HemaSphere最新文献

{"title":"The bidirectional relationship between JAK2V617F allele burden and inflammation in polycythaemia vera: Insights from interferon and ruxolitinib therapy","authors":"Tiziano Barbui, Paola Guglielmelli, Alessandro Maria Vannucchi","doi":"10.1002/hem3.70464","DOIUrl":"https://doi.org/10.1002/hem3.70464","url":null,"abstract":"<p>Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal hematopoietic stem cell disorders driven by recurrent mutations in <i>JAK2</i>, <i>CALR</i>, or <i>MPL</i>, resulting in constitutive activation of the JAK–STAT signaling pathway.</p><p>Although these mutations are central to disease initiation, accumulating evidence indicates that chronic inflammation plays a pivotal role in disease progression and clinical manifestations, making it a relevant therapeutic target.<span><sup>1</sup></span></p><p>In PV, the interplay between inflammation and clonal hematopoiesis appears particularly important as inflammatory signals may promote the expansion and persistence of the <i>JAK2V617F</i> mutant clone, thereby influencing its accumulation over time. Within this context, the two principal targeted agents, pegylated interferon-α and ruxolitinib, both exert anti-inflammatory effects. Interferon therapy in PV evolved from conventional and pegylated IFN-α2a to ropeginterferon alfa-2b (Ropeg), a long-acting formulation that enables sustained treatment while preserving disease-modifying activity.</p><p>Recent data indicate that ropeginterferon and ruxolitinib differ in clonal suppression, likely due to distinct interactions with the inflammatory microenvironment, providing the rationale for this brief review of their biological and therapeutic implications.</p><p>Among inflammatory mediators, IL-1 signaling appears particularly relevant. Elevated IL-1 levels have been demonstrated in both MPN patients and <i>JAK2V617F</i> mouse models. Genetic deletion of IL-1R1 normalizes blood counts, reduces splenomegaly and fibrosis, and decreases mutant hematopoietic stem/progenitor cells, whereas exogenous IL-1β promotes myeloid expansion and fibrosis.<span><sup>2</sup></span> Complementary studies showed that IL-1β is produced by <i>JAK2V617F</i> hematopoietic cells and contributes to bone marrow niche damage, myelofibrosis, and osteosclerosis, with additive therapeutic effects observed when IL-1β suppression is combined with ruxolitinib.<span><sup>2</sup></span> Importantly, IL-1β also appears involved in disease initiation, since its inhibition reduces engraftment and clonal expansion of JAK2-mutant HSCs and delays progression from <i>JAK2V617F</i> CHIP to overt MPN.<span><sup>3</sup></span></p><p>Upstream of IL-1β, the NLRP3 inflammasome has emerged as a critical regulator of inflammatory activation. Deletion of Nlrp3 abolishes IL-1β and IL-18 release and attenuates thrombocytosis, granulocytosis, HSPC expansion, splenomegaly, and fibrosis in <i>JAK2V617F</i> models. Pharmacologic NLRP3 inhibition reverses established disease manifestations, supporting its therapeutic potential.<span><sup>4</sup></span></p><p>TNF-α also promotes clonal dominance<i>. JAK2V617F</i> induces TNF-α production, while mutant progenitors display resistance to TNF-α-mediated suppression, unlike nor","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70464","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148784109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased risk of secondary malignancies after autologous transplantation in R/R follicular lymphoma: Long-term results from FIL-FLAZ12 Phase III trial","authors":"Rita Tavarozzi, Andrea Evangelista, Manuela Zanni, Chiara Consoli, Alessandra Tucci, Barbara Botto, Silvia Bolis, Pietro Lauzzana, Vittorio Ruggero Zilioli, Benedetta Puccini, Annalisa Arcari, Vincenzo Pavone, Gloria Margiotta-Casaluci, Monica Tani, Federica Cavallo, Antonio Pinto, Chiara Ghiggi, Domenico Pastore, Paolo Corradini, Andrés José María Ferreri, Angelo Palmas, Caterina Patti, Francesca Re, Fabio Benedetti, Giuseppe Milone, Stefano Luminari, Elsa Pennese, Elisa Bossi, Carola Boccomini, Antonella Anastasia, Chiara Bottelli, Donato Mannina, Samantha Pozzi, Catello Califano, Luca Arcaini, Flavio Falcinelli, Giuseppe Pietrantuono, Ilaria Del Giudice, Sara Usai, Jacopo Olivieri, Filippo Gherlinzoni, Attilio Olivieri, Tommasina Perrone, Fabrizio Pomponi, Giovannino Ciccone, Umberto Vitolo, Marco Ladetto","doi":"10.1002/hem3.70453","DOIUrl":"10.1002/hem3.70453","url":null,"abstract":"<p>In the rituximab era, autologous stem cell transplantation (ASCT) has historically been employed as consolidation therapy in relapsed/refractory (R/R) follicular lymphoma (FL), largely based on retrospective series and registry studies.