HemaSphere最新文献

{"title":"Human erythroid models of sickle cell disease","authors":"Deborah E. Daniels,&nbsp;Maria A. Lizarralde-Iragorri,&nbsp;Fatima O. Oyawoye,&nbsp;David C. Rees,&nbsp;Jan Frayne,&nbsp;Sara El Hoss","doi":"10.1002/hem3.70488","DOIUrl":"https://doi.org/10.1002/hem3.70488","url":null,"abstract":"<p>Sickle cell disease (SCD) is a group of severe inherited red blood cell disorders causing a major global healthcare burden. Despite recent advances in gene therapy and stem cell transplantation, treatment options remain very limited, highlighting the urgent need for the development of new therapeutic approaches. Human erythroid model systems of SCD represent emerging tools for the discovery of disease-modifying strategies through drug screening and mechanistic studies. This review describes the range of models available, including patient-derived red blood cells, hematopoietic stem cells, induced pluripotent stem cells, and immortalized cell lines, and summarizes their relative advantages and disadvantages, as well as potential integration with more complex integrated co-culture and organoid models. Overall, these cellular systems represent an expanding toolkit available to SCD researchers with the potential to reduce reliance on the use of animal models.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 10","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70488","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149205668","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":"EZH2 mutation status predicts inferior outcomes after bendamustine-based immunochemotherapy in frontline follicular lymphoma: A GELTAMO multicenter validation study","authors":"Carolina Martínez-Laperche,&nbsp;Pilar Lancho-Lavilla,&nbsp;Antonio Gutiérrez,&nbsp;Antonio Salar,&nbsp;Javier López-Jiménez,&nbsp;Blanca Ferrer-Lores,&nbsp;Alicia Serrano,&nbsp;Ana Jiménez-Ubieto,&nbsp;María Poza,&nbsp;Francisco Javier Díaz-Crespo,&nbsp;Paula Fernández-Caldas,&nbsp;Laura Sanz-Villanueva,&nbsp;Javier Menárguez-Palanca,&nbsp;Ismael Buño,&nbsp;María García-Álvarez,&nbsp;Paula Muñiz,&nbsp;Pablo Silva-de-Tena,&nbsp;Ramón García-Sanz,&nbsp;Miguel Alcoceba,&nbsp;Mariana Bastos-Oreiro","doi":"10.1002/hem3.70500","DOIUrl":"https://doi.org/10.1002/hem3.70500","url":null,"abstract":"&lt;p&gt;Follicular lymphoma (FL) is the most common indolent lymphoma,&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; a biologically and clinically heterogeneous entity with a diverse genetic landscape and characterized by slowly progressive but relapsing clinical course.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; The t(14;18) translocation driving BCL-2 overexpression is present in 85%–90% of patients&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; although additional genetic events are required for lymphomagenesis. Next-generation sequencing (NGS) studies have identified recurrent mutations in chromatin-modifying genes (&lt;i&gt;KMT2D&lt;/i&gt;, &lt;i&gt;CREBBP&lt;/i&gt;, and &lt;i&gt;EZH2&lt;/i&gt;).&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; &lt;i&gt;EZH2&lt;/i&gt; encodes the catalytic subunit of the Polycomb repressor complex 2 and mediates &lt;i&gt;H3K27&lt;/i&gt; methylation. Missense mutations in &lt;i&gt;EZH2&lt;/i&gt;, present in 20%–25% of patients, impair transcriptional programs regulating cell cycle and plasma-cell differentiation, promoting oncogenic transformation.&lt;span&gt;&lt;sup&gt;7-11&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;These insights led to the development of the m7-FLIPI risk model, which includes the mutational status of seven genes.&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt; &lt;i&gt;EZH2&lt;/i&gt; mutations carry the strongest weight and are associated with a more favorable prognosis in patients receiving chemoimmunotherapy. However, m7-FLIPI's prognostic performance depends on treatment regimen, performing less well with rituximab (R)-bendamustine or chemo-free approaches.&lt;span&gt;&lt;sup&gt;13, 14&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Frontline treatment of newly diagnosed FL commonly involves R-bendamustine or R plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). R-bendamustine is non-inferior in terms of efficacy and has less toxicity, but none of them has demonstrated benefits in overall survival (OS).&lt;span&gt;&lt;sup&gt;15-17&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;A previous retrospective single-center study by Martínez-Laperche et al.