HemaSphere最新文献

{"title":"Expanding the phenotypic and genetic landscape of congenital neutropenia through whole-exome and genome sequencing","authors":"Séverine Marti,&nbsp;Philippe Pellet,&nbsp;Blandine Beaupain,&nbsp;Léa Durix,&nbsp;Julien Buratti,&nbsp;Yves Réguerre,&nbsp;Nathalie Aladjidi,&nbsp;Saba Azarnoush,&nbsp;Severine Clauin,&nbsp;Wahid Abou Chahla,&nbsp;Gilles Blaison,&nbsp;Jeremy Bertand,&nbsp;Damien Bodet,&nbsp;Benoit Brethon,&nbsp;Jessica Chane-Teng,&nbsp;Manon Delafoy,&nbsp;Chrystelle Dupraz,&nbsp;Virginie Gandemer,&nbsp;Philippe Denizeau,&nbsp;Alice Goldenberg,&nbsp;Pierre Hirsch,&nbsp;Anaïs l'Haridon,&nbsp;Aude Marie-Cardine,&nbsp;Gabriella Vera,&nbsp;Brigitte Nelken,&nbsp;Laure Nizery,&nbsp;Marie Nolla,&nbsp;Marlène Pasquet,&nbsp;Jérémie Rosain,&nbsp;Louis Terriou,&nbsp;Isabelle Plo,&nbsp;Jean Donadieu,&nbsp;Christine Bellanné-Chantelot","doi":"10.1002/hem3.70150","DOIUrl":"https://doi.org/10.1002/hem3.70150","url":null,"abstract":"<p>Congenital neutropenia (CN) comprises a heterogeneous group of rare genetic disorders. While some CN cases present only with neutropenia, others present with additional extra-hematological manifestations. The most common cause of CN is variants in <i>ELANE</i>; however, approximately 30 other genes have been implicated. Despite this, the genetic basis remains unknown in roughly 30% of cases. The clinical and genetic heterogeneity of CN makes diagnosis particularly challenging. To address this, we conducted exome or genome sequencing of 60 patients with a suspected diagnosis of CN that remained unresolved following targeted sequencing. A genetic diagnosis was established in 25 patients (42%). Variants were identified in 15 different genes. Half of these cases involved genes traditionally associated with hereditary immunodeficiencies (<i>GINS4</i>, <i>CARD11</i>, <i>ADA2</i>, <i>GINS1</i>, <i>LCP1</i>, <i>SASH3</i>, and <i>WAS</i>). One-third of the cases carried variants in genes linked to syndromic disorders (<i>VPS13B</i>, <i>TAFAZZIN</i>, <i>CLPB</i>, and <i>TONSL</i>), demonstrating variable penetrance of extra-hematological phenotypes. A smaller subset (15%) harbored variants in genes associated with inherited bone marrow failure syndromes (<i>BLM</i>, <i>RPL18</i>, <i>SAMD9</i>, and <i>SRP72</i>), identified incidentally due to atypical presentations. Compared to patients with ELANE-CN, these individuals were diagnosed later, had fewer severe bacterial infections and gingivitis, exhibited less profound neutropenia, lacked monocytosis, and had a granulocytic maturation arrest, often beyond the promyelocytic stage. A shared feature among these cases was a tendency toward reduced lymphocyte subsets, particularly NK cells. This study highlights the significant contribution of exome and genome sequencing in diagnosing CN, given the phenotypic overlap, genetic heterogeneity, and variable penetrance of immunological and extra-hematological features.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 6","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70150","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144264538","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":"Development of myeloid neoplasia associated with prolonged immune cell-associated hematotoxicity after CAR T-cell treatment of B-cell lymphoma: Should we surveille for pre-existing myeloid mutations?","authors":"Mattias Carlsten,&nbsp;Elisa Linnea Lindfors Rossi,&nbsp;Martin Jädersten,&nbsp;Bianca Tesi,&nbsp;Sulaf Abd Own,&nbsp;Brigitta Sander,&nbsp;Stefan Deneberg,&nbsp;Anne Ivinskiy,&nbsp;Kristina Sonnevi,&nbsp;Hanna Sjölund,&nbsp;Gunilla Enblad,&nbsp;Björn Wahlin,&nbsp;Stephan Mielke","doi":"10.1002/hem3.70160","DOIUrl":"https://doi.org/10.1002/hem3.70160","url":null,"abstract":"&lt;p&gt;Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the outcome of patients with B-cell malignancies as recently exemplified by the Swedish cohort.