HemaSphere最新文献

{"title":"Validation of the diagnostic potential of 17 immunophenotypic core markers defined by the ELN-iMDS-Flow Working Group in an independent cohort of patients with MDS","authors":"Coen R. Veenstra, Canan Alhan, Theresia M. Westers, Arjan A. van de Loosdrecht","doi":"10.1002/hem3.70075","DOIUrl":"https://doi.org/10.1002/hem3.70075","url":null,"abstract":"<p>Myelodysplastic neoplasms (MDS) are a group of heterogeneous clonal hematopoietic stem cell disorders with complex diagnostic challenges.<span><sup>1</sup></span> Extensive diagnostic criteria published by the World Health Organization (WHO), combining hematological, morphological, cytogenetic, and molecular features aid clinicians in establishing an early diagnosis.<span><sup>2</sup></span> Despite these well-defined criteria, the diagnostic process remains challenging, especially in low-risk MDS.</p><p>Flow cytometric (FC) evaluation of the bone marrow, supported and recommended by the WHO, is an additional tool in this diagnostic process.<span><sup>3-5</sup></span> Several FC-based methods have been published and validated.<span><sup>6</sup></span> The <i>Ogata Score</i>, consisting of four parameters, and the <i>Integrated Flow Score</i> (<i>iFS</i>), consisting of 44 parameters, are well-established methods for FC evaluation in the diagnostic work-up of MDS (Supporting Information S1: Table S1).<span><sup>7-9</sup></span></p><p>However, a survey amongst 200+ laboratories revealed a need to harmonize and optimize MDS-FC protocols to ensure broad clinical application.<span><sup>9-11</sup></span> Therefore, the European LeukemiaNet/International Myelodysplastic Syndrome Flow Cytometry Working Group (ELN-iMDS) performed a multicenter study in which they identified 17 immunophenotypic core markers (ELN Scoring System) that, when aberrant, are independently indicative of MDS and/or chronic myelomonocytic leukemia (CMML) (Supporting Information S1: Table S2). A cut-off of ≥3 aberrancies resulted in 80% concordance with cytomorphology and having >3% myeloid progenitor cells (MPC) had a Positive Predictive Value (PPV) of 98%.<span><sup>12</sup></span></p><p>Here, we validated the ELN Scoring System and the >3% MPC cut-off compared to an integrated diagnostic approach, including cytomorphology, cytogenetics, next-generation sequencing (NGS), and two flow cytometry-based scores, that is, Ogata score and iFS, in an independent cohort. We specifically focused on low-risk MDS cases, as these are considered the major diagnostic challenge.<span><sup>13</sup></span></p><p>In total, 180 MDS patients and 54 pathological controls (PC) were enrolled in this study (Supporting Information S1: Figure S1 and Supporting Information S1: Tables S3 and S4); 76% of the MDS patients were considered low-risk based on bone marrow blast percentage (defined as <5%), and 62% by using IPSS-M (defined as “Very Low,” “Low,” and “Moderate Low”).</p><p>First, we assessed the aberrancies according to the ELN Scoring System. MDS patients had a median of five aberrancies (range: 1–11); PC two aberrancies (range: 0–6). Having ≥3 aberrant markers resulted in an overall diagnostic accuracy of 87% as compared to an integrated diagnostic approach (<i>p</i> < 0.001). The iFS and Ogata Score had an overall accuracy of 91% and 71%, respectively (Figure 1A). The sensitivity of t","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143571402","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":"TIF Guidelines for the Management of Transfusion-Dependent β-Thalassemia","authors":"Khaled M. Musallam, Maria Domenica Cappellini, John B. Porter, Dimitrios Farmakis, Androulla Eleftheriou, Michael Angastiniotis, Ali T. Taher","doi":"10.1002/hem3.70095","DOIUrl":"https://doi.org/10.1002/hem3.70095","url":null,"abstract":"<p>The prospect of patients with transfusion-dependent β-thalassemia (TDT), once considered a fatal childhood disorder, has completely transformed over the past 50 years.<span><sup>1</sup></span> This is primarily attributed to the adoption of hemovigilance in transfusion therapy, the development of effective iron chelators, the validation of non-invasive tools for monitoring organ-specific iron loading, and the introduction of multidisciplinary care. Regrettably, access to these advances and optimal application of best practices remain largely confined to nations with robust economies, where comprehensive health and social care systems provide universal access to treatment.