HemaSphere最新文献

{"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}

{"title":"Elevated serum heme oxygenase-1 in pediatric sickle cell disease: Insights from the SickleGenAfrica Network","authors":"Anna M. Sowa,&nbsp;William Kudzi,&nbsp;Vivian Paintsil,&nbsp;Amma A. Benneh-Akwasi Kuma,&nbsp;Catherine I. Segbefia,&nbsp;Edeghonghon Olayemi,&nbsp;David Nana Adjei,&nbsp;Anastasia N. K. Bruce,&nbsp;Jeffrey R. Gruen,&nbsp;Ellis Owusu-Dabo,&nbsp;Solomon Fiifi Ofori-Acquah,&nbsp;The SickleGenAfrica Network","doi":"10.1002/hem3.70209","DOIUrl":"https://doi.org/10.1002/hem3.70209","url":null,"abstract":"<p>Sickle cell disease (SCD) is characterized by chronic hemolysis, resulting in the release of extracellular heme, which contributes to oxidative stress and inflammation. Heme oxygenase-1 (HO-1), an inducible enzyme that degrades heme into cytoprotective by-products, plays a critical role in mitigating heme-induced toxicity. This study analyzed serum HO-1 levels in 2309 individuals with SCD (53% female; median age: 12 years) from the SickleGenAfrica cohort, comprising 57% hemoglobin SS disease (Hb SS), 30% hemoglobin SC disease (Hb SC), 3.1% Hb sickle beta plus thalassemia (Sβ+ thalassemia), and 9.9% Hb S-hereditary persistence of fetal hemoglobin (Hb S-HPFH). Median HO-1 levels were threefold higher in children under 16 years (69.8 ng/mL; interquartile range [IQR]: 29.8–137.6) compared to adults (23.1 ng/mL; IQR: 7.8–62.4; P &lt; 0.001), with peak levels observed in the 6–10-year age group. Across all subgroups, including sex, genotype, and hydroxyurea use, children consistently exhibited higher HO-1 levels than adults, with Hb SS patients showing the highest levels. Haptoglobin and hemopexin, key scavengers of hemoglobin and heme, respectively, were depleted in all patients, particularly in children. Overall, HO-1 levels in SCD patients were markedly elevated compared to healthy populations. These findings highlight the pronounced elevation of HO-1 in pediatric SCD patients, suggesting its potential protective role against heme-induced toxicity, especially during childhood.</p>","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/hem3.70209","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145110924","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 “Ex vivo drug responses and molecular profiles of 597 pediatric acute lymphoblastic leukemia patients”","authors":"","doi":"10.1002/hem3.70221","DOIUrl":"https://doi.org/10.1002/hem3.70221","url":null,"abstract":"<p>Enblad AP, Krali O, Gezelius H, et al. Ex vivo drug responses and molecular profiles of 597 pediatric acute lymphoblastic leukemia patients. <i>HemaSphere</i>. 2025;9(7):e70176. doi:10.1002/hem3.70176</p><p>The supplemental methods mentioned in the subsection titled “DNA methylation and RNA-sequencing data” was not included in the Supporting Information. This file has been added and cited at the applicable instance in the article.</p><p>We apologize for this error.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 9","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70221","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145101753","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":"ZRSR2 loss causes aberrant splicing in JAK2V617F-driven myeloproliferative neoplasm but is not sufficient to drive disease progression","authors":"Ranran Zhang,&nbsp;Jasmin Straube,&nbsp;Yashaswini Janardhanan,&nbsp;Rohit Haldar,&nbsp;Leanne Cooper,&nbsp;Noah Hayes,&nbsp;Charles Laurore,&nbsp;Chulwoo J. Kim,&nbsp;Marlise R. Luskin,&nbsp;Robert C. Lindsley,&nbsp;Maximilian Stahl,&nbsp;Ann Mullally,&nbsp;Anna E. Marneth,&nbsp;Megan Bywater,&nbsp;Steven W. Lane","doi":"10.1002/hem3.70225","DOIUrl":"10.1002/hem3.70225","url":null,"abstract":"&lt;p&gt;Myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are clonal disorders driven by mutations in hematopoietic stem cells (HSCs).