HemaSphere最新文献

{"title":"Xq24/IL13RA1 aberrations as key drivers of female bias in primary mediastinal large B-cell lymphoma","authors":"Lukas Marcelis,&nbsp;Ryan Nicolaas Allsop,&nbsp;Marlies Vanden Bempt,&nbsp;Koen Debackere,&nbsp;Félicien Renard,&nbsp;Stefania Tuveri,&nbsp;Daan Dierickx,&nbsp;Adrian Janiszewski,&nbsp;Bradley Philip Balaton,&nbsp;Johanna Vets,&nbsp;Barbara Dewaele,&nbsp;Lucienne Michaux,&nbsp;Peter Vandenberghe,&nbsp;Jan Cools,&nbsp;Joris Robert Vermeesch,&nbsp;Thomas Tousseyn,&nbsp;Vincent Pasque,&nbsp;Iwona Wlodarska","doi":"10.1002/hem3.70200","DOIUrl":"https://doi.org/10.1002/hem3.70200","url":null,"abstract":"<p>Female-biased incidence in primary mediastinal large B-cell lymphoma (PMBCL) is enigmatic and points to a potential contribution of the X chromosome in this disease. To elucidate the postulated involvement of X-linked factor(s), we profiled the X chromosome in 48 diagnostic PMBCLs of male (21) and female (27) origin. Molecular cytogenetic analysis detected copy number gain of X/Xq in all male patients and 59.3% (16/27) of female patients. The remaining female cases revealed either a cytogenetically cryptic copy-neutral loss of heterozygosity (CNLOH) of X/Xq (14.8%) or germline XX (25.9%). Remarkably, RNAseq data of 28 cases indicated a nonrandom involvement of transcriptionally active X homolog in gain/CNLOH, validated by <i>h</i>XIST RNA-fluorescence in situ hybridization (FISH) in two PMBCL-derived cell lines. Further transcriptomic analysis revealed <i>IL13RA1</i> (Xq24) as the target of the Xq aberrations. In agreement with this, the vast majority (32/38, 84.2%) of PMBCL cases were IL13RA1-positive by immunohistochemistry. The intriguing finding of IL13RA1 protein expression in female PMBCLs with germline XX suggests epigenetic reactivation and expression of <i>IL13RA1</i> on the inactive X. Functional in vitro studies performed on Ba/F3 cells showed that overexpressed IL13RA1 is potent to transform murine pro-B cells and constitutively activate the oncogenic JAK-STAT signaling pathway. The novel pathogenic Xq24/<i>IL13RA1</i> defects appeared as disease-defining aberrations driving PMBCL and contributing to the related sex disparity. Our findings indicate that female predominance in PMBCL is due to the higher risk of women of acquiring pathogenic Xq24/<i>IL13RA1</i> defects by female-exclusive genetic/epigenetic mechanisms (CN-LOHX and reactivation of <i>IL13RA1</i> on Xi) not operating in males.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 9","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70200","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145146974","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":"Transcriptome profiling of megakaryocytes and platelets: Application to GP9- and IKZF5-related thrombocytopenia","authors":"Koenraad De Wispelaere,&nbsp;Fabienne Ver Donck,&nbsp;Kato Ramaekers,&nbsp;Chantal Thys,&nbsp;Koji Eto,&nbsp;Veerle Labarque,&nbsp;Ernest Turro,&nbsp;Kathleen Freson","doi":"10.1002/hem3.70217","DOIUrl":"https://doi.org/10.1002/hem3.70217","url":null,"abstract":"<p>Platelets are anucleate cells produced in the bone marrow and derived from large progenitor cells called megakaryocytes (MKs). Platelets receive RNA transcripts from their progenitorial MKs during thrombopoiesis. However, the correspondence between platelet and MK transcriptomes is poorly understood, particularly in the context of germline mutations that cause platelet formation defects or thrombocytopenia. We have studied the effects of two such mutations on MK and platelet transcriptomes. We generated immortalized MK cell line (imMKCL)-based models of Bernard–Soulier syndrome and <i>IKZF5</i>-related thrombocytopenia. MKs derived from imMKCLs with either a homozygous deletion of <i>GP9</i> (<i>GP9</i>^−/−) or a heterozygous Y121F variant in <i>IKZF5</i> (<i>IKZF5</i>^WT/Y121F) exhibited reduced proplatelet formation (reductions of 96% and 57%, respectively). Platelets from patients with either <i>GP9</i>^−/− or <i>IKZF5</i>^WT/Y121F genotypes had broad transcriptomic dysregulation, suggesting that (pro)platelet formation defects due to mutations in glycoprotein receptor and transcription factor genes such as <i>GP9</i> and <i>IKZF5</i> already affect the MK transcriptome. RNA-seq data from MKs at four stages of differentiation revealed widespread but distinct changes in expression over time between the <i>GP9</i>^−/− and the <i>IKZF5</i>^WT/Y121F genotypes. Dysregulated genes in <i>GP9</i>^−/− MKs were enriched for RNA metabolism and actin/tubulin folding pathways, whereas those in <i>IKZF5</i>^WT/Y121F MKs were enriched for cell cycle pathways. Most of these genes were also dysregulated in the platelets of patients with the corresponding diseases. Our results suggest that patients with inherited forms of thrombocytopenia present with specific transcriptomic changes during platelet formation.