HemaSphere最新文献

{"title":"Prevalence of type I Gaucher disease in patients with smoldering or multiple myeloma: Results from the prospective, observational CHAGAL study","authors":"Sonia Morè, Irene Federici, Alessandra Bossi, Serena Rupoli, Erika Morsia, Valentina M. Manieri, Attilio Olivieri, Maria T. Petrucci, Francesca Fazio, Chiara Lisi, Silvia Sorella, Adele D. Paoli, Francesca Farina, Anna Mele, Rossella De Francesco, Antonino Greco, Francesca Fioritoni, Carmine Liberatore, Tommaso C. De Toritto, Attilio Tordi, Agostina Siniscalchi, Marino Brunori, Nicola Sgherza, Pellegrino Musto, Angela Amendola, Angelo Vacca, Antonio G. Solimando, Assunta Melaccio, Antonio Palma, Lorella M. A. Melillo, Lucia Ciuffreda, Silvia Gentili, Gabriele Buda, Maria L. Del Giudice, Antonietta P. Falcone, Patrizia Tosi, Simona Tomassetti, Francesco Rotondo, Alessandro Gozzetti, Piero Galieni, Miriana Ruggieri, Ferdinando Frigeri, Rosario Bianco, Alessandra Lombardo, Fabio Trastulli, Laura Corvatta, Carmela Zizzo, Giovanni Duro, Massimo Offidani","doi":"10.1002/hem3.70079","DOIUrl":"10.1002/hem3.70079","url":null,"abstract":"<p>Gaucher disease (GD) represents a lysosomal storage disease caused by a genetic defect of the enzyme β-glucocerebrosidase (GBA) involved in the breakdown of complex glycosphingolipids, which are important components of cell membranes. Deficient GBA enzyme activity causes the accumulation of substrate glucosylceramide in lysosomes of cells of the reticuloendothelial system and the characteristic macrophages loaded with glucosylceramide defined as “Gaucher cells.”<span><sup>1</sup></span> Type 1 GD (GD1), affecting more than 90% of patients with GD from Europe and North America, can be diagnosed at any age since initial symptoms (fatigue, asthenia, bone pain) are nonspecific. The subsequent main clinical findings, such as bone disease, hepatosplenomegaly, anemia, thrombocytopenia, and coagulation abnormalities can be misdiagnosed, due to the rarity of the disease and heterogeneity of the clinical picture. Being inherited in an autosomal recessive manner, identification of biallelic pathogenic variants in <i>GBA1</i> on molecular genetic test is required to confirm the diagnosis of GD1, besides glucocerebrosidase activity measurement in peripheral blood leukocytes. The incidence is associated with particular populations such as those of Ashkenazi Jewish descent among whom GD1 was estimated at 1 in 450 births. In contrast, in a recent review, the incidence was estimated at 0.45–22.9/100,000 live births in Europe and North America (4.5/100,000 live births in Italy). Estimated prevalence per 100,000 population was 0.26–0.63 in Europe.<span><sup>2</sup></span></p><p>Evidence has accumulated over time for a risk for multiple myeloma (MM) occurrence from 5.9 to 51.1 times greater in patients with GD1 compared to the general population.<span><sup>3-5</sup></span> However, no studies explored the concurrent GD1 in patients diagnosed with MM except a small retrospective study.<span><sup>5</sup></span> Herein, we reported the results of a multicentre, observational, cross-sectional study, designed to evaluate the prevalence of GD1 in patients with smoldering MM (SMM) and newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM),<span><sup>6</sup></span> aged >18 years giving written informed consent. The study was approved by the competent Ethics Committee for each center, and it was conducted in accordance with the Good Clinical Practice (ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996 Directive 91/507/EEC; D.M. 15.7.1997).