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Although the development of secondary cancers such as T-cell lymphomas following viral transduction has been a major concern from the very beginning,&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; relatively few such cases have been reported. Instead, there is accumulating evidence that myeloid malignancies such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) can occur in up to 5%–7% of patients, which, together with a smaller proportion of other secondary malignancies, constitutes the second most common cause of non-relapse mortality after CAR T-cell therapy.&lt;span&gt;&lt;sup&gt;3-6&lt;/sup&gt;&lt;/span&gt; However, so far, we do not understand the biology behind therapy-related myeloid neoplasia (tMN), nor can we predict who is at risk. To better understand this, we have launched an ex vivo correlative study (Ethical Review Board Dnr 2021-04692) to which we enroll our patients undergoing CAR T-cell treatment.&lt;/p&gt;&lt;p&gt;In this study, we present two patients with B-cell lymphoma who developed tMN after receiving CD19-directed CAR T-cell therapy that triggered long-lasting immune effector cell-associated hematotoxicity (ICAHT)&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; (Table 1 and Figure 1). Both patients were males diagnosed with follicular lymphoma (FL) for which they received Rituximab–Bendamustine as the first line. Both patients transformed to large B-cell lymphoma (LBCL) and were primary refractory to Obinutuzumab–Cyclophosphamide–Vincristine–Doxorubicine–Dexamethasone (HyperCVAD), therefore qualifying for CAR T-cell therapy with Axi-cel as standard of care. Patient A received bridging therapy with Ifosfamide–Carboplatin–Etoposide (ICE) combined with radiotherapy, and patient B received Rituximab–Gemcitabine–Oxaliplatin (GemOx), resulting in a partial response in both cases. Axi-cel was administrated after lymphodepletion with Fludarabine and Cyclophosphamide. Patient A had no CRS or ICANS, while patient B developed a grade I CRS and received Tocilizumab. The course of treatment for each patient is summarized in Figure 1.&lt;/p&gt;&lt;p&gt;After cell infusion, patient A developed early ICAHT grade III that resulted in primary aplastic bone marrow while patient B developed biphasic ICAHT grade III in both its early and late stages. Both patients were promptly treated with G-CSF with suboptimal responses. The schedules for G-CSF administration slightly differed between the patients; while patient A was treated with 1-3 doses/week, patient B received 1-2 doses/week. The CAR/Hematotox&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; score was retrospectively calculated for both patients and determined high, underscoring the relevance of this tool on predicting later complications. In particular patient B was allocated to the same group even if lacking ferritin levels since a total score of 5 was achieved. Of note, patient A had several CM","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 6","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70160","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144213864","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":"Efficacy of erythroid-stimulating agent and luspatercept in VEXAS syndrome: A multicenter retrospective study by the FRENVEX group","authors":"Maël Heiblig,&nbsp;Vincent Jachiet,&nbsp;Jérôme Hadjadj,&nbsp;Lin Pierre Zhao,&nbsp;Thibault Comont,&nbsp;Hervé Lobbes,&nbsp;Valentin Lacombe,&nbsp;Anne Blandine Boutin,&nbsp;Joris Galland,&nbsp;Benjamin Terrier,&nbsp;Sophie Georgin-Lavialle,&nbsp;Pierre Fenaux,&nbsp;Arsène Mekinian,&nbsp;the FRENVEX Group","doi":"10.1002/hem3.70156","DOIUrl":"https://doi.org/10.1002/hem3.70156","url":null,"abstract":"&lt;p&gt;VEXAS syndrome (for Vacuoles in myeloid progenitors, E1 ubiquitin activating enzyme, X-linked, Autoinflammatory manifestations, and Somatic) is due to somatically acquired &lt;i&gt;UBA1&lt;/i&gt; mutations within hematopoietic stem/progenitor cells.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; It is characterized clinically by a variety of autoinflammatory manifestations and biologically by marked cytopenia and more specifically macrocytic anemia.