<span><sup>1-4</sup></span> Despite growing concerns regarding long-term toxicity,<span><sup>5, 6</sup></span> contemporary data from the European Society for Blood and Marrow Transplantation (EBMT) registry indicate that ASCT continues to be used in a non-negligible fraction of FL patients,<span><sup>7-9</sup></span> in the absence of randomized comparisons with less intensive approaches. The FIL-FLAZ12 trial (NCT01827605) was designed to address this gap by directly comparing ASCT with an anti-CD20 radioimmunotherapy (RIT) as consolidation in this setting.<span><sup>10</sup></span> Initial analyses showed no advantage for ASCT in progression-free (PFS) or overall survival (OS), while revealing greater acute toxicity.<span><sup>10</sup></span> We provide here the updated results of this trial, after a median follow-up (mFU) of 103 months, offering a comprehensive evaluation of long-term survival, causes of deaths and the occurrence of secondary malignancies (SMs).</p><p>Eligible patients were 18–65 years old with histologically confirmed FL, R/R after at least one prior line of systemic therapy, without major comorbidities or history of active prior malignancy.<span><sup>10</sup></span></p><p>After three courses of investigator-selected immunochemotherapy (R-CHOP, R-DHAP, R-FM, R-ICE, R-IEV, or R-bendamustine), responders were randomized 1:1 to ASCT (BEAM/FEAM conditioning) or RIT (rituximab plus 90Y-ibritumomab tiuxetan). Both arms received eight courses of rituximab maintenance after response evaluation. The primary endpoint was PFS. Full study details and primary analysis have been previously published.<span><sup>10</sup></span></p><p>During this long-term analysis, data collection focused on PFS, OS, cause of death, and incidence of SMs, which were systematically updated across participating centers. Cumulative incidence of SMs and cause-specific mortality were analyzed using competing-risks methods (Gray's test and Fine–Gray models), with death and causes of death, respectively, treated as competing events.<span><sup>11</sup></span></p><p>Between August 2012 and September 2019, 164 patients were enrolled across Fondazione Italiana Linfomi (FIL) centers in Italy. Of these, 141 responders were randomized: 70 to ASCT and 71 to RIT. After randomization, 61 in the ASCT arm and 63 in the RIT arm proceeded beyond mobilization and constituted the per-protocol population.<span><sup>10</sup></span> The median age was 57 years (49–62), 55% of patients were male, 57% Stage IV, and 20% presented bulky disease. Baseline characteristics have been detailed previously.<span><sup>10</sup></span></p><p>With a mFU of 103 months, the 84-month PFS and OS from consent in the overall population were 44% (95% CI: 36–52; Figure S1A","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13460027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148712109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Venetoclax plus azacitidine, low-dose cytarabine, aclarubicin, and G-CSF (VA-CAG regimen) for newly diagnosed young patients with acute myeloid leukemia: A prospective, multicenter, single-arm Phase II clinical trial","authors":"Xiaoping Li,&nbsp;Qiurong Zhang,&nbsp;Xiaoyan Li,&nbsp;Lin Liu,&nbsp;Yonglin Shen,&nbsp;Yu Li,&nbsp;Lihui Peng,&nbsp;Chaoyang Zhou,&nbsp;Chie Qiu,&nbsp;Zhongtao Yuan,&nbsp;Shiqian Hou,&nbsp;Youcheng Wang,&nbsp;Lihua Zhang,&nbsp;Jingqiong Li,&nbsp;Liang Zhao,&nbsp;Qiuyuan Tang,&nbsp;Zucong Chen,&nbsp;Jing Feng,&nbsp;Xuejuan Zhang,&nbsp;Guoxiu Bao,&nbsp;Kui Zhang,&nbsp;Renpeng Zhang,&nbsp;Shiqi Li,&nbsp;Yingnian Chen,&nbsp;Jianhua Rao,&nbsp;Yancheng Dong,&nbsp;Dingsong Zhang,&nbsp;Yueyuan Wang,&nbsp;Aifang Li,&nbsp;Xi Ye,&nbsp;Lei Lei,&nbsp;Jiao Chen,&nbsp;Sufen Xu,&nbsp;Yanling Jin,&nbsp;Chaoen Zheng,&nbsp;Yang Liang,&nbsp;Sanbin Wang","doi":"10.1002/hem3.70449","DOIUrl":"10.1002/hem3.70449","url":null,"abstract":"<p>We