&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;V617F&lt;/sup&gt; is the most recurrent driver mutation in MPN and results in the constitutive activation of the JAK-STAT pathway.&lt;span&gt;&lt;sup&gt;3-6&lt;/sup&gt;&lt;/span&gt; Mutations in &lt;i&gt;ZRSR2&lt;/i&gt; have been found in &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;V617F&lt;/sup&gt;-driven MPNs and are associated with disease progression and poor prognosis. However, the functional consequences of mutations in &lt;i&gt;ZRSR2&lt;/i&gt; in terms of disease progression in &lt;i&gt;JAK2&lt;/i&gt;&lt;sup&gt;V617F&lt;/sup&gt;-driven MPN have not been determined. In MPN, somatic mutations in &lt;i&gt;ZRSR2&lt;/i&gt; occur across the entire coding transcript, are predicted to confer a loss-of-function, and are primarily observed in male patients (Supporting Information: Figure S1).&lt;span&gt;&lt;sup&gt;7-9&lt;/sup&gt;&lt;/span&gt; Herein, using CRISPR-Cas9, we generated concomitant ZRSR2 loss in JAK2-mutated human megakaryoblastic cell lines (SET2, CHRF-288-11) and a mouse model of MPN to investigate its role in promoting disease progression. We confirmed ZRSR2 loss in both human cell lines and this mouse model by sequencing and immunoblotting (Supporting Information: Figures S2 and S3).&lt;/p&gt;&lt;p&gt;&lt;i&gt;ZRSR2&lt;/i&gt; is mainly involved in minor spliceosome assembly, with &lt;i&gt;ZRSR2&lt;/i&gt; loss previously shown to result in the mis-splicing of U12-type introns in myelodysplastic syndromes (MDSs).&lt;span&gt;&lt;sup&gt;10, 11&lt;/sup&gt;&lt;/span&gt; We therefore performed replicate multivariate analysis of transcript splicing (rMATS)&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt; to detect differential intron retention between &lt;i&gt;ZRSR2&lt;/i&gt; knockout (KO) megakaryoblastic cells and controls, and identified significantly increased retained intron (RI) events false discovery rate [FDR] &lt; .05) in SET-2 &lt;i&gt;ZRSR2&lt;/i&gt; KO cell lines, but not in CHRF-288-11. However, in both megakaryoblastic cell lines, RI events tended to be more prominent in genes containing U12-type introns in the context of &lt;i&gt;ZRSR2&lt;/i&gt; loss (Figure 1A). Differential gene expression analysis was performed to assess how &lt;i&gt;ZRSR2&lt;/i&gt; loss impacts transcription. Gene set enrichment analysis (GSEA) showed enrichment for genes containing U12-type introns in both ZRSR2 KO megakaryoblastic cell lines versus control cells (Supporting Information: Figure S4A). We observed significant enrichment for megakaryocyte progenitors (MkPs) and E2F target gene sets, which are involved in MkPs and myeloid differentiation, in CHRF-288-11 &lt;i&gt;ZRSR2&lt;/i&gt; KO cells, but not in SET-2 &lt;i&gt;ZRSR2&lt;/i&gt; KO cells (Supporting Information: Figure S4B). Taken together, we conclude that &lt;i&gt;ZRSR2&lt;/i&gt; loss causes U12-type intron retention and transcriptional changes in genes containing U12-type introns in human &lt;i&gt;JAK2&lt;/i&gt;-mutant megakaryoblastic cell lines.&lt;/p&gt;&lt;p&gt;&lt;i&gt;Zrsr2&lt;/i&gt; loss in &lt;i&gt;Jak2&lt;/i&gt;&lt;sup&gt;V617F&lt;/sup&gt;-driven murine MPN was achieved by isolating bone marro","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 9","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080287","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}