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 9","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70217","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145146332","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":"Burnout symptoms among hematology professionals: An EHA survey","authors":"Côme Bommier,&nbsp;Adela Perolla,&nbsp;Ana Zelić Kerep,&nbsp;Ruxandra Irimia,&nbsp;Nikolia Iatrou,&nbsp;Elizabeth Macintyre,&nbsp;Nuno Borges,&nbsp;EHA Burnout Survey Initiative","doi":"10.1002/hem3.70226","DOIUrl":"10.1002/hem3.70226","url":null,"abstract":"&lt;p&gt;Burnout, a work-related syndrome characterized by emotional exhaustion, depersonalization, and reduced personal accomplishment, has reached epidemic levels in medicine, posing significant threats to healthcare providers, patients, and systems.&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; Associated with reduced empathy, impaired judgment, and compromised patient safety,&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; burnout is generally driven by excessive workload, inefficient processes, administrative burden, and work–home conflict, alongside personal factors like neglect of self-care.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt; Younger and female physicians report higher burnout rates, with women experiencing more emotional exhaustion and men greater depersonalization.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; In high-stress specialties like oncology, nearly 45% of US oncologists report burnout, with long clinical hours and caseloads as dominant predictors.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Hematology professionals face similar pressures, managing life-threatening diseases while balancing clinical and research roles.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; However, dedicated studies on burnout in hematologists remain scarce.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; To address this gap, the European Hematology Association (EHA) launched the Burnout Survey Initiative in 2024, with the goal of assessing and characterizing the prevalence and key drivers of burnout within the hematology community. Using a validated instrument, the survey sought to quantify the burden of burnout in this population and to explore both personal and work-related factors associated with its occurrence. Ultimately, our aim was to generate hematology-specific insights that could inform targeted well-being interventions for professionals in the field.&lt;/p&gt;&lt;p&gt;We conducted a cross-sectional survey of EHA members between September and October 2024, targeting hematology professionals worldwide, including clinical hematologists, laboratory hematologists, researchers, and trainees. The survey, disseminated by the EHA Membership Matters Center via email to 7890 members, was anonymous and voluntary, with 14,065 email communications sent, including reminders, to improve response rates. The questionnaire, accessible online from September 10 to October 31, 2024, collected no personally identifiable information, ensuring confidentiality. Burnout was assessed using the Maslach Burnout Inventory-General Survey (MBI-GS), a validated tool measuring emotional exhaustion, depersonalization, and personal accomplishment. Burnout was defined as emotional exhaustion ≥27 and/or depersonalization ≥10; low personal accomplishment when &lt;34.