Pub Date : 2024-10-31DOI: 10.1182/blood.2024024631
Othman Al-Sawaf, Sandra Robrecht, Can Zhang, Stefano Olivieri, Yi Meng Chang, Anna Maria Fink, Eugen Tausch, Christof Schneider, Matthias Ritgen, Karl-Anton Kreuzer, Liliya Sivchev, Carsten Utoft Niemann, Anthony Schwarer, Javier Loscertales, Robert Weinkove, Dirk Strumberg, Allanah Kilfoyle, Beenish S Manzoor, Dureshahwar Jawaid, Nnadozie Emechebe, Jacob Devine, Michelle Boyer, Eva D Runkel, Barbara Eichhorst, Stephan Stilgenbauer, Yanwen Jiang, Michael Hallek, Kirsten Fischer
Abstract: In the CLL14 study, patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting conditions were randomized to 12 cycles of venetoclax-obinutuzumab (Ven-Obi, n = 216) or chlorambucil-obinutuzumab (Clb-Obi, n = 216). Progression-free survival (PFS) was the primary end point. Key secondary end points included time-to-next-treatment (TTNT), rates of undetectable minimal residual disease (uMRD), overall survival (OS), and rates of adverse events. Patient reported outcomes of time until definitive deterioration (TUDD) in quality of life (QoL) were analyzed. At a median observation time of 76.4 months, PFS remained superior for Ven-Obi compared with Clb-Obi (median, 76.2 vs 36.4 months; hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.31-0.52; P < .0001). Likewise, TTNT was longer after Ven-Obi (6-year TTNT, 65.2% vs 37.1%; HR, 0.44; 95% CI, 0.33-0.58; P < .0001). In the Ven-Obi arm, presence of del(17p), unmutated immunoglobulin heavy-chain variable region, and lymph node size of ≥5 cm were independent prognostic factors for shorter PFS. The 6-year OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR, 0.69; 95% CI, 0.48-1.01; P = .052). A significantly longer TUDD in global health status/QoL was observed in the Ven-Obi than in the Clb-Obi arm (median, 82.1 vs 65.1 months; HR, 0.70; 95% CI, 0.51-0.97). Follow-up-adjusted second primary malignancies incidence rates were 2.3 and 1.4 per 1000 patient-months in the Ven-Obi and Clb-Obi arm, respectively. The sustained long-term survival and QoL benefits support the use of 1-year fixed-duration Ven-Obi in CLL. This trial was registered at www.ClinicalTrials.gov as #NCT02242942.
Venetoclax-obinutuzumab(Ven-Obi)是既往未经治疗的慢性淋巴细胞白血病(CLL)患者的标准疗法。在CLL14研究中,既往未经治疗的CLL合并症患者被随机分配到12个周期的Ven-Obi(n=216)或氯布嘧啶-奥比布珠单抗(Clb-Obi,n=216)治疗中。无进展生存期(PFS)是主要终点。主要次要终点包括下次治疗时间(TTNT)、检测不到的最小残留病(uMRD)率、总生存期(OS)和不良反应率。此外,还分析了患者报告的生活质量(QoL)恶化时间(TUDD)。中位观察时间为 76.4 个月时,Ven-Obi 的 PFS 仍优于 Clb-Obi(中位 76.2 个月 vs 36.4 个月;HR 0.40[95%CI 0.31-0.52], p
{"title":"Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 6-year results of the randomized phase 3 CLL14 study.","authors":"Othman Al-Sawaf, Sandra Robrecht, Can Zhang, Stefano Olivieri, Yi Meng Chang, Anna Maria Fink, Eugen Tausch, Christof Schneider, Matthias Ritgen, Karl-Anton Kreuzer, Liliya Sivchev, Carsten Utoft Niemann, Anthony Schwarer, Javier Loscertales, Robert Weinkove, Dirk Strumberg, Allanah Kilfoyle, Beenish S Manzoor, Dureshahwar Jawaid, Nnadozie Emechebe, Jacob Devine, Michelle Boyer, Eva D Runkel, Barbara Eichhorst, Stephan Stilgenbauer, Yanwen Jiang, Michael Hallek, Kirsten Fischer","doi":"10.1182/blood.2024024631","DOIUrl":"10.1182/blood.2024024631","url":null,"abstract":"<p><strong>Abstract: </strong>In the CLL14 study, patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting conditions were randomized to 12 cycles of venetoclax-obinutuzumab (Ven-Obi, n = 216) or chlorambucil-obinutuzumab (Clb-Obi, n = 216). Progression-free survival (PFS) was the primary end point. Key secondary end points included time-to-next-treatment (TTNT), rates of undetectable minimal residual disease (uMRD), overall survival (OS), and rates of adverse events. Patient reported outcomes of time until definitive deterioration (TUDD) in quality of life (QoL) were analyzed. At a median observation time of 76.4 months, PFS remained superior for Ven-Obi compared with Clb-Obi (median, 76.2 vs 36.4 months; hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.31-0.52; P < .0001). Likewise, TTNT was longer after Ven-Obi (6-year TTNT, 65.2% vs 37.1%; HR, 0.44; 95% CI, 0.33-0.58; P < .0001). In the Ven-Obi arm, presence of del(17p), unmutated immunoglobulin heavy-chain variable region, and lymph node size of ≥5 cm were independent prognostic factors for shorter PFS. The 6-year OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR, 0.69; 95% CI, 0.48-1.01; P = .052). A significantly longer TUDD in global health status/QoL was observed in the Ven-Obi than in the Clb-Obi arm (median, 82.1 vs 65.1 months; HR, 0.70; 95% CI, 0.51-0.97). Follow-up-adjusted second primary malignancies incidence rates were 2.3 and 1.4 per 1000 patient-months in the Ven-Obi and Clb-Obi arm, respectively. The sustained long-term survival and QoL benefits support the use of 1-year fixed-duration Ven-Obi in CLL. This trial was registered at www.ClinicalTrials.gov as #NCT02242942.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":null,"pages":null},"PeriodicalIF":21.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141854765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1182/blood.2024024487
Jing Nie, Chunmeng Wang, Liangtao Zheng, Yang Liu, Chengcheng Wang, Yixin Chang, Yudi Hu, Bing Guo, Yuting Pan, Qingming Yang, Xueda Hu, Weidong Han