</p><p>The primary aim of the study was the prevalence of unrecognized GD1 in a selected adult population with a confirmed diagnosis of SMM or MM. The secondary endpoint was to assess if, in patients with a final diagnosis of GD1, distinctive features could be identified to draw a diagnostic algorithm for early identification of genetic disease.</p><p>Peripheral blood of enrolled patients was drawn using EDTA as an anticoagulant, and it was applied to a specific adsorbent paper spot (dried blood spot, DBS) which","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028734","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":"Mastering fate: Redistributing a pioneer protein to rewrite leukemia's script","authors":"Yizhou Huang, Charles E. de Bock","doi":"10.1002/hem3.70084","DOIUrl":"10.1002/hem3.70084","url":null,"abstract":"<p>The pioneer transcription factor PU.1 plays a crucial role in hematopoiesis, particularly during myeloid and lymphoid differentiation. PU.1 dysregulation has been implicated in leukemia development, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). However, developing therapeutic agents that directly target transcription factors has been challenging. This is partly due to the lack of well-defined active sites amenable to pharmacological inhibition, making them undruggable and indispensable functions in healthy cells.<span><sup>1</sup></span></p><p>In a new study led by Samuel Taylor in the laboratory of Ulrich Steidl, the authors took another approach to block PU.1 activity using a small molecule inhibitor that specifically blocked PU.1's interaction with DNA. Interestingly, rather than a global loss of PU.1 binding, the authors found that PU.1 was redistributed to alternative DNA sites within the genome, activating cellular differentiation.<span><sup>2</sup></span> The implications of this therapeutic concept, particularly in relation to differentiation therapy, represent an important new development for the treatment of leukemia.</p><p>Unlike kinases or other enzymes, transcription factors lack catalytic domains that can be inhibited, making direct pharmacological intervention more challenging. The new agents used by Taylor et al. are DNA-binding heterocyclic diamidines, designed to specifically bind adenine–thymine (AT)-rich minor grooves at DNA sites targeted by PU.1, thereby inhibiting PU.1 binding. Treatment of AML cells with this class of agents (DB2115, DB2373, DB2826, and DB2313) resulted in a significant decrease in AML cell proliferation. Originally, the authors hypothesized that this was a consequence of drug-induced global loss of PU.1 binding across the genome. Surprisingly, they then found that not only did the vast majority of PU.1 sites remain unchanged after drug treatment, but there was nearly an equivalent loss and gain of PU.1 binding sites. Their data instead support a model in which PU.1 is redistributed to alternative genomic regions rather than global loss of binding (Figure 1).