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Anemia in VEXAS is usually non-regenerative and red blood cell (RBC) transfusion dependency is observed in 23%–83% of cases.&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt; Precise mechanisms underlying anemia in VEXAS are not completely elucidated. Chronic inflammation certainly contributes, as RBC transfusion independency (TI) might be reached by controlling inflammatory burden.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Besides RBC transfusion, there is no validated therapeutic option regarding anemia management. Erythroid-stimulating agents (ESA) and more recently luspatercept (LUSPA) have been approved for the treatment of anemia in MDS.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; The aim of this multicenter retrospective study was to evaluate erythroid response to those drugs (HI-E according to IWG-2018 criteria) in VEXAS patients with anemia treated with ESA and LUSPA.&lt;/p&gt;&lt;p&gt;Anemic (Hb&lt;10 g/dL) VEXAS patients, with or without MDS, who were treated with ESA and/or LUSPA between 2020 and 2024 in eight centers of the French Vexas (FRENVEX) group (Lyon Sud, Clermont-Ferrant, Toulouse, Paris Saint-Antoine, Paris Saint-Louis, Bourg-en-Bresse, Centre Alpes-Léman, and Angers)&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; were included. Definitions and responses criteria are defined in Supporting Information.&lt;/p&gt;&lt;p&gt;Overall, 45 VEXAS patients received ESA (&lt;i&gt;N&lt;/i&gt; = 26 darbepoietin, &lt;i&gt;N&lt;/i&gt; = 15 epoietin-alfa, &lt;i&gt;N&lt;/i&gt; = 3 epoietin-beta) as the first-line treatment, 8 of whom were switched to LUSPA after ESA failure. Regarding delay between &lt;i&gt;UBA1&lt;/i&gt; molecular diagnosis and ESA initiation, 33% (15/45) of patients started ESA before a formal VEXAS diagnosis (median time before diagnosis: 11.1 months) (95% CI: 0.95–85.1), while the others (30/45) initiated ESA with a median time of 6.6 months (95% CI: 0.31–121.1) after VEXAS diagnosis. Median age at ESA initiation was 73.3 (range: 49–87.7). Regarding &lt;i&gt;UBA1&lt;/i&gt; variants, 14 (31%), 14 (31%), 6 (13%), and 11 (24%) harbored p.Met41Thr, pMet41Leu, p.Met41Val, and alternative variants (seven splice, three S56, and one active adenylation domain) mutations, respectively (Figure S1A). Sixteen patients (35.5%) were non-RBC transfusion dependent (NTD), 13 (29%) had high transfusion burden (HTB), and 16 (35.5%) low TB (LTB) before ESA initiation according to IWG 2018 criteria. Clinical and biological characteristics of patients with and without RBC transfusion dependency were similar (Table S1). Thirty seven (82%) patients had associated MDS (IPSS-R/M characteristics are reported in Figure S1A). Detailed hematological features are reported i","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 6","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70156","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197218","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":"New horizons in the pharmacological management of venous thromboembolism","authors":"Andreas Verstraete,&nbsp;Quentin Van Thillo,&nbsp;Thomas Vanassche,&nbsp;Peter Verhamme","doi":"10.1002/hem3.70143","DOIUrl":"https://doi.org/10.1002/hem3.70143","url":null,"abstract":"<p>Many patients suffer from venous thromboembolism (VTE) and its consequences. Despite substantial advancements with the introduction of direct oral anticoagulants (DOACs), patients and clinicians still encounter challenges in the acute and long-term management of VTE, such as recurrent events, anticoagulant-related bleeding complications, and post-thrombotic symptoms. Additionally, certain patient populations, including those with advanced kidney failure and liver cirrhosis and elderly individuals, were excluded from phase 3 clinical DOAC trials. Therefore, the call for innovative anticoagulants in the acute and long-term management of VTE resonates, not only to mitigate long-term recurrences and post-thrombotic symptoms but also to maintain the delicate harmony of hemostasis. Novel