Blood Cancer Discovery最新文献

{"title":"Genetic Evidence against Clonotypic B Lymphocytes as a Reservoir for Plasma-cell Cancers.","authors":"Carmen Gonzalez, Juan-Jose Garces, Hector Gracia, Camila Guerrero, Mattia D'Agostino, Alejandro Medina-Herrera, Mario Nuvolone, Noemi Puig, Maria-Teresa Cedena, Marta Lasa, Diego Alignani, Aitziber Lopez, Sarai Sarvide, Paula Aguirre-Ruiz, José Maria Lamo-Espinosa, Felipe Prosper, Paula Rodriguez-Otero, Jose A Martinez-Climent, Francesca Lattarulo, Alice Nevone, Margherita Massa, Giovannni Palladini, Giuseppe Bertuglia, Francesca Gay, Laura Rosiñol, Ramón García-Sanz, Joaquin Martinez-Lopez, Maria-Victoria Mateos, Juan-Jose Lahuerta, Joan Bladé, Jesus F San-Miguel, Bruno Paiva","doi":"10.1158/2643-3230.BCD-25-0102","DOIUrl":"10.1158/2643-3230.BCD-25-0102","url":null,"abstract":"<p><p>Whether multiple myeloma (MM) and light-chain amyloidosis (AL) stem from terminally differentiated plasma cells (PC) or earlier clonotypic B cells remains under debate. Addressing this issue would improve accurate diagnosis and treatment monitoring. We performed single-cell and exome sequencing on highly purified MM and AL samples to define in which B-cell development stage the driver genetic alterations are present. Clonotypic B-cell receptors (BCR) were detected in ≤0.4% of B-cell precursors and mature B cells from patients with MM and AL. Paired single-cell transcriptomes confirmed the immature phenotype of these clonotypic cells. Driver genetic alterations were primarily detected in tumor PCs but very rarely in immature B-cell stages sequenced during treatment. Additional analysis suggested that clonotypic B cells may sporadically result in false-positive minimal residual disease assessments based on next-generation sequencing of BCR. Our results define clonotypic B cells as preneoplastic precursors of malignant PCs that are unlikely to be involved in disease progression.</p><p><strong>Significance: </strong>The cellular origin of MM and light-chain AL remains unknown. Here, we show that these tumors stem from clonotypic B cells, but driver genetic alterations are mainly contained within phenotypically aberrant PCs. These results shed light on the pathogenesis and inform on how to monitor PC neoplasms. See related commentary by Kim and Ghobrial, p. 503.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"558-571"},"PeriodicalIF":12.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147436311","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":"Multiomic and Longitudinal Dissection of Immune Dynamics Associated with Parkinsonism after Ciltacabtagene Autoleucel Therapy.","authors":"Sofie-Katrin Kadel, Lukas Scheller, Alexander M Leipold, Tobias Krammer, Tamás Raskó, Miriam Alb, Philipp Weis, Maria Leberzammer, Friederike Schmitt, Clara Stetter, Yoko Tamamushi, Alicia Köck, Philipp Köberle, Martin Reich, Thomas Musacchio, Kathrin Doppler, Claudia Sommer, Nadine Cebulla, Rhonda McFleder, Chi Wang Ip, Jens Volkmann, Matthias Kallius, Sebastian E Serfling, Philipp E Hartrampf, Andreas K Buck, Amit Pande, Dennis Löffler, Michael Gernert, Johannes Duell, Max S Topp, Julia Mersi, Johannes Waldschmidt, Hermann Einsele, Michael Hudecek, Antoine-Emmanuel Saliba, Leo Rasche, K Martin Kortüm","doi":"10.1158/2643-3230.BCD-25-0278","DOIUrl":"10.1158/2643-3230.BCD-25-0278","url":null,"abstract":"<p><p>We report a fatal case of parkinsonism following treatment with ciltacabtagene autoleucel (cilta-cel). To investigate underlying mechanisms, we performed a multipronged longitudinal analysis using single-cell RNA (scRNA)/T-cell receptor (TCR) sequencing, flow cytometry, and cytokine measurements including cerebrospinal fluid (CSF) and peripheral blood (PB) samples, spanning more than 6 months after chimeric antigen receptor (CAR) T-cell therapy. Combined clinical and molecular findings revealed a biphasic immunologic process in the CSF. The early phase was characterized by a selective influx of predominantly CD4+ CAR T cells, accompanied by the evidence of endothelial dysfunction, prior to the clinical manifestation of parkinsonism. A second phase was preceded by a locally restricted inflammatory process in the CSF. Subsequently, an increase in the CSF to serum albumin ratio indicated disruption of the blood-brain barrier, coinciding with a pronounced influx of T cells-primarily CAR T cells but also clonally expanded, cytotoxic CD8+ non-CAR T cells-which was associated with neuronal injury and clinical decline.