</p><p>To understand the molecular biology underlying this observation, the authors used numerous elegant sequencing techniques such as CLICK-on-CUT&Tag, ATAC-sequencing, and ChIP-sequencing temporally to directly show where the drug bound, PU.1 was lost and chromatin then closed. Conversely, closed chromatin regions that gained PU.1 binding were remodeled to become more accessible. Using transcriptomics and gene set enrichment analysis, the authors showed that these gained PU.1-bound regions were involved in “cellular differentiation,” whereas the PU.1-lost regions were enriched for a “stem cell signature” (Figure 1). Hence, these drugs pharmacologically reprogrammed PU.1-mediated transcriptional activity to drive cellular differentiation instead of completely suppressing its activity. This represents a signific","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11754763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143028625","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":"Detection of clinically relevant variants in the TP53 gene below 10% allelic frequency: A multicenter study by ERIC, the European Research Initiative on CLL","authors":"Sarka Pavlova,&nbsp;Jitka Malcikova,&nbsp;Lenka Radova,&nbsp;Silvia Bonfiglio,&nbsp;Jack B. Cowland,&nbsp;Christian Brieghel,&nbsp;Mette K. Andersen,&nbsp;Maria Karypidou,&nbsp;Bella Biderman,&nbsp;Michael Doubek,&nbsp;Gregory Lazarian,&nbsp;Inmaculada Rapado,&nbsp;Matthijs Vynck,&nbsp;Naomi A. Porret,&nbsp;Martin Andres,&nbsp;Dina Rosenberg,&nbsp;Dvora Sahar,&nbsp;Carolina Martínez-Laperche,&nbsp;Ismael Buño,&nbsp;Andrew Hindley,&nbsp;David Donaldson,&nbsp;Julio B. Sánchez,&nbsp;José A. García-Marco,&nbsp;Alicia Serrano-Alcalá,&nbsp;Blanca Ferrer-Lores,&nbsp;Concepción Fernández-Rodriguez,&nbsp;Beatriz Bellosillo,&nbsp;Stephan Stilgenbauer,&nbsp;Eugen Tausch,&nbsp;Hero Nikdin,&nbsp;Fiona Quinn,&nbsp;Emer Atkinson,&nbsp;Lisette van de Corput,&nbsp;Cafer Yildiz,&nbsp;Cristina Bilbao-Sieyro,&nbsp;Yanira Florido,&nbsp;Christian Thiede,&nbsp;Caroline Schuster,&nbsp;Anastazja Stoj,&nbsp;Sylwia Czekalska,&nbsp;Anastasia Chatzidimitriou,&nbsp;Stamatia Laidou,&nbsp;Audrey Bidet,&nbsp;Charles Dussiau,&nbsp;Friedel Nollet,&nbsp;Giovanna Piras,&nbsp;Maria Monne,&nbsp;Svetlana Smirnova,&nbsp;Eugene Nikitin,&nbsp;Ivan Sloma,&nbsp;Alexis Claudel,&nbsp;Laetitia Largeaud,&nbsp;Loïc Ysebaert,&nbsp;Peter J. M. Valk,&nbsp;Amy Christian,&nbsp;Renata Walewska,&nbsp;David Oscier,&nbsp;Marta Sebastião,&nbsp;Maria Gomes da Silva,&nbsp;Piero Galieni,&nbsp;Mario Angelini,&nbsp;Davide Rossi,&nbsp;Valeria Spina,&nbsp;Sónia Matos,&nbsp;Vânia Martins,&nbsp;Tomasz Stokłosa,&nbsp;Monika Pepek,&nbsp;Panagiotis Baliakas,&nbsp;Rafa Andreu,&nbsp;Irene Luna,&nbsp;Tiina Kahre,&nbsp;Ülle Murumets,&nbsp;Tereza Pikousova,&nbsp;Terezia Kurucova,&nbsp;Sophie Laird,&nbsp;Daniel Ward,&nbsp;Miguel Alcoceba,&nbsp;Ana Balanzategui,&nbsp;Lydia Scarfo,&nbsp;Francesca Gandini,&nbsp;Ettore Zapparoli,&nbsp;Adoración Blanco,&nbsp;Pau Abrisqueta,&nbsp;Ana E. Rodríguez-Vicente,&nbsp;Rocío Benito,&nbsp;Clotilde Bravetti,&nbsp;Frédéric Davi,&nbsp;Paula Gameiro,&nbsp;Joaquin Martinez-Lopez,&nbsp;Bárbara Tazón-Vega,&nbsp;Fanny Baran-Marszak,&nbsp;Zadie Davis,&nbsp;Mark Catherwood,&nbsp;Andrey Sudarikov,&nbsp;Richard Rosenquist,&nbsp;Carsten U. Niemann,&nbsp;Kostas Stamatopoulos,&nbsp;Paolo Ghia,&nbsp;Sarka Pospisilova","doi":"10.1002/hem3.70065","DOIUrl":"10.1002/hem3.70065","url":null,"abstract":"<p>In chronic lymphocytic leukemia, the reliability of next-generation sequencing (NGS) to detect <i>TP53</i> variants ≤10% allelic frequency (low-VAF) is debated. We tested the ability to detect 23 such variants in 41 different laboratories using their NGS method of choice. The sensitivity was 85.6%, 94.5%, and 94.8% at 1%, 2%, and 3% VAF cut-off, respectively. While only one false positive (FP) result was reported at &gt;2% VAF, it was more challenging to distinguish true variants &lt;2% VAF from