Pub Date : 2024-04-01DOI: 10.1053/j.seminhematol.2024.04.002
John T. Patton, Jennifer A. Woyach
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.
{"title":"Targeting the B cell receptor signaling pathway in chronic lymphocytic leukemia","authors":"John T. Patton, 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":null,"pages":null},"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}
Pub Date : 2024-04-01DOI: 10.1053/j.seminhematol.2024.01.003
Elizabeth R. Francis , Jennifer Vu , Catherine Ostos Perez , Clare Sun
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 pathogens. However, the immunocompromised status of CLL patients poses challenges in eliciting an adequate humoral and cellular immune response 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 in patients with CLL.
{"title":"Vaccinations in patients with chronic lymphocytic leukemia","authors":"Elizabeth R. Francis , Jennifer Vu , Catherine Ostos Perez , 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":null,"pages":null},"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}
Pub Date : 2024-04-01DOI: 10.1053/j.seminhematol.2024.02.002
Riccardo Moia, Gianluca Gaidano
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 & wait since no survival benefit has been identified in clinical trials with chemoimmunotherapy and with BTK inhibitors. In patients requiring treatment TP53 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 TP53 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.
{"title":"Prognostication in chronic lymphocytic leukemia","authors":"Riccardo Moia, 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 & 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":null,"pages":null},"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}
Pub Date : 2024-04-01DOI: 10.1053/j.seminhematol.2024.01.015
Inhye E. Ahn, Matthew S. Davids
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 TP53 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 BCL2 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.
{"title":"Therapeutic targeting of apoptosis in chronic lymphocytic leukemia","authors":"Inhye E. Ahn, 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":null,"pages":null},"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}
Pub Date : 2024-04-01DOI: 10.1053/S0037-1963(24)00062-3
{"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":null,"pages":null},"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}
Pub Date : 2024-04-01DOI: 10.1053/j.seminhematol.2024.03.002
Barbara Eichhorst , Elisa ten Hacken
{"title":"Special issue on chronic lymphocytic leukemia: Prognostication and therapeutic options introductory editorial","authors":"Barbara Eichhorst , 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":null,"pages":null},"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}
Pub Date : 2024-04-01DOI: 10.1053/j.seminhematol.2024.01.009
Amit Sud , Erin M. Parry , Catherine J. Wu
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.
从单克隆 B 细胞淋巴细胞增多症的早期阶段到慢性淋巴细胞性白血病(CLL),再到某些情况下的里克特综合征(RS),B 细胞的克隆扩增为癌症的演变提供了一个全面的模型,其显著的形态转变和不同的临床表型令人瞩目。通过对大量患者进行高通量测序和单细胞研究,绘制出了 CLL 以及最近 RS 的分子图谱,从而对这些疾病和克隆进化有了基本的了解。对部分 CLL 驱动基因进行了功能检测,从而对 CLL 的生物学特性有了新的认识。这些发现有可能通过风险分层、治疗选择和药物发现对患者护理产生影响。然而,这一分子图谱仍不完整,现存的问题涉及 B 细胞克隆的起源、TME 的作用、细胞间和细胞内异质性以及治疗耐药机制。通过在不同组织、疾病状态和临床环境中应用多模式单细胞技术,这些问题现在都可以得到解决,其答案很有希望产生可转化的知识,从而改善患者护理。
{"title":"The molecular map of CLL and Richter's syndrome","authors":"Amit Sud , Erin M. Parry , 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":null,"pages":null},"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}
Pub Date : 2024-04-01DOI: 10.1053/j.seminhematol.2024.01.001
Azra Borogovac, Tanya Siddiqi
Immunotherapies, such as chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies or T-cell engagers, have revolutionized the treatment landscape for various B-cell malignancies, 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 immunosuppressive tumor microenvironment (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 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.
免疫疗法,如嵌合抗原受体(CAR)T 细胞疗法和双特异性抗体或 T 细胞激活剂,已经彻底改变了各种 B 细胞恶性肿瘤(包括 B 型急性淋巴细胞白血病和许多非霍奇金淋巴瘤)的治疗格局。尽管它们对这些恶性肿瘤产生了重大影响,但它们在慢性淋巴细胞白血病(CLL)治疗中的应用在很大程度上仍在研究之中。虽然 CD19 引导的 CAR T 细胞疗法在三名多次复发的 CLL 患者身上取得了初步成功,其中两名患者存活超过 10 年未复发,但最近在 CLL 中进行的 CAR T 细胞疗法试验显示,与对其他 B 细胞恶性肿瘤的疗效相比,其反应率有所下降。在 CLL 中使用免疫疗法面临的挑战之一是,CLL 相关的抗原刺激和免疫抑制性肿瘤微环境(TME)会损害 T 细胞的适应性。这些挑战凸显了对当前疗法不耐受或耐药的 CLL 患者在治疗选择上的关键差距,强调了有效免疫疗法的重要作用。令人鼓舞的是,克服这些挑战的创新策略正在出现。这些策略包括整合伊布替尼(ibrutinib)等增效剂来增强 CAR T 细胞的功能和持久性,以及设计针对不同抗原或采用双重靶向方法的新型 CAR T 细胞构建体。对于这些患者来说,双特异性抗体是一个令人兴奋的 "现成 "前景,目前对它们在CLL中的应用研究已进入临床试验阶段。此外,异体 CAR T 细胞和来自健康供体的自然杀伤(NK)细胞的开发也为解决 CLL 患者 T 细胞功能减退的问题提供了一种前景广阔的解决方案。本综述深入探讨了免疫疗法在 CLL 中的作用、复杂的耐药机制以及一系列应对治疗挑战的创新方法等方面的最新见解。
{"title":"Transforming CLL management with immunotherapy: Investigating the potential of CAR T-cells and bispecific antibodies","authors":"Azra Borogovac, 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":null,"pages":null},"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}
Pub Date : 2024-02-01DOI: 10.1053/j.seminhematol.2024.01.005
Enrico Attardi , Seth J. Corey , Marcin W. Wlodarski
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.
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Pub Date : 2024-02-01DOI: 10.1053/j.seminhematol.2024.01.002
Simona Pagliuca , Francesca Ferraro
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.
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.
免疫监视机制在应对病理刺激和异常细胞状态以维持终身免疫平衡方面发挥着至关重要的作用。然而,它们的持续存在,尤其是在长期暴露于抗原的情况下,会为免疫逃避创造肥沃的土壤。这些逃避免疫的细胞表型携带多种基因组和转录组异常,主要是人类白细胞抗原(HLA)和抗原递呈机制基因,它们可能存活并增殖,形成具有免疫失败特征的克隆细胞扩增。历史文献强调,逃避 HLA 介导的识别是病毒为躲避免疫系统而采取的一种策略,这暗示了在慢性感染情况下免疫异常细胞扩增的可能性。此外,在特发性再生障碍性贫血中,HLA克隆逃避作为一种能够挽救衰竭造血的机制,可能在自身免疫性疾病中发挥作用,特别是在异常免疫反应所针对的组织中。此外,衰老细胞状态作为刺激 T 细胞反应的免疫原表型出现,可能成为选择这种免疫逃逸克隆的瓶颈,从而模糊了肿瘤转化、衰老和炎症之间的界限。在这里,我们对这种免疫驱动的克隆细胞扩增进行了全新的概述和透视,将暴露于免疫监视下的肿瘤、自身免疫、感染和衰老过程的病理生理特征联系起来。
{"title":"Immune-driven clonal cell selection at the intersection among cancer, infections, autoimmunity and senescence","authors":"Simona Pagliuca , 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":null,"pages":null},"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}