</p><p><strong>Significance: </strong>This article examines central nervous system immune dynamics in a patient developing parkinsonism after cilta-cel. A longitudinal real-world dataset of CSF (n = 8) and PB (n = 6) from six matched time points was analyzed using scRNA/TCR sequencing over 6 months, capturing disease onset and progression.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"544-557"},"PeriodicalIF":12.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147522109","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":"Rapid Transcription Dynamics Confers Cytarabine Resistance in Acute Myeloid Leukemia.","authors":"Goichi Tatsumi, Rajni Kumari, Yutaro Suzuki, Shuting Li, Russell Scharf, Samuel J Taylor, Sriram Sundaravel, Amit Verma, Justin C Wheat, Ulrich Steidl","doi":"10.1158/2643-3230.BCD-25-0317","DOIUrl":"10.1158/2643-3230.BCD-25-0317","url":null,"abstract":"<p><p>Chemotherapy resistance remains a critical challenge in the treatment of patients with cancer, including acute myeloid leukemia (AML). Although genetic alterations can contribute to resistance, the role of rapid-adaptive nongenetic mechanisms, particularly transcription dynamics, remains poorly understood. In this article, we demonstrate that short-term treatment of AML cells with the widely used chemotherapeutic cytarabine (AraC) leads to the rapid emergence of a cell population with significant RNA induction and increased AraC resistance in cell lines and primary patient samples. Mechanistically, transcriptomic and targeted high-resolution analysis of transcription dynamics using single-molecule RNA FISH revealed rapid induction of transcriptional dynamics and upregulation of key transcription factors (TF)-which we term \"AraC rapid response TFs.\" Functionally, short-term pre- and cotreatment with RNA transcription inhibitors suppressed chemotherapy-induced RNA induction and prevented resistance acquisition in vitro and in vivo. Furthermore, CRISPR-mediated suppression of TFs PU.1 and GATA1 significantly attenuated AraC resistance. Our findings reveal a role of rapid-adaptive transcriptional dynamics in AML chemotherapy resistance.</p><p><strong>Significance: </strong>This study reveals a role of rapid-adaptive transcriptional dynamics in AML chemotherapy resistance, highlighting master TFs as key regulators. These insights offer a pharmacologically accessible approach to potentially alleviate the major clinical problem of chemotherapy resistance.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"624-641"},"PeriodicalIF":12.2,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13320223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147975991","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":"Multiplexed Imaging Reveals Immune-Metabolic Niches in Multiple Myeloma Linked to Progression and Bone Disease.","authors":"Ingrid Aass Roseth, Lukas Hatscher, Chiara Schiller, Håkon Skjalg Selland Johnstuen, Tobias S Slørdahl, Håkon Hov, Denis Schapiro, Therese Standal","doi":"10.1158/2643-3230.BCD-25-0334","DOIUrl":"10.1158/2643-3230.BCD-25-0334","url":null,"abstract":"<p><p>Multiple myeloma is a plasma cell (PC) cancer that depends on the bone marrow (BM) microenvironment for disease establishment and progression. In this study, we spatially mapped BM biopsies from patients with multiple myeloma, smoldering multiple myeloma, and monoclonal gammopathy of undetermined significance by imaging mass cytometry. We found that PCs near bone surfaces displayed markers of quiescence and demonstrated a distance-to-bone-dependent expression of IL32 in patients with bone disease, consistent with their role in promoting bone loss in multiple myeloma. We identified two distinct PC neighborhoods termed PC OXPHOS, characterized by focal PC growth, enrichment of endothelial cells, and oxidative phosphorylation, and PC MYELOID, characterized by PCs interspersed with immune cells, featuring a glycolytic phenotype. Notably, imaging-inferred interactions between PCs and CD4+ T cells were an independent negative predictor for progression-free survival (PFS). Our work underscores spatial context as a key factor in understanding multiple myeloma pathogenesis and the potential for spatial analyses to improve multiple myeloma risk stratification.