<span><sup>2</sup></span> Consequently, multimorbidity and shortened survival continue to burden patients in countries with limited resources, where most of TDT patients live.<span><sup>3</sup></span> In high-income settings, improved survival of TDT did not come without its own “side effect,” where aging allowed several previously unrecognized morbidities to manifest, especially in patients who were exposed to the harmful effects of under- or sub-optimal treatment in the past.<span><sup>4, 5</sup></span> Thus, the “gold standard” in TDT care is now fundamentally recognized as being a multidisciplinary approach to management, preferably in expert or reference centers, and with active engagement of patients and their families.<span><sup>6</sup></span></p><p>Since its inception in 1986, the Thalassaemia International Federation (TIF) has remained committed to supporting patients/families and patient organizations, healthcare professionals, and policymakers to promote optimal care for patients with thalassemia and other hemoglobinopathies across the world. The preparation, publication, translation, and free distribution of management guidelines is a cornerstone of its educational mission. Widely recognized for their significant impact on the care of patients with TDT, and broadly endorsed by the international medical community, these guidelines serve as a critical resource for healthcare providers and a foundation upon which national policies and practices can be built.</p><p>The 5th edition of TIF “Guidelines for the Management of Transfusion-Dependent β-Thalassemia (TDT)” has now become available (available for free download at: https://thalassaemia.org.cy/tif-publications/).<span><sup>7</sup></span> In keeping with the many and multiple unmet needs of patients in different geographies, the guidelines have been carefully crafted to offer evidence-based recommendations (key points and recommendations from select chapters on diagnosis and disease management are provided in Table 1, and a summary of monitoring recommendations is provided in Supporting Information S1: Table S1) while also suggesting solutions and pathways for care in resource-limited settings. Recommendations are provided by a global and diverse group of experts with decades of experience in patient care, through 1","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 3","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70095","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143554556","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":"Salvage treatment after covalent BTKi failure: An unmet need in clinical practice in Waldenstrom macroglobulinemia","authors":"Anna Maria Frustaci, Arianna Zappaterra, Andrea Galitzia, Andrea Visentin, Michele Merli, Rita Rizzi, Isacco Ferrarini, Simone Ferrero, Vanessa Innao, Claudia Baratè, Pierluigi Zinzani, Benedetta Puccini, Francesco Autore, Monica Tani, Angela Ferrari, Gioacchino Catania, Maura Nicolosi, Raffaella Pasquale, Marina Motta, Roberta Murru, Silvia Gambara, Francesca Rezzonico, Marzia Varettoni, Emanuele Cencini, Enrico Lista, Nicolò Danesin, Bianca Maria Granelli, Marina Deodato, Francesco Piazza, Alessandra Tedeschi","doi":"10.1002/hem3.70094","DOIUrl":"https://doi.org/10.1002/hem3.70094","url":null,"abstract":"<p>Waldenstrom Macroglobulinemia (WM) therapeutic scenario has radically changed over the past 20 years with the development of effective therapies able to improve patients’ outcomes.<span><sup>1</sup></span> The approval of covalent Bruton Tyrosine Kinase inhibitors (cBTKi), ibrutinib since 20 15<span><sup>2</sup></span> and zanubrutinib afterwards,<span><sup>3</sup></span> replaced the role of chemoimmunotherapy (CIT) at least in the relapsed/refractory setting. However, despite the remarkable efficacy of cBTKi, the continuous treatment paradigm is associated with resistance development, clonal evolution and relapses, with about 13% of progressions with both zanubrutinib and ibrutinib at the ASPEN trial final analysis.