Gaidano","doi":"10.1053/j.seminhematol.2024.02.002","DOIUrl":"10.1053/j.seminhematol.2024.02.002","url":null,"abstract":"<div><p>Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries. CLL is a highly heterogeneous disease: some patients may never require therapy and others relapse several times after different therapeutic strategies. Therefore, in CLL, prognostic markers are essential to capture high-risk patients for different clinical endpoints including early treatment requirement, early progression after BTK or BCL2 inhibitors and Richter transformation. In early stage CLL, different biological and clinical biomarkers have been identified to predict time to treatment requirement that could be used to identify the most appropriate population for early intervention clinical trial. However, at the moment, the standard of care for early stage CLL remains watch &amp; wait since no survival benefit has been identified in clinical trials with chemoimmunotherapy and with BTK inhibitors. In patients requiring treatment <em>TP53</em> disruptions identify high-risk patients who benefit the most from long-term continuous therapy with BTKi. On the opposite side of the spectrum, IGHV mutated patients devoid of <em>TP53</em> disruption benefit the most from fixed-duration therapy with venetoclax-obinutuzumab. In between, the highly heterogenous subgroup of patients with IGHV unmutated genes represents the group in which further efforts are needed to identify additional prognostic biomarkers aimed at selecting patients who can benefit from fixed-duration and patients who can benefit from long term BTKi therapy. In the context of the aggressive transformation of CLL, namely Richter syndrome, the clonal relationship to the CLL counterpart represents the strongest prognostic biomarker. Clonally related Richter syndrome still represents an unmet clinical need which requires further efforts to identify new therapeutic strategies.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 83-90"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0037196324000386/pdfft?md5=b6d513be92a17e8615a4b2dc5cef6458&pid=1-s2.0-S0037196324000386-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140057523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Special issue on chronic lymphocytic leukemia: Prognostication and therapeutic options introductory editorial","authors":"Barbara Eichhorst ,&nbsp;Elisa ten Hacken","doi":"10.1053/j.seminhematol.2024.03.002","DOIUrl":"10.1053/j.seminhematol.2024.03.002","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 69-72"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0037196324000556/pdfft?md5=8df5c206157416b9e199e1a6d6a9ad49&pid=1-s2.0-S0037196324000556-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140400955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The molecular map of CLL and Richter's syndrome","authors":"Amit Sud ,&nbsp;Erin M. Parry ,&nbsp;Catherine J. Wu","doi":"10.1053/j.seminhematol.2024.01.009","DOIUrl":"10.1053/j.seminhematol.2024.01.009","url":null,"abstract":"<div><p>Clonal expansion of B-cells, from the early stages of monoclonal B-cell lymphocytosis through to chronic lymphocytic leukemia (CLL), and then in some cases to Richter's syndrome (RS) provides a comprehensive model of cancer evolution, notable for the marked morphological transformation and distinct clinical phenotypes. High-throughput sequencing of large cohorts of patients and single-cell studies have generated a molecular map of CLL and more recently, of RS, yielding fundamental insights into these diseases and of clonal evolution. A selection of CLL driver genes have been functionally interrogated to yield novel insights into the biology of CLL. Such findings have the potential to impact patient care through risk stratification, treatment selection and drug discovery. However, this molecular map remains incomplete, with extant questions concerning the origin of the B-cell clone, the role of the TME, inter- and intra-compartmental heterogeneity and of therapeutic resistance mechanisms. Through the application of multi-modal single-cell technologies across tissues, disease states and clinical contexts, these questions can now be addressed with the answers holding great promise of generating translatable knowledge to improve patient care.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 73-82"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S003719632400009X/pdfft?md5=e6b68a13a1d84b6cd8bb87a533d2c797&pid=1-s2.0-S003719632400009X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139584477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transforming CLL management with immunotherapy: Investigating the potential of CAR T-cells and bispecific antibodies","authors":"Azra Borogovac,&nbsp;Tanya Siddiqi","doi":"10.1053/j.seminhematol.2024.01.001","DOIUrl":"10.1053/j.seminhematol.2024.01.001","url":null,"abstract":"<div><p><span><span>Immunotherapies<span><span>, such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies or T-cell engagers, have revolutionized the </span>treatment landscape for various B-cell </span></span>malignancies<span><span>, including B-acute lymphoblastic leukemia and many non-Hodgkin lymphomas. Despite their significant impact on these malignancies, their application in chronic lymphocytic leukemia (CLL) management is still largely under investigation. Although the initial success of CD19-directed CAR T-cell therapy was observed in 3 multiply relapsed CLL patients, with 2 of them surviving over 10 years without relapse, recent CAR T-cell therapy trials in CLL have shown reduced response rates compared to their efficacy in other B-cell malignancies. One of the challenges with using immunotherapy in CLL is the compromised