&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; suggested that &lt;i&gt;EZH2&lt;/i&gt; status may influence treatment response and guide regimen selection: patients with &lt;i&gt;EZH2&lt;/i&gt;-mutated FL achieved improved progression-free survival (PFS) and OS when treated with R-CHOP compared to R-bendamustine (4-year PFS 92% vs. 40%, OS 100% vs. 78% P = 0.039), whereas patients with wild-type &lt;i&gt;EZH2&lt;/i&gt; could obtain a greater benefit from R-bendamustine. These observations have not yet been confirmed, and clinical guidelines do not recommend routine use of &lt;i&gt;EZH2&lt;/i&gt; status to guide first-line therapy.&lt;/p&gt;&lt;p&gt;The aim of this study was to evaluate the predictive value of &lt;i&gt;EZH2&lt;/i&gt; mutation status for frontline treatment efficacy in FL and to validate whether &lt;i&gt;EZH2&lt;/i&gt; mutations identify patients who have a differential benefit from R-CHOP versus R-bendamustine in a multicenter real-world cohort.&lt;/p&gt;&lt;p&gt;We performed a retrospective multicenter analysis of 324 patients diagnosed with FL between 2002 and 2020 at six Spanish academic hospitals. Only patients who completed or were planned to receive six full-dose cycles of R-CHOP or R-bendamustine were included. Pa","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 10","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70500","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149205666","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":"Zanubrutinib monotherapy in CD79B-mutated relapsed or refractory diffuse large B-cell lymphoma: A multicenter Phase 2 study","authors":"Li Wang,&nbsp;Keshu Zhou,&nbsp;Fei Li,&nbsp;Qingyuan Zhang,&nbsp;Hui Zhou,&nbsp;Ou Bai,&nbsp;Liping Su,&nbsp;Chunhong Hu,&nbsp;Zhi-Ming Li,&nbsp;Kaiyang Ding,&nbsp;Qunyi Guo,&nbsp;Xiaoling Li,&nbsp;Xiaoxi Zhou,&nbsp;Wenjuan Yu,&nbsp;Shuhua Yi,&nbsp;Zhixia Wei,&nbsp;Wenbin Qian,&nbsp;Feiheng Chen,&nbsp;Guohui Cui,&nbsp;Zhiyu Liang,&nbsp;Qingchao Zeng,&nbsp;Jiaoyan Lyu,&nbsp;Yang Liu,&nbsp;Pan Zhang,&nbsp;Zhirong Shen,&nbsp;Zaixing Shi,&nbsp;Jing Rong,&nbsp;Wei-Li Zhao","doi":"10.1002/hem3.70504","DOIUrl":"https://doi.org/10.1002/hem3.70504","url":null,"abstract":"&lt;p&gt;Diffuse large B-cell lymphoma (DLBCL) remains a clinically and molecularly heterogeneous disease,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; with approximately one-third of patients developing relapsed or refractory (R/R) disease following frontline immunochemotherapy.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; Among molecularly defined subgroups, &lt;i&gt;CD79B&lt;/i&gt; mutations occur in 5%–25% of DLBCL, and tumors harboring &lt;i&gt;CD79B&lt;/i&gt; mutations represent a biologically distinct entity characterized by chronic active B-cell receptor (BCR) signaling and constitutive activation of the NF-κB pathway, conferring inferior outcomes with conventional therapy.&lt;span&gt;&lt;sup&gt;3-7&lt;/sup&gt;&lt;/span&gt; &lt;i&gt;CD79B&lt;/i&gt; mutations are enriched in the ABC subtype, consistent with their role in subtype-specific BCR signaling.&lt;span&gt;&lt;sup&gt;7-9&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Bruton tyrosine kinase (BTK) is a central mediator of BCR signaling, providing a strong biological rationale for BTK inhibition in &lt;i&gt;CD79B&lt;/i&gt;-mutated DLBCL.&lt;span&gt;&lt;sup&gt;10, 11&lt;/sup&gt;&lt;/span&gt; However, prospective data evaluating BTK inhibitor monotherapy specifically in this genetically defined population remain limited. Here, we report the efficacy, safety, and exploratory biomarker analyses from a multicenter, Phase 2 study of zanubrutinib monotherapy in patients with &lt;i&gt;CD79B&lt;/i&gt;-mutated R/R DLBCL. This was an open-label, single-arm, multicenter, Phase 2 study conducted in China (NCT05068440). Adult patients with histologically confirmed DLBCL harboring &lt;i&gt;CD79B&lt;/i&gt; mutations detected using a validated amplification refractory mutation system polymerase chain reaction (PCR) assay and R/R disease after at least one prior systemic therapy were eligible. Zanubrutinib was administered orally at 160 mg (as two 80-mg capsules) twice daily in continuous 28-day cycles until progressive disease (PD), unacceptable toxicity, or study discontinuation. All patients who permanently discontinued zanubrutinib remained in long-term survival follow-up. Safety follow-up visits occurred ~30 days (±7 days) after the last dose of zanubrutinib and included planned safety assessments, laboratory assessments, and recording of alternative anticancer therapy given after the last dose of the study drug. Long-term follow-up continued until PD, start of alternative anticancer therapy, loss to follow-up, or study end, whichever occurred first. The primary endpoint was investigator-assessed overall response rate (ORR) according to the Lugano 2014 criteria.