</p><p><strong>Significance: </strong>This study demonstrates that multiple myeloma cells in different neighborhoods experience unique metabolic conditions and immune environments, and that neighbor preference of CD4+ T cells and PCs is associated with poorer PFS. These data highlight the value of spatially resolved analyses in uncovering potential pathophysiologic mechanisms of multiple myeloma.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"460-478"},"PeriodicalIF":12.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147285296","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":"The B-cell Receptor Blueprint in Lymphoma: Mechanisms and Therapeutic Opportunities.","authors":"Stefano Casola, Gabriele Varano","doi":"10.1158/2643-3230.BCD-25-0303","DOIUrl":"10.1158/2643-3230.BCD-25-0303","url":null,"abstract":"<p><p>The B-cell receptor (BCR) is central to normal and malignant B-cell biology, integrating intrinsic programs with microenvironmental cues to shape cell fate. Across mature B-cell lymphomas, differences in BCR expression, class, and signaling mode define distinct pathogenetic routes and therapeutic vulnerabilities, ranging from BCR-dependent to BCR-silent states. We propose a BCR blueprint that positions these tumors along a continuum of signaling modes and class-imposed functions, emphasizing germinal center-derived lymphomas. This framework links specific BCR states to genetic lesions and microenvironmental niches, underscoring the value of routinely monitoring BCR features to track tumor evolution and inform therapy.</p><p><strong>Significance: </strong>B-cell lymphomas exploit diverse BCR expression levels, classes, and signaling modes that span BCR-addicted to BCR-silent states and shape their genetic programs and therapeutic dependencies. A unified BCR blueprint reframes these diseases along a continuum of BCR signaling and isotype-driven biology, particularly in germinal center-derived entities. Embedding this blueprint into routine clinical testing has the potential to improve prediction of response or resistance to BCR-targeted and other mechanism-based therapies.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"380-393"},"PeriodicalIF":12.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147327261","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":"Endogenous CD28 Drives the Persistent Activity of CAR T Cells in Myeloma and Lymphoma Models.","authors":"Mackenzie M Lieberman, Jason H Tong, Nkechi U Odukwe, Colin A Chavel, Gina G Bishara, Kimberly M Crasti, Megan M Herr, Payal Goala, Terence J Purdon, Rebecca Burchett, Bryan M Gillard, Craig M Brackett, Joseph D Tario, Spencer R Rosario, A J Robert McGray, Jonathan L Bramson, Marco L Davila, Renier J Brentjens, Ehsan Malek, Kelvin P Lee, Scott H Olejniczak","doi":"10.1158/2643-3230.BCD-25-0092","DOIUrl":"10.1158/2643-3230.BCD-25-0092","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy has reshaped the therapeutic landscape for multiple myeloma, yet most patients treated with BCMA-targeted CAR T cells experience disease relapse. Consequently, we sought to determine if inhibition of CD28 survival signaling could increase multiple myeloma sensitivity to CAR T-cell therapy. Contrary to expectations, blockade of CD28 interaction with CD80/86 accelerated tumor regrowth in preclinical multiple myeloma and lymphoma CAR T-cell therapy models. Knockout studies revealed that endogenous CD28 on 4-1BB costimulated CAR T cells prolonged in vivo activity, reprogrammed mitochondrial metabolism to maintain redox balance, and stimulated proliferation and release of tumor model-specific inflammatory cytokines in the tumor microenvironment (TME). Intriguingly, transient CD28 blockade decreased levels of certain TME cytokines without significantly affecting survival of CAR T cell-treated mice. Collectively, these data provide direct evidence that endogenous CD28 signaling modulates CAR T-cell responses in multiple myeloma and lymphoma models.