Blood Cancer Discovery最新文献

{"title":"Genetic Mutation and Epigenetic Silencing Drive Antigen-Negative Relapse in CD7 CAR T-Treated T-cell Lymphoid Malignancies.","authors":"Rongrong Chen, Haiqiong Zheng, Wenxin Wang, Shan Fu, Mingming Zhang, Jingjing Feng, Alex H Chang, Jiangtao Ren, Shanshan Pei, He Huang, Yongxian Hu","doi":"10.1158/2643-3230.BCD-25-0489","DOIUrl":"10.1158/2643-3230.BCD-25-0489","url":null,"abstract":"<p><p>CD7 is a promising target for chimeric antigen receptor (CAR) T-cell therapy in T-cell lymphoid malignancies; however, antigen loss-mediated relapse has emerged as a major challenge. In this study, we systematically analyzed the genetic and epigenetic alterations of paired specimens (pretreatment and relapsed) from 10 patients with T-cell lymphoma/leukemia receiving CD7 CAR T cells. Overall, we identified three distinct mechanisms underlying CD7 loss: first, frameshift insertion (patient 4; c.164dupG:p.R55fs) or deletion (patient 7; c.122delG:p.G41Efs*19) resulting in truncation of the CD7 transmembrane domain in two of 10 patients; second, hypermethylation of the CD7 promoter in seven of 10 patients without CD7 mutation; third, simultaneous occurrence of promoter region hypermethylation and multiple in-frame mutations with predicted functional interference in one of 10 patients (patient 2). Collectively, these findings demonstrate that both clonal heterogeneity and epigenetic plasticity drive antigen-negative relapse in T-cell lymphoid malignancies under the selective pressure of CD7 CAR T-cell therapy.</p><p><strong>Significance: </strong>Understanding mechanisms of antigen-negative relapse is critical for developing effective CD7-targeting CAR-T therapies against T-cell lymphoid malignancies. Our study identifies both genetic truncation mutations and epigenetic silencing as contributors to CD7-negative relapse. Monitoring and preventing these events is warranted to improve treatment outcomes.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"687-696"},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148413218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Patient-Derived Xenograft Repository Capturing Clinical and Molecular Heterogeneity of Large B-cell Lymphoma.","authors":"Haopeng Yang, Kotaro Arita, Kevin Bowman, Dai Chihara, Jared Henderson, Griffin Rost, Estela Rojas, Sydney Parsons, Priya Lakra, Aneela Syeda Abedin, Sattva S Neelapu, Paolo Strati, Loretta J Nastoupil, Luis E Fayad, Swaminathan P Iyer, Maria Alma Rodriguez, Fredrick B Hagemeister, Luis Malpica, Hun Lee, Laura K Hilton, David W Scott, R Eric Davis, Christopher R Flowers, Jason R Westin, Giorgio Inghirami, Francisco Vega, Michael R Green","doi":"10.1158/2643-3230.BCD-26-0005","DOIUrl":"10.1158/2643-3230.BCD-26-0005","url":null,"abstract":"<p><p>Large B-cell lymphomas (LBCL) are a clinically and molecularly diverse group of malignancies with a rapidly evolving therapeutic landscape that has introduced new areas of clinical need, such as post-CD19 chimeric antigen receptor T (CART19) progression. Patient-derived xenograft (PDX) models are an important tool for mechanistic studies and preclinical evaluation of new therapies and can be generated from a variety of clinical contexts that capture tumor-intrinsic resistance mechanisms. We therefore undertook a comprehensive effort to generate PDX models that encompass the molecular landscape of LBCLs and include important clinical scenarios for new drug development. Here, we describe the first 48 models within this publicly available repository, capturing the transcriptional and genetic subsets of LBCL. These models also include 23 generated from post-CART19 progression patient biopsies, which reproduce patterns of progression driven by CD19 mutation or expression loss, as well as tumor cell-intrinsic CART19 resistance that we validated in vivo.