&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt; Secondary endpoints included complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Detailed eligibility criteria and full methodological details, including molecular profiling, circulating tumor DNA (ctDNA) analysis, RNA sequencing, and statistical analysis, are provided in the Supplemental Methods.&lt;/p&gt;&lt;p&gt;Demographics, baseline clinical characteristics, and safety data were summarized descriptively. For response rates, two-sided Clopper–Pearson","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 10","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70504","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149205667","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":"Comment on \"EHA Guidelines on management of chronic lymphocytic leukemia and Richter transformation\".","authors":"Alessandra Tedeschi, Raul Cordoba, Alessandra Ferrajoli, George Follows, Anna Maria Frustaci, Anne Sophie Michallet, Talha Munir, Susan O'Brien, John F Seymour, Tait Shanafelt, Clemens Martin Wendtner, Pier Luigi Zinzani, Stephan Stilgenbauer","doi":"10.1002/hem3.70494","DOIUrl":"https://doi.org/10.1002/hem3.70494","url":null,"abstract":"","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 10","pages":"e70494"},"PeriodicalIF":11.3,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181487","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":"Immune and cellular determinants of response to HMA-venetoclax regimens in acute myeloid leukemia","authors":"Alfredo Marchetti,&nbsp;Francesca Lazzaroni,&nbsp;Matteo Claudio Da Via',&nbsp;Marta Lionetti,&nbsp;Giulia Maggioni,&nbsp;Alessia Campagna,&nbsp;Denise Ventura,&nbsp;Giorgio A. Croci,&nbsp;Alessio Marella,&nbsp;Akihiro Maeda,&nbsp;Antonio Matera,&nbsp;Emanuele Calvi,&nbsp;Margherita Scopetti,&nbsp;Filippo Viviani,&nbsp;Nicolò Rampi,&nbsp;Davide Bonometti,&nbsp;Elena Benzoni,&nbsp;Manuela Zappa,&nbsp;Sonia Fabris,&nbsp;Marzia Barbieri,&nbsp;Stefania Pioggia,&nbsp;Claudia Leoni,&nbsp;Antony Ricchiuti,&nbsp;Matteo G. D. Porta,&nbsp;Mariarita Sciumè,&nbsp;Francesco Passamonti,&nbsp;Nicola S. Fracchiolla,&nbsp;Niccolò Bolli","doi":"10.1002/hem3.70498","DOIUrl":"10.1002/hem3.70498","url":null,"abstract":"<p>Hypomethylating agents (HMAs) combined with Venetoclax have reshaped the therapeutic landscape of acute myeloid leukemia (AML), yet the biological determinants of response remain unclear. We integrated clinical and genomic profiling in 132 newly diagnosed or relapsed/refractory AML patients treated with HMA-Venetoclax and performed single-cell RNA sequencing and T cell receptor (TCR) profiling in 10 newly diagnosed cases to define cellular and immune correlates of response. Response rates and survival aligned with published data. DNA Sequencing confirmed the favorable impact of IDH2 and the poor prognosis of TP53 mutations. scRNA-seq and TCR analysis showed that responders exhibited expansion of cytotoxic CD8⁺ T cells, increased TCR clonal diversity, and activation of antigen-presentation pathways. Nonresponders displayed baseline inflammatory signaling, impaired myeloid maturation, and a suppressive microenvironment enriched in IDO1⁺ dendritic cells. Resistant AMLs showed stem-like dedifferentiation and sustained EMT. LAG-3 expression marked dysfunctional T cell states and emerged as a potential biomarker and therapeutic target.