background noise (37 FPs reported by 9 laboratories). The impact of low-VAF variants on time-to-second-treatment (TTST) and overall survival (OS) was investigated in a series of 1092 patients. Among patients not treated with targeted agents, patients with low-VAF <i>TP53</i> variants had shorter TTST and OS versus wt-<i>TP53</i> patients, and the relative risk of second-line treatment or death increased continuously with increasing VAF. Targeted therapy in ≥2 line diminished the difference in OS between patients with low-VAF <i>TP53</i> variants and wt-<i>TP53</i> patients, while patients with high-VAF <i>TP53</i> variants had inferior OS compared to wild type-<i>TP53</i> cases. Altogether, NGS-based approaches are technically capable of detecting low-VAF variants. No strict threshold can be suggested from a technical standpoint, laboratories reporting <i>TP53</i> mutations should participate in a standardized validation set-up. Finally, whereas low-VAF variants affected outcomes in patients receiving chemoimmunotherapy, their impact on those treated with novel therapies remains undetermined. Our results pave the way for the harmonized and accurate <i>TP53</i> assessment, which is indispensable for elucidating the role of <i>TP53</i> mutations in targeted treatment.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004481","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 anti-PD1 therapy in extranodal NK/T cell lymphoma: A matched cohort analysis from the LYSA","authors":"Amira Marouf,&nbsp;Sammara Chaubard,&nbsp;Raphaël Liévin,&nbsp;Jean-Marie Michot,&nbsp;Nicolas Molinari,&nbsp;Julien Rossignol,&nbsp;Doriane Cavalieri,&nbsp;Camille Golfier,&nbsp;Olivier Allangba,&nbsp;Laure Philippe,&nbsp;Benoît Tessoulin,&nbsp;Adrien Chauchet,&nbsp;Bénédicte Deau,&nbsp;Lucie Oberic,&nbsp;Jacques Vargaftig,&nbsp;Aline Moignet,&nbsp;Aline Clavert,&nbsp;Rémy Dulery,&nbsp;Gabriel Brisou,&nbsp;Stéphanie Tardy,&nbsp;Virginie Fataccioli,&nbsp;Roch Houot,&nbsp;René O. Casasnovas,&nbsp;Catherine Thieblemont,&nbsp;Hervé Ghesquières,&nbsp;Sylvain Carras,&nbsp;Steven Le Gouill,&nbsp;Guillaume Cartron,&nbsp;Vincent Ribrag,&nbsp;Morgane Cheminant,&nbsp;Ambroise Marçais,&nbsp;Felipe Suarez,&nbsp;Aurélien Marabelle,&nbsp;Olivier Tournilhac,&nbsp;Gandhi Damaj,&nbsp;Philippe Gaulard,&nbsp;Laurence De Leval,&nbsp;François Lemonnier,&nbsp;Emmanuel Bachy,&nbsp;Sylvie Chevret,&nbsp;Olivier Hermine,&nbsp;Lucile Couronné,&nbsp;Arnaud Jaccard","doi":"10.1002/hem3.70081","DOIUrl":"10.1002/hem3.70081","url":null,"abstract":"&lt;p&gt;Extranodal NK/T cell lymphoma (ENKTCL) is a mature T/NK-cell malignancy associated with Epstein Barr Virus.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Although asparaginase-based treatments have improved outcomes, the prognosis remains poor for relapsed or refractory (R/R) patients. Increased expression of PD-L1at tumor cell surface is a frequent mechanism of immune evasion in ENKTCL.&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; Consequently, anti-PD1 (aPD1) therapy, either alone&lt;span&gt;&lt;sup&gt;4-9&lt;/sup&gt;&lt;/span&gt; or combined with chemotherapy,&lt;span&gt;&lt;sup&gt;10, 11&lt;/sup&gt;&lt;/span&gt; has been evaluated in patients with R/R ENKTCL, showing promising results. These initial findings were primarily observed in Asian patients where the prevalence of the disease is higher. Due to the limited data from Western countries and the lack of comparative studies, we assessed the efficacy of aPD1 therapy in a large French cohort of ENKTCL patients and compared it with a historical national cohort of R/R ENKTCL patients treated before the introduction of immunotherapies.