</p><p><strong>Significance: </strong>Here, we describe X-LYMPH (Xenografts of Lymphoma), a publicly available and molecularly annotated PDX repository that captures the heterogeneity of LBCL. X-LYMPH includes models of CAR T-cell resistance, providing a shared foundation for mechanistic research and therapeutic development for lymphomas. See related commentary by Evgin and Steidl, p. 655.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"829-844"},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148319517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RAS Pathway Activation and Microenvironmental Adaptation as Hallmarks of Myeloid Sarcoma.","authors":"Bettina Nadorp, Audrey Lasry, Sanam Loghavi, Ravi Patel, Hager Mansour, Pier Edoardo Rovatti, Benjamin J Kelly, Christopher J Walker, Jill Buss, Isaiah Boateng, Wafa Al-Santli, Zoe Ciantra, Rebecca Austin, Helee Desai, Hasan Abaza, Linda Procell, Tejas Patel, Benjamin Kaffenberger, Saranga Wijeratne, Maria Guillamot, Maria Velegraki, Luis A Chiriboga, Zihai Li, Daniel A Pollyea, Christine M McMahon, Arwa Shanaah, John C Byrd, Manel Esteller, Eirini P Papapetrou, Aristotelis Tsirigos, Alice S Mims, Elaine R Mardis, Iannis Aifantis, Ann-Kathrin Eisfeld","doi":"10.1158/2643-3230.BCD-26-0160","DOIUrl":"10.1158/2643-3230.BCD-26-0160","url":null,"abstract":"<p><p>Myeloid sarcoma, an aggressive extramedullary subtype of acute myeloid leukemia (AML), occurs in approximately 20% of patients and remains strikingly understudied in large-scale genomic and multiomic investigations. The key drivers of its tumor evolution are largely unknown; timely detection in asymptomatic patients poses a clinical challenge, and effective treatment options are limited, as patients are often excluded from clinical trials, rendering it a largely neglected disease entity. In this study, we demonstrate that myeloid sarcoma evolves from medullary AML but exhibits distinct site-specific clonal evolution. This is supported by unique transcriptional signatures of myeloid sarcoma, reflecting adaptation to the extramedullary microenvironment. We establish a proof of concept that circulating tumor DNA (ctDNA) sequencing captures the molecular composition of myeloid sarcoma, offering a potential noninvasive approach for molecular profiling of extramedullary AML. Our findings highlight marked differences between medullary AML and myeloid sarcoma, including universal molecular evolution and RAS pathway activation as disease hallmarks.</p><p><strong>Significance: </strong>We provide a comprehensive multiomic characterization of myeloid sarcoma, identifying key molecular pathways that contribute to its development, and suggest ctDNA as a noninvasive method of detection. We identify RAS pathway activation and transcriptional adaptation to the solid tissue microenvironment as cardinal features of myeloid sarcoma, suggesting novel therapeutic avenues.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"759-773"},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147983555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Nicotinamide Salvage Pathway Is a Metabolic Vulnerability of High-Risk MDS Stem Cells.","authors":"Sweta B Patel, Daniel R Moskop, Steven Moreira, Stephanie Gipson, Colin C Anderson, Alexandra Crook, Maxwell McCabe, Daniel Stephenson, Hannah E Terry, Andrew Kent, Tracy N Young, Anna E Krug, Connon I Thomas, Caitlin Price, Monica Ransom, Regan Miller, Ana Vujovic, Mohammad Minhajuddin, Mark J Althoff, Anthony J Saviola, Brett M Stevens, Robert S Welner, Ekaterina L Andrianova, Andrei V Gudkov, Anza Darehshouri, Julie A Reisz, Travis Nemkov, Angelo D'Alessandro, Austin E Gillen, Daniel A Pollyea, Craig T Jordan, Eric M Pietras","doi":"10.1158/2643-3230.BCD-25-0498","DOIUrl":"10.1158/2643-3230.BCD-25-0498","url":null,"abstract":"<p><p>High-risk myelodysplastic syndrome (HR-MDS) is a malignant clonal disorder originating in hematopoietic stem and progenitor cells (HSPC). The current standard of care for patients with HR-MDS has a poor response, thus necessitating exploration of the vulnerabilities of HR-MDS HSPCs for better clinical outcomes. We demonstrate