Abstract: DNA methyltransferase inhibitor decitabine plus anti-programmed cell death 1 (DP) therapy was effective in relapsed/refractory classic Hodgkin lymphoma (cHL). However, a subset of patients experienced primary resistance or relapse/progression after DP therapy. In this study, we evaluated the efficacy and safety of a triplet regimen consisting of the histone deacetylase inhibitor chidamide, decitabine, and anti-PD-1 camrelizumab (CDP) in 52 patients who previously received DP therapy. CDP treatment was well tolerated and resulted in an objective response rate of 94% (95% confidence interval [CI], 84-99), with 50% (95% CI, 36-64) of patients achieving complete response (CR). Notably, all patients who were recalcitrant to previous DP treatment exhibited therapeutic responses after CDP therapy, although their CR rate was lower than patients responsive to prior DP. Overall, the median progression-free survival was 29.4 months. Through single-cell RNA sequencing of pretreatment and on-treatment cHL tumor biopsy samples, we observed the heterogeneity of rare malignant Hodgkin Reed/Sternberg (HRS)-like cells. The classical CD30+ HRS-like cells interacted with abundant immunosuppressive IL21+CD4+ T helper cells, forming a positive feedback loop that supported their survival. While the CD30- HRS-like cell population showed potential resistance to anti-PD-1 immunotherapy. CDP treatment promoted the activation of diverse tumor-reactive CD8+ T cells and suppressed the proliferation of IL21+CD4+ T cells by inhibiting STAT1/3 signaling, thereby alleviating their immunosuppressive effects. These findings provide insights into the cHL microenvironment that contributes to anti-PD-1 resistance and highlight the therapeutic effectiveness of dual epi-immunotherapy in overcoming immunotherapy resistance. This trial was registered at www.clinicaltrials.gov as #NCT04233294.
{"title":"Epigenetic agents plus anti-PD-1 reprogram the tumor microenvironment and restore antitumor efficacy in Hodgkin lymphoma.","authors":"Jing Nie, Chunmeng Wang, Liangtao Zheng, Yang Liu, Chengcheng Wang, Yixin Chang, Yudi Hu, Bing Guo, Yuting Pan, Qingming Yang, Xueda Hu, Weidong Han","doi":"10.1182/blood.2024024487","DOIUrl":"10.1182/blood.2024024487","url":null,"abstract":"<p><strong>Abstract: </strong>DNA methyltransferase inhibitor decitabine plus anti-programmed cell death 1 (DP) therapy was effective in relapsed/refractory classic Hodgkin lymphoma (cHL). However, a subset of patients experienced primary resistance or relapse/progression after DP therapy. In this study, we evaluated the efficacy and safety of a triplet regimen consisting of the histone deacetylase inhibitor chidamide, decitabine, and anti-PD-1 camrelizumab (CDP) in 52 patients who previously received DP therapy. CDP treatment was well tolerated and resulted in an objective response rate of 94% (95% confidence interval [CI], 84-99), with 50% (95% CI, 36-64) of patients achieving complete response (CR). Notably, all patients who were recalcitrant to previous DP treatment exhibited therapeutic responses after CDP therapy, although their CR rate was lower than patients responsive to prior DP. Overall, the median progression-free survival was 29.4 months. Through single-cell RNA sequencing of pretreatment and on-treatment cHL tumor biopsy samples, we observed the heterogeneity of rare malignant Hodgkin Reed/Sternberg (HRS)-like cells. The classical CD30+ HRS-like cells interacted with abundant immunosuppressive IL21+CD4+ T helper cells, forming a positive feedback loop that supported their survival. While the CD30- HRS-like cell population showed potential resistance to anti-PD-1 immunotherapy. CDP treatment promoted the activation of diverse tumor-reactive CD8+ T cells and suppressed the proliferation of IL21+CD4+ T cells by inhibiting STAT1/3 signaling, thereby alleviating their immunosuppressive effects. These findings provide insights into the cHL microenvironment that contributes to anti-PD-1 resistance and highlight the therapeutic effectiveness of dual epi-immunotherapy in overcoming immunotherapy resistance. This trial was registered at www.clinicaltrials.gov as #NCT04233294.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":null,"pages":null},"PeriodicalIF":21.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1182/blood.2024024649
Charlotte M Thomas, M Khalid F Salamat, Florian Almela, Jillian K Cooper, Kaetan Ladhani, Mark E Arnold, Daisy Bougard, Olivier Andréoletti, E Fiona Houston
Abstract: Variant Creutzfeldt-Jakob disease (vCJD) is a devastating disease caused by transmission of bovine spongiform encephalopathy to humans. Although vCJD cases are now rare, evidence from appendix surveys suggests that a small proportion of the United Kingdom population may be infected without showing signs of disease. These "silent" carriers could present a risk of iatrogenic vCJD transmission through medical procedures or blood/organ donation, and currently there are no validated tests to identify infected asymptomatic individuals using easily accessible samples. To address this issue, we evaluated the performance of 3 blood-based assays in a blinded study, using longitudinal sample series from a well-established large animal model of vCJD. The assays rely on amplification of misfolded prion protein (PrPSc; a marker of prion infection) and include real-time quaking-induced conversion (RT-QuIC), and 2 versions of protein misfolding cyclic amplification (PMCA). Although diagnostic sensitivity was higher for both PMCA assays (100%) than RT-QuIC (61%), all 3 assays detected prion infection in blood samples collected 26 months before the onset of clinical signs and gave no false-positive results. Parallel estimation of blood prion infectivity titers in a sensitive transgenic mouse line showed positive correlation of infectivity with PrPSc detection by the assays, suggesting that they are suitable for detection of asymptomatic vCJD infection in the human population. This study represents, to our knowledge, the largest comparison to date of preclinical prion detection in blood samples from a relevant animal model. The outcomes will guide efforts to improve early detection of prion disease and reduce infection risks in humans.