targets within the coagulation and fibrinolytic system, as well as mechanisms governing adherence to the vessel wall, are currently being explored to address these unmet needs. First, factor XI inhibitors have shown promise in preclinical and phase 2 clinical studies to tackle thrombosis while preserving hemostasis, although phase 3 trials are required for confirmation. Next, there is interest to boost the endogenous fibrinolytic system, with α2-antiplasmin, thrombin-activatable fibrinolysis inhibitor, and plasminogen activator inhibitor-1 emerging as potential attractive targets. Finally, strategies to inhibit the interaction between leucocytes and the vessel wall are also under exploration. This review provides an overview of the latest clinical advancements in the pharmacological management of VTE.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 6","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70143","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144197216","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":"Characterization of cancer-associated fibroblasts and their spatial architecture reveals heterogeneity and survival associations in classic Hodgkin lymphoma","authors":"Suvi-Katri Leivonen,&nbsp;Kristiina Karihtala,&nbsp;Teijo Pellinen,&nbsp;Marja-Liisa Karjalainen-Lindsberg,&nbsp;Tomohiro Aoki,&nbsp;Christian Steidl,&nbsp;Sirpa Leppä","doi":"10.1002/hem3.70145","DOIUrl":"https://doi.org/10.1002/hem3.70145","url":null,"abstract":"<p>Cancer-associated fibroblasts (CAFs) are a heterogeneous population of stromal cells, which modulate the immune system and can have both pro- and anti-tumorigenic effects. In classic Hodgkin lymphoma (cHL), the role of CAFs has remained largely undefined. We applied multiplexed immunofluorescence imaging and spatial analysis on tumor samples from two independent cHL patient cohorts (<i>n</i> = 131 and <i>n</i> = 148) to study CAFs and their interactions with Hodgkin Reed–Sternberg (HRS) and tumor microenvironment (TME) cells at the single-cell resolution. We show that higher proportions of CAFs are associated with favorable outcomes, independent of the clinical covariables. In contrast, a subset of CD45⁺ immune cells with strong fibroblast-activation protein positivity, classified as macrophages, was less abundant in nodular sclerosis subtype and associated with worse outcomes. Neighborhood analysis allowed for the identification of colocalization or regional exclusion of phenotypically defined cell types and recurrent cellular neighborhoods. Despite the positive impact of CAF proportions on survival, patients with enrichment of platelet-derived growth factor receptor beta (PDGFRB)-positive CAFs in the vicinity of HRS cells had worse survival in both cohorts, independent of the clinical determinants. Our findings distinguish various subsets of CAFs and macrophages impacting survival in cHL and underscore the importance of the spatial arrangements in the TME.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 5","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70145","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140620","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":"Antigen selection reflected in the subclonal architecture of the B-cell receptor immunoglobulin gene repertoire in splenic marginal zone lymphoma","authors":"Laura Zaragoza-Infante,&nbsp;Andreas Agathangelidis,&nbsp;Anastasia Iatrou,&nbsp;Valentin Junet,&nbsp;Nikos Pechlivanis,&nbsp;Maria Karypidou,&nbsp;Triantafyllia Koletsa,&nbsp;Giorgos Karakatsoulis,&nbsp;Alessio Bruscaggin,&nbsp;Zadie Davis,&nbsp;Valeria Spina,&nbsp;Aurelie Verney,&nbsp;Eleftheria Polychronidou,&nbsp;Fotis Psomopoulos,&nbsp;David Oscier,&nbsp;Alexandra Traverse-Glehen,&nbsp;Maria Papaioannou,&nbsp;Paolo Ghia,&nbsp;Davide Rossi,&nbsp;Anastasia Chatzidimitriou,&nbsp;Kostas Stamatopoulos","doi":"10.1002/hem3.70147","DOIUrl":"https://doi.org/10.1002/hem3.70147","url":null,"abstract":"<p>Almost one-third of all splenic marginal zone lymphoma (SMZL) cases express B-cell receptor immunoglobulin (BcR IG) encoded