&lt;span&gt;&lt;sup&gt;1, 11&lt;/sup&gt;&lt;/span&gt; The survey included MBI-GS items, demographics (age, gender, and country), and professional characteristics (role, experience, workload, and patient contact). Participants with incomplete MBI-GS or demographic data were excluded. Descriptive statistics characterized the sample and burnout prevalence. Univariate associations used chi-sq","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 9","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137314","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":"Large B-cell lymphoma (LBCL): EHA Clinical Practice Guidelines for diagnosis, treatment, and follow-up","authors":"Catherine Thieblemont,&nbsp;Maria Gomes Da Silva,&nbsp;Sirpa Leppä,&nbsp;Georg Lenz,&nbsp;Anne-Ségolène Cottereau,&nbsp;Christopher Fox,&nbsp;Armando Lopez-Guillermo,&nbsp;Timothy Illidge,&nbsp;Wojciech Jurczak,&nbsp;Hans Eich,&nbsp;Igor Aurer,&nbsp;Marek Trneny,&nbsp;Andy Andreas Rosenwald,&nbsp;Andrew Davies,&nbsp;Ben (Gerben) Zwezerijnen,&nbsp;Natacha Bolanos,&nbsp;Maja Marković,&nbsp;Jean-Philippe Jais,&nbsp;Florence Broussais,&nbsp;Martin Dreyling,&nbsp;Umberto Vitolo,&nbsp;Hervé Tilly,&nbsp;Marie-José Kersten","doi":"10.1002/hem3.70207","DOIUrl":"10.1002/hem3.70207","url":null,"abstract":"<p>Large B-cell lymphoma (LBCL) accounts for about one-third of adult lymphoma cases. Diagnosis requires specialized hematopathology laboratories, with immunophenotypic analysis essential for confirming B-cell lineage and identifying variants. <i>MYC</i> and <i>BCL2</i> rearrangements indicate a poor prognosis. Staging and prognosis rely on positron emission tomography computed tomography (PET-CT). The International Prognostic Index (IPI) aids risk stratification. PET-CT is critical for assessing treatment response and guiding strategies. First-line management for LBCL can be informed by interim PET to assess chemosensitivity, with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or polatuzumab vedotin rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) for advanced stages depending on IPI scores. Primary mediastinal B-cell lymphoma (PMBCL) management favors R-CHOP given every 14 days (R-CHOP14) or dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab (DA-EPOCH-R) without radiotherapy in complete responders. Elderly patients, unfit or not (≥80 years or &lt;80 with poor fitness), need geriatric assessment to guide therapy, often R-miniCHOP or non-anthracycline regimens. Frail patients should have adapted treatments. Prephase corticosteroids improve performance status, and supportive treatment should be optimized. The value of central nervous system (CNS) prophylaxis remains uncertain. CNS-IPI scores and specific anatomical sites help identify high-risk patients; magnetic resonance imaging (MRI) and colony-stimulating factor (CSF) analysis are recommended. Approximately 30%–40% of patients with LBCL experience relapsed or refractory disease after 1L treatment. Treatment strategies vary based on the timing of relapse (&lt;1 year or ≥1 year). For those refractory or relapsing within &lt;1 year and fit for therapy, chimeric antigen receptor T (CART) are the gold standard in 2L. CART in CART-naïve patients and bispecific antibodies appear to be the best approach in 3L. Follow-up includes clinical examination for 2 years and management for long-term side effects, such as cardiotoxicity, osteoporosis, immune dysfunction, neurocognitive impairment, endocrine dysfunction, fatigue, neuropathy, and mental distress.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 9","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137377","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":"ATMPs prepared under hospital exemption: European Blood Alliance position paper","authors":"Dragoslav Domanović,&nbsp;Marc Turner,&nbsp;Christof Jungbauer,&nbsp;Bernardo Rodrigues,&nbsp;Johanna Nystedt,&nbsp;Primož Rožman,&nbsp;Monique Debattista,&nbsp;Tengyu Wang,&nbsp;Einar Klæboe Kristoffersen,&nbsp;Kalinga Perera,&nbsp;Urban Švajger,&nbsp;Lilian Hook,&nbsp;Marjolaine Jacques,&nbsp;Ana Paula Sousa,&nbsp;Marten Hansen,&nbsp;Peter O'Leary,&nbsp;Pierre Tiberghien,&nbsp;European Blood Alliance Ad Hoc ATMPs Group","doi":"10.1002/hem3.70215","DOIUrl":"10.1002/hem3.70215","url":null,"abstract":"&lt;p&gt;In the European Union, advanced therapy medicinal products (ATMPs)—including somatic cell therapies, gene therapies, and tissue-engineered products—are generally subject to centralized marketing authorization by the European Medicines Agency (EMA). However, the ATMP Regulation (EC) No 1394/2007 also allows their production and use within the country under the hospital exemption (HE) clause, provided that specific criteria are met and approved by the National Competent Authorities.