<span><sup>4</sup></span> Intolerance represents another main reason for discontinuation and this is more true with the first-in-class cBTKi (20% vs. 8.9% with zanubrutinib)<span><sup>4</sup></span> and in clinical practice, where unselected patients are treated. While toxicity-related withdrawal allows a window of opportunity for administering alternative cBTKi,<span><sup>5</sup></span> few therapeutic options have been evaluated for relapsed/refractory,<span><sup>6, 7</sup></span> and none have received approval, rendering this scenario the most significant unmet clinical need in WM. We conducted this retrospective analysis to assess salvage therapy outcomes following cBTKi (cBTKi-S) in 22 Italian centers. This study was institutional review board approved by each participating institution in accordance with the Declaration of Helsinki. All patients receiving at least one dose of cBTKi-S were considered. Baseline clinical and disease characteristics at cBTKi-S initiation were reviewed. <i>MYD88</i> and <i>CXCR4</i> mutation tests were locally performed by Sanger sequencing. Duration of first cBTKi was calculated from therapy initiation to discontinuation. Reasons for cBTKi discontinuation, type of cBTKi-S, responses and progression assessment, according to modified IWWM-11 criteria<span><sup>8</sup></span> and duration of response (DOR) were reviewed. DOR was calculated in responding patients from cBTKi-S initiation to progression. Progression-free survival (PFS) was defined as the time from cBTKi-S to progression or death due to any cause, OS as the time from cBTKi-S to death due to any cause. Kaplan-Meier analysis was used to estimate cBTKi-S survival outcomes and the log-rank test was applied to compare time to event outcomes between groups. From December 2015 to November 2023, 233 consecutive WM patients treated with cBTKi were included. Of these, 78 (33.5%) discontinued cBTKi (74 ibrutinib, 4 zanubrutinib) and received subsequent salvage therapies, representing our study population. Median age of the 78 patients was 75.5 years (range, 46.8–92.8). All but two received cBTKi for relapsed/refractory disease after a median of two prior lines (range, 1–6), including CIT in 92.3%. Primary reasons for cBTKi discontinuation were pr","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70094","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455778","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":"Outcomes of patients with relapsed or refractory primary mediastinal B-cell lymphoma treated with anti-CD19 CAR-T cells: CARTHYM, a study from the French national DESCAR-T registry","authors":"Jean Galtier,&nbsp;Charles Mesguich,&nbsp;Pierre Sesques,&nbsp;Vivien Dupont,&nbsp;Emmanuel Bachy,&nbsp;Roberta Di Blasi,&nbsp;Catherine Thieblemont,&nbsp;Thomas Gastinne,&nbsp;Guillaume Cartron,&nbsp;Gabriel Brisou,&nbsp;François-Xavier Gros,&nbsp;Justine Decroocq,&nbsp;Franck Morschhauser,&nbsp;Marie-Thérèse Rubio,&nbsp;Laurianne Drieu La Rochelle,&nbsp;Fabien Le Bras,&nbsp;Sylvain Carras,&nbsp;Adrien Chauchet,&nbsp;Jacques-Olivier Bay,&nbsp;Magalie Joris,&nbsp;Mickael Loschi,&nbsp;Aline Tanguy-Schmidt,&nbsp;Alexandra Marquet,&nbsp;Vincent Camus,&nbsp;Steven Le Gouill,&nbsp;Roch Houot,&nbsp;Krimo Bouabdallah","doi":"10.1002/hem3.70091","DOIUrl":"https://doi.org/10.1002/hem3.70091","url":null,"abstract":"<p>Primary mediastinal B-cell lymphoma (PMBL) is often cured with dose-dense anthracycline-based regimens but the prognosis at relapse or progression remains poor. While anti-CD19 CAR-T cell therapy has dramatically improved outcomes in relapsed or refractory large B-cell lymphoma, far less is known about their efficacy in PMBL. Using the systematic record of all patients treated with CAR-T cells prospectively included in the DESCAR-T registry in France, along with centrally reviewed positon-emission tomography (PET) imaging, we describe the outcomes and key determinants of treatment success in PMBL patients treated over a 6-year period. Among 82 patients infused in the registry we observed a best complete response (CR) rate, 2-year progression-free survival (PFS), and 2-year overall survival (OS) of 68.1%, 57.4%, and 73.8%, respectively. Outcomes were even better for the 62 patients infused with axicabtagene ciloleucel, with best CR rate, 2-year PFS, and 2-year OS reaching 74.5%, 70.4%, and 86.9%, respectively. Achieving a Deauville score of 1–4 or a ΔSUVmax reduction of more than 24% at the 1-month evaluation was associated with excellent outcomes, whereas increased total metabolic tumor volume baseline PET increased the risk of treatment failure. Surprisingly, neither the response to bridging therapy nor the type of bridging therapy (chemotherapy versus immune checkpoint inhibitors) were associated with long-term outcomes. In conclusion, this study confirms that anti-CD19 CAR-T cells as a valid standard-of-care for relapsed and refractory PMBL and highlights key determinants of treatment success.