conducted a prospective, multicenter, Phase II study to evaluate the safety and efficacy of venetoclax/azacitidine/low-dose cytarabine/aclarubicin/granulocyte colony-stimulating factor (G-CSF) (VA-CAG) in young patients with newly diagnosed acute myeloid leukemia (ND-AML). The VA-CAG regimen included venetoclax (100 mg/day, Days 1–2; 200 mg, Day 3; 400 mg/day, Days 4–21), azacitidine (75 mg/m², Days 1–7), cytarabine (10 mg/m²/12 h, Days 1–7), aclarubicin (12 mg/m², Days 1, 3, 5, and 7), and G-CSF (5 μg/kg/day, Days 0–8). The primary endpoint was the complete remission (CR) rate after Cycle 1; the secondary endpoints included measurable residual disease (MRD)-negative remission rate, adverse events, and duration of remission (DOR). A total of 120 subjects were enrolled. The median age was 50 years (interquartile range, IQR, 36–57). The CR and composite complete response (CRc) rates were 91% (95% CI 86%–96%) and 95% (95% CI 91%–99%), respectively; 84% (95% CI 81%–88%) of the CRc patients achieved MRD-negative remission. Common Grade ≥4 adverse events included neutropenia (96%), thrombocytopenia (86%), febrile neutropenia (24%), pneumonia (4%), and sepsis (4%). The median times to recovery of absolute neutrophil count (ANC) ≥ 0.5 × 10⁹/L and platelet count ≥ 20 × 10⁹/L for responding patients were 14 days (IQR, 9–19) and 10 days (IQR, 4–16), and the 60-day mortality rate was 0%. With a median follow-up of 22.1 months (95% CI 20.4–23.7 months), 34 subjects subsequently received hematopoietic stem cell transplantation (HSCT). The median DOR values of all patients and the patients who did not receive HSCT were not reached. Hence, the VA-CAG regimen is a safe and effective first-line induction chemotherapy for ND-AML patients.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13460025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148712112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isn't it ironic? Confessions of a pregnant, iron deficient hematologist","authors":"Lauren E. Merz","doi":"10.1002/hem3.70450","DOIUrl":"10.1002/hem3.70450","url":null,"abstract":"&lt;p&gt;It is well documented that iron deficiency (with or without anemia) has an atrociously high prevalence among pregnant people (up to 80%), causes myriad symptoms that impact quality of life and maternal–fetal outcomes, and treatment simply involves replenishing iron stores with intravenous (IV) or oral (PO) iron supplementation.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; It should not be difficult for anyone to obtain testing and treatment for iron deficiency during pregnancy. And yet, here I am: a hematologist specializing in women's health, currently 33 weeks into my first pregnancy, and struggling to obtain iron testing and treatment. The evidence around iron deficiency in pregnancy is clear—why does it remain so difficult to test and treat?&lt;/p&gt;&lt;p&gt;At my very first obstetrics visit around 9 weeks of gestation, I asked my obstetrician if we could add a serum ferritin to the routine blood work planned after the visit. After a slight pause, I rushed to remind her that this was a hazard of caring for a hematologist. Likely as a professional courtesy, she agreed to my request. However, when attempting to sign the order, a warning flashed on the screen indicating that a single serum ferritin test linked to the billing code of an initial prenatal care encounter would not be covered by my insurance plan and could cost hundreds of dollars. Flustered, we both agreed to skip testing for now and continue taking prenatal vitamins that included the recommended 28 mg of iron daily. As we parted, she stated, “Don't worry—if your hemoglobin is low, we can definitely check the ferritin!”&lt;/p&gt;&lt;p&gt;My excellent obstetrician was quoting from the 2008 American College of Obstetricians and Gynecology (ACOG) Practice Bulletin, which indeed recommends screening for anemia in the first trimester with a complete blood count, but only recommends iron testing if anemia is detected.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; Additionally, 2024 guidance from the US Preventive Services Task Force (USPSTF) concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening for iron deficiency in pregnant people to prevent adverse maternal and infant health outcomes.