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Since the ATMP Regulation was introduced in 2007, the ATMP field has experienced significant scientific and technological advancements, whereas the regulatory framework remains largely unchanged and appears overly restrictive, potentially hindering the development and availability of these innovative therapies. Although many health conditions may benefit from ATMP therapies, the high development and manufacturing costs, which are also driven by regulatory requirements, often discourage commercial investment, especially for rare diseases or niche applications. In some instances, marketing authorizations have been withdrawn or not renewed, mainly for commercial reasons rather than due to clinical issues.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In contrast, HE is widely acknowledged as a valuable tool, enabling access to innovative and often life-saving treatments in cases of unmet clinical need. However, the current HE provisions—restricting production to the same Member State, requiring nonroutine preparation within the hospital, and assigning responsibility to a single practitioner—are ill-suited to today's clinical and manufacturing realities. These limitations reduce the scalability and broader applicability of ATMP production, thereby affecting supply. Furthermore, disparities in how Member States interpret and implement HE have resulted in inconsistent quality, safety, and efficacy standards across the EU.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Additionally, the EU lacks a system for monitoring health outcomes in patients treated with ATMPs through HE. Developing such a system is crucial to ensure transparency in quality and safety, generate scientific knowledge, enhance healthcare efficiency, and raise stakeholder awareness.&lt;/p&gt;&lt;p&gt;A further challenge lies in the ambiguous regulatory classification boundary between ATMPs and substances of human origin (SoHO), which results in legal uncertainty over applicable frameworks. The European Commission's 2023 proposal to revise the Medicinal Products Directive includes provisions for improved data collection and annual reviews of ATMPs produced under HE, with public reporting through an EMA-managed repository. Recital 18 of the proposal also suggests the potential for an adapted framework for less complex ATMPs manufactured under HE.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Although industry associations have generally supported tighter restrictions on the use of HE,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; the European Blood Alliance (EB","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 9","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456094/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137343","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 impact of reduced dosing frequency of elranatamab on patient-reported outcomes in patients with relapsed or refractory multiple myeloma: Results from MagnetisMM-3","authors":"Nizar J. Bahlis,&nbsp;Ajay K. Nooka,&nbsp;Marco DiBonaventura,&nbsp;Sharon T. Sullivan,&nbsp;Mohammad A. Chaudhary,&nbsp;Didem Aydin,&nbsp;Mohamad Mohty","doi":"10.1002/hem3.70224","DOIUrl":"10.1002/hem3.70224","url":null,"abstract":"&lt;p&gt;Multiple myeloma (MM) is associated with a range of clinical symptoms, including bone pain, anemia, renal dysfunction, and hypercalcemia.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; Given the chronic nature of MM, its symptom burden, and the side effects of its treatments, monitoring health-related quality of life (HRQOL) via patient-reported outcomes (PROs) has emerged as a critical aspect of patient care.&lt;span&gt;&lt;sup&gt;3-5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Elranatamab, a humanized bispecific antibody that targets B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells, has demonstrated efficacy and safety in patients with relapsed or refractory MM (RRMM) in the registrational Phase 2 MagnetisMM-3 clinical trial (NCT04649359).&lt;span&gt;&lt;sup&gt;6-8&lt;/sup&gt;&lt;/span&gt; Patients in the MagnetisMM-3 study reported improvements in PROs, regardless of prior exposure to BCMA-directed therapy, with notable reductions in pain and disease symptoms, and improvements in patients' outlook on their future health.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Reduction in the dosing frequency of bispecific antibodies offers convenience and flexibility to patients.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; In the MagnetisMM-3 study, patients who received weekly (QW) elranatamab for ≥6 cycles and achieved a partial response (PR) or better persisting for ≥2 months were eligible to transition to an every 2-week (Q2W) dosing schedule.