{"title":"Longitudinal detection of prion infection in preclinical sheep blood samples compared using 3 assays.","authors":"Charlotte M Thomas, M Khalid F Salamat, Florian Almela, Jillian K Cooper, Kaetan Ladhani, Mark E Arnold, Daisy Bougard, Olivier Andréoletti, E Fiona Houston","doi":"10.1182/blood.2024024649","DOIUrl":"10.1182/blood.2024024649","url":null,"abstract":"<p><strong>Abstract: </strong>Variant Creutzfeldt-Jakob disease (vCJD) is a devastating disease caused by transmission of bovine spongiform encephalopathy to humans. Although vCJD cases are now rare, evidence from appendix surveys suggests that a small proportion of the United Kingdom population may be infected without showing signs of disease. These \"silent\" carriers could present a risk of iatrogenic vCJD transmission through medical procedures or blood/organ donation, and currently there are no validated tests to identify infected asymptomatic individuals using easily accessible samples. To address this issue, we evaluated the performance of 3 blood-based assays in a blinded study, using longitudinal sample series from a well-established large animal model of vCJD. The assays rely on amplification of misfolded prion protein (PrPSc; a marker of prion infection) and include real-time quaking-induced conversion (RT-QuIC), and 2 versions of protein misfolding cyclic amplification (PMCA). Although diagnostic sensitivity was higher for both PMCA assays (100%) than RT-QuIC (61%), all 3 assays detected prion infection in blood samples collected 26 months before the onset of clinical signs and gave no false-positive results. Parallel estimation of blood prion infectivity titers in a sensitive transgenic mouse line showed positive correlation of infectivity with PrPSc detection by the assays, suggesting that they are suitable for detection of asymptomatic vCJD infection in the human population. This study represents, to our knowledge, the largest comparison to date of preclinical prion detection in blood samples from a relevant animal model. The outcomes will guide efforts to improve early detection of prion disease and reduce infection risks in humans.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":null,"pages":null},"PeriodicalIF":21.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1182/blood.2023021790
Tony Marchand, Thierry Lamy, Thomas P Loughran
Abstract: Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative chronic disorder characterized by expansion of either T or natural killer (NK) cytotoxic cells. In contrast to Epstein-Barr virus-induced aggressive NK-LGLL, chronic T-LGLL and NK-LGLL are indolent diseases affecting older patients with a median age of 66.5 years. LGLL is frequently associated with autoimmune disorders, most frequently rheumatoid arthritis. An auto-/alloantigen is tentatively implicated in disease initiation. Large granular lymphocyte expansion is then triggered by proinflammatory cytokines such as interleukin-15, macrophage inflammatory protein 1 (MIP-1), and RANTES (regulated upon activation, normal T cell expressed, and secreted). This proinflammatory environment contributes to deregulation of proliferative and apoptotic pathways. After the initial description of the JAK-STAT pathway signaling activation in the majority of patients, recurrent STAT3 gain-of-function mutations have been reported. The JAK-STAT pathway plays a key role in LGL pathogenesis by promoting survival, proliferation, and cytotoxicity. Several recent advances have been made toward understanding the molecular landscapes of T- and NK-LGLL, identifying multiple recurrent mutations affecting the epigenome, such as TET2 or KMT2D, and cross talk with the immune microenvironment, such as CCL22. Despite an indolent course, published series suggest that the majority of patients eventually need treatment. However, it is noteworthy that many patients may have a long-term observation period without ever requiring therapy. Treatments rely upon immunosuppressive drugs, namely cyclophosphamide, methotrexate, and cyclosporine. Recent advances have led to the development of targeted approaches, including JAK-STAT inhibitors, cytokine targeting, and hypomethylating agents, opening new developments in a still-incurable disease.