that compared with healthy HSPCs, HR-MDS HSPCs have significant upregulation of metabolic proteins leading to increased oxygen consumption, suggesting an increased metabolic rate. Corroboratively, compared with healthy HSPCs, HR-MDS HSPCs have an increased abundance of NADH dehydrogenases, which are crucial for energy production. Therefore, we investigated whether HR-MDS HSPCs are functionally reliant on nicotinamide phosphoribosyl transferase (NAMPT), the rate-limiting enzyme in the nicotinamide salvage pathway of NAD anabolism. NAMPT inhibition reduced the oxygen-consuming capacity of HR-MDS HSPCs compared with healthy controls. Importantly, NAMPT inhibition significantly impaired function, increased cell death, and reduced disease burden specifically of HR-MDS HSPCs. Collectively, our data suggest that NAMPT is a promising therapeutic target to eradicate HR-MDS HSPCs.</p><p><strong>Significance: </strong>HR-MDS remains a clinically challenging blood disorder, posing a dire need to identify therapeutic targets that improve clinical outcomes. We show that the nicotinamide salvage pathway is a promising target to eliminate HR-MDS HSPCs, the source of the disease.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"796-812"},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148537307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapy-persistent leukemia is selectively vulnerable to SLC23A1 restoration via targeting KHSRP.","authors":"Qingyu Luo, Karley S Whalen, Xiaowei Wu, Amanda L Fortune, Jacqueline S Garcia, Kate Marinchev, Lin Zhang, Weiye Qian, Evangeline G Raulston, Yabing Nan, Christopher A G Booth, Kezhi Yan, David E Root, John G Doench, Andrew A Lane","doi":"10.1158/2643-3230.BCD-26-0030","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-26-0030","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is prone to relapse driven by therapy-persistent residual cells. To discover specific vulnerabilities in this population, we performed genome-wide CRISPR interference screens in leukemia cells treated with multiple agents. KHSRP was the top hit, whose depletion sensitized AML cells to therapy and substantially prolonged survival in treated AML-bearing mice. Analysis of in vivo residual disease after venetoclax/azacitidine treatment identified downregulation of the vitamin C and uric acid transporter SLC23A1, which mediated resistance to multiple therapies. KHSRP depletion restored SLC23A1 expression by preventing its ZC3H4-mediated nuclear mRNA degradation. KHSRP depletion therefore enhanced the synergistic cytotoxicity of vitamin C and uric acid, particularly in therapy-persistent leukemia cells. Re-expression of TET2 overrode the chemosensitizing effect of KHSRP depletion in TET2-mutant leukemia, suggesting that KHSRP-linked phenotypes were related to vitamin C and uric acid-mediated TET activation. These findings nominate targeting KHSRP to enhance treatment efficacy and selectively eradicate residual AML.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148881910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial profiling identifies a distinct and topographically-defined tumor microenvironment that emerges during multiple myeloma evolution.","authors":"Marnix Koops, Luca Bertamini, Natalie Papazian, Charlotte Korst, Mátyás János Budai, Remco M Hoogenboezem, Mathijs A Sanders, Bronno van der Holt, Mark van Duin, Annemiek Broijl, Péter Balogh, Sonja Zweegman, Marc Hgp Raaijmakers, Niels W C J van de Donk, Zoltán Kellermayer, Pieter Sonneveld, Tom Cupedo","doi":"10.1158/2643-3230.BCD-26-0080","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-26-0080","url":null,"abstract":"<p><p>The pathobiology of multiple myeloma is influenced by cells of the bone marrow, but whether tumor support is organized in a spatially-defined tumor microenvironment (TME) remains unclear. Using spatial transcriptomics and imaging mass cytometry, we show that myeloma cells initially exist as scattered cells throughout the marrow, yet