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 10","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13660835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181457","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 maturation of precision medicine into pragmatic, patient-centered care: A commentary on the 2026 EHA CLL Guidelines.","authors":"Stefano Molica, Talha Munir, David Allsup","doi":"10.1002/hem3.70491","DOIUrl":"https://doi.org/10.1002/hem3.70491","url":null,"abstract":"","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 10","pages":"e70491"},"PeriodicalIF":11.3,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13659396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181426","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":"Response to two comments on “EHA Guidelines on management of chronic lymphocytic leukemia and Richter transformation” by S. Molica and A. Tedeschi: Beyond the binary choice","authors":"Barbara Eichhorst,&nbsp;Paolo Ghia,&nbsp;Francesc Bosch,&nbsp;Ruth Clifford,&nbsp;Michael Gregor,&nbsp;Romain Guieze,&nbsp;Arnon P. Kater,&nbsp;Carsten U. Niemann,&nbsp;Sarka Pospisilova,&nbsp;Tadeusz Robak,&nbsp;Anna Schuh,&nbsp;Kostas Stamatopoulos,&nbsp;Tamar Tadmor,&nbsp;Nick York","doi":"10.1002/hem3.70492","DOIUrl":"10.1002/hem3.70492","url":null,"abstract":"&lt;p&gt;In this issue of &lt;i&gt;HemaSphere&lt;/i&gt;, two timely comments to the recently disseminated “EHA Guidelines on management of chronic lymphocytic leukemia and Richter transformation”&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; have been published (Molica et al., Tedeschi et al.), underscoring the great interest and attention for these updates from the scientific community that see them as a valuable tool to deliver optimal care to patients with chronic lymphocytic leukemia (CLL). This open and constructive discussion is vital for our community at large, of both patients and physicians, and will help shape the next updates (that from now on will be annual) aiming to use these guidelines as a living document for continuous improvement in the management of CLL.&lt;/p&gt;&lt;p&gt;Both groups of authors recognized the actual novelty of these guidelines. More importantly, as also acknowledged in the commentary by Molica et al., the European Hematology Association (EHA) Guidelines have become more patient-centric, a result achieved thanks to having not only a patient representative as coauthor but also a group of patient representatives who provided advice. This led to a vision where these guidelines advocate for maximizing net clinical benefit.&lt;/p&gt;&lt;p&gt;Given the novelty and inherent complexity of this reasoning and presentation approach, the discussion emerging in the scientific community is expected and valuable. We welcome the constructive feedback pointing out inevitable inconsistencies that may occur due to the profound restyling of the new guidelines. Some of these have been already addressed in the recently published Erratum.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Some others, such as the inclusion of a discussion on frail patients, will be taken care of in the next update by adding frailty as an additional feature to the integrated vision of Figure 2. To this end, it is useful to keep in mind that “frailty” in CLL is an undefined situation, as much as “fitness,” that should be carefully evaluated and for which specific data are limited. In general, we appreciate the solicitation to elaborate more on the reasoning behind some first-line treatment statements: this gives us the opportunity to clarify some aspects that were overlooked in the original manuscript. Future editions will, inevitably, provide more robust justification while avoiding a systematic review-style manuscript that goes beyond the aims of guidelines.&lt;/p&gt;&lt;p&gt;It is worth noting that, rather than being an expert consensus, the guidelines were built on objective measurements as they systematically provided level of evidence (LoE), grade of recommendation and, for the first time, European Society for Medical Onology Magnitude of Clinical Benefit Scale for Haematological Malignancies (ESMO-MCBS:H) scores. This first application of the ESMO-MCBS:H score for a hematological malignancy was recommended by EHA and provides an opportunity to assess its value in clinical practice and identify areas for further refinement, particularly in a dise","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 10","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13649005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136538","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 thrombopoietin receptor S264F mutant drives MPN with marrow fibrosis through a dual mechanism","authors":"Charlotte Lees,&nbsp;Emile Brandt,&nbsp;Emmanuel Dutranoix,&nbsp;Gabriel Levy,&nbsp;Bogdan I. Iorga,&nbsp;Hosuk Ryou,&nbsp;Jens Rittscher,&nbsp;Daniel Royston,&nbsp;Stefan N. Constantinescu,&nbsp;Adam J. Mead","doi":"10.1002/hem3.70437","DOIUrl":"10.1002/hem3.70437","url":null,"abstract":"&lt;p&gt;The thrombopoietin (TPO)/TPO receptor (TPOR/MPL) axis is fundamental for megakaryocyte (MK) differentiation, platelet production, and maintenance of hematopoietic stem cells. TPO is produced in the kidney, liver, and bone marrow and binds the extracellular domain (ECD) of TPOR on the cell surface, leading to receptor dimerization and activation of the JAK-STAT pathway.