{"title":"A modern view of LGL leukemia.","authors":"Tony Marchand, Thierry Lamy, Thomas P Loughran","doi":"10.1182/blood.2023021790","DOIUrl":"10.1182/blood.2023021790","url":null,"abstract":"<p><strong>Abstract: </strong>Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative chronic disorder characterized by expansion of either T or natural killer (NK) cytotoxic cells. In contrast to Epstein-Barr virus-induced aggressive NK-LGLL, chronic T-LGLL and NK-LGLL are indolent diseases affecting older patients with a median age of 66.5 years. LGLL is frequently associated with autoimmune disorders, most frequently rheumatoid arthritis. An auto-/alloantigen is tentatively implicated in disease initiation. Large granular lymphocyte expansion is then triggered by proinflammatory cytokines such as interleukin-15, macrophage inflammatory protein 1 (MIP-1), and RANTES (regulated upon activation, normal T cell expressed, and secreted). This proinflammatory environment contributes to deregulation of proliferative and apoptotic pathways. After the initial description of the JAK-STAT pathway signaling activation in the majority of patients, recurrent STAT3 gain-of-function mutations have been reported. The JAK-STAT pathway plays a key role in LGL pathogenesis by promoting survival, proliferation, and cytotoxicity. Several recent advances have been made toward understanding the molecular landscapes of T- and NK-LGLL, identifying multiple recurrent mutations affecting the epigenome, such as TET2 or KMT2D, and cross talk with the immune microenvironment, such as CCL22. Despite an indolent course, published series suggest that the majority of patients eventually need treatment. However, it is noteworthy that many patients may have a long-term observation period without ever requiring therapy. Treatments rely upon immunosuppressive drugs, namely cyclophosphamide, methotrexate, and cyclosporine. Recent advances have led to the development of targeted approaches, including JAK-STAT inhibitors, cytokine targeting, and hypomethylating agents, opening new developments in a still-incurable disease.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":null,"pages":null},"PeriodicalIF":21.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141287748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1182/blood.2023021786
Laurence de Leval, Philippe Gaulard, Ahmet Dogan
Abstract: T- and natural killer (NK)-cell lymphomas are neoplasms derived from immature T cells (lymphoblastic lymphomas), or more commonly, from mature T and NK cells (peripheral T-cell lymphomas, PTCLs). PTCLs are rare but show marked biological and clinical diversity. They are usually aggressive and may present in lymph nodes, blood, bone marrow, or other organs. More than 30 T/NK-cell-derived neoplastic entities are recognized in the International Consensus Classification and the classification of the World Health Organization (fifth edition), both published in 2022, which integrate the most recent knowledge in hematology, immunology, pathology, and genetics. In both proposals, disease definition aims to integrate clinical features, etiology, implied cell of origin, morphology, phenotype, and genetic features into biologically and clinically relevant clinicopathologic entities. Cell derivation from innate immune cells or specific functional subsets of CD4+ T cells such as follicular helper T cells is a major determinant delineating entities. Accurate diagnosis of T/NK-cell lymphoma is essential for clinical management and mostly relies on tissue biopsies. Because the histological presentation may be heterogeneous and overlaps with that of many benign lymphoid proliferations and B-cell lymphomas, the diagnosis is often challenging. Disease location, morphology, and immunophenotyping remain the main features guiding the diagnosis, often complemented by genetic analysis including clonality and high-throughput sequencing mutational studies. This review provides a comprehensive overview of the classification and diagnosis of T-cell lymphoma in the context of current concepts and scientific knowledge.
T细胞淋巴瘤和NK细胞淋巴瘤是由未成熟T细胞(淋巴母细胞淋巴瘤)或更常见的成熟T细胞和NK细胞(外周T细胞淋巴瘤,PTCLs)演变而来的肿瘤。PTCLs 很罕见,但在生物和临床上表现出明显的多样性。它们通常具有侵袭性,可能出现在淋巴结、血液、骨髓或其他器官中。国际共识分类》(International Consensus Classification)和《世界卫生组织分类(第五版)》(World Health Organization,均于 2022 年出版)整合了血液学、免疫学、病理学和遗传学方面的最新知识,确认了 30 多种由 T/NK 细胞衍生的肿瘤实体。在这两份提案中,疾病定义旨在将临床特征、病因学、隐含的起源细胞、形态学、表型和遗传学特征整合为生物学和临床相关的临床病理学实体。细胞来源于先天性免疫细胞或 CD4+ T 细胞的特定功能亚群(如滤泡辅助性 T 细胞)是划分实体的主要决定因素。T/NK细胞淋巴瘤的准确诊断对临床治疗至关重要,主要依赖于组织活检。由于组织学表现可能是异质性的,并与许多良性淋巴细胞增生和B细胞淋巴瘤重叠,因此诊断往往具有挑战性。疾病位置、形态学和免疫分型仍是指导诊断的主要特征,通常辅以基因分析,包括克隆性和高通量测序突变研究。本综述结合当前的概念和科学知识,全面概述了 T 细胞淋巴瘤的分类和诊断。