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; However, I was not reassured by this approach nor these guidelines. One study in pregnant women presenting for their first prenatal visit between 8 and 10 weeks of gestation with hemoglobin of 12 g/dL or higher (non-anemic) found that over a third were already iron deficient.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; In recognition of this reality, both the European Hematology Association (EHA) and the International Federation on of Gynecology Obstetrics (FIGO) recommend regular assessment of both hemoglobin and iron studies as early as possible in pregnancy.&lt;span&gt;&lt;sup&gt;2, 7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;A few weeks later, my savvy primary care physician managed to order a serum ferritin test with an insurance-approved billing code. My ferritin was 34 ng/mL. While the World Health Organization (WHO) guidelines ha","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13455533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148706318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “EHA Guidelines on management of chronic lymphocytic leukemia and Richter transformation”","authors":"","doi":"10.1002/hem3.70457","DOIUrl":"10.1002/hem3.70457","url":null,"abstract":"<p>Eichhorst B, Ghia P, Bosch F, et al. EHA Guidelines on management of chronic lymphocytic leukemia and Richter transformation. <i>HemaSphere</i>. 2026;10(6):e70403. doi:10.1002/hem3.70403.</p><p>In Figure 1, a level-of-evidence designation was omitted from one first-line therapy treatment recommendation, and three typographical errors were identified. Figure 1 has been corrected accordingly.</p><p>Figure 2 was adapted from a previously published source. The appropriate attribution has now been added, and the corresponding reference has been included in the reference list. As a result, subsequent references and in-text citations have been renumbered.</p><p>The original article has been updated. We apologize for these errors.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13449934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The case for targeting enhancer regions in high-risk TCF3::HLF-positive B-cell acute lymphoblastic leukemia","authors":"Zahra Sheybani,&nbsp;Charles E. de Bock","doi":"10.1002/hem3.70442","DOIUrl":"10.1002/hem3.70442","url":null,"abstract":"&lt;p&gt;Overall survival for children diagnosed with acute lymphoblastic leukemia (ALL) is now above 90%. However, this statistic can be misleading because not all genetic subtypes of ALL patients share in this success. Amongst the worst are children diagnosed with TCF3::HLF-positive B-cell ALL (B-ALL), arising from the translocation t(17;19)(q22;p13). Although rare at less than 1% of cases, these patients have a 5-year event-free survival of approximately 25%, respond poorly to induction chemotherapy and essentially fatal at relapse.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; This TCF3::HLF fusion has been shown to rewire the transcriptional program in committed lymphoid progenitors towards a stem-like, myeloid-biased state, overwhelmingly by binding to enhancer elements in intronic and intergenic regions rather than at promoters.&lt;span&gt;&lt;sup&gt;2, 4&lt;/sup&gt;&lt;/span&gt; However, direct links between TCF3::HLF-bound enhancers and target genes have remained unclear. Furthermore, progress on understanding the early steps of TCF3::HLF-driven leukemogenesis has in part been due to the inability to generate a genetically engineered mouse model.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Now two new studies&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; provide new mechanistic insight on how the TCF3::HLF fusion drives leukemogenesis and supports cell proliferation.