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431741","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":"HLA evolutionary divergence score after donor lymphocyte infusion following allogeneic hematopoietic stem cell transplantation","authors":"Sophie Le Grand,&nbsp;Juliette Villemonteix,&nbsp;Etienne Daguindau,&nbsp;Marylise Fort,&nbsp;Sophie Caillat-Zucman,&nbsp;Vincent Allain,&nbsp;Anne Dormoy,&nbsp;Veronique De Mas,&nbsp;Eric Delabesse,&nbsp;Christian Recher,&nbsp;Regis Peffault de Latour,&nbsp;Nicolas Vallet,&nbsp;David Michonneau,&nbsp;Sarah Guenounou,&nbsp;Anne Huynh","doi":"10.1002/hem3.70088","DOIUrl":"https://doi.org/10.1002/hem3.70088","url":null,"abstract":"<p>Donor lymphocyte infusion (DLI) prevents acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) relapses following hematopoietic stem cell transplantation. Given the life-threatening toxicities such as graft versus host disease (GVHD), the identification of variables associated with response without toxicities is warranted. We hypothesized that HLA evolutionary divergence (HED), defined by the diversity between two given alleles of the same HLA gene, may be such a factor. A retrospective multicenter case-control study was conducted to evaluate the outcomes of pre-emptive (preDLI) and prophylactic DLI (proDLI) regarding their HED score, in AML or MDS patients. DLI-treated patients were matched with controls (1:2 matched) from French transplantation centers according to hospital, hemopathy, donor type, and risk classification. In total, 201 patients were included (<i>N</i> = 147 in the preDLI group, <i>N</i> = 54 in the proDLI group). Relapse-free survival was significantly better in the preDLI group (hazard ratio [HR] = 0.23, 95% confidence interval [CI]: 0.14–0.55, <i>p</i> &lt; 0.001) than in controls. However, this benefit was offset by a higher incidence of severe GVHD (HR = 4.88, 95% CI: 2.30–10.32, <i>p</i> &lt; 0.001). HED A, B, C, DQA1, DQB1, DPB1, and DRB1 were calculated for 65 DLI-treated patients. High-class II HED was significantly associated with higher GVHD and relapse-free survival (GRFS, HR = 0.33, 95% CI: 0.20–0.77, <i>p</i> = 0.005). Specific DQAB associations directly improved GRFS (HR = 0.23, 95% CI: 0.09–0.58, <i>p</i> = 0.004). In conclusion, screening the class II HED score identifies patients eligible for DLI treatment who will benefit the most from this strategy.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70088","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143396766","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 luspatercept can be predicted and improves overall survival in the real-life treatment of LR-MDS","authors":"Angela Consagra,&nbsp;Luca Lanino,&nbsp;Najla H. Al Ali,&nbsp;Luis Aguirre,&nbsp;Zhuoer Xie,&nbsp;Onyee Chan,&nbsp;Gloria Andreossi,&nbsp;Marco G. Raddi,&nbsp;Luca Rigodanza,&nbsp;Alessandro Sanna,&nbsp;Giorgio Mattiuz,&nbsp;Elena Tofacchi,&nbsp;Cristina Amato,&nbsp;Michele Tanturli,&nbsp;Sven De Pourcq,&nbsp;Alison Walker,&nbsp;Andrew Kuykendall,&nbsp;Jeffrey Lancet,&nbsp;Eric Padron,&nbsp;David A. Sallman,&nbsp;Francesco Restuccia,&nbsp;Alessandra Perego,&nbsp;Marta Ubezio,&nbsp;Bruno Fattizzo,&nbsp;Marta Riva,&nbsp;Giulia Maggioni,&nbsp;Alessia Campagna,&nbsp;Matteo G. Della Porta,&nbsp;Valeria Santini,&nbsp;Rami S. Komrokji","doi":"10.1002/hem3.70086","DOIUrl":"https://doi.org/10.1002/hem3.70086","url":null,"abstract":"<p>We explored the impact of luspatercept therapy on overall survival (OS) and possible predictors of response in low-risk (LR) myelodysplastic syndrome (MDS) patients. We evaluated 331 anemic patients treated with luspatercept. Hematological response (HI) was defined as (i) hemoglobin (Hb) increase of ≥1.5 g/dL in nontransfusion-dependent (NTD) patients, and (ii) red blood cell (RBC) transfusion independence (TI) with a concomitant Hb increase of ≥1.5 g/dL, or RBC-TI without an Hb increase of 1.5 g/dL, or &gt;50% reduction in RBC transfusion burden (TB) for TD patients. Response was observed in 166 patients (50.2%), with significantly higher response in NTD and low TB versus high TB patients (<i>p</i> &lt; 0.001). A significant correlation between lower Molecular