with disease evolution condense into a spatially-defined TME. Dense tumor nodules contain a cellular ecosystem distinct from the surrounding marrow, enriched for macrophages, conventional dendritic cells, and CD8⁺ T cells, as well as endothelial cells and THY1⁺ mesenchymal stromal cells. Conversely, neutrophil lineage cells are absent from this TME but interact with scattered myeloma cells outside of dense nodules. Presence of the dense tumor architecture at diagnosis confers a worse prognosis, emphasizing the relevance of spatial organization of the bone marrow. Together, these findings define a discrete spatial and cellular myeloma TME, that provides spatially-guided insights into patient stratification and disease pathobiology.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148867041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation.","authors":"Lin Zhang, Arnold Bolomsky, Omar S Al-Odat, Callie K VanWinkle, Aaliyah Battle, Papiya Chakraborty, Ronald J Holewinski, Thorkell Andresson, Bjorn Haupl, Thomas Oellerich, Elizabeth Hill, Mehmet Kocoglu, Qingcai Meng, James D Phelan, Jagan Muppidi, Ryan M Young","doi":"10.1158/2643-3230.BCD-26-0028","DOIUrl":"10.1158/2643-3230.BCD-26-0028","url":null,"abstract":"<p><p>Oncogenic KRAS and NRAS mutations are common in hematologic malignancies, but their signaling in this context remains less well characterized than in carcinomas. Using multi-omics screens in multiple myeloma, we sought to identify regulators of RAS activity. We found that the phosphatase PP1C dephosphorylated conserved RAS residue T148, permitting LZTR1-dependent proteasomal degradation. LZTR1 was ineffective against KRAS A146 gain-of-function mutations, which lie adjacent to T148 and are enriched in hematologic cancers, such as diffuse large B cell lymphoma and acute myeloid leukemia. Remarkably, KRAS protein stability was four-fold lower in hematologic versus carcinoma cells, revealing a unique therapeutic opportunity targeting RAS protein stability. PAK1 and PAK2 shielded RAS from LZTR1-dependent degradation by phosphorylating T148, and inhibiting PAK1/2 activity improved RAS-directed therapy. Collectively, these findings reveal a regulatory circuit governing RAS stability that is preferentially active in blood cancers and potentially druggable.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148866917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor CD19 Expression Determines Distinct Clinical Outcomes After CD19 CAR T-Cell Therapy in Large B-Cell Lymphoma.","authors":"Magdalena Corona, Aaron Gillmor, Kimon V Argyropoulos, Teng Fei, Maria Isabel Sotelo-Alva, Mohammad Alhomoud, Parastoo B Dahi, Anthony F Daniyan, Mark T A Donoghue, Sigrun Einarsdottir, Lorenzo Falchi, Qi Gao, Gregory Goldgof, Marina Gomez-Llobell, Erel Joffe, Richard J Lin, Alejandro Luna de Abia, Efrat Luttwak, M Lia Palomba, Jae H Park, Sandeep S Raj, Kai Rejeski, Alfredo Rivas-Delgado, Gilles Salles, Jaime Sanz, Michael Scordo, Gunjan L Shah, Sulov Chalise, Manik Uppal, Anna Gurevich-Shapiro, Menglei Zhu, Miguel-Angel Perales, Allison L Richards, Mikhail Roshal, Roni Shouval","doi":"10.1158/2643-3230.BCD-25-0501","DOIUrl":"10.1158/2643-3230.BCD-25-0501","url":null,"abstract":"<p><p>It remains uncertain whether lower CD19 expression is clinically relevant for outcomes of CD19 CAR-T therapy of large B-cell lymphoma (LBCL). We conducted an integrative analysis of tumor CD19 levels with centralized quantitative assessment by flow cytometry (FC), immunohistochemistry and RNA-sequencing in a LBCL cohort (n=301). Pre-treatment CD19 by FC correlated with 1-year progression-free survival following axicabtagene ciloleucel or lisocabtagene maraleucel (16%, 53% and 64% for CD19low, CD19intermediate and CD19high, respectively; p=0.005). After CAR-T relapse, proportion of CD19low tumors increased (from 17% to 35%). Concordant associations were observed by immunohistochemistry and RNA-sequencing. Transcriptomic profiling linked lower CD19 to inflammatory pathways, validated in an external LBCL cohort (n=1,017). Genetic loss of the CD19 locus was observed in 8% of pre-CAR-T and 11% of post-CAR-T tumors (p=0.82), while no CD19 coding mutations were identified. Overall, CD19 expression is a clinically meaningful determinant of CAR-T outcomes, supporting quantitative assessment to improve risk stratification.