&lt;/p&gt;&lt;p&gt;In the first study by Priebe et al.,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; the authors provide a comprehensive three-dimensional map of the TCF3::HLF regulome. Using TCF3::HLF-HiChIP in HAL-01 cells, they demonstrate that 94% of bound sites were within intronic or intergenic regions enriched at chromatin with H3K27ac and H3K4me1 that demarcate enhancers. The authors then ranked the interactions by cumulative contact frequency and found &lt;i&gt;MEF2C&lt;/i&gt; (myocyte enhancer factor 2C) at the very top of this list. The functional importance of this interaction and &lt;i&gt;MEF2C&lt;/i&gt; was validated using CRISPR-mediated disruption of the HLF binding motif within the &lt;i&gt;MEF2C&lt;/i&gt; intragenic enhancer. This selectively decreased the proliferation of HAL-01 cells but not in 697 cells harboring the related TCF3::PBX1 fusion. Direct &lt;i&gt;MEF2C&lt;/i&gt; knockout reproduced the same block in HAL-01 and a second TCF3::HLF-positive cell line YCUB-2 and was equivalent to loss of TCF3::HLF itself. This new data suggests that a single enhancer–promoter interaction in the MEF2C locus sits at the apex of the TCF3::HLF oncogenic hierarchy, sustaining a self-renewal program as essential to leukemia maintenance as the fusion protein itself (Figure 1A).&lt;/p&gt;&lt;p&gt;In the second study by Suzuki et al.,&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; the authors independently address two other critical knowledge gaps: the lack of a faithful murine model and the unexplained clinical association of TCF3::HLF B-ALL with hypercalcaemia and osteolytic bone disease. Using induced leukocyte stem cells transduced with TCF3::HLF, the authors generated a mouse model that recapitulates aggressive pro-B-like leukemia and also an osteolytic bone phen","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13446278/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of the new IMS/IMWG consensus genomic staging (CGS) of high-risk multiple myeloma (HRMM) in a contemporary cohort of 1209 patients","authors":"Efstathios Kastritis,&nbsp;Charalampos Filippatos,&nbsp;Maria Gavriatopoulou,&nbsp;Foteini Theodorakakou,&nbsp;Eirini Solia,&nbsp;Ioannis Ntanasis-Stathopoulos,&nbsp;Panagiotis Malandrakis,&nbsp;Nikolaos Kanellias,&nbsp;Evangelos Eleutherakis-Papaiakovou,&nbsp;Magdalini Migkou,&nbsp;Vasiliki Spiliopoulou,&nbsp;Ilias Katsadouros,&nbsp;Aikaterini Vlachou,&nbsp;Despina Fotiou,&nbsp;Konstantinos Giannakas,&nbsp;Erasmia Boutakoglou,&nbsp;Stavroula Giannouli,&nbsp;Panagiotis Tsirigotis,&nbsp;Asimina Papanikolaou,&nbsp;Evangelos Terpos,&nbsp;Meletios A. Dimopoulos","doi":"10.1002/hem3.70435","DOIUrl":"10.1002/hem3.70435","url":null,"abstract":"<p>Due to its high clinical and biological complexity, multiple myeloma (MM) is a malignancy of heterogeneous prognoses and outcomes. The International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) formulated a consensus genomic staging (CGS) of high-risk MM (HRMM), aiming to refine and homogenize the classification of high-risk disease. We evaluated the new HRMM criteria in a cohort of 1209 consecutive newly diagnosed MM patients with complete CGS data (except TP53 mutations), treated in a single center with contemporary regimens, including triplets and quadruplets, between 2010 and 2024. Based on CGS criteria, 25.2% of our cohort's patients were classified as HRMM. High-risk status was associated with significantly inferior outcomes: median overall survival (OS) was 44 months for HRMM versus 93 months for standard-risk (SR) patients (hazard ratio [HR] 1.81; P &lt; 0.001), corresponding to 5-year OS rates of 40% versus 61%. Similarly, median progression-free survival was 21.3 months for HRMM versus 36 months for SR (HR 1.64; P &lt; 0.001). The presence of ≥2 high-risk features identified an ultra-high-risk group (4.4% of patients) with a threefold increased risk of death, compared to SR patients. CGS remained prognostic irrespective of renal dysfunction, stratifying patients with sCr &gt; 1.2 mg/dL (HR 1.71; P &lt; 0.001) and retained prognostic significance across different age groups, transplant eligibility, and treatment eras (pre- and post-2020). The IMS/IMWG CGS effectively stratified patients in a large cohort treated at a tertiary academic center, identifying a substantially high-risk population with poor outcomes despite modern therapies. This validation supports its deployment in clinical practice and research to enhance the precision of risk-adapted management.