Blood最新文献

{"title":"Functional Classification of Monoallelic TP53 Mutations Refines Prognostic Stratification in Myelodysplastic Neoplasms","authors":"Alexander Streuer,Yotaro Ochi,Stephan Hutter,Vladimir Riabov,Yasuhito Nannya,Laurenz Steiner,Mohammed Abba,Georgia Metzgeroth,Eva Altrock,Felicitas Rapp,Verena Nowak,Edin Hepgülüm,Steffen Boettcher,Torsten Haferlach,Daniel Nowak,Wolf-Karsten Hofmann,Seishi Ogawa,Nanni Schmitt","doi":"10.1182/blood.2026034224","DOIUrl":"https://doi.org/10.1182/blood.2026034224","url":null,"abstract":"TP53 mutations represent one of the strongest adverse prognostic factors in myelodysplastic neoplasms (MDS). While multi-hit TP53 (TP53multiHit) alterations uniformly lead to very poor outcomes, the prognostic relevance of monoallelic TP53 (TP53mono) mutations remains controversial. TP53 variants can cause dominant-negative, loss-of-function, or gain-of-function effects. We hypothesized that functional heterogeneity among TP53 variants contributes to the variable clinical behavior observed in TP53mono-mutated MDS. Therefore, we analyzed pretreatment samples from 4,505 patients with MDS from two independent cohorts (IWG: n=3,173; J-MDS: n=1,332), including 271 patients with TP53mono and 499 with TP53multiHit. Functional annotation of TP53 variants was performed using a previously published phenotype score (PS) derived from saturation mutagenesis screens, capturing dominant-negative and loss-of-function effects. Median leukemia-free survival (LFS) differed significantly by TP53 allelic state (TP53 wild-type (TP53wt) 37.2 months; TP53mono 19.2 months; TP53multiHit 7.8 months; p<0.001). Within the TP53mono subgroup, functional annotation identified marked heterogeneity. Patients with high PS (≥7) showed a significantly inferior median LFS compared with those with low PS (12.6 vs. 43.3 months; p<0.001), particularly for IPSS-R and IPSS-M low-risk cases. Combining PS and variant allele frequency (VAF) further improved risk stratification. TP53mono patients with PS ≥7 and VAF ≥22% had a median LFS comparable to TP53multiHit cases (9.2 vs. 7.8 months, p=0.3), whereas those with PS <7 and VAF <22% exhibited a median LFS similar to TP53wt cases (44.7 vs. 37.2 months, p=0.8). Overall, functional annotation of TP53 variants refines prognostication in TP53mono-mutated MDS and may enhance individualized risk assessment.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"13 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088606","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}

{"title":"A single-cell atlas identifies oncogenic transcriptional programs and immune escape mechanisms in CTCL.","authors":"Chenguang Wang, Xiangrong Geng, Suhaib Abdelrahman, Yao Fu, Nermin Kady, Mohd A Rauf, Alexandra Hristov, Trilokraj Tejasvi, Carlos Murga-Zamalloa, Lam C Tsoi, Joshua Welch, Jennifer Fox, Shannon Carty, Johann E Gudjonsson, Ryan A Wilcox","doi":"10.1182/blood.2025032507","DOIUrl":"10.1182/blood.2025032507","url":null,"abstract":"<p><strong>Abstract: </strong>Primary cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of extranodal non-Hodgkin lymphomas. Outcomes for patients with advanced-stage disease are suboptimal, because few complete and durable responses are achieved with currently available therapeutic agents. However, improved understanding of oncogenic transcriptional programs in malignant T cells and their engagement with the tumor microenvironment (TME) may unveil therapeutic vulnerabilities. Therefore, we have compiled the largest available single-cell RNA-sequencing CTCL atlas that includes >2 million skin and blood cells from 116 individual patients. We identified recurrent transcriptional programs in malignant T cells, a subset of which are associated with GATA binding protein 3-dependent transcriptional programs, especially in the setting of large cell transformation and advanced-stage disease. Many of the transcriptional programs identified are therapeutically targetable with clinically available agents, including HDAC, XPO1, CDK9, JAK/CSF1R, and IKZF1/IKZF3 antagonists. The CTCL TME is dominated by infiltrating and exhausted effector and cytotoxic T cells that are restrained by a robust infiltrate of regulatory T cells, transcriptionally polarized monocytes/macrophages, and cancer-associated fibroblasts. Collectively, these findings have significant implications for the rational design of combinatorial strategies targeting immune checkpoints, including programmed cell death protein 1. We have identified transcriptional programs, driven by oncogenic transcription factors, and constituents of the TME as therapeutic vulnerabilities in CTCL, and hope that the CTCL atlas constructed will provide a valuable resource for future studies exploiting these therapeutic vulnerabilities.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1816-1832"},"PeriodicalIF":23.9,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359495","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}