&lt;span&gt;&lt;sup&gt;7-9&lt;/sup&gt;&lt;/span&gt; While prior analyses have examined the impact of a Q2W dosing schedule on clinical outcomes,&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; here we report the effect of switching from QW to Q2W elranatamab dosing on PROs among both BCMA-naive and -exposed patients from the MagnetisMM-3 study, hypothesizing that HRQOL would, at a minimum, be maintained as the incidence of TEAEs decreased after a reduction in dosing frequency while most patients maintained their response to elranatamab.&lt;/p&gt;&lt;p&gt;MagnetisMM-3 (NCT04649359) is an open-label, multicenter, nonrandomized, Phase 2 registrational study evaluating the efficacy and safety of elranatamab monotherapy in patients with RRMM.&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt; Eligibility criteria have been previously described.&lt;span&gt;&lt;sup&gt;7-9&lt;/sup&gt;&lt;/span&gt; Two patient cohorts were enrolled, those without (BCMA naive) or with (BCMA exposed) prior exposure to a BCMA-directed antibody–drug conjugate and/or chimeric antigen receptor T-cell therapy. The study was conducted in accordance with the International Council for Harmonisation guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki. The study protocol was approved by local or independent institutional review boards or ethics committees at participating sites. All patients provided written informed consent.&lt;/p&gt;&lt;p&gt;Patient-reported outcomes (PROs) were a prespecified exploratory endpoint of the MagnetisMM-3 study.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; All PRO measures were administered electronically on D1 and D15 of the first three cycles and D1 of each subsequent cycle through Cycle 12. Thereafter,","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 9","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137326","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":"Elevated circulating tumor cells reflect high proliferation and genomic complexity in multiple myeloma","authors":"Juan-Jose Garces,&nbsp;Benjamin Diamond,&nbsp;Tereza Sevcikova,&nbsp;Serafim Nenarokov,&nbsp;Daniel Bilek,&nbsp;Eva Radova,&nbsp;Ondrej Venglar,&nbsp;Veronika Kapustova,&nbsp;Ross Firestone,&nbsp;Kylee Maclachlan,&nbsp;Anish Simhal,&nbsp;Lucie Broskevicova,&nbsp;Jan Vrana,&nbsp;Ludmila Muronova,&nbsp;Tereza Popkova,&nbsp;Jana Mihalyova,&nbsp;Hana Plonkova,&nbsp;Michael Durante,&nbsp;Bachisio Ziccheddu,&nbsp;Michal Simicek,&nbsp;Hearn Jay Cho,&nbsp;George Mulligan,&nbsp;Jonathan Keats,&nbsp;David Zihala,&nbsp;Ola Landgren,&nbsp;Roman Hajek,&nbsp;Saad Usmani,&nbsp;Francesco Maura,&nbsp;Tomas Jelinek","doi":"10.1002/hem3.70218","DOIUrl":"10.1002/hem3.70218","url":null,"abstract":"<p>Circulating tumor cells (CTCs) have emerged as a key prognostic factor in newly diagnosed multiple myeloma (NDMM). However, it remains unclear if high CTC counts represent a mere surrogate of tumor burden or might reflect a distinct genomic or transcriptomic entity. In this study, we characterized the genomic and transcriptomic features associated with CTC burden and assessed their combined prognostic value in NDMM patients. We analyzed 540 NDMM patients from the CoMMpass dataset with available baseline CTC information and matched bone marrow transcriptomic (<i>n</i> = 374) and genomic (<i>n</i> = 460) sequencing data. We then validated the results on an external cohort of 135 NDMM patients with CTCs enumerated by next-generation flow cytometry. Higher CTC levels were significantly associated with high-risk clinical features (e.g., ISS or IMS/IMWG 2024). Furthermore, genomic analyses revealed that high CTC counts were associated with complex genomic features such as chromothripsis, APOBEC mutagenesis, and loss of key tumor suppressors, typically linked to high-risk disease. Transcriptomic analyses revealed that elevated CTCs were enriched in cell cycle and proliferation (PR) genes while presenting a reduced association with immune response. Importantly, CTCs also emerged as a surrogate for PR transcriptomic signatures and demonstrated prognostic superiority, potentially simplifying application in the clinical setting. Elevated CTC levels reflect aggressive biological features of multiple myeloma and outperform prognostic markers such as PR signatures. Integrating CTC data into genomic and transcriptomic classifiers could enhance risk stratification and provide a streamlined and powerful tool for clinical decision-making in NDMM.