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Upon binding its receptor on MKs and platelets, TPO is internalized and degraded, regulating its level via a negative feedback mechanism. Hence, in normal human hematopoiesis, TPO levels correlate inversely with platelet count.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;TPOR is encoded by the &lt;i&gt;MPL&lt;/i&gt; gene on chromosome 1. Activating germline mutations of TPOR have been implicated in hereditary thrombocytosis.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Somatic TPOR mutations are phenotypic driver mutations in myeloproliferative neoplasms (MPN), occurring in 5%–7% essential thrombocythemia (ET) cases, classically at positions 515 and 505 in exon 10, which covers the transmembrane domain (TMD),&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; leading to constitutive JAK-STAT activation&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; and an MPN phenotype in mouse models with an increase in MK and platelet numbers.&lt;span&gt;&lt;sup&gt;6, 7&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Conversely, homozygous knockout of &lt;i&gt;MPL&lt;/i&gt; in mice causes significant thrombocytopenia and high TPO levels due to a lack of receptor-mediated clearance.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; In humans, inherited inactivating TPOR mutations are implicated in congenital amegakaryocytic thrombocytopenia (CAMT), an autosomal recessive disease characterized by thrombocytopenia and progression to trilineage aplasia; these patients also exhibit high TPO levels. Most mutations in CAMT are missense mutations, predominantly affecting TPO-binding residues 102 and 104, causing absent cell surface expression or inability to bind TPO, respectively.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Intriguingly, reduced surface TPOR due to germline mutations can paradoxically result in thrombocytosis.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; For example, the CAMT mutation &lt;i&gt;MPL&lt;/i&gt; R102P exerts the opposite phenotype of thrombocytosis when heterozygous. It is thought that the partial trafficking defect leads to insufficient clearance of TPO, which drives thrombocytosis via the remaining wild-type (WT) receptor.&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;We present a somatic &lt;i&gt;MPL&lt;/i&gt; mutation not previously reported in MPN, identified in a 51-year-old white British male, who presented clinically well but with an incidental thrombocytosis of 840 × 10&lt;sup&gt;9&lt;/sup&gt;/L. Other blood parameters were normal (Supporting Information S1: Figure S1). Blood film examination confirmed thrombocytosis but was otherwise unremarkable. Bone marrow trephine demonstrated MPN features with grade MF1–MF2 fibrosis but no excess of blasts. Using Continuous Indexing of Fibrosis (CIF) analysis,&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt; this trephine lies in the prefibrotic primary myelofibrosis (pre-PM","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 10","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136468","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":"Dual targeting of BCMA and GPRC5D with the trispecific antibody ramantamig addresses antigenic heterogeneity in myeloma","authors":"Chloe O'Neill,&nbsp;Marloes E. C. Broekmans,&nbsp;Charlotte L. B. M. Korst,&nbsp;Maria Krevvata,&nbsp;Giada Dal Collo,&nbsp;Richard W. Groen,&nbsp;Bing Li,&nbsp;Serena R. Baglio,&nbsp;Ulrike Philippar,&nbsp;Kodandaram Pillarisetti,&nbsp;Sonja Zweegman,&nbsp;Deeksha Vishwamitra,&nbsp;Tuna Mutis,&nbsp;Niels W. C. J. van de Donk","doi":"10.1002/hem3.70487","DOIUrl":"10.1002/hem3.70487","url":null,"abstract":"<p>Despite advances in terms of bispecific antibodies (BsAbs) targeting single tumor-associated antigens in multiple myeloma (MM), not all patients respond, and most eventually relapse. Using flow cytometry, we found that BCMA and GPRC5D expression is highly heterogeneous within and between patients. Dual