by the IGHV1-2*04 gene, implicating antigen selection in disease ontogeny. Evidence supporting this notion mostly derives from low-throughput sequencing approaches, which have limitations in capturing the full complexity of the BcR IG gene repertoire. This hinders the comprehensive assessment of the subclonal architecture of SMZL as shaped by antigen selection. To address this, we conducted a high-throughput immunogenetic investigation of SMZL aimed at the comprehensive characterization of the somatic hypermutation (SHM) and intraclonal diversification within the IG genes. We identified significant differences in the SHM and ID profiles between cases expressing the IGHV1-2*04 gene and those expressing other IGHV genes. Specifically, IGHV1-2*04 cases displayed (i) targeted SHM resulting in recurrent replacement SHMs, and (ii) significantly more pronounced intraclonal diversification, reflecting ongoing antigen selection. Overall, our findings suggest that SMZL cases expressing the IGHV1-2*04 gene have a distinct immunogenetic signature shaped by microenvironmental pressure on the clonotypic BcR IG, corroborating the idea that this group may represent a distinct molecular variant of SMZL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 5","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70147","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140621","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":"Oncogenomic profiling in infant–toddler T-ALL identifies NKX2 family genes as drivers linked to favorable outcomes","authors":"Manon Delafoy,&nbsp;Estelle Balducci,&nbsp;Mathieu Simonin,&nbsp;Antoine Pinton,&nbsp;Guillaume Charbonnier,&nbsp;Lucien Courtois,&nbsp;Ludovic Lhermitte,&nbsp;Camille Gillet,&nbsp;Mélanie Féroul,&nbsp;Aurore Touzart,&nbsp;Agata Cieslak,&nbsp;Charlotte Smith,&nbsp;Marianne Courgeon,&nbsp;Margaux Wiber,&nbsp;Thomas Mercher,&nbsp;Sylvain Latour,&nbsp;Isabelle Arnoux,&nbsp;Paul Saultier,&nbsp;Pierre-Simon Rohrlich,&nbsp;Damien Bodet,&nbsp;Nathalie Grardel,&nbsp;Marion Lubnau,&nbsp;Isabelle Pellier,&nbsp;Sandrine Thouvenin,&nbsp;Nathalie Garnier,&nbsp;Cédric Pastoret,&nbsp;Benoit Brethon,&nbsp;Arnaud Petit,&nbsp;Elizabeth Macintyre,&nbsp;André Baruchel,&nbsp;Vahid Asnafi","doi":"10.1002/hem3.70154","DOIUrl":"https://doi.org/10.1002/hem3.70154","url":null,"abstract":"<p>T-cell acute lymphoblastic leukemia (T-ALL) is a rare and aggressive hematological malignancy primarily affecting adolescents and young adults and is scarce in infants and toddlers under age 3. Unlike B-ALL, T-ALL in this young population remains poorly characterized due to limited data and lacks evidence-based guidelines to help clinicians determine the optimal treatment approach. In this study, we conducted a comprehensive genetic analysis of infant/toddler T-ALL cases from a French national cohort, utilizing high-throughput targeted sequencing, optical genome mapping, and RNA sequencing. Genetic analysis revealed the absence of <i>TLX1/3</i> dysregulation. Instead, we identified a significant prevalence of <i>NKX2</i> rearrangements (<i>n</i> = 9, 33%), co-occurring with <i>MYB</i> alterations (<i>n</i> = 5/9) or chromothripsis-like events (<i>n</i> = 3/9). Additional findings included <i>TAL1/-like</i> anomalies (30%), <i>STAG2::LMO2</i> (15%), <i>ETS</i> rearrangements (15%), and rarely, <i>KMT2A</i> rearrangements (7%). Comparative analyses with 245 patients aged 3–18 years, enrolled in the pediatric FRALLE2000T French protocol, underscored the distinct clinical and genetic profiles of infants/toddlers. Despite presenting with higher rates of hyperleukocytosis and slower responses to treatment, they demonstrated comparable survival outcomes to older pediatric patients, with a 5-year overall survival (OS) rate of 75.4% (95% confidence interval [CI]: 60.0%–94.8%) versus 75.2% (95% CI: 69.8%–81.1%), <i>p</i> = 0.86. Notably, alterations in <i>NKX2</i>, <i>KMT2A</i>, and <i>STAG2::LMO2</i> delineated oncogenic subgroups exhibiting a remarkable 100% OS rate, while patients with <i>TAL1</i> or <i>ETS</i> dysregulation experienced less favorable outcomes. This was further supported by analyses of data from the COG AALL0434 trial, enhancing our understanding of T-ALL in infants/toddlers. Large-scale collaborative studies remain essential to confirm these findings and refine treatment strategies.