T-cell fitness from persistent CLL-related antigenic stimulation, and an </span>immunosuppressive<span> tumor microenvironment<span> (TME). These challenges underscore a critical gap in therapeutic options for CLL patients intolerant or resistant to current therapies, emphasizing the imperative role of effective immunotherapy. Encouragingly, innovative strategies are emerging to overcome these challenges. These include integrating synergistic agents like ibrutinib to enhance CAR T-cell function and persistence and engineering newer CAR T-cell constructs targeting diverse antigens or employing dual-targeting approaches. Bispecific antibodies are an exciting \"off-the-shelf\" prospect for these patients, with their investigation in CLL currently entering the realm of </span></span></span></span>clinical trials. Additionally, the development of allogeneic CAR T-cells and natural killer (NK) cells from healthy donors presents a promising solution to address the diminished T-cell fitness observed in CLL patients. This comprehensive review delves into the latest insights regarding the role of immunotherapy in CLL, the complex landscape of resistance mechanisms, and a spectrum of innovative approaches to surmount therapeutic challenges.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 2","pages":"Pages 119-130"},"PeriodicalIF":3.6,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139376452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clonal hematopoiesis in children with predisposing conditions","authors":"Enrico Attardi ,&nbsp;Seth J. Corey ,&nbsp;Marcin W. Wlodarski","doi":"10.1053/j.seminhematol.2024.01.005","DOIUrl":"10.1053/j.seminhematol.2024.01.005","url":null,"abstract":"<div><p>Clonal hematopoiesis in children and young adults differs from that occuring in the older adult population. A variety of stressors drive this phenomenon, sometimes independent of age-related processes. For the purposes of this review, we adopt the term clonal hematopoiesis in predisposed individuals (CHIPI) to differentiate it from classical, age-related clonal hematopoiesis of indeterminate potential (CHIP). Stress-induced CHIPI selection can be extrinsic, such as following immunologic, infectious, pharmacologic, or genotoxic exposures, or intrinsic, involving germline predisposition from inherited bone marrow failure syndromes. In these conditions, clonal advantage relates to adaptations allowing improved cell fitness despite intrinsic defects affecting proliferation and differentiation. In certain contexts, CHIPI can improve competitive fitness by compensating for germline defects; however, the downstream effects of clonal expansion are often unpredictable - they may either counteract the underlying pathology or worsen disease outcomes. A more complete understanding of how CHIPI arises in young people can lead to the definition of preleukemic states and strategies to assess risk, surveillance, and prevention to leukemic transformation. Our review summarizes current research on stress-induced clonal dynamics in individuals with germline predisposition syndromes.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 1","pages":"Pages 35-42"},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0037196324000064/pdfft?md5=4ec64461a4831e4dcae2bf65e1bfb1a1&pid=1-s2.0-S0037196324000064-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139470232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immune-driven clonal cell selection at the intersection among cancer, infections, autoimmunity and senescence","authors":"Simona Pagliuca ,&nbsp;Francesca Ferraro","doi":"10.1053/j.seminhematol.2024.01.002","DOIUrl":"10.1053/j.seminhematol.2024.01.002","url":null,"abstract":"<div><p>Immune surveillance mechanisms play a crucial role in maintaining lifelong immune homeostasis in response to pathologic stimuli and aberrant cell states. However, their persistence, especially in the context of chronic antigenic exposure, can create a fertile ground for immune evasion. These escaping cell phenotypes, harboring a variety of genomic and transcriptomic aberrances, chiefly in human leukocyte antigen (HLA) and antigen presentation machinery genes, may survive and proliferate, featuring a scenario of clonal cell expansion with immune failure characteristics. While well characterized in solid and, to some extent, hematological malignancies, little is known about their occurrence and significance in other disease contexts.</p><p>Historical literature highlights the role for escaping HLA-mediated recognition as a strategy adopted by virus to evade from the immune system, hinting at the potential for immune aberrant cell expansion in the context of chronic infections. Additionally, unmasked in idiopathic aplastic anemia as a mechanism able to rescue failing hematopoiesis, HLA clonal escape may operate in autoimmune disorders, particularly in tissues targeted by aberrant immune responses. Furthermore, senescent cell status emerging as immunogenic phenotypes stimulating T cell responses, may act as a bottleneck for the selection of such immune escaping clones, blurring the boundaries between neoplastic transformation, aging and inflammation. Here we provide a fresh overview and perspective on this immune-driven clonal cell expansion, linking pathophysiological features of neoplastic, autoimmune, infectious and senescence processes exposed to immune surveillance.</p></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"61 1","pages":"Pages 22-34"},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0037196324000015/pdfft?md5=735f93d1eb51fc06c833a2ce8eddfcac&pid=1-s2.0-S0037196324000015-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139500726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}