{"title":"A practical approach to the modern diagnosis and classification of T- and NK-cell lymphomas.","authors":"Laurence de Leval, Philippe Gaulard, Ahmet Dogan","doi":"10.1182/blood.2023021786","DOIUrl":"10.1182/blood.2023021786","url":null,"abstract":"<p><strong>Abstract: </strong>T- and natural killer (NK)-cell lymphomas are neoplasms derived from immature T cells (lymphoblastic lymphomas), or more commonly, from mature T and NK cells (peripheral T-cell lymphomas, PTCLs). PTCLs are rare but show marked biological and clinical diversity. They are usually aggressive and may present in lymph nodes, blood, bone marrow, or other organs. More than 30 T/NK-cell-derived neoplastic entities are recognized in the International Consensus Classification and the classification of the World Health Organization (fifth edition), both published in 2022, which integrate the most recent knowledge in hematology, immunology, pathology, and genetics. In both proposals, disease definition aims to integrate clinical features, etiology, implied cell of origin, morphology, phenotype, and genetic features into biologically and clinically relevant clinicopathologic entities. Cell derivation from innate immune cells or specific functional subsets of CD4+ T cells such as follicular helper T cells is a major determinant delineating entities. Accurate diagnosis of T/NK-cell lymphoma is essential for clinical management and mostly relies on tissue biopsies. Because the histological presentation may be heterogeneous and overlaps with that of many benign lymphoid proliferations and B-cell lymphomas, the diagnosis is often challenging. Disease location, morphology, and immunophenotyping remain the main features guiding the diagnosis, often complemented by genetic analysis including clonality and high-throughput sequencing mutational studies. This review provides a comprehensive overview of the classification and diagnosis of T-cell lymphoma in the context of current concepts and scientific knowledge.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":null,"pages":null},"PeriodicalIF":21.0,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140903565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1182/blood.2024025987
Jan Eckmann, Tanja Fauti, Marlene Biehl, Aintzane Zabaleta, Laura Blanco, Iva Lelios, Stefan Gottwald, Richard Rae, Stefanie Lechner, Christa Bayer, Quincy Dekempe, Franz Osl, Nadège Carrié, Sahar Kassem, Stefan Lorenz, Tony Christopeit, Alejandro Carpy, Alexander Bujotzek, Ann-Marie E Bröske, Iryna Dekhtiarenko, Jan Attig, Leo Kunz, Floriana Cremasco, Roberto Adelfio, Georg Fertig, Stefan Dengl, Christian Gassner, Felix Bormann, Claudia Kirstenpfad, Thomas Emanuel Kraft, Sarah Diggelmann, Melanie Knobloch, Carina Hage, Romi Feddersen, Gordon Heidkamp, Thomas Pöschinger, Maud Lea Mayoux, Luise Bernasconi, Charles Dumontet, Felipe Prosper, Ludovic Martinet, Stephane Leclair, Wei Xu, Bruno Paiva, Christian Klein, Pablo Umaña
Despite several approved therapies, multiple myeloma (MM) remains an incurable disease with high unmet medical need. "Off-the-shelf" T-cell bispecific antibodies (TCBs) targeting BCMA and GPRC5D have demonstrated high objective response rates (ORR) in heavily pre-treated MM patients, however, primary resistance, short duration of response and relapse driven by antigen shift frequently occurs. Although GPRC5D represents the most selective target in MM, recent findings indicate antigen loss occurs more frequently than with BCMA. Thus, anti-GPRC5D immunotherapies must hit hard during a short period of time to kill as many myeloma cells as possible. Here, we characterize forimtamig, a novel GPRC5D-targeting TCB with 2+1 format, using preclinical models of MM. Bivalent binding of forimtamig to the N-terminus of GPRC5D confers higher affinity as compared to classical 1+1 TCB formats correlating with formation of more stable immunological synapses and higher potency in tumor cell killing and T cell activation. Using an orthotopic mouse model of MM, forimtamig recruited T effector cells to the bone marrow and induced rapid tumor killing even after the introduction of step-up dosing to mitigate cytokine release. Combination of forimtamig with standard-of-care (SoC) agents including anti-CD38 antibodies, immunomodulatory drugs and proteasome inhibitors improved depth and duration of response. The combination of forimtamig with novel therapeutic agents including BCMA-TCB and Cereblon E3 Ligase Modulatory Drugs (CELMoDs) was potent and prevented occurrence of GPRC5D-negative tumor relapse. Forimtamig is currently being evaluated in Phase 1 clinical trials in relapsed and refractory myeloma (RRMM) patients for monotherapy and in combination treatments. NCT04557150.
尽管有多种疗法获得批准,但多发性骨髓瘤(MM)仍是一种无法治愈的疾病,有大量医疗需求尚未得到满足。以 BCMA 和 GPRC5D 为靶点的 "现成 "T 细胞双特异性抗体(TCBs)已在接受过大量预处理的 MM 患者中显示出较高的客观反应率(ORR),但由于抗原转移而导致的原发性耐药、反应持续时间短和复发的情况时有发生。虽然 GPRC5D 是 MM 中最具选择性的靶点,但最近的研究结果表明,抗原丢失比 BCMA 更常发生。因此,抗 GPRC5D 免疫疗法必须在短时间内重创尽可能多的骨髓瘤细胞。在这里,我们利用MM的临床前模型对forimtamig进行了表征,它是一种新型的GPRC5D靶向TCB,具有2+1形式。与传统的 1+1 TCB 形式相比,forimtamig 与 GPRC5D N 端的二价结合具有更高的亲和力,这与形成更稳定的免疫突触以及更高的肿瘤细胞杀伤力和 T 细胞活化能力相关。通过使用正位小鼠 MM 模型,forimtamig 将 T 效应细胞招募到骨髓中,并诱导快速杀伤肿瘤,即使在采用阶梯剂量以减少细胞因子释放之后也是如此。forimtamig与标准治疗(SoC)药物(包括抗CD38抗体、免疫调节药物和蛋白酶体抑制剂)联用可提高反应的深度和持续时间。forimtamig与新型治疗药物(包括BCMA-TCB和脑龙E3连接酶调节药物(CELMoDs))的联合治疗效果显著,可防止GPRC5D阴性的肿瘤复发。目前,Forimtamig正在复发性和难治性骨髓瘤(RRMM)患者的单药治疗和联合治疗的1期临床试验中接受评估。NCT04557150。