</p><p><strong>Significance: </strong>This study provides direct evidence that endogenous CD28 on 4-1BB costimulated CAR T cells promotes cytotoxic activity and the production of inflammatory cytokines in the TME. These findings have important implications for ongoing efforts to improve CAR T-cell therapy for the treatment of hematologic malignancies. See related commentary by Hamieh and Sadelain, p. 343.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"441-459"},"PeriodicalIF":12.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12969838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146107626","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":"Prognostic Model Combining Mutational and Cytogenetic Profiles in Acute Myeloid Leukemia Treated with Venetoclax and Hypomethylating Agents.","authors":"Dimitrios Drekolias, Fatima Tuz Zahra, Caroline Fileni, David A Sallman, Qianxing Mo, Onyee Chan, Ling Zhang, Nicole D Vincelette, Xiaoqing Yu, Rinzine Sammut, Jungwon Moon, Junyoung Park, Sura-Attha Umasangtongkul, Felyschia M Lledo, Tiffany N Razabdouski, Chia-Ho Cheng, Dahui Qin, Kathy Mai, Somedeb Ball, Rory M Shallis, Zhuoer Xie, Andrew T Kuykendall, Eric Padron, Kendra Sweet, Alison R Walker, Rami S Komrokji, Jeffrey E Lancet, Sandrine Niyongere, Thomas Cluzeau, Seongseok Yun","doi":"10.1158/2643-3230.BCD-25-0193","DOIUrl":"10.1158/2643-3230.BCD-25-0193","url":null,"abstract":"<p><p>Venetoclax (VEN) combined with hypomethylating agents (HMA) improves outcomes for patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy, yet overall survival (OS) remains variable. We analyzed 506 patients with AML treated with first-line HMA/VEN at Moffitt Cancer Center to develop a genetics-based prognostic model. In multivariate analysis, mutations in TP53, KRAS, JAK2, U2AF1, CBL, and cytogenetic lesions del(7q)/-7, del(17p)/-17/i(17q), del(20q), and MECOM rearrangements predicted inferior OS, whereas IDH1/2 mutations were favorable. A point-based system stratified patients into low-, intermediate-, and high-risk groups with median OS of 54.2, 22.3, and 7.5 months, respectively [P < 0.0001; concordance index (C-index) 0.648]. External validation (n = 126) retained prognostic separation (median OS 24.7, 17.4, and 4.3 months, P = 0.0005; C-index 0.626). Compared with existing HMA/VEN-specific models, our model demonstrated superior low- versus intermediate-risk discrimination (31.9-month separation, P = 0.002; hazard ratio = 0.45, P = 0.003), with a comparable C-index. Our model supports personalized risk stratification for HMA/VEN-treated AML, pending broader validation.</p><p><strong>Significance: </strong>This study identifies key mutational and cytogenetic markers associated with treatment response and OS in patients with AML receiving HMA/VEN therapy. By integrating these genetic markers, our new prognostic model offers improved risk stratification, guiding personalized treatment strategies for patients ineligible for intensive chemotherapy. See related commentary by Lachowiez and Loghavi, p. 339.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"403-413"},"PeriodicalIF":12.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12967238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146167083","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":"Reading the \"T\" Leaves: Predicting Outcomes with Bispecific Antibodies in Multiple Myeloma.","authors":"Rahul Banerjee, Madhav V Dhodapkar","doi":"10.1158/2643-3230.BCD-26-0041","DOIUrl":"10.1158/2643-3230.BCD-26-0041","url":null,"abstract":"<p><p>In this issue of Blood Cancer Discovery, Frenking and colleagues demonstrate the prognostic potential of three risk score models to predict hematotoxicity, infections, response rates, and survival following bispecific T-cell engager (TCE) therapy in multiple myeloma. These risk score models, which the authors validated using retrospective real-world data from 278 patients, can easily be calculated using routine blood testing and offer the potential to improve the efficacy and safety of TCE therapy. See related article by Frenking et al., p. 479.