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13446282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-line treatment with epcoritamab in combination with bendamustine plus rituximab induces sustained remissions beyond 3 years in patients with follicular lymphoma","authors":"Umberto Vitolo,&nbsp;Lorenzo Falchi,&nbsp;Per-Ola Andersson,&nbsp;Marcel Nijland,&nbsp;Fritz Offner,&nbsp;Sylvia Snauwaert,&nbsp;Jacob H. Christensen,&nbsp;Michael R. Clausen,&nbsp;Alexander Fosså,&nbsp;Pilar G. Prieto,&nbsp;Eliza A. Hawkes,&nbsp;Judit M. Jørgensen,&nbsp;Yasmin H. Karimi,&nbsp;Catharina Lewerin,&nbsp;Joost S. P. Vermaat,&nbsp;Björn E. Wahlin,&nbsp;Poliana Patah,&nbsp;Christopher Morehouse,&nbsp;Malene Risum,&nbsp;Zhu Li,&nbsp;Jennifer Marek,&nbsp;Joshua D. Brody","doi":"10.1002/hem3.70443","DOIUrl":"https://doi.org/10.1002/hem3.70443","url":null,"abstract":"<p>First-line (1L) bendamustine plus rituximab (BR) leads to high response rates in follicular lymphoma (FL), but maintaining durable remissions remains challenging. We report the 3-year follow-up from arm 3 of the phase 1b/2 EPCORE NHL-2 trial (NCT04663347) of epcoritamab, a subcutaneously administered CD3×CD20 bispecific antibody, combined with BR in patients with newly diagnosed FL. Twenty-five patients received epcoritamab plus BR, followed by epcoritamab monotherapy for up to 2 years. At a median follow-up of 41.3 months, the best overall response and CR rates were both 96%. The median time to CR was 1.5 (range 1–6) months. At 3 years, 87% of responders maintained CR. High CR rates were observed across subgroups, including 100% of patients with bulky disease (≥7 cm), 93% with Follicular Lymphoma International Prognostic Index score ≥3, and 100% with bone marrow involvement. The three-year progression-free survival and overall survival rates were 83% and 96%, respectively. Three patients progressed within 24 months of initiating treatment. Long-term data were consistent with prior reports and the known safety profiles of the individual agents, with no high-grade cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome events. Infections occurred in 92% of patients; COVID-19 was the most common (84%). Overall, 1L FL treatment with epcoritamab plus BR resulted in deep, durable responses beyond 3 years with a consistent safety profile. These results compare favorably with BR alone, although they require confirmation in further studies, and highlight the versatility of epcoritamab in combination with various standards of care and in improving outcomes in FL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70443","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148662508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"First-line treatment with epcoritamab in combination with bendamustine plus rituximab induces sustained remissions beyond 3 years in patients with follicular lymphoma","authors":"Umberto Vitolo,&nbsp;Lorenzo Falchi,&nbsp;Per-Ola Andersson,&nbsp;Marcel Nijland,&nbsp;Fritz Offner,&nbsp;Sylvia Snauwaert,&nbsp;Jacob H. Christensen,&nbsp;Michael R. Clausen,&nbsp;Alexander Fosså,&nbsp;Pilar G. Prieto,&nbsp;Eliza A. Hawkes,&nbsp;Judit M. Jørgensen,&nbsp;Yasmin H. Karimi,&nbsp;Catharina Lewerin,&nbsp;Joost S. P. Vermaat,&nbsp;Björn E. Wahlin,&nbsp;Poliana Patah,&nbsp;Christopher Morehouse,&nbsp;Malene Risum,&nbsp;Zhu Li,&nbsp;Jennifer Marek,&nbsp;Joshua D. Brody","doi":"10.1002/hem3.70443","DOIUrl":"https://doi.org/10.1002/hem3.70443","url":null,"abstract":"<p>First-line (1L) bendamustine plus rituximab (BR) leads to high response rates in follicular lymphoma (FL), but maintaining durable remissions remains challenging. We report the 3-year follow-up from arm 3 of the phase 1b/2 EPCORE NHL-2 trial (NCT04663347) of epcoritamab, a subcutaneously administered CD3×CD20 bispecific antibody, combined with BR in patients with newly diagnosed FL. Twenty-five patients received epcoritamab plus BR, followed by epcoritamab monotherapy for up to 2 years. At a median follow-up of 41.3 months, the best overall response and CR rates were both 96%. The median time to CR was 1.5 (range 1–6) months. At 3 years, 87% of responders maintained CR. High CR rates were observed across subgroups, including 100% of patients with bulky disease (≥7 cm), 93% with Follicular Lymphoma International Prognostic Index score ≥3, and 100% with bone marrow involvement. The three-year progression-free survival and overall survival rates were 83% and 96%, respectively. Three patients progressed within 24 months of initiating treatment. Long-term data were consistent with prior reports and the known safety profiles of the individual agents, with no high-grade cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome events. Infections occurred in 92% of patients; COVID-19 was the most common (84%). Overall, 1L FL treatment with epcoritamab plus BR resulted in deep, durable responses beyond 3 years with a consistent safety profile. These results compare favorably with BR alone, although they require confirmation in further studies, and highlight the versatility of epcoritamab in combination with various standards of care and in improving outcomes in FL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70443","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148662506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic success and epidemiological failure in hematology","authors":"Pierre Sujobert","doi":"10.1002/hem3.70447","DOIUrl":"https://doi.org/10.1002/hem3.70447","url":null,"abstract":"&lt;p&gt;What is the goal of onco-hematology? While perspectives may differ, improving cure rates for patients with hematological malignancies (HMs) is widely considered as the primary objective. Encouragingly, substantial progress has been made toward this goal, as reflected by the marked improvement in 5-year overall survival (OS) for patients with HMs over the past three decades according to the Surveillance, Epidemiology, and End Results (SEER) database&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; (Figure 1A). Between 1992 and 2017, major gains in 5-year OS were observed in chronic myeloid leukemia (CML, 31%–69%, +38%), multiple myeloma (MM, 27%–64%, +37%), and non-Hodgkin lymphomas (NHLs, 51%–78%, +27%). These improvements are consistent with already published data,&lt;span&gt;&lt;sup&gt;2-4&lt;/sup&gt;&lt;/span&gt; and largely attributable to therapeutic innovations, including targeted therapies (e.g., imatinib, bortezomib, and thalidomide derivatives) and monoclonal antibodies (such as rituximab). Significant advances have also been achieved in acute leukemias, including acute lymphoblastic leukemia (ALL, 58%–76%, +18%) and acute myeloid leukemia (AML, 18%–34%, +16%). Improvements have likewise been observed in diseases that already had relatively high 5-year OS rates in 1992, such as chronic lymphocytic leukemia (CLL, 77%–92%, +15%) and Hodgkin lymphoma (HL, 85%–93%, +8%). The continued integration of highly effective treatments such as CAR T-cell therapies, bispecific antibodies, and novel targeted agents like menin inhibitors is expected to drive further progress in the coming years.&lt;/p&gt;&lt;p&gt;On the basis of these impressive therapeutic advances, one might conclude that hematology is on track to achieve its goal, moving toward the cure or chronic management of most HMs. However, this conclusion warrants reconsideration. The ultimate objective of hematology should not be limited to improve survival, but also to reduce the burden of diseases in the overall population.&lt;/p&gt;&lt;p&gt;From this perspective, epidemiological data paint a more sobering picture. According to SEER data, which are adjusted on age and population size, disease-specific mortality has declined between 1975 and 2022 for HL (−80%), childhood leukemia (−73%), CML (−71%), ALL (−41%), CLL (−23%), and NHL (−16%). In contrast, mortality has remained relatively stable for MM (−3%) and AML (+4%) (Figure 1B). These trends appear inconsistent with major therapeutic advances observed over the same period.&lt;/p&gt;&lt;p&gt;This apparent paradox can largely be explained by concurrent changes in disease incidence. The age-adjusted SEER data show that, with the exception of HL, whose incidence is decreasing since 1975 (−27%), and CML, whose incidence is stable (−2%), all other HM are more frequent in 2022: AML (+21%), childhood leukemia (+22%), CLL (+26%), MM (+43%), ALL (+58%), and NHL (+69%) (Figure 1C).&lt;/p&gt;&lt;p&gt;When incidence and mortality are considered jointly, five distinct epidemiological patterns emerge (Figure 2). The most favorable pattern—declin","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 8","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70447","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148662507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}