International Prognostic Scoring System (IPSS-M) risk scores and response was observed. No statistically significant difference in HI was found in <i>SF3B1-</i>mutated versus wild-type MDS patients (53.8% vs. 40.1%, respectively). <i>SF3B1</i>mut hotspots (K700E vs. others) and variant allele frequencies (VAFs; &lt;38% VAF vs. ≥38% VAF) did not impact on HI. <i>SF3B1-</i>mutated MDS with del5q showed inferior HI compared to other LR-MDS (<i>p</i> = 0.046). The median treatment duration overall was 35 weeks (20.86–90.29), the median time to response was 11 weeks (8.71–21.86), and the median duration of response was 65 weeks (26.5–114). After a median follow-up of 13 months, median OS was not reached (NR) for responders and 24 months for nonresponders (hazard ratio [HR] 0.25, 95% confidence interval 0.14–0.44, <i>p </i>&lt; 0.001). This analysis of 331 luspatercept real-life-treated LR-MDS patients demonstrated a significant OS benefit upon luspatercept response. Low baseline RBC-TB and lower risk IPSS-M scores correlated with higher HI and could constitute predictive markers of response.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70086","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143389154","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":"Single-cell DNA and surface protein characterization of high hyperdiploid acute lymphoblastic leukemia at diagnosis and during treatment","authors":"Margo Aertgeerts,&nbsp;Sarah Meyers,&nbsp;Olga Gielen,&nbsp;Jochen Lamote,&nbsp;Barbara Dewaele,&nbsp;Mercedeh Tajdar,&nbsp;Johan Maertens,&nbsp;Jolien De Bie,&nbsp;Kim De Keersmaecker,&nbsp;Nancy Boeckx,&nbsp;Lucienne Michaux,&nbsp;Anne Uyttebroeck,&nbsp;Sofie Demeyer,&nbsp;Heidi Segers,&nbsp;Jan Cools","doi":"10.1002/hem3.70085","DOIUrl":"https://doi.org/10.1002/hem3.70085","url":null,"abstract":"<p>High hyperdiploid (HeH) B-cell acute lymphoblastic leukemia (B-ALL) is the most prevalent subtype of childhood ALL. This leukemia is characterized by trisomies and tetrasomies of specific chromosomes and additional point mutations. Here, we used single-cell targeted DNA and antibody sequencing to determine the clonal evolution of HeH B-ALL during development and chemotherapy treatment. Chromosomal copy number changes were mostly stable over all the leukemia cells, while mutations were typically subclonal. Within all 13 cases, at least one <i>RAS</i> mutant (<i>KRAS</i> or <i>NRAS</i>) subclone was detected (range: 1 to 4 subclones with <i>RAS</i> mutations), indicating the importance of <i>RAS</i> signaling in HeH B-ALL development. <i>NSD2</i> mutations were detected in 4 out of 13 cases and always in a subclone with <i>RAS</i> signaling mutations. Single-cell DNA sequencing detected residual leukemia cells during chemotherapy treatment, and analysis of chromosomal copy number changes aided in the accurate detection of these cells. Our single-cell data demonstrate that chromosomal changes are acquired prior to additional mutations and that RAS signaling mutations are present in all HeH cases, often as subclonal mutations. This single-cell multi-omics study enabled us to extensively characterize the genetic and surface protein heterogeneity in patients with HeH B-ALL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143388950","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":"What's wrong with drug development for sickle cell disease?","authors":"Valentine Brousse,&nbsp;David Rees,&nbsp;Raffaella Colombatti","doi":"10.1002/hem3.70082","DOIUrl":"https://doi.org/10.1002/hem3.70082","url":null,"abstract":"&lt;p&gt;The repeated failure to bring new disease-modifying or curative therapies to individuals with sickle cell disease (SCD) has sadly been demonstrated yet again.&lt;/p&gt;&lt;p&gt;Newly marketed drugs, which were much awaited by patients with SCD and provisionally approved for use in many countries, were withdrawn because of clinical trials showing a lack of benefit and/or possible harm. More specifically, crizanlizumab, an antiadhesive monoclonal antibody failed to demonstrate meaningful clinical benefit in a confirmatory phase 3 trial and had its approval withdrawn across Europe by the EMA and equivalent authorities.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; More recently, in September 2024, voxelotor, an anti-sickling agent, approved by the FDA and EMA, was abruptly withdrawn from the market and ongoing clinical trials by the manufacturer, following trial and registry data showing an unexpected excess of deaths and clinical complications in patients taking the drug.