{"title":"Forimtamig, a novel GPRC5D-targeting T-cell bispecific antibody with a 2+1 format, for the treatment of multiple myeloma.","authors":"Jan Eckmann, Tanja Fauti, Marlene Biehl, Aintzane Zabaleta, Laura Blanco, Iva Lelios, Stefan Gottwald, Richard Rae, Stefanie Lechner, Christa Bayer, Quincy Dekempe, Franz Osl, Nadège Carrié, Sahar Kassem, Stefan Lorenz, Tony Christopeit, Alejandro Carpy, Alexander Bujotzek, Ann-Marie E Bröske, Iryna Dekhtiarenko, Jan Attig, Leo Kunz, Floriana Cremasco, Roberto Adelfio, Georg Fertig, Stefan Dengl, Christian Gassner, Felix Bormann, Claudia Kirstenpfad, Thomas Emanuel Kraft, Sarah Diggelmann, Melanie Knobloch, Carina Hage, Romi Feddersen, Gordon Heidkamp, Thomas Pöschinger, Maud Lea Mayoux, Luise Bernasconi, Charles Dumontet, Felipe Prosper, Ludovic Martinet, Stephane Leclair, Wei Xu, Bruno Paiva, Christian Klein, Pablo Umaña","doi":"10.1182/blood.2024025987","DOIUrl":"https://doi.org/10.1182/blood.2024025987","url":null,"abstract":"<p><p>Despite several approved therapies, multiple myeloma (MM) remains an incurable disease with high unmet medical need. \"Off-the-shelf\" T-cell bispecific antibodies (TCBs) targeting BCMA and GPRC5D have demonstrated high objective response rates (ORR) in heavily pre-treated MM patients, however, primary resistance, short duration of response and relapse driven by antigen shift frequently occurs. Although GPRC5D represents the most selective target in MM, recent findings indicate antigen loss occurs more frequently than with BCMA. Thus, anti-GPRC5D immunotherapies must hit hard during a short period of time to kill as many myeloma cells as possible. Here, we characterize forimtamig, a novel GPRC5D-targeting TCB with 2+1 format, using preclinical models of MM. Bivalent binding of forimtamig to the N-terminus of GPRC5D confers higher affinity as compared to classical 1+1 TCB formats correlating with formation of more stable immunological synapses and higher potency in tumor cell killing and T cell activation. Using an orthotopic mouse model of MM, forimtamig recruited T effector cells to the bone marrow and induced rapid tumor killing even after the introduction of step-up dosing to mitigate cytokine release. Combination of forimtamig with standard-of-care (SoC) agents including anti-CD38 antibodies, immunomodulatory drugs and proteasome inhibitors improved depth and duration of response. The combination of forimtamig with novel therapeutic agents including BCMA-TCB and Cereblon E3 Ligase Modulatory Drugs (CELMoDs) was potent and prevented occurrence of GPRC5D-negative tumor relapse. Forimtamig is currently being evaluated in Phase 1 clinical trials in relapsed and refractory myeloma (RRMM) patients for monotherapy and in combination treatments. NCT04557150.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":null,"pages":null},"PeriodicalIF":21.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543580","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1182/blood.2022017717
Sushree S Sahoo, Miriam Erlacher, Marcin W Wlodarski
SAMD9 and SAMD9L (SAMD9/9L) are paralogous genes encoding antiviral proteins that negatively regulate cell proliferation. Heterozygous germline gain-of-function (GoF) SAMD9/9L variants cause multisystem syndromes with variable manifestations. The unifying features are cytopenia, immunodeficiency, infections, bone marrow failure (BMF), myelodysplasia (MDS) and monosomy 7. Non-hematopoietic presentations can affect almost every organ system. Growth impairment and adrenal insufficiency are typical in SAMD9, while progressive neurologic deficits characterize SAMD9L. Most patients (>90%) carry germline missense GoF variants. A subgroup of patients presenting with SAMD9L-associated inflammatory disease (SAAD) carry frameshift truncating variants that are also GoF. Somatic genetic rescue occurs in >2/3 of patients and involves monosomy 7, which may spontaneously disappear (transient monosomy 7) or progress to MDS/leukemia, and adaptive clones with somatic SAMD9/9L compensatory mutations or uniparental disomy 7q (UPD7q), both associated with remission. This manuscript examines the clinical and genetic spectrum, therapies and outcome based on 243 published patients compiled in our registry with additional genetic information on 62 unpublished cases. We consolidate the diverse clinical manifestations and diagnostic challenges of SAMD9/9L syndromes to enhance recognition and improve patient care. We highlight the knowledge gaps in pathomechanisms and emphasize the importance of genetic surveillance assessing disease remission versus disease progression. Insights are provided into variant curation and the necessity of testing for somatic SAMD9/9L mutations and UPD7q. Multidisciplinary care in specialized centers is critical to manage these complex disorders. Future natural history studies, especially in patients with monosomy 7, will help formulate evidence-based surveillance protocols and optimize transplant timing and outcomes.