&lt;/p&gt;&lt;p&gt;This study included 37 patients from 24 French centers treated with at least one cycle of aPD1 therapy for relapse or progression between March 2017 and March 2022. Among them, 12 patients were enrolled in the prospective AcSé Pembrolizumab study (Unicancer), a phase II, open-label, multicentric study investigating pembrolizumab monotherapy in rare cancers (NCT03012620). The remaining 25 patients were treated with aPD1 alone or combined with chemotherapy or targeted therapy (Supporting Information S1: Table 1), following the recommendations issued by the T-cell lymphomas committee (TENOMIC) of the LYmphoma Study Association (LYSA). These patients were designated as “real-life” patients. The inclusion criteria are detailed in the Supporting Information Methods.&lt;/p&gt;&lt;p&gt;The median age was 52 [19–79], with a sex ratio M/F of 2/1. At diagnosis, 21 patients (57%) presented with disseminated disease, and 15 patients (42%) had a high PINK score. Overall, the clinical characteristics of patients included in the AcSé study were comparable to those of the “real-life” patients. Although not reaching statistical significance, the rate of disseminated disease and high PINK score at diagnosis tended to be higher in the “real-life” group (64% vs. 41.7%, &lt;i&gt;p&lt;/i&gt; = 0.35, and 50% vs. 25%, &lt;i&gt;p&lt;/i&gt; = 0.22, respectively). At relapse, no significant difference was observed except for LDH serum level, which was higher in the “real-life” cohort (&lt;i&gt;p&lt;/i&gt; = 0.023) (Supporting Information S1: Table 2).&lt;/p&gt;&lt;p&gt;All patients had previously received frontline chemotherapy containing asparaginase including MOGAD or MGAD (in accordance with current French guidelines) in 17 (46%) and 12 (32%) patients, respectively, resulting in a 70% complete response (CR) rate after first-line therapy. Prior treatments before aPD1 salvage also included autologous (&lt;i&gt;n&lt;/i&gt; = 5) and allogenic (&lt;i&gt;n&lt;/i&gt; = 1) stem cell transplants and external radiotherapy (&lt;i&gt;n&lt;/i&gt; = 21).&lt;/p&gt;&lt;p&gt;Thirty-six","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004485","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":"Secondary lesions and sensitivity to signaling inhibitors in iAMP21 acute lymphoblastic leukemia","authors":"Femke M. Hormann,&nbsp;Anna Østergaard,&nbsp;Stijn van den Broek,&nbsp;Aurélie Boeree,&nbsp;Cesca van de Ven,&nbsp;Gabriele Escherich,&nbsp;Edwin Sonneveld,&nbsp;Judith M. Boer,&nbsp;Monique L. den Boer","doi":"10.1002/hem3.70069","DOIUrl":"10.1002/hem3.70069","url":null,"abstract":"<p>Intrachromosomal amplification of chromosome 21 (iAMP21) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in children is a high-risk subtype for which targeted drugs are lacking. In this study, we determined the frequency of secondary lesions in 28 iAMP21 BCP-ALL patient samples and investigated cellular sensitivity for candidate-targeted drugs. iAMP21 was enriched in <i>FLT3</i> aberrations (10.7% vs. 50.0%, <i>p</i> = 0.003) and <i>SH2B3</i> inactivation (7.14% vs. 46.4%, <i>p</i> = 0.002), compared with 28 B-other cases, and these alterations co-occurred in 21.4%. The occurrence of lesions in <i>CRLF2</i> and <i>IL7R</i> was similar between iAMP21 and B-other cases (25% vs. 17.9%, <i>p</i> = 0.746 and 7.14% vs. 0%, <i>p</i> = 0.491 