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148867058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Personalized Circulating Tumor DNA Profiling Enables Superior and Universal Residual Disease Detection in Acute Myeloid Leukemia.","authors":"Ruwan Gunaratne, Crystal M Zhou, Sanjeeth Rajaram, Jesse W Tai, Kailee L Tanaka, Charu Tiwari, Emily Y Yang, Sky Kim, Grace Gao, Raymond Yin, Mia Carleton, Matthew S Alkaitis, Matthew Schwede, Brian J Sworder, Gabriel N Mannis, Michael S Khodadoust, Ravindra Majeti, David M Kurtz, Tian Yi Zhang","doi":"10.1158/2643-3230.BCD-26-0159","DOIUrl":"10.1158/2643-3230.BCD-26-0159","url":null,"abstract":"<p><p>Relapsed and/or refractory disease remains the leading cause of death in AML, highlighting the need for broadly applicable, high-sensitivity approaches to MRD detection. We developed AML-CAPP-Seq (Cancer Personalized Profiling by Deep Sequencing), a personalized hybrid-capture assay that tracks both canonical AML drivers and patient-specific variants identified by whole-exome sequencing. In 56 patients with longitudinal plasma and matched peripheral blood and bone marrow samples, AML-CAPP-Seq enabled universal MRD assessment and resolution of clonal dynamics using a median of 30.5 variants per patient. Plasma ctDNA outperformed cellular compartments for MRD detection and more strongly predicted relapse-free (HR 17.8, p<0.0001) and overall survival (HR 17.0, p<0.0001) than standard-of-care MRD methods. Among 29 allogeneic transplant recipients, peri-transplant ctDNA-MRD dynamics markedly improved relapse risk stratification (HR 36.0, p=0.0009). Together, these results establish personalized ctDNA profiling as a minimally invasive, highly sensitive, and generalizable platform for enhanced clinical MRD detection and clonal surveillance in AML.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148713861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glofitamab-Based Therapy for Relapsed or Refractory CNS Lymphoma: A Multicenter Retrospective Study.","authors":"Ruixian Xing, Apeng Yang, Juan Huang, Liang Wang, Wei Guo, Qu Cui, Xiaoqiong Tang, Yuanyuan Ma, Kai Hu, Tianheng He, Danyang Wu, Xiaofang Deng, Yajing Zhang, Kaili Zhong, Yang Liu, Yixian Guo, Ying Wang, Chan Long, Chongyang Wu, Xin Lu, Fengmin Li, Jiefei Bai, Jun Qian, Xuefei Sun, Wenrong Huang, Hui Zhou, Huilai Zhang, Ou Bai, Xiaobing Huang, Zhiyong Zeng, Lin Fu","doi":"10.1158/2643-3230.BCD-26-0128","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-26-0128","url":null,"abstract":"<p><p>Relapsed or refractory CNS lymphoma (R/R CNSL) has limited treatment options. This multicenter retrospective study enrolled 84 consecutive R/R CNSL patients (median age 59 years; 53 PCNSL, 31 SCNSL) to evaluate efficacy and safety profiles of glofitamab therapy. With a median of 2.5 prior lines of therapy, the objective response rates (ORR) and complete response rates (CRR) for PCNSL were 88% (CRR 59%) with glofitamab monotherapy (n=32) and 100% (CRR 81%) with combination therapy (n=21), respectively; for SCNSL, ORR and CRR were 88% (CRR 75%) with glofitamab monotherapy (n=8) and 91% (CRR 65%) with combination therapy (n=23). At 14.7 months follow-up, median progression-free survival was 19.5 months for PCNSL and 13.5 months for SCNSL. Cytokine release syndrome occurred in 40% (all grade 1-2) of patients, and ICANS in 8%. Glofitamab-based therapy demonstrated substantial activity with manageable toxicity in this study, offering a promising treatment paradigm for R/R CNSL patients.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148713845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}