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"345-347"},"PeriodicalIF":12.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147436281","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":"Genomic Insights into the Biology of T-lineage Acute Lymphoblastic Leukemia.","authors":"Petri Pölönen, David T Teachey, Charles G Mullighan","doi":"10.1158/2643-3230.BCD-25-0206","DOIUrl":"10.1158/2643-3230.BCD-25-0206","url":null,"abstract":"<p><p>Relapsed and refractory T-lineage acute lymphoblastic leukemia (T-ALL) has a poor prognosis, emphasizing the need to identify high-risk patients. T-ALL classification has relied on immunophenotype, including identification of early T-cell precursor ALL, but few genetic alterations reproducibly predict outcome in T-ALL independently of measurable residual disease. Here, the biologic and genetic basis of T-ALL is reviewed, with an emphasis on large-scale genomic analyses that have shed light on the spectrum of genetic subtypes, their drivers, mechanisms of oncogene activation, and developmental stage. We describe how genomics-based approaches can improve T-ALL classification and risk stratification.</p><p><strong>Significance: </strong>Whole-genome and whole-transcriptome sequencing enable biologically and clinically meaningful T-ALL subtype classification with greater precision than immunophenotype-based approaches. The genomic landscape of T-ALL is heavily influenced by noncoding alterations, posing a challenge for clinical applications, as their detection often requires whole-genome sequencing. Studies have identified genomic subtypes and genetic alterations that improve the accuracy of patient outcome prediction.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"353-368"},"PeriodicalIF":12.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147640064","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":"Ibrutinib with Venetoclax in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: A Phase II Study.","authors":"Mahesh Swaminathan, Alessandra Ferrajoli, Philip A Thompson, Jan Burger, Gautam Borthakur, Koichi Takahashi, Zeev Estrov, Vanthana Bharathi, Alex Bataller, Tapan M Kadia, Naveen Pemmaraju, Naval Daver, Elias Jabbour, Prithviraj Bose, Rashmi Kanagal-Shamanna, Keyur P Patel, Sa A Wang, Naveen Garg, Hyunsoo Hwang, Xuemei Wang, Wei Qiao, Xun Xu, Nichole Cruz, Ana Ayala, Sherry Pierce, William Plunkett, Deepa Sampath, Hagop M Kantarjian, Michael J Keating, Varsha Gandhi, William G Wierda, Nitin Jain","doi":"10.1158/2643-3230.BCD-25-0345","DOIUrl":"10.1158/2643-3230.BCD-25-0345","url":null,"abstract":"<p><p>We explored the efficacy of the combination of ibrutinib + venetoclax in patients with relapsed and/or refractory (R/R) chronic lymphocytic leukemia (CLL). This phase II study enrolled 80 patients between July 2016 and September 2018. Patients received ibrutinib for the first 3 cycles, followed by ibrutinib + venetoclax for 24 cycles. Of the 79 treated patients, the median age was 61 years (IQR, 56-69); 65 (65/76, 86%) had unmutated IGHV and 29 (37%) had either del(17p) or a TP53 mutation. The median number of prior treatments was 1 (range, 1-3). The primary endpoint, best complete remission (CR) and CR with incomplete count recovery (CRi), was 67%, with a bone marrow undetectable measurable residual disease [10-4 sensitivity (U-MRD4)] rate of 61%. At 95.5 months of median follow-up, the estimated 7-year progression-free survival rate was 63.3%. Grade ≥3 neutropenia and thrombocytopenia occurred in 38% and 13% of patients, respectively. The 24-cycle ibrutinib + venetoclax combination led to high rates of CR/CRi and bone marrow U-MRD4 in patients with R/R CLL.</p><p><strong>Significance: </strong>The 24-cycle ibrutinib + venetoclax combination led to high rates of CR/CRi and bone marrow U-MRD4 in patients with R/R CLL. Responses were durable, including in patients with high-risk genomics.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"431-440"},"PeriodicalIF":12.2,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146182618","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}