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 9","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455875/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137379","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 “Salvage treatment after covalent BTKi failure: An unmet need in clinical practice in Waldenstrom macroglobulinemia”","authors":"","doi":"10.1002/hem3.70219","DOIUrl":"10.1002/hem3.70219","url":null,"abstract":"<p>Frustaci AM, Zappaterra A, Galitzia A, et al. Salvage treatment after covalent BTKi failure: An unmet need in clinical practice in Waldenstrom macroglobulinemia. <i>HemaSphere</i>. 2025;9(2):e70094. doi:10.1002/hem3.70094</p><p>In the Funding section, the funder was incorrectly listed. The funder statement now reads: “Open access publishing facilitated by Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, as part of the Wiley – SBBL agreement.”</p><p>The original article has been updated. We apologize for this error.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 9","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137362","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":"Bridging gaps in clinical trial accessibility and reimbursement for large B-cell lymphoma therapies across Europe","authors":"Florence Broussais,&nbsp;Elise Pennings,&nbsp;Natacha Bolanos,&nbsp;Lorna Warwick,&nbsp;Robin Doeswijk,&nbsp;Gauthier Quinonez,&nbsp;Andrii Lebeda,&nbsp;Maria Gomes Da Silva,&nbsp;Sirpa Leppä,&nbsp;Georg Lenz,&nbsp;Anne-Ségolène Cottereau,&nbsp;Christopher Fox,&nbsp;Armando Lopez-Guillermo,&nbsp;Timothy Illidge,&nbsp;Wojciech Jurczak,&nbsp;Hans Eich,&nbsp;Igor Aurer,&nbsp;Marek Trneny,&nbsp;Andy Andreas Rosenwald,&nbsp;Andrew Davies,&nbsp;Ben (Gerben) Zwezerijnen,&nbsp;Jean-Philippe Jais,&nbsp;Martin Dreyling,&nbsp;Umberto Vitolo,&nbsp;Hervé Tilly,&nbsp;Catherine Thieblemont,&nbsp;Marie Jose Kersten","doi":"10.1002/hem3.70204","DOIUrl":"10.1002/hem3.70204","url":null,"abstract":"&lt;p&gt;Large B-cell lymphoma (LBCL), including its most common subtype diffuse LBCL, is the most frequent aggressive lymphoma, accounting for 30%–40% of cases worldwide. It is a clinically heterogeneous disease, with outcomes influenced by molecular subtypes, comorbidities, and access to effective treatment. Although R-CHOP has long been the standard of care, approximately 30%–40% of patients relapse or are refractory to first-line therapy. Historically, salvage chemotherapy followed by autologous stem cell transplantation offered a potential cure, but only about half of patients are eligible, leaving a large unmet need for alternative therapies.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Since 2018, the therapeutic landscape has rapidly evolved with the approval of nine new treatments across 12 indications in Europe, including CAR-T therapies, bispecific antibodies, antibody–drug conjugates, and targeted immunotherapies such as tafasitamab–lenalidomide. These advances have broadened the treatment arsenal beyond chemotherapy, offering potentially curative options for chemotherapy-resistant patients and effective alternatives for those ineligible for intensive approaches. This shift toward more targeted and less toxic therapies represents a significant step forward in addressing prior treatment limitations.&lt;/p&gt;&lt;p&gt;However, access to these innovations remains uneven across Europe. Disparities stem from fragmented national reimbursement systems, inconsistent use of early access programs (EAPs), and geographic variations in clinical trial availability. While 29 out of 35 European countries have implemented EAPs,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; differences in structure, funding, and transparency create unequal opportunities for early treatment access. Furthermore, health technology assessments (HTAs) and pricing negotiations often delay or restrict reimbursement, particularly in lower income or decentralized healthcare systems. The EU HTA Regulation (effective 2025) may harmonize clinical evaluations&lt;span&gt;&lt;sup&gt;3-6&lt;/sup&gt;&lt;/span&gt; but will not resolve national pricing autonomy.&lt;span&gt;&lt;sup&gt;7, 8&lt;/sup&gt;&lt;/span&gt; To achieve equitable access, stronger coordination, pricing transparency, and integration of real-world patient outcomes into decision-making are urgently needed to ensure that innovation benefits all LBCL patients, regardless of geography or system structure.