respectively) as were mutations in <i>JAK1</i> and <i>JAK2</i> (3.57% vs. 0% and 10.7% vs. 10.7%, <i>p</i> = 1 for both). Sensitivity to the FLT3 inhibitor gilteritinib did not differ between iAMP21 and B-other cases irrespective of FLT3 status. However, iAMP21 samples harboring both <i>FLT3-</i>ITD and <i>SH2B3</i> lesions showed the highest sensitivity. <i>CRLF2-</i>rearranged iAMP21 samples were slightly more sensitive to JAK inhibitor ruxolitinib than those without, although a lack of sensitivity was present in 50% of iAMP21 cases. Trametinib sensitivity varied among iAMP21 samples with over half of iAMP21 samples being sensitive irrespective of RAS-pathway mutation status or other secondary lesions. In summary, iAMP21 leukemias were enriched in <i>FLT3</i> and in <i>SH2B3</i> lesions, which when co-occurring affected sensitivity to FLT3 inhibition by gilteritinib but not JAK inhibition by ruxolitinib. Together, our results suggest that FLT3 and RAS signaling inhibitors are of interest for further (pre)clinical evaluation in iAMP21 BCP-ALL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004545","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 CD123 antibody–drug conjugate pivekimab sunirine exerts profound activity in preclinical models of pediatric acute lymphoblastic leukemia","authors":"Ben Watts,&nbsp;Christopher M. Smith,&nbsp;Kathryn Evans,&nbsp;Andrew J. Gifford,&nbsp;Sara M. A. Mohamed,&nbsp;Stephen W. Erickson,&nbsp;Eric J. Earley,&nbsp;Steven Neuhauser,&nbsp;Timothy M. Stearns,&nbsp;Vivek M. Philip,&nbsp;Jeffrey H. Chuang,&nbsp;Patrick A. Zweidler-McKay,&nbsp;Sribalaji Lakshmikanthan,&nbsp;Emily L. Jocoy,&nbsp;Carol J. Bult,&nbsp;Beverly A. Teicher,&nbsp;Malcolm A. Smith,&nbsp;Richard B. Lock","doi":"10.1002/hem3.70063","DOIUrl":"10.1002/hem3.70063","url":null,"abstract":"<p>Antibody–drug conjugates (ADCs) combining monoclonal antibodies with cytotoxic payloads are a rapidly emerging class of immune-based therapeutics with the potential to improve the treatment of cancer, including children with relapse/refractory acute lymphoblastic leukemia (ALL). CD123, the α subunit of the interleukin-3 receptor, is overexpressed in ALL and is a potential therapeutic target. Here, we show that pivekimab sunirine (PVEK), a recently developed ADC comprising the CD123-targeting antibody, G4723A, and the cytotoxic payload, DGN549, was highly effective in vivo against a large panel of pediatric ALL patient-derived xenograft (PDX) models (<i>n</i> = 39). PVEK administered once weekly for 3 weeks resulted in a median event-free survival (EFS) of 57.2 days across all PDXs. CD123 mRNA and protein expression was significantly higher in B-lineage (<i>n</i> = 65) compared with T-lineage (<i>n</i> = 25) ALL PDXs (<i>p</i> &lt; 0.0001), and mice engrafted with B-lineage PDXs achieved significantly longer EFS than those engrafted with T-lineage PDXs (<i>p</i> &lt; 0.0001). PVEK treatment also resulted in significant clearance of human leukemia cells in hematolymphoid organs in mice engrafted with B-ALL PDXs. Notably, our results showed no direct correlation between CD123 expression and mouse EFS, indicating that CD123 is necessary but not sufficient for in vivo PVEK activity. Importantly, a PDX with very high CD123 cell surface expression but resistant to in vivo PVEK treatment, failed to internalize the G4723A antibody while remaining sensitive to the PVEK payload, DGN549, suggesting a novel mechanism of resistance. In conclusion, PVEK was highly effective against a large panel of B-ALL PDXs supporting its clinical translation for B-lineage pediatric ALL.