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; In the last 5 years, several other drugs have also been dropped after failing to show benefit in late-stage clinical trials in SCD, including rivipansel, sevuparin, ticagrelor, prasugrel, and poloxamer 188.&lt;span&gt;&lt;sup&gt;3-7&lt;/sup&gt;&lt;/span&gt; To date, no drug targeting acute vaso-occlusive pain, the major debilitating and recurrent symptom of the disease, has been successfully developed. At the end of 2024, patients are left with hydroxyurea, a 150-year-old drug, which is effective but definitely not curative. Last but not least, effective curative treatments involving gene therapies are currently not available in Europe, despite highly promising results. So, what is wrong with drug development for SCD?&lt;/p&gt;&lt;p&gt;At this stage, it is not entirely clear where the blame lies. It seems possible that useful drugs have been lost to individuals with SCD because of badly designed or executed clinical trials with inappropriate endpoints, complex socioeconomic issues, or other selection biases, possibly driven by the desire of pharmaceutical companies to complete trials and access the market rapidly for economic reasons. Equally, it is possible that ineffective and potentially harmful drugs were prematurely approved for use by many authorities across the world and promoted by healthcare providers and patient associations, eager to have an additional treatment. Clearly, it is important to learn from these experiences.&lt;/p&gt;&lt;p&gt;First, it is vital to try and design more appropriate clinical trials. Important factors to consider include how outcomes in SCD vary very widely across different countries and continents, and that the effects of a drug in European countries, where more than 95% of children with sickle cell disease survive to adulthood, may be very different to the effects in some African countries, where fewer than 20%–50% affected children survive.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; Similarly, it is important to focus on appropriate endpoints, with the recent voxelotor experience perhaps illustrating that althoug","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70082","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248898","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":"Chimeric antigen receptor T-cell therapy outcomes in T cell/histiocyte-rich large B-cell lymphoma and subsequent treatment strategies after disease progression: A GELTAMO/GETH study","authors":"Mariana Bastos-Oreiro,&nbsp;Gloria Iacoboni,&nbsp;Víctor N. Garcés,&nbsp;Ana C. Caballero,&nbsp;Nuria Martínez,&nbsp;Javier Delgado,&nbsp;Aitana Balaguer,&nbsp;Mi Kwon,&nbsp;Sonia Gonzalez de Villambrosia,&nbsp;Rafael Hernani,&nbsp;Ana Jimenez-Ubieto,&nbsp;Rebeca Bailen,&nbsp;Izaskun Zaberio,&nbsp;Alejandro Martín García-Sancho,&nbsp;Pere Barba","doi":"10.1002/hem3.70077","DOIUrl":"https://doi.org/10.1002/hem3.70077","url":null,"abstract":"&lt;p&gt;Chimeric antigen receptor T-cell therapy (CAR-T) is an effective approach for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, some rare variants do not seem to respond as well to this T-cell redirecting strategy. T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is an infrequent subtype of LBCL which typically develops in young, male patients, characterized by an aggressive clinical course and chemo-refractory disease.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; THRLBCL has unique biological characteristics and a inhibitory tumor immune microenvironment.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; It is well-known that the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is a key driver of immune escape;&lt;span&gt;&lt;sup&gt;5, 6&lt;/sup&gt;&lt;/span&gt; this lymphoma subtype has been associated with PD-L1 gene alterations, such as PD-L1 copy gains and high PD-L1 expression on malignant B cells (often surrounded by abundant PD-L1–expressing macrophages and PD-1 + T cells). This distinct clinical behavior, together with its low incidence, have led to an underrepresentation of THRLBCL patients in most clinical trials, including those evaluating CAR T-cell therapy. Therefore, real-world data with this entity is highly anticipated. Taking all of this into consideration, we aimed to assess the safety and efficacy outcomes of THRLBCL after CAR T-cell therapy, outside of the clinical trial setting, as well as the efficacy of postrelapse approaches.