{"title":"The Iron Chaperone PCBP2 Controls Systemic Iron Homeostasis by Regulating Iron Flux in Red Pulp Macrophages.","authors":"Manuel Grander, Lukas Mueller, Manuel Trebo, Richard Hilbe, Natascha Brigo, Lukas Lanser, Markus Seifert, Sebastian Peer, Iana Portnaia, Laura Homs Pérez, Stefanie Dichtl, Nidhi Srinivasan, Rupert Oberhuber, Michaela Plaikner, Stefan Salcher, Timon E Adolph, Dominik Wolf, David Haschka, Guenter Weiss","doi":"10.1182/blood.2026034230","DOIUrl":"https://doi.org/10.1182/blood.2026034230","url":null,"abstract":"<p><p>Systemic iron homeostasis critically depends on macrophages for the recycling of iron from senescent erythrocytes. The iron chaperone poly(rC)-binding protein 2 (PCBP2) is considered to direct intracellular iron trafficking. However, its specific role in macrophage-mediated iron redistribution remains unclear. We show that iron deficiency induces PCBP2 expression in macrophages of mice and humans. Mice lacking PCBP2 in macrophages develop features of iron-restricted erythropoiesis, including reduced bone marrow iron, altered peripheral erythrocytes, and suppressed hepcidin levels. Despite medullary iron deficiency, these mice accumulate iron in the spleen. By profiling splenic cell subsets, we identify red pulp macrophages (RPMs) with dysregulated iron homeostasis: although increasing intracellular iron, PCBP2 depletion limits iron bioavailability. We further provide evidence that this paradox reflects defective iron trafficking due to the lack of PCBP2. First, PCBP2 deficiency restricts the metabolically accessible iron pool and promotes ferritin iron sequestration. Second, heme, the primary iron source for RPMs, requires PCBP2 for its degradation and subsequent iron release. Systemically, PCBP2-dependent macrophage iron flux enables adaptation to dietary iron changes by limiting erythropoiesis during iron deficiency and protecting iron-recycling macrophages from iron overload and oxidative stress during iron excess. These findings identify PCBP2-dependent iron trafficking as a regulator linking macrophage iron bioavailability to systemic iron and erythropoietic adaptation.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079716","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}

{"title":"Endotheliopathy and VWF-ADAMTS13 axis dysfunction in VEXAS thrombogenicity.","authors":"Anne-Marije Hulshof, Emma M Groarke, Sonja Schneppenheim, Jochen Wilhelm, Bhavisha A Patel, Diego Quinones Raffo, Alice Fike, Peter C Grayson, Shouguo Gao, Zhijie Wu, Neal S Young, Ellie Karampini, Gemma Leon, Caoimhe Dowd, Timon Albrecht, Ciara Byrne, Roger J S Preston, Ferdows Atiq, James S O'Donnell","doi":"10.1182/blood.2026035534","DOIUrl":"https://doi.org/10.1182/blood.2026035534","url":null,"abstract":"<p><p>Markedly increased risk of thrombosis has been described as a key clinical feature of the recently described VEXAS (vacuoles, E1 enzyme, X linked, autoinflammatory, somatic) syndrome. Critically however, the pathological mechanisms underlying VEXAS-associated hypercoagulability remain poorly understood. We addressed this question in a cohort of 40 VEXAS patients referred to the National Institutes of Health with defined pathological UBA1 sequence variants. In keeping with previous reports, twenty-one (52.5%) VEXAS patients in our cohort experienced thrombotic events. Plasma VWF and FVIII activity levels were both increased in VEXAS compared to age-matched controls. Consistent with endothelial cell (EC) activation and Weibel Palade body exocytosis, plasma VWF propeptide and angiopoietin II levels were also significantly elevated in VEXAS subjects. Furthermore, an accumulation of high molecular weight VWF multimers was seen in VEXAS patients. In keeping with ongoing endotheliopathy, plasma levels of soluble Vascular Cell adhesion Molecule-1 (VCAM-1) and soluble thrombomodulin (sTM) were significantly higher in VEXAS patients compared to controls. Finally, significantly increased thrombin generation and activated protein C resistance (APCR) were also observed in plasma from VEXAS patients. In conclusion, our novel findings demonstrate that VEXAS syndrome is associated with significant EC activation and endotheliopathy. This results in both quantitative and qualitative alterations in plasma VWF levels, increased FVIII levels, enhanced thrombin generation and an APCR phenotype. Further studies will be required to determine whether therapeutic interventions targeted at EC and/or the VWF-ADAMTS13 axis may be useful in VEXAS management.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079684","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}

{"title":"Multipotent Progenitor-3 Cells Are Reprogrammed by Bone-derived DKK1 to Drive Myelopoiesis in Breast Cancer","authors":"Emily Eul,Giulia Furesi,Wentao Han,Seunghyun Lee,Mark Watson,Rebecca Aft,Grant Challen,Roberta Faccio","doi":"10.1182/blood.2026033782","DOIUrl":"https://doi.org/10.1182/blood.2026033782","url":null,"abstract":"The expansion of immunosuppressive myeloid cells drives tumor progression, yet clinical strategies aimed at depleting these populations have shown limited effects and high toxicity. Because myeloid cells arise from hematopoietic progenitors, we asked whether solid tumors durably reprogram hematopoietic stem and progenitor cells (HSPCs) to sustain pathological myeloid bias. Here, we show treatment-naïve stage-III breast cancer (BC) patients and murine models of primary BC exhibited expansion of bone marrow HSPCs with enhanced myeloid output. Transplantation assays further demonstrated that tumor-educated HSPCs retained durable myeloid bias following transfer into healthy recipients and promoted tumor progression upon secondary challenge, accompanied by selective expansion of multi-potent progenitors (MPPs) and mature myeloid cells. In contrast, transplantation of long-term HSCs did not confer durable hematopoietic changes or enhanced tumor growth, indicating that tumor-induced myeloid bias is mediated by downstream progenitors. Consistently, depletion of mature myeloid cells did not alter HSCs but triggered rapid MPP expansion and myeloid rebound in tumor-bearing mice compared to no-tumor controls. Among progenitor subsets, MPP3s emerged as the principal drivers of tumor-associated myelopoiesis. Single-cell RNA sequencing of BC patient bone marrow revealed reduced Wnt-β-catenin signaling in HSPCs and identified DKK1, a bone-derived Wnt inhibitor elevated during BC progression, as a mediator of MPP3 reprogramming. Targeting bone-derived DKK1 limited HSPC engraftment following transplantation into naïve mice, and reduced BC progression, MPP3 expansion, and myeloid output in tumor bearing mice. These findings highlight solid tumor-induced hematopoietic reprogramming and identify bone-derived DKK1 as a regulator of MPP3 fate.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"7 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049078","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}

{"title":"Characterization of disease-initiating hematopoietic stem cells in calreticulin-mutated myeloproliferative neoplasms.","authors":"Camélia Benlabiod, Laetitia Borderon, Gurvan Hermange, Quentin Blampey, Maxime Evrard, Antonio Rodriguez-Romera, Stephanie G Moreno, Nathalie Gault, Philippe Rameau, Cyril Catelain, Elodie Rosa, Guillemette Fouquet, Lionel Faivre, Florence Pasquier, Bethan Psaila, Claus Nerlov, Sten Eirik W Jacobsen, William Vainchenker, Hana Raslova, Paul-Henry Cournède, Isabelle Plo, Caroline Marty","doi":"10.1182/blood.2026033236","DOIUrl":"10.1182/blood.2026033236","url":null,"abstract":"<p><p>Myeloproliferative neoplasms (MPNs) arise following the acquisition of a mutation in a hematopoietic stem cell (HSC) that causes oncogenic cytokine receptor signaling. Mutations in the calreticulin (CALR) gene are the second most common key driver mutations in MPNs, yet the identity of the disease-initiating HSCs and the mechanisms underlying their clonal expansion remain elusive. Knock-in mice bearing CALRdel52 and CALRins5 mutations recapitulate disease phenotypes, with a greater HSC amplification in CALRdel52 mice. Here, we crossed these strains with transgenic reporter mice expressing GFP under the control of the Von willebrand factor (Vwf) promoter, enabling discrimination between different HSC subsets. We show that CALR-mutated MPNs are mainly initiated from the expansion of platelet-biased, Vwf-positive HSCs, without substantially altering their lineage bias. Notably, the selective amplification of Vwf-positive CALRdel52 compared to CALRins5 HSCs is associated with increased signaling of the thrombopoietin receptor MPL and activation of the integrated stress response as evidenced by eIF2a phosphorylation downstream of PERK kinase triggered by endoplasmic reticulum stress. This pathway is also transcriptionally upregulated in CALRdel52-like compared with CALRins5-like patient hematopoietic stem and progenitor cells (HSPCs), as supported by reanalysis of a previous dataset, and is associated with increased phosphorylation of eIF2a. Pharmacological inhibition of PERK markedly reduces the proliferation of mouse CALRdel52 HSCs and impairs the megakaryocytic differentiation of CALRdel52-like HSPCs from patients while sparing cells from healthy donors. These findings identify the PERK/eIF2a pathway as a mechanistic vulnerability in the MPN cell-of-origin and offer a rationale for exploring new treatment approaches.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":23.9,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058416","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}