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 5","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70154","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144140614","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":"Genetic evolution and relapse-associated mutations in adult T-cell acute lymphoblastic leukemia patients treated in PETHEMA trials","authors":"Celia González-Gil,&nbsp;Thaysa Lopes,&nbsp;Mireia Morgades,&nbsp;Francisco Fuster-Tormo,&nbsp;Pau Montesinos,&nbsp;Carlos Rodríguez Medina,&nbsp;Lourdes Hermosín,&nbsp;Teresa González-Martínez,&nbsp;María-Paz Queipo,&nbsp;José González-Campos,&nbsp;Pilar Martínez-Sánchez,&nbsp;Marina Díaz-Beya,&nbsp;Rosa Coll,&nbsp;Clara Maluquer,&nbsp;Lurdes Zamora,&nbsp;Teresa Artola,&nbsp;Ferran Vall-Llovera,&nbsp;Mar Tormo,&nbsp;Anna Torrent,&nbsp;Carolina Martínez-Laperche,&nbsp;Cristina Gil-Cortés,&nbsp;Pere Barba,&nbsp;Marta Cervera,&nbsp;Jordi Ribera,&nbsp;Manuel Fernández-Delgado,&nbsp;Rosa Ayala,&nbsp;Antonia Cladera,&nbsp;María Carmen Mateos,&nbsp;María Jesús Vidal,&nbsp;Jesús Feliu,&nbsp;Ana Torres,&nbsp;Gemma Azaceta,&nbsp;María José Calasanz,&nbsp;Anna Bigas,&nbsp;Manel Esteller,&nbsp;Alberto Orfao,&nbsp;Josep Maria Ribera,&nbsp;Eulalia Genescà","doi":"10.1002/hem3.70148","DOIUrl":"https://doi.org/10.1002/hem3.70148","url":null,"abstract":"<p>Relapse is the main cause of treatment failure in T-cell acute lymphoblastic leukemia (T-ALL). Despite this, data from adult T-ALL patients treated with specific chemotherapeutic regimens that examine predictive markers and describe relapse mechanisms are scarce. In this study, we studied 74 paired diagnosis-relapse samples from 37 patients homogeneously treated with three consecutive measurable residual disease-oriented trials to identify genetic determinants involved in relapse in adult T-ALL. Analysis of single-nucleotide variants and copy number alterations consistently found <i>N/KRAS</i> mutations (20% relapsed cases) at diagnosis and at relapse (resistance profile). <i>N/KRAS</i>^<i>mut</i> patients frequently relapse early during consolidation treatment. Relapse-specific mutations in <i>NT5C2, NR3C1</i>, <i>SMARCA4</i>, and <i>TP53</i> (40% relapse cases) were not detected at diagnosis by conventional molecular techniques (relapse profile). However, single-cell-based analysis revealed a very minor clone containing the NT5C2(p.R367Q) variant at diagnosis. Patients with the NT5C2(p.R367Q) variant mostly relapse later during maintenance treatment. Tracking the <i>NT5C2</i> variant by digital PCR confirm the expansion of the NT5C2 clone at maintenance treatment. Overall, our exploratory analysis suggests a role for these genetic events, most of which have already been described in pediatric cases, driving resistance associated to specific chemotherapeutic agents, contributing to the relapse of a high proportion of adult T-ALL patients (60%).</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 5","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70148","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135704","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":"Applications of machine learning for immunophenotypic measurable residual disease assessment in acute myeloid leukemia","authors":"Tim R. Mocking,&nbsp;Arjan A. van de Loosdrecht,&nbsp;Jacqueline Cloos,&nbsp;Costa Bachas","doi":"10.1002/hem3.70138","DOIUrl":"https://doi.org/10.1002/hem3.70138","url":null,"abstract":"<p>Immunophenotypic detection and quantification of residual leukemic cells by multiparameter flow cytometry is increasingly adopted in the clinical practice of acute myeloid leukemia (AML) to assess measurable residual disease (MRD). However, MRD levels quantified by manual gating analysis can differ based on differences in gating strategy between trained