{"title":"Genetic and Clinical Spectrum of SAMD9 and SAMD9L Syndromes: from Variant Interpretation to Patient Management.","authors":"Sushree S Sahoo, Miriam Erlacher, Marcin W Wlodarski","doi":"10.1182/blood.2022017717","DOIUrl":"https://doi.org/10.1182/blood.2022017717","url":null,"abstract":"<p><p>SAMD9 and SAMD9L (SAMD9/9L) are paralogous genes encoding antiviral proteins that negatively regulate cell proliferation. Heterozygous germline gain-of-function (GoF) SAMD9/9L variants cause multisystem syndromes with variable manifestations. The unifying features are cytopenia, immunodeficiency, infections, bone marrow failure (BMF), myelodysplasia (MDS) and monosomy 7. Non-hematopoietic presentations can affect almost every organ system. Growth impairment and adrenal insufficiency are typical in SAMD9, while progressive neurologic deficits characterize SAMD9L. Most patients (>90%) carry germline missense GoF variants. A subgroup of patients presenting with SAMD9L-associated inflammatory disease (SAAD) carry frameshift truncating variants that are also GoF. Somatic genetic rescue occurs in >2/3 of patients and involves monosomy 7, which may spontaneously disappear (transient monosomy 7) or progress to MDS/leukemia, and adaptive clones with somatic SAMD9/9L compensatory mutations or uniparental disomy 7q (UPD7q), both associated with remission. This manuscript examines the clinical and genetic spectrum, therapies and outcome based on 243 published patients compiled in our registry with additional genetic information on 62 unpublished cases. We consolidate the diverse clinical manifestations and diagnostic challenges of SAMD9/9L syndromes to enhance recognition and improve patient care. We highlight the knowledge gaps in pathomechanisms and emphasize the importance of genetic surveillance assessing disease remission versus disease progression. Insights are provided into variant curation and the necessity of testing for somatic SAMD9/9L mutations and UPD7q. Multidisciplinary care in specialized centers is critical to manage these complex disorders. Future natural history studies, especially in patients with monosomy 7, will help formulate evidence-based surveillance protocols and optimize transplant timing and outcomes.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":null,"pages":null},"PeriodicalIF":21.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-30DOI: 10.1182/blood.2024025707
Adrien Cottu, Stéphanie Guillet, Jean-François Viallard, Etienne Riviere, Stéphane Cheze, Delphine Gobert, Antoine Neel, Julie Graveleau, Jean-Pierre Marolleau, François Lefrere, Guillaume Moulis, Jean-Christophe Lega, Aline Moignet, Ailsa Robbins, Etienne Crickx, Emmanuelle Boutin, Nicolas Noel, Marion Malphettes, Lionel Galicier, Sylvain Audia, Bernard Bonnotte, Olivier Lambotte, Olivier Fain, Mathieu Gerfaud-Valentin, Louis Terriou, Nihal Martis, Anne-Sophie Morin, Antoinette Perlat, Thomas Le Gallou, Frédérique Roy-Peaud, Matthieu Puyade, Thibault Comont, Nicolas Limal, Laetitia Languille, Marc Michel, Bertrand Godeau, Matthieu Mahevas
An open prospective, multicenter study enrolled 48 selected patients with chronic immune thrombocytopenia who achieved complete response for 1 year on thrombopoietin receptor agonists, half of the patients maintained a sustained response off treatment 4 years after treatment discontinuation. NCT03119974.
{"title":"Long term follow-up of the STOPAGO study.","authors":"Adrien Cottu, Stéphanie Guillet, Jean-François Viallard, Etienne Riviere, Stéphane Cheze, Delphine Gobert, Antoine Neel, Julie Graveleau, Jean-Pierre Marolleau, François Lefrere, Guillaume Moulis, Jean-Christophe Lega, Aline Moignet, Ailsa Robbins, Etienne Crickx, Emmanuelle Boutin, Nicolas Noel, Marion Malphettes, Lionel Galicier, Sylvain Audia, Bernard Bonnotte, Olivier Lambotte, Olivier Fain, Mathieu Gerfaud-Valentin, Louis Terriou, Nihal Martis, Anne-Sophie Morin, Antoinette Perlat, Thomas Le Gallou, Frédérique Roy-Peaud, Matthieu Puyade, Thibault Comont, Nicolas Limal, Laetitia Languille, Marc Michel, Bertrand Godeau, Matthieu Mahevas","doi":"10.1182/blood.2024025707","DOIUrl":"10.1182/blood.2024025707","url":null,"abstract":"<p><p>An open prospective, multicenter study enrolled 48 selected patients with chronic immune thrombocytopenia who achieved complete response for 1 year on thrombopoietin receptor agonists, half of the patients maintained a sustained response off treatment 4 years after treatment discontinuation. NCT03119974.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":null,"pages":null},"PeriodicalIF":21.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BCR::ABL1-negative myeloproliferative neoplasms (MPN) are clonal hematological malignancies resulting from the proliferation of myeloid cells harboring a JAK-STAT pathway activating driver mutation. MPN management recommendations are based on the evaluation of different risks to prevent disease evolution associated events while preserving patients' quality of life. Such risks can be common across all MPN or specific to each subtype (polycythemia vera (PV), essential thrombocythemia (ET), prefibrotic myelofibrosis (pre-MF), primary myelofibrosis (PMF)). MF-patients harbor the worse prognosis and hematopoietic stem cell transplantation (HSCT) is the only curative treatment, at the expense of a high morbi-mortality. Therefore, accurate scoring systems to estimate overall survival are crucial for MF patients' management and selection for HSCT. In PV and ET, vascular events prediction is prioritized given their higher incidence and related morbi-mortality. Finally, quality of life evaluation is important for all subtypes. To predict these risks and adapt MPN therapeutic strategies, clinical risk scores have been developed over the past decades, more recently including molecular risk factors for more accurate risk stratification. The large number of scoring systems available in combination with disease heterogeneity and the necessity to predict diverse outcomes, make it difficult for clinicians to choose the most appropriate score to evaluate their patients' risk in 2024. Here, we provide an overview of MPN disease evolution associated events incidence and conduct an exhaustive comparative review of the scoring systems currently available for each risk. Finally, we propose an algorithm for the use of these scores in clinical practice in each MPN subtype.