targeting with ramantamig (JNJ-79635322), a trispecific antibody targeting both BCMA and GPRC5D on the tumor cell surface, has been hypothesized to improve efficacy by overcoming heterogeneous target expression and preventing resistance due to antigen escape. Using T-cells from healthy donors, ramantamig was significantly more effective than mono-targeting antibodies against BCMA⁺GPRC5D⁺ MM cell lines, and also efficiently eliminated single antigen-positive MM cell lines. Additionally, ramantamig effectively induced MM cell lysis in 32 BM samples from MM patients (mean lysis with 0.4 nM: 60%), demonstrating superior cytotoxic activity compared to BCMA- and GPRC5D-mono-targeting BsAbs (13% and 5%, respectively). There was no difference in ramantamig-mediated lysis of MM cells from newly diagnosed or heavily pretreated, BsAb-naïve patients. Importantly, tumor cell target expression was an important determinant of <i>ex vivo</i> response, shown by superior MM cell lysis in samples with higher than median baseline proportion of GPRC5D/BCMA double-antigen-positive MM cells, when compared to lower GPRC5D/BCMA expression. Notably, ramantamig potency was less affected by the presence of soluble BCMA, compared to the BCMA-mono-targeting control antibody. Finally, ramantamig showed superior potency, compared to the combination of two single-targeted BsAbs, probably due to higher avidity against heterogeneous targets. In conclusion, dual-antigen targeting with ramantamig represents a significant advancement in overcoming tumor heterogeneity and preventing antigen escape-mediated resistance.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 10","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136513","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":"Long-term mutational analysis, clonal metrics, and dynamics in patients with chronic idiopathic neutropenia","authors":"Grigorios Tsaknakis,&nbsp;Irene Mavroudi,&nbsp;Marco Roncador,&nbsp;Anna Maria Perantonaki,&nbsp;Erasmia Boutakoglou,&nbsp;Stavros Papadakis,&nbsp;Anna Gallì,&nbsp;Stamatia Laidou,&nbsp;Charalampos Pontikoglou,&nbsp;Anastasia Chatzidimitriou,&nbsp;Luca Malcovati,&nbsp;Helen A. Papadaki","doi":"10.1002/hem3.70496","DOIUrl":"10.1002/hem3.70496","url":null,"abstract":"<p>Characterization of the presence and evolution of clonal hematopoiesis (CH) in patients with unexplained cytopenias is fundamental to risk-stratifying patients and optimizing clinical surveillance for malignant progression. We investigated the mutational spectrum and clonal metrics in a cohort of 256 patients with chronic idiopathic neutropenia (CIN)—clinically overlapping with idiopathic cytopenia of undetermined significance with isolated neutropenia (ICUS-N)—and assessed clonal presence and dynamics through longitudinal tracking of 104 patients with a median follow-up of 32 months. CH was identified in 12.5% of patients, primarily involving single <i>DNMT3A</i> or <i>TET2</i> mutations. Longitudinal analysis revealed two distinct mutational patterns: an age-related pattern, predominantly involving <i>DNMT3A</i> and <i>TET2</i> single mutations, which showed marginal changes in clone size and associated with stable disease course, and a high-risk pattern, primarily driven by <i>SRSF2</i> and <i>IDH1/2</i> mutations, characterized by higher clonal expansion and a high risk of malignant progression. Malignant transformation in CIN was significantly associated with baseline variant allele frequency (VAF) (VAF &gt; 10%), the presence of multiple mutations, and detection of specific driver mutations (<i>SRSF2</i>, <i>IDH1/2</i>). An annual VAF increase (ΔVAF/year) ≥7.5% was found to optimally predict evolution, thus showing that clonal dynamics can serve as an indicator of disease outcome. Longitudinal assessment of peripheral blood hematologic parameters was found not to display clinically significant changes. These findings provide important insight into high-risk evolutionary patterns in CIN and underscore the importance of longitudinal monitoring with next-generation sequencing (NGS) for clinical decision-making and risk-adapted management in CIN patients with clonal cytopenia.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"10 10","pages":""},"PeriodicalIF":11.3,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13641289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149108639","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}