&lt;/p&gt;&lt;p&gt;We carried out a retrospective, multicentre study including all adult patients with this diagnosis registered in the GELTAMO/GETH-TC database (Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea/Grupo Español de Trasplante Hematopoyético y Terapia Celular) from April 2019 to January 2024 who had received a CD19-targeted CAR T-cell infusion. The primary endpoint was overall survival (OS) and the secondary endpoints were response rate, progression-free survival (PFS), duration of response (DR), and subsequent therapy outcome. Twenty patients with R/R THRLBCL from 11 Spanish centers received CAR T-cell therapy from April 2019 to December 2023. If the patient had experienced disease progression after CAR-T, participating centers completed an additional database on subsequent treatments and their outcomes. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT consensus criteria.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Response assessment followed the Lugano recommendations.&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; OS and PFS were determined from CAR-T cell infusion for CAR T-cell outcomes and since the start of the first subsequent treatment for the following approaches. These were calculated using the Kaplan–Meier method and the Cox model to obtain hazard ratios (HR) with 95% confidence intervals (CI) and &lt;i&gt;p&lt;/i&gt;-values. All reported &lt;i&gt;p&lt;/i&gt;-values were two-sided, and statistical significance was defined at &lt;i&gt;p&lt;/i&gt; &lt; 0.05","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111652","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":"Dynamic evolution of TCF3-PBX1 leukemias at the single-cell level under chemotherapy pressure","authors":"Mira Kusterer,&nbsp;Mari Lahnalampi,&nbsp;Minna Voutilainen,&nbsp;Alexandra Brand,&nbsp;Sandra Pennisi,&nbsp;Johana Norona,&nbsp;Gaia Gentile,&nbsp;Heike Herzog,&nbsp;Gabriele Greve,&nbsp;Michael Lübbert,&nbsp;Mikko Sipola,&nbsp;Emma Kaartinen,&nbsp;Roman Sankowski,&nbsp;Marco Prinz,&nbsp;Saskia Killmer,&nbsp;Marilyn S. Lago,&nbsp;Bertram Bengsch,&nbsp;Stepan R. Cysar,&nbsp;Konrad Aumann,&nbsp;Martin Werner,&nbsp;Justus Duyster,&nbsp;Olli Lohi,&nbsp;Merja Heinäniemi,&nbsp;Jesús Duque-Afonso","doi":"10.1002/hem3.70071","DOIUrl":"https://doi.org/10.1002/hem3.70071","url":null,"abstract":"<p>Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. The translocation t(1;19), encoding the TCF3-PBX1 fusion, is associated with intermediate risk and central nervous system (CNS) infiltration at relapse. Using our previously generated TCF3-PBX1 conditional knock-in mice, we established a model to study relapsed clones after in vivo chemotherapy treatment, CNS infiltration, and clonal dynamic evolution of phenotypic diversity at the single cell-level using next-generation sequencing technologies and mass cytometry. Mice transplanted with TCF3-PBX1^<b>+</b> leukemia cells and treated with vehicle succumbed to disease, whereas 40% of treated mice with prednisolone or daunorubicin survived. Bulk and single-cell RNA sequencing of FACS-sorted GFP+ cells from TCF3-PBX1^<b>+</b> leukemias arising after chemotherapy treatment revealed that apoptosis, interleukin-, and TGFβ-signaling pathways were regulated in CNS-infiltrating leukemic cells. Across tissues, upregulation of the MYC signaling pathway was detected in persisting leukemic cells and its downregulation by BRD3/4 inhibition increased sensitivity to chemotherapy. In TCF3-PBX1⁺ leukemia cells collected after chemotherapy treatment, mass cytometry identified increased phosphorylation of STAT3/5 upon preBCR stimulation, which was susceptible to inhibition by the proteasome inhibitor bortezomib. In summary, we developed a TCF3-PBX1⁺ ALL mouse model and characterized relapsed disease after in vivo chemotherapy and cell phenotype dependence on microenvironment. Transcriptomics and phospho-proteomics revealed distinct pathways that may underlie chemotherapy resistance and might be suitable for pharmacological interventions in human ALL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 2","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143111164","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}