{"title":"Current myeloproliferative neoplasm scoring systems for clinical practice.","authors":"Hélène Pasquer, Jean-Jacques Kiladjian, Lina Benajiba","doi":"10.1182/blood.2024025459","DOIUrl":"https://doi.org/10.1182/blood.2024025459","url":null,"abstract":"<p><p>BCR::ABL1-negative myeloproliferative neoplasms (MPN) are clonal hematological malignancies resulting from the proliferation of myeloid cells harboring a JAK-STAT pathway activating driver mutation. MPN management recommendations are based on the evaluation of different risks to prevent disease evolution associated events while preserving patients' quality of life. Such risks can be common across all MPN or specific to each subtype (polycythemia vera (PV), essential thrombocythemia (ET), prefibrotic myelofibrosis (pre-MF), primary myelofibrosis (PMF)). MF-patients harbor the worse prognosis and hematopoietic stem cell transplantation (HSCT) is the only curative treatment, at the expense of a high morbi-mortality. Therefore, accurate scoring systems to estimate overall survival are crucial for MF patients' management and selection for HSCT. In PV and ET, vascular events prediction is prioritized given their higher incidence and related morbi-mortality. Finally, quality of life evaluation is important for all subtypes. To predict these risks and adapt MPN therapeutic strategies, clinical risk scores have been developed over the past decades, more recently including molecular risk factors for more accurate risk stratification. The large number of scoring systems available in combination with disease heterogeneity and the necessity to predict diverse outcomes, make it difficult for clinicians to choose the most appropriate score to evaluate their patients' risk in 2024. Here, we provide an overview of MPN disease evolution associated events incidence and conduct an exhaustive comparative review of the scoring systems currently available for each risk. Finally, we propose an algorithm for the use of these scores in clinical practice in each MPN subtype.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":null,"pages":null},"PeriodicalIF":21.0,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1182/blood.2024024341
Meng-Xiao Luo, Tania Tan, Marie Trussart, Annika Poch, Minh-Hanh Thi Nguyen, Terence P Speed, Damien G Hicks, Esther Bandala-Sanchez, Hongke Peng, Stephane Chappaz, Charlotte Slade, Daniel T Utzschneider, Rachel M Koldej, David Ritchie, Andreas Strasser, Rachel Thijssen, Matthew E Ritchie, Constantine Si Lun Tam, Geoffrey J Lindeman, David Ching Siang Huang, Thomas E Lew, Mary Ann Anderson, Andrew W Roberts, Charis E Teh, Daniel H D Gray
Venetoclax, a first-in-class BH3 mimetic drug targeting BCL-2, has improved outcomes for patients with chronic lymphocytic leukemia (CLL). Early measurements of the depth of the venetoclax treatment response, assessed by minimal residual disease, are strong predictors of long-term clinical outcomes. Yet, there are limited data concerning the early changes induced by venetoclax treatment that might inform strategies to improve responses. To address this gap, we conducted longitudinal mass cytometric profiling of blood cells from patients with CLL during the first five weeks of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients distinguished by proliferative, metabolic and cell survival proteins. Venetoclax induced significant reduction in all CLL subpopulations coincident with rapid upregulation of pro-survival BCL-2, BCL-XL and MCL-1 proteins in surviving cells, which had reduced sensitivity to the drug. Mouse models recapitulated the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persisted in vivo, with genetic models demonstrating that extensive apoptosis and access to the B cell cytokine, BAFF, were essential. Accordingly, analysis of patients with CLL that were treated with venetoclax or the anti-CD20 antibody obinutuzumab exhibited marked elevation of BAFF and increased pro-survival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies via homeostatic factors and support co-targeting of cytokine signals to achieve deeper and more durable long-term responses.
{"title":"Venetoclax Dose Escalation Rapidly Activates a BAFF/BCL-2 Survival Axis in Chronic Lymphocytic Leukemia.","authors":"Meng-Xiao Luo, Tania Tan, Marie Trussart, Annika Poch, Minh-Hanh Thi Nguyen, Terence P Speed, Damien G Hicks, Esther Bandala-Sanchez, Hongke Peng, Stephane Chappaz, Charlotte Slade, Daniel T Utzschneider, Rachel M Koldej, David Ritchie, Andreas Strasser, Rachel Thijssen, Matthew E Ritchie, Constantine Si Lun Tam, Geoffrey J Lindeman, David Ching Siang Huang, Thomas E Lew, Mary Ann Anderson, Andrew W Roberts, Charis E Teh, Daniel H D Gray","doi":"10.1182/blood.2024024341","DOIUrl":"https://doi.org/10.1182/blood.2024024341","url":null,"abstract":"<p><p>Venetoclax, a first-in-class BH3 mimetic drug targeting BCL-2, has improved outcomes for patients with chronic lymphocytic leukemia (CLL). Early measurements of the depth of the venetoclax treatment response, assessed by minimal residual disease, are strong predictors of long-term clinical outcomes. Yet, there are limited data concerning the early changes induced by venetoclax treatment that might inform strategies to improve responses. To address this gap, we conducted longitudinal mass cytometric profiling of blood cells from patients with CLL during the first five weeks of venetoclax monotherapy. At baseline, we resolved CLL heterogeneity at the single-cell level to define multiple subpopulations in all patients distinguished by proliferative, metabolic and cell survival proteins. Venetoclax induced significant reduction in all CLL subpopulations coincident with rapid upregulation of pro-survival BCL-2, BCL-XL and MCL-1 proteins in surviving cells, which had reduced sensitivity to the drug. Mouse models recapitulated the venetoclax-induced elevation of survival proteins in B cells and CLL-like cells that persisted in vivo, with genetic models demonstrating that extensive apoptosis and access to the B cell cytokine, BAFF, were essential. Accordingly, analysis of patients with CLL that were treated with venetoclax or the anti-CD20 antibody obinutuzumab exhibited marked elevation of BAFF and increased pro-survival proteins in leukemic cells that persisted. Overall, these data highlight the rapid adaptation of CLL cells to targeted therapies via homeostatic factors and support co-targeting of cytokine signals to achieve deeper and more durable long-term responses.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":null,"pages":null},"PeriodicalIF":21.0,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}