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004590","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":"Disease characteristics and outcomes of acute myeloid leukemia in germline RUNX1 deficiency (Familial Platelet Disorder with associated Myeloid Malignancy)","authors":"Martijn P. T. Ernst,&nbsp;Jurjen Versluis,&nbsp;Peter J. M. Valk,&nbsp;Marc Bierings,&nbsp;Rienk Y. J. Tamminga,&nbsp;Louise H. Hooimeijer,&nbsp;Konstanze Döhner,&nbsp;Paolo Gresele,&nbsp;Kiran Tawana,&nbsp;Saskia M. C. Langemeijer,&nbsp;Bert A. Van der Reijden,&nbsp;Helena Podgornik,&nbsp;Matjaz Sever,&nbsp;Tor H. A. Tvedt,&nbsp;Tom Vulliamy,&nbsp;Jude Fitzgibbon,&nbsp;Inderjeet Dokal,&nbsp;Panagiotis Baliakas,&nbsp;José M. Bastida,&nbsp;Christian Pohlkamp,&nbsp;Torsten Haferlach,&nbsp;Lise Larcher,&nbsp;Jean Soulier,&nbsp;Roger E. G. Schutgens,&nbsp;Kathleen Freson,&nbsp;Nicolas Duployez,&nbsp;Bob Löwenberg,&nbsp;Katrin Ericson,&nbsp;Jörg Cammenga,&nbsp;Tim Ripperger,&nbsp;Marc H. G. P. Raaijmakers","doi":"10.1002/hem3.70057","DOIUrl":"10.1002/hem3.70057","url":null,"abstract":"<p>Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM, FPD/AML, <i>RUNX1</i>-FPD), caused by monoallelic deleterious germline <i>RUNX1</i> variants, is characterized by bleeding diathesis and predisposition for hematologic malignancies, particularly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical data on FPDMM-associated AML (FPDMM-AML) are limited, complicating evidence-based clinical decision-making. Here, we present retrospective genetic and clinical data of the largest cohort of FPDMM patients reported to date. We describe 159 European patients (from 94 families) of whom 134 were evaluable for the development of malignant disease. Sixty developed a hematologic malignancy (44.8%), most frequently AML (36/134, 26.9%) or MDS (18/134, 13.4%). Somatic alterations of <i>RUNX1</i> by gene mutation (48%) and chromosome 21 aberrations (14.3%) were the most common somatic genetic aberrations in FPDMM-AML, followed by <i>FLT3-ITD</i> mutations (24.1%). Somatic <i>RUNX1</i> and <i>FLT3-ITD</i> mutations were not detected in FPDMM-associated MDS, suggesting important contributions to leukemic transformation. Remission-induction chemotherapy resulted in complete remission in 80% of FPDMM-AML patients with a 5-year overall survival (OS) of 50.4%. Survival outcome was non-inferior compared to a large cohort of newly diagnosed adult <i>RUNX1</i>-mutated AML (5-year OS 36.6%, <i>p</i> = 0.5), with relatively infrequent concurrent adverse risk somatic aberrations (<i>ASXL1</i> mutation, monosomal karyotype, monosomy 5/del 5q) in FPDMM-AML. Collectively, data support the notion that step-wise leukemic evolution in FPDMM is associated with distinct genetic events and indicate that a substantial subset of FPDMM-AML patients achieves prolonged survival with conventional AML treatment, including allogeneic stem cell transplant. These findings are anticipated to inform personalized clinical decision-making in this rare disorder.