Bon Park,Kyung Ju Ryu,Min Kyu Choi,Sang Eun Yoon,Won Seog Kim,Seok Jin Kim
{"title":"Circulating CD20-positive extracellular vesicles impair rituximab efficacy and predict outcomes in diffuse large B-cell lymphoma.","authors":"Bon Park,Kyung Ju Ryu,Min Kyu Choi,Sang Eun Yoon,Won Seog Kim,Seok Jin Kim","doi":"10.1038/s41408-026-01556-1","DOIUrl":"https://doi.org/10.1038/s41408-026-01556-1","url":null,"abstract":"Rituximab, an anti-CD20 monoclonal antibody, is a cornerstone of therapy for diffuse large B-cell lymphoma (DLBCL), yet a substantial proportion of patients develop treatment failure. While loss of CD20 expression has been considered a major mechanism of resistance, additional mechanisms limiting effective antibody binding remain incompletely understood. We hypothesized that circulating CD20-positive large extracellular vesicles (EVlarge) act as antigen sinks that sequester rituximab and attenuate its therapeutic activity. Circulating CD20-positive EVlarge were quantified from archived serum samples of newly diagnosed DLBCL patients treated with R-CHOP. The prognostic impact of EVlarge levels was evaluated in a training cohort (n = 26) and an independent validation cohort (n = 90). Functional effects of tumor-derived EVlarge were assessed using OCI-Ly1 and U2932 lymphoma cell models and T cell cytotoxicity assays. Rituximab binding to tumor-derived EVlarge was visualized using light-field 4D microscopy. CD20 positivity was consistently higher in EVlarge than in EVsmall across lymphoma cell lines. Tumor-derived CD20-positive EVlarge enhanced lymphoma cell proliferation and attenuated rituximab-mediated growth inhibition. EVlarge also impaired rituximab-mediated cytotoxicity in T cell co-culture assays. Light-field 4D microscopy demonstrated binding of rituximab to EVlarge near the tumor cell surface with reduced antibody binding to lymphoma cells, supporting an antigen-decoy mechanism. Clinically, high pre-treatment levels of circulating CD20-positive EVlarge were associated with significantly inferior disease-specific and overall survival in both training and validation cohorts and remained independently prognostic after adjustment for International Prognostic Index risk. In conclusion, tumor-derived CD20-positive EVlarge represent a novel mechanism of rituximab resistance by reducing effective antibody exposure and impairing immune-mediated cytotoxicity. Circulating CD20-positive EVlarge provide a biologically informative biomarker that predicts clinical outcomes independently of established prognostic factors and may guide optimization of antibody-based therapy in DLBCL.","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"9 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148348905","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}
Elias Jabbour,Caitlin R Rausch,Hannah Goulart,Nitin Jain,Farhad Ravandi,Abhishek Maiti,Yesid Alvarado,Jan Burger,Musa Yilmaz,Issa Khouri,Partow Kebriaei,Jeffrey Jorgensen,Sa A Wang,Xuemei Wang,Ejiroghene Mayor,Rebecca S Garris,Nicholas J Short,Hagop Kantarjian
{"title":"Inotuzumab ozogamicin therapy for measurable residual disease in adult acute lymphoblastic leukemia.","authors":"Elias Jabbour,Caitlin R Rausch,Hannah Goulart,Nitin Jain,Farhad Ravandi,Abhishek Maiti,Yesid Alvarado,Jan Burger,Musa Yilmaz,Issa Khouri,Partow Kebriaei,Jeffrey Jorgensen,Sa A Wang,Xuemei Wang,Ejiroghene Mayor,Rebecca S Garris,Nicholas J Short,Hagop Kantarjian","doi":"10.1038/s41408-026-01551-6","DOIUrl":"https://doi.org/10.1038/s41408-026-01551-6","url":null,"abstract":"Inotuzumab ozogamicin, an anti-CD22 antibody-drug conjugate, has demonstrated high response rates and measurable residual disease (MRD)-negativity in acute lymphoblastic leukemia (ALL). This phase 2 single-center study evaluated inotuzumab 0.6 mg/m2 day 1 and 0.3 mg/m2 day 8 (cycle 1) followed by 0.3 mg/m2 days 1 and 8 (cycles 2-6) for adults with B-cell ALL in morphologic remission with detectable MRD (≥1 × 10-4 by multiparameter flow cytometry, BCR::ABL1 transcripts ≥0.01% by polymerase chain reaction [PCR], or ≥1 × 10-6 by next-generation sequencing [NGS]). Thirty-seven patients (median age 49 years) were treated, including 17 with Philadelphia-chromosome (Ph)-negative ALL and 20 with Ph-positive ALL. Twenty-eight patients (76%) were in first remission (CR1). Overall, 26 patients (70%) achieved MRD-negativity, including 76% of patients with Ph-negative ALL and 65% of patients with Ph-positive ALL. The NGS MRD-negativity rate was 73%. With a median follow-up of 50 months, the median overall survival (OS) was 61 months, with a median relapse-free survival (RFS) of 40 months. Patients treated in CR1 vs CR2+ had a median OS that was not reached versus 14 months, respectively (p = 0.056). Three cases (8%) of non-fatal sinusoidal obstructive syndrome (SOS) were observed. Inotuzumab was safe and effective at eradicating MRD.","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"35 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148336179","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":"Pola-R-CHP as frontline therapy for diffuse large B-cell lymphoma: a systematic review and meta-analysis of randomized trials and real-world evidence.","authors":"Salvatore Perrone,Matteo Molica,Diana Giannarelli,Giada Pacitto,Simone Ferrero","doi":"10.1038/s41408-026-01552-5","DOIUrl":"https://doi.org/10.1038/s41408-026-01552-5","url":null,"abstract":"Pola-R-CHP regimen is the new standard of care for untreated diffuse large B-cell lymphoma (DLBCL) patients, following the POLARIX trial. This study evaluates whether clinical trial (RCT) efficacy and safety are reproducible in real-world evidence (RWE) settings. This systematic review and meta-analysis compared outcomes between RCTs and RWE studies. Primary endpoints were complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). Meta-regression explored heterogeneity using age, International Prognostic Index (IPI), and activated B-cell-like (ABC) subtype as moderators. Data from 2 RCTs and 10 RWE studies (3472 patients) were integrated. The pooled CR rate was 78% (95% CI: 74-82%), with RWE studies showing a significantly higher CR (80%) than RCTs (69%, P < 0.001). The pooled 1-year PFS was 85%, significantly higher in RWE (86%) than RCTs (81%, P = 0.02). Pooled 1-year OS was 91%, with no significant difference between RWE (90%) and RCTs (94%, P = 0.35). Despite high heterogeneity (I2 74-91%), meta-regression confirmed that age, IPI score, and ABC subtype did not significantly influence treatment effects, though trends for improved CR and PFS were noted. In conclusion, this meta-analysis confirms that Pola-R-CHP outcomes in real-world practice are consistent with, and occasionally exceed, those observed in clinical trials. Despite inherent heterogeneity in RWE, these findings support Pola-R-CHP as a robust frontline therapy for a broad DLBCL population, regardless of baseline clinical characteristics.","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"23 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148336025","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":"Outcomes of patients with relapsed or refractory classic Hodgkin lymphoma after frontline brentuximab vedotin.","authors":"Shin Yeu Ong,Lu Chen,Jomel Meeko Manzano,Reid Merryman,Harsh Shah,Robert Stuver,Sanjal H Desai,Ann LaCasce,Ayo Falade,Kelsey Baron,Nivetha Ganesan,Tiffany Chang,Urshila Durani,Tamer Othman,Philippe Armand,Matthew Mei,Alison J Moskowitz,Alex F Herrera","doi":"10.1038/s41408-026-01547-2","DOIUrl":"https://doi.org/10.1038/s41408-026-01547-2","url":null,"abstract":"Frontline therapy for classic Hodgkin Lymphoma (cHL) incorporating brentuximab vedotin (BV) improves outcomes compared with traditional chemotherapy, but up to 20% of patients relapse and need salvage treatment. Prior retrospective studies examining salvage therapies are mostly limited to patients who received chemotherapy-based treatment in frontline without novel agents. We evaluated outcomes in 116 patients with relapsed/refractory (R/R) cHL who received brentuximab and anthracycline-containing frontline treatment. High risk factors at relapse or progression were common, including primary refractory disease (62%), advanced stage (63%), and extranodal disease (46%). At first salvage, 73% of patients received PD-1 blockade (58% in conjunction with chemotherapy), and 81% received PD-1 blockade at any salvage line. Overall, 78% of patients proceeded to ASCT. With a median follow-up of 19 months, the 2-year PFS and OS from the start of salvage in all patients were 61% and 97% respectively. Among patients with ASCT, the 2-year post-transplant PFS (PFSHCT) was 76% for patients who had PD-1 blockade as salvage before ASCT, compared with 59% for those who did not. In univariate analysis, PD-1 blockade use in first salvage was significantly associated with improved PFSHCT, and this association remained statistically significant after adjusting for stage, extranodal involvement, and primary refractory disease (HR 0.31, p = 0.04). Primary refractory disease after BV-AVD emerged as an ongoing unmet need with a significantly inferior 2-year PFSHCT compared with relapsed patients (58% vs 86%, p = 0.017). Among primary refractory patients who received ASCT, first salvage incorporating a PD-1 blockade showed a trend toward improved PFSHCT compared with non-PD-1 blockade salvage. These results support PD-1 blockade incorporation as preferred first salvage in R/R cHL after BV-containing frontline therapy.","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"8 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148322717","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}
Sanjal H Desai,Susan M Geyer,Levi Pederson,Michael A Spinner,Veronika Bachanova,Andrew M Evens,Gaurav Goyal,Brad Kahl,Kathleen Dorritie,Jacques Azzi,Vaishalee P Kenkre,Cheryl Chang,Brendon Fusco,Nuttavut Sumransub,Haris Hatic,Raya Saba,Uroosa Ibrahim,Elyse I Harris,Harsh Shah,Nina Wagner-Johnston,Deepa Jagadeesh,Kristie A Blum,Catherine Diefenbach,Siddharth Iyengar,K C Rappazzo,Firas Baidoun,Yun Choi,Ranjana H Advani,Heidi Mocikova,Alice Sykorova,Jozef Michalka,Vit Prochazka,Ivana N Micallef
{"title":"Efficacy of post-transplant brentuximab vedotin maintenance by pre-transplant disease status in relapsed/refractory classic Hodgkin lymphoma.","authors":"Sanjal H Desai,Susan M Geyer,Levi Pederson,Michael A Spinner,Veronika Bachanova,Andrew M Evens,Gaurav Goyal,Brad Kahl,Kathleen Dorritie,Jacques Azzi,Vaishalee P Kenkre,Cheryl Chang,Brendon Fusco,Nuttavut Sumransub,Haris Hatic,Raya Saba,Uroosa Ibrahim,Elyse I Harris,Harsh Shah,Nina Wagner-Johnston,Deepa Jagadeesh,Kristie A Blum,Catherine Diefenbach,Siddharth Iyengar,K C Rappazzo,Firas Baidoun,Yun Choi,Ranjana H Advani,Heidi Mocikova,Alice Sykorova,Jozef Michalka,Vit Prochazka,Ivana N Micallef","doi":"10.1038/s41408-026-01523-w","DOIUrl":"https://doi.org/10.1038/s41408-026-01523-w","url":null,"abstract":"Patients with classic Hodgkin lymphoma (cHL) with primary refractory disease, early relapse, or extranodal disease have a higher risk of relapse after salvage therapy and autologous stem cell transplant (ASCT). Post-ASCT brentuximab vedotin (BV) maintenance improved progression-free survival (PFS) in high-risk relapsed/refractory (R/R) cHL in the AETHERA trial, but subgroup analysis suggested that the benefit in patients transplanted in complete metabolic response (CMR) is unclear. In a large international real-world cohort, we assessed the efficacy of BV maintenance stratified by pre-ASCT metabolic response and by the number of clinical risk factors as defined in the AETHERA trial. Adult patients with R/R cHL who met AETHERA risk criteria were included. Utilizing propensity score analyses, PFS and OS were assessed overall and in subgroups of CMR (442 pts) and partial metabolic response (PMR, 249 pts). We observed that post-ASCT BV maintenance was associated with significantly higher PFS in the subgroup with PMR (5-year PFS: 59.6% vs 43.3% HR = 0.52, CI95: 0.33-0.82; p = 0.007). In the subgroup of patients with CMR, BV maintenance did not significantly improve PFS (5-year PFS: 75.8% vs 62.3% HR = 0.88, CI95: 0.59-1.32; p = 0.29). However, when focusing on patients with CMR treated post-FDA approval of BV, there was a significant PFS benefit observed in those treated with BV maintenance vs. not (5-year PFS: 81.2% vs 55.2% HR = 0.40, CI95: 0.22-0.72; p = 0.003). Overall, BV maintenance after ASCT remains an important therapy for high-risk R/R cHL patients, especially for those in PMR or those in CMR.","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"52 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148313370","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":"MM-derived exosomes promote M2 macrophage polarization and immunosuppressive microenvironment: therapeutic opportunities.","authors":"Qi Li,Yilei Shi,Wenzhuo Zhuang,Bingzong Li","doi":"10.1038/s41408-026-01548-1","DOIUrl":"https://doi.org/10.1038/s41408-026-01548-1","url":null,"abstract":"Multiple myeloma (MM) progression involves extensive immunosuppressive remodeling of the bone marrow microenvironment. In this study, we performed a comprehensive mass spectrometry-based proteomic analysis of exosomes derived from MM cells (MM-Exos), revealing that these exosomal proteins are predominantly enriched in pathways associated with immune regulation. We demonstrated that MM-Exos effectively drive macrophage polarization toward the M2 phenotype, thereby facilitating the establishment and maintenance of an immunosuppressive tumor microenvironment. Mechanistically, we identified the ERK1/2 signaling pathway as a critical mediator of MM-Exo-induced macrophage polarization. Importantly, we found that simvastatin, a widely used inhibitor of cholesterol biosynthesis, effectively impaired exosome secretion from MM cells and subsequently reduced M2 macrophage polarization. Collectively, our study reveals a novel mechanism of immune evasion in MM, in which MM-Exos promote the polarization of macrophages toward the M2 phenotype via ERK1/2 pathway activation. These findings underscore the therapeutic potential of targeting exosome-mediated intercellular communication within the MM bone marrow microenvironment to improve clinical outcomes.","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"22 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148322716","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}
Niels W C J van de Donk,Fredrik Schjesvold,Bronno van der Holt,Monique C Minnema,Ka Lung Wu,Annemiek Broijl,Wilfried W H Roeloffzen,Alain Gadisseur,Giuseppe Pietrantuono,Ludek Pour,Vincent H J van der Velden,Thomas Lund,Massimo Offidani,Sara Bringhen,Luisa Giaccone,Wida Razawy,Paola Tacchetti,Katia Mancuso,Trine Silkjaer,Jo Caers,Sonja Zweegman,Roman Hájek,Reuben Benjamin,Annette Juul Vangsted,Mario Boccadoro,Francesca Gay,Pieter Sonneveld,Pellegrino Musto
{"title":"Long-term follow-up of the transplant-eligible cohort of the EMN12/HOVON-129 study for primary plasma cell leukemia patients.","authors":"Niels W C J van de Donk,Fredrik Schjesvold,Bronno van der Holt,Monique C Minnema,Ka Lung Wu,Annemiek Broijl,Wilfried W H Roeloffzen,Alain Gadisseur,Giuseppe Pietrantuono,Ludek Pour,Vincent H J van der Velden,Thomas Lund,Massimo Offidani,Sara Bringhen,Luisa Giaccone,Wida Razawy,Paola Tacchetti,Katia Mancuso,Trine Silkjaer,Jo Caers,Sonja Zweegman,Roman Hájek,Reuben Benjamin,Annette Juul Vangsted,Mario Boccadoro,Francesca Gay,Pieter Sonneveld,Pellegrino Musto","doi":"10.1038/s41408-026-01549-0","DOIUrl":"https://doi.org/10.1038/s41408-026-01549-0","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"1 1","pages":""},"PeriodicalIF":12.8,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148304930","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}
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