{"title":"You Are Already Trained for This: The Hematologist/Oncologist's Role in Radiation Mass Casualty Response","authors":"Nelson J. Chao,Leif Stenke,Ann A Jakubowski","doi":"10.1182/blood.2026035692","DOIUrl":"https://doi.org/10.1182/blood.2026035692","url":null,"abstract":"A large-scale radiation injury or nuclear incident requires an immediate, coordinated medical response that vastly exceeds traditional disaster management frameworks. While specialized networks exist, the initial surge of casualties will inevitably place a heavy burden on regional healthcare systems. Hematologists and oncologists possess the core clinical competencies necessary to manage the hematologic complications of acute radiation syndrome (ARS), yet barriers to active engagement persist. This manuscript reviews current operational strategies for disaster readiness, emphasizing the utilization of established point-of-care resources. Key components include: Leveraging Existing Infrastructure: Integrating clinical guidance from the Radiation Injury Treatment Network (RITN), EBMT and the Radiation Emergency Medical Management (REMM) website, including newly updated order sets and \"just-in-time\" training modules designed for clinical support teams. Transitioning to Outpatient Care: Addressing the logistics of managing a greater volume of stable, exposed individuals in the outpatient setting. Core Competency Mobilization: Demonstrating how daily expertise in managing treatment-related cytopenias, bone marrow failure, and opportunistic infections directly translates to managing radiation-induced marrow suppression. Hematologists and oncologists do not require extensive retraining to play a pivotal role in a radiation emergency; rather, they must be aware of how to activate and apply their existing expertise. Utilizing updated RITN, EBMT and REMM resources ensures that care can be efficiently orchestrated across both inpatient and expanding outpatient networks, significantly strengthening national resilience against radiation events.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"5 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049080","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}

{"title":"HIF-1α/ADPGK-driven glycolytic reprogramming provokes platelet hyperactivation by fueling RHOA lactylation","authors":"Qigang Lan,Yaqin Wang,Minhua Xie,Baichuan Xu,Yuewen Sun,Wang Xin,Shaozong Qin,Jun Chen,Shuiqin Gong,Liangjing Lv,Qing Xin,Jiachuan Xiong,Mengying Yao,Yang Xu,Junping Wang,Jinghong Zhao","doi":"10.1182/blood.2026033745","DOIUrl":"https://doi.org/10.1182/blood.2026033745","url":null,"abstract":"Platelet hyperactivation is the primary driver of thrombosis, which frequently occurs under physiological and pathological hypoxic conditions. Platelet activation is energy-intensive, while it is puzzling to explain hypoxia-associated platelet hyperactivation with energy metabolism. Here, we demonstrate that HIF-1α-driven glycolytic reprogramming induces platelet hyperactivation by fueling RHOA activation in chronic kidney disease (CKD) and high-altitude cohorts. We show that CKD-associated or hypoxia-induced upregulation of HIF-1α stabilizes ADP-dependent glucokinase (ADPGK) by shielding its lysine 125 from ubiquitin-mediated degradation, and ADPGK then utilizes ADP to drive glycolysis, resulting in lactate accumulation in platelets. Subsequently, accumulated lactate induces RHOA lactylation at lysine 7 to enhance its activation, thereby promoting cytoskeletal remodeling and platelet hyperactivation. Pharmacological inhibition of ADPGK with a screened compound Z809269780 effectively alleviates hypoxia-associated platelet hyperactivation and thrombosis. Our findings uncover an unrecognized non-histone lactylation mechanism of platelet hyperactivation and identify a potential therapeutic avenue for hypoxia-induced thrombotic complications.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"9 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149050286","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}

{"title":"Venetoclax plus Inotuzumab Ozogamicin for Relapsed and Refractory Acute Lymphoblastic Leukemia","authors":"Marlise R. Luskin,Julia H. Keating,Benjamin F. Frost,Stella Louise Jaeckle,Shai Shimony,Yael Flamand,Jacqueline S. Garcia,Richard M Stone,Matthew Booker,Chase M Weizer,Jeremy Adam Ryan,Jessica Lee,Ilene A Galinsky,Sujal I Shah,Emma Smith,Arpita Kulkarni,Michael Tolstorukov,Evan C. Chen,Eric S Winer,Anthony Letai,Mark A. Murakami,Daniel J DeAngelo","doi":"10.1182/blood.2026035238","DOIUrl":"https://doi.org/10.1182/blood.2026035238","url":null,"abstract":"In relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL), responses to the CD22 antibody-drug conjugate inotuzumab ozogamicin (INO) are frequent but short-lived. Based on preclinical evidence of synergy, we conducted a phase 1 trial of the BCL-2 inhibitor venetoclax (VEN) plus standard-dose INO for adults with R/R CD22+ ALL/LBL. Twenty-three patients enrolled (15 ALL, 8 LBL): three at dose level 1 (DL1; VEN 200 mg/day), six at DL2 (VEN 400 mg/day), and fourteen in an expansion cohort (VEN 400 mg/day). The recommended dose was VEN 400 mg/day for 21 days per cycle. No dose-limiting toxicities or early mortality occurred. Patients received a median of 2 cycles (range 1-5). The most common grade ³3 adverse events were thrombocytopenia (43.5%) and neutropenia (39.1%). Four patients (17.4%) developed sinusoidal obstructive syndrome. Of 22 evaluable patients, 21 (95.5%) achieved complete remission, including 19 after one cycle. Measurable residual disease (MRD) cleared in 16/18 (88.9%) by flow cytometry (&amp;lt;10-4) and 14/19 (73.7%) by next-generation sequencing (&amp;lt;10-6). Fourteen (63.6%) patients proceeded to HSCT. With a median follow-up of 25.3 months (95% CI 19.0-32.4), two-year disease-free (DFS) and overall survival (OS) were 48% (95% CI 24-72%); median DFS was 22.1 months (95% CI 10.4-NA), and median OS was not reached. MRD-positivity was associated with lower baseline BCL-2 dependence. Correlates of progression included acquired MCL-1 dependence, CD22 antigen escape, drug efflux gene ABCB1 expression, and oncogenic mutations. In summary, VEN+INO is safe and effective for R/R B-ALL/LBL, producing frequent and durable MRD-negative remissions. NCT05016947","PeriodicalId":9102,"journal":{"name":"Blood","volume":"96 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049079","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}

{"title":"Venetoclax plus pediatric regimen in adolescents and adults with Ph-negative acute lymphoblastic leukemia.","authors":"Xiaoyuan Gong, Yuntao Liu, Qiuyun Fang, Runxia Gu, Kaiqi Liu, Dong Lin, Chunlin Zhou, Guangji Zhang, Benfa Gong, Shuning Wei, Yan Li, Shouyun Li, Ying Wang, Shaowei Qiu, Bingcheng Liu, Ying Wang, Yingchang Mi, Hui Wei, Jianxiang Wang","doi":"10.1182/blood.2026033577","DOIUrl":"10.1182/blood.2026033577","url":null,"abstract":"<p><strong>Abstract: </strong>The B-cell lymphoma 2 inhibitor venetoclax has shown promise in acute lymphoblastic leukemia (ALL), but its role in first-line therapy for newly diagnosed (ND) Philadelphia chromosome-negative (Ph-) ALL is undefined. In this prospective phase 2 study, 167 adolescents and adults (aged 14-60 years) with ND Ph- ALL received venetoclax combined with pediatric-inspired chemotherapy. The primary end point was the rate of measurable residual disease (MRD) negativity by multiparameter flow cytometry (MFC) after induction. The complete remission rate was 91.0%, and 73.0% of responders achieved MFC-MRD negativity, meeting the primary end point. After a median follow-up of 19.3 months, median overall and disease-free survival were not reached; estimated 2-year survival rates were 78.5% and 76.7%, respectively. Propensity score-matched analysis confirmed superior survival compared with historical chemotherapy-only controls. Grade ≥3 adverse events were primarily hematologic toxicities and infections, with an incidence comparable with that of the historical cohort. These results demonstrate that adding venetoclax to pediatric-inspired chemotherapy significantly improves MRD response and survival outcomes in newly diagnosed (ND) Ph- ALL, with a manageable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT05660473.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"1670-1682"},"PeriodicalIF":23.9,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147986562","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}