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004482","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":"Extracellular vesicles from chronic lymphocytic leukemia cells promote leukemia aggressiveness by inducing the differentiation of monocytes into nurse-like cells via an RNA-dependent mechanism","authors":"Nathan Dubois,&nbsp;David Van Morckhoven,&nbsp;Laurentijn Tilleman,&nbsp;Filip Van Nieuwerburgh,&nbsp;Dominique Bron,&nbsp;Laurence Lagneaux,&nbsp;Basile Stamatopoulos","doi":"10.1002/hem3.70068","DOIUrl":"10.1002/hem3.70068","url":null,"abstract":"<p>Chronic lymphocytic leukemia (CLL) cells receive several stimuli from surrounding cells, such as B-cell receptor (BCR) stimulation, and can manipulate their microenvironment via extracellular vesicle (EV) release. Here, we investigated the small RNA content (microRNA and YRNA) of CLL-EVs from leukemic cells cultured with/without BCR stimulation. We highlight an increase of miR-155-5p, miR-146a-5p, and miR-132-3p in EVs and in cells after BCR stimulation (<i>p</i> &lt; 0.05, <i>n</i> = 25). CLL-EVs were preferentially internalized by monocytes (<i>p</i> = 0.0019, <i>n</i> = 6) and able to deliver microRNAs and the hY4 RNA. Furthermore, BCR CLL-EV induced modifications in monocytes (shape change, microRNA and gene expression, secretome) suggesting nurse-like cell (NLC) differentiation, the tumor-associated macrophages of CLL. Functionally, monocytes treated with BCR CLL-EVs protect CLL cells from spontaneous apoptosis by pro-survival cytokine production and induce their migration as well as the migration of other immune cells. We finally reported by transfection experiments that hY4 is able to induce the expression of CCL24, a key gene in M2 macrophage differentiation. In conclusion, we showed that BCR stimulation modifies the small RNA content of CLL-EVs and that the addition of leukemic EVs to monocytes leads to monocyte differentiation into NLCs establishing a protective microenvironment that supports leukemic cell survival.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004500","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":"Idecabtagene vicleucel or ciltacabtagene autoleucel for relapsed or refractory multiple myeloma: An international multicenter study","authors":"Maximilian Merz,&nbsp;Anca-Maria Albici,&nbsp;Bastian von Tresckow,&nbsp;Kristin Rathje,&nbsp;Roland Fenk,&nbsp;Tobias Holderried,&nbsp;Fabian Müller,&nbsp;Natalia Tovar,&nbsp;Aina Oliver-Cáldes,&nbsp;Vladan Vucinic,&nbsp;Soraya Kharboutli,&nbsp;Ben-Niklas Bärmann,&nbsp;Francis Ayuk,&nbsp;Uwe Platzbecker,&nbsp;Friedrich Stölzel,&nbsp;Nathalie Schub,&nbsp;Friederike Schmitz,&nbsp;David Fandrei,&nbsp;Patrick Born,&nbsp;Cyrus Khandanpour,&nbsp;Christine Hanoun,&nbsp;Keven Hörster,&nbsp;Marcel Teichert,&nbsp;Barbara Jeker,&nbsp;Michele Hoffmann,&nbsp;Nicolaus Kröger,&nbsp;Carlos Fernández de Larrea,&nbsp;Thomas Pabst,&nbsp;Nico Gagelmann","doi":"10.1002/hem3.70070","DOIUrl":"10.1002/hem3.70070","url":null,"abstract":"<p>Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have revolutionized the treatment of relapsed/refractory multiple myeloma (RRMM), but direct comparisons are lacking. Leveraging an international multicenter RRMM cohort, we compared the outcome of ide-cel (<i>n</i> = 162) versus cilta-cel (<i>n</i> = 42). Co-primary efficacy endpoints of the study were overall response rate (ORR) and progression-free survival (PFS). Co-primary safety endpoints were the incidence of cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS). Median turnaround time between apheresis and infusion was 47 days for ide-cel versus 68 days for cilta-cel (<i>p</i> &lt; 0.001). Cilta-cel showed significantly higher ORR (93% vs. 79%; <i>p</i> &lt; 0.001), with complete response at Day 30 of 48% versus 26% (<i>p</i> &lt; 0.001). The 10-month PFS and overall survival (OS) was 82% and 90% for cilