Blood Cancer Discovery最新文献

{"title":"Understanding the Molecular Mechanisms Underlying Anemia in Myelodysplastic Syndromes: From Erythropoiesis to New Therapeutic Approaches.","authors":"Vera Adema, Francesco Pesce, Guillermo Garcia-Manero, Valeria Santini, Simona Colla","doi":"10.1158/2643-3230.BCD-25-0393","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-25-0393","url":null,"abstract":"<p><p>Minimizing the transfusion burden is one of the primary clinical goals for most patients with myelodysplastic syndromes (MDS), which are incurable hematopoietic stem cell neoplasms. In some patients, supportive red blood cell transfusions can lead to clinical improvement, but frequent transfusions induce iron overload, which can have detrimental effects on cardiac and hepatic function, affect patients' quality of life, and incur additional healthcare costs. In this review, we summarize how erythropoiesis is regulated under steady-state conditions, dissect the molecular mechanisms underlying anemia in MDS, and review therapeutic approaches to overcome ineffective erythropoiesis in patients with these diseases.</p><p><strong>Significance: </strong>A better understanding of the biological mechanisms underlying anemia in MDS is needed to develop targeted therapies for a personalized treatment approach. Anemia, a hallmark of MDS, highly affects patients' quality of life and contributes to overall morbidity. Current knowledge of the mechanisms of action of the available drugs targeting anemia in MDS is limited.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"OF1-OF12"},"PeriodicalIF":11.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147843626","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":"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":11.5,"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":11.5,"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":11.5,"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":11.5,"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":11.5,"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":11.5,"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":11.5,"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}

{"title":"Models, Models, Everywhere: But Which One Should Guide Care?","authors":"Curtis A Lachowiez, Sanam Loghavi","doi":"10.1158/2643-3230.BCD-26-0055","DOIUrl":"10.1158/2643-3230.BCD-26-0055","url":null,"abstract":"<p><p>Drekolias and colleagues report a therapy-specific prognostic model integrating mutational and cytogenetic features to risk-stratify survival in patients with acute myeloid leukemia treated with venetoclax-based regimens, providing a clinically relevant framework amid a rapidly expanding landscape of competing models. See related article by Drekolias et al., p. 403.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"339-342"},"PeriodicalIF":11.5,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147582353","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":"Clinical Scores to Predict Toxicities and Outcomes in Patients with Multiple Myeloma Undergoing Bispecific T-cell Engager Therapy.","authors":"Jan H Frenking, Christine Riedhammer, Thomas Hielscher, Christoph Schaefers, Lisa B Leypoldt, Marie Harzer, David Sedloev, Valentine Landrin, Niklas Kehl, Mirco J Friedrich, Xiang Zhou, Maximilian Steinhardt, Philipp Weis, Julia Mersi, Johannes Waldschmidt, Niels Weinhold, K Martin Kortüm, Carsten Müller-Tidow, Hermann Einsele, Sandra Sauer, Katja Weisel, Tim Richardson, Raphael Teipel, Leo Rasche, Marc S Raab","doi":"10.1158/2643-3230.BCD-25-0062","DOIUrl":"10.1158/2643-3230.BCD-25-0062","url":null,"abstract":"<p><p>The significant clinical benefit of bispecific T-cell engagers (TCE) for the treatment of relapsed/refractory multiple myeloma (RRMM) may be offset by serious toxicities and treatment failure. Risk scores such as the CAR-HEMATOTOX (HTX), Endothelial Activation and Stress Index (EASIX), and modified EASIX (m-EASIX) can identify patients at risk for complications before chimeric antigen receptor (CAR) T-cell therapy, but their utility prior to TCE therapy remains elusive. We analyzed associations with outcomes and toxicities in independent discovery (n = 123) and validation (n = 155) cohorts treated with TCEs. Patients with HTX ≥3 or m-EASIX > median (>0.86) had a significantly increased risk of prolonged hospitalization, antibiotic treatment, and fever during step-up dosing. We also observed associations with cytopenias requiring therapeutic intervention, higher severe infection and intervention densities, as well as inferior response rates and reduced progression-free and overall survival. Our findings highlight the potential of these clinical scores to improve risk stratification before TCE therapy.</p><p><strong>Significance: </strong>Scores such as HTX, EASIX, and m-EASIX have emerged as helpful tools to enable risk stratification before CAR T-cell therapy. In this study, we demonstrate their utility in patients with RRMM receiving TCEs. HTX ≥3 and m-EASIX > median (>0.86) proved to be risk markers for infections, therapeutic interventions, and poor outcomes. See related commentary by Banerjee and Dhodapkar, p. 345.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"479-495"},"PeriodicalIF":11.5,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146195633","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}