operators and clinical centers. Manual gating requires extensive training, is time-consuming in daily practice, and faces a significant hurdle in analyzing data from next-generation cytometry platforms. To address these challenges, several computational approaches involving machine learning and artificial intelligence algorithms have been proposed to automate or aid the assessment of MRD. However, the immunophenotypic variability between patients and the relatively low proportions of residual leukemic cells in AML challenge most algorithms and require innovative approaches. This review provides an overview of recent efforts in using computational methods for immunophenotypic AML-MRD assessment. We first explain the technical and conceptual background of the different algorithms that have been explored. Next, we discuss their strengths and limitations in the disease-specific context of AML. Finally, we highlight how computational approaches offer a unique opportunity to standardize or even outperform current manual gating analyses, and ultimately, improve the treatment of AML patients.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 5","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70138","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100936","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":"Efficacy and safety of CAR T-cell therapy in patients with primary or secondary CNS lymphoma: A study on behalf of the EBMT and the GoCART coalition","authors":"Anna Ossami Saidy,&nbsp;Christophe Peczynski,&nbsp;Catherine Thieblemont,&nbsp;Michael Daskalakis,&nbsp;Marc Wehrli,&nbsp;David Beauvais,&nbsp;Jürgen Finke,&nbsp;Elisabeth Schorb,&nbsp;Peter Vandenberghe,&nbsp;Philipp Berning,&nbsp;Matthias Stelljes,&nbsp;Francis Ayuk,&nbsp;Ron Ram,&nbsp;Malte Von Bonin,&nbsp;Peter Dreger,&nbsp;Wolfgang Bethge,&nbsp;Andrea Kuhnl,&nbsp;Lasse Jost,&nbsp;Friedrich Stölzel,&nbsp;Bastian von Tresckow,&nbsp;Christoph Renner,&nbsp;Stephan Fuhrmann,&nbsp;Jacques-Emmanuelle Galimard,&nbsp;Eva Michel,&nbsp;Ali Bazarbachi,&nbsp;Anna Sureda Balari,&nbsp;Norbert Schmitz,&nbsp;Bertram Glass","doi":"10.1002/hem3.70146","DOIUrl":"https://doi.org/10.1002/hem3.70146","url":null,"abstract":"<p>Patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary central nervous system (CNS) lymphoma (SCNSL) face a dismal prognosis. They have been excluded from most clinical CAR T-cell trials as investigators feared an increased risk for severe immune effector cell-associated neurotoxicity (ICANS). To investigate the potential of anti-CD19 CAR T-cell therapy (CART) in such patients, we analyzed data of 100 patients with CNS manifestation treated with CART between January 2018 and July 2023 and reported to European Society for Blood and Marrow Transplantation. Median age was 62 years. Of patients, 58% had failed ≥3 treatment lines, and 40% had received autologous stem-cell transplantation before CART. Fifty-nine patients received axicabtagene ciloleucel, 38 patients were treated with tisagenlecleucel, three patients received other products. At the time of CART, 67 patients had active CNS disease. Overall and progression-free survival (PFS) at 24 months were 37% and 28%. Relapse incidence (RI) at 24 months was 59%, whereas non-relapse mortality at 1 year was 7%. Cytokine release syndrome (CRS) and ICANS of any grade occurred in 83% and 42% of patients, respectively. CRS grade 3 occurred in 11 and ICANS grades 3–4 in 17 patients. Two patients died of neurotoxicity. Elevated lactate dehydrogenase was an independent risk factor for RI and PFS (hazard ratio [HR] 2.4, <i>p</i> = 0.003; HR: 1.9, <i>p</i> = 0.016). Patients with ECOG 2–3 had a significantly increased risk for the development of ICANS (HR 2.68, <i>p</i> = 0.002). These data support the implementation of CART as treatment for patients with r/r PCNSL and SCNSL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 5","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70146","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144100937","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}