&lt;/p&gt;&lt;p&gt;While developing the European LBCL guidelines,&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; the writing committee identified substantial variability in access to innovative therapies across Europe. To assess how these disparities could impact guideline implementation, the committee conducted an analysis of clinical trial activity and national reimbursement patterns. Data were obtained from EU CTIS, ClinicalTrials.gov, and direct consultations with industry stakeholders on the reimbursement status of EMA-approved therapies. The analysis focused on two areas: (I) the geographic distribution of active LBCL trials and (II) national reimbur","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 9","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12455876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137382","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":"Friends in need: The value of supportive colleagues in research","authors":"Freda K. Stevenson,&nbsp;Federico Caligaris Cappio","doi":"10.1002/hem3.70223","DOIUrl":"https://doi.org/10.1002/hem3.70223","url":null,"abstract":"&lt;p&gt;Sometimes the way research in science and medicine works seems far out of the public reach. Yet we know that it is carried out by ordinary people who happen to have followed a path which interests them, and which might carry the benefit of helping patients. As for most human activities, it can be a difficult world racked with ambition, competition, emotion, and deception. It can also be fascinating and rewarding. The historical career structure was made for men and it has always been difficult for women. In the end, the zigzag path to achievement depends on determination, talent, and on luck. One aspect not often mentioned is the importance of friendship between colleagues, often soured by competition. Our story is of a platonic partnership, in research into chronic lymphocytic leukemia (CLL), between two individuals, one an Italian male clinical scientist and the other a British female scientist (Figure 1). We did not work directly together, but in parallel, sharing the good things and supporting each other through the bad. The results of our efforts were to help to transform our knowledge of CLL, with insight into the biology providing the best prognostic indicator for patients and clinicians. The expansion of understanding then formed a foundation for novel targeted therapies. Our careers in translational hematology reflect the twists and turns of research during our time. Things have changed, but the excitement and fun of research remain for the next generations to enjoy.&lt;/p&gt;&lt;p&gt;&lt;i&gt;Freda:&lt;/i&gt; In my time it was difficult for a lone woman to make a difference in medical research. Not only did society load on all the expectations which go with being female, especially when there are children, but the male-dominated structures blocked progress. I look back at a career in what became “translational science,” operating at the interface between the laboratory and the clinic, beginning in the 1960s to the present. Many things have improved, with more awareness by institutions and male colleagues of problems facing women, but there are still many challenges. Hematology has always been open to science, but the power structure lies with clinicians, so results from the laboratory have to be first, comprehensible, and second, relevant to human disease.&lt;/p&gt;&lt;p&gt;It might seem odd now but, although I went through the usual undergraduate/postgraduate training, emerging with a DPhil from Oxford, I gave little thought to my career. The overwhelming ambition for women was to marry and have children so that is what I did. But, since my husband, George, was Australian and we moved there, I cheekily applied for a Lectureship in Biochemistry at Sydney University. In those days there was a shortage of applications and I forgot to mention that I was pregnant so I became a lecturer. This was pivotal because I was thrust into the academic structure and forced to find child care. It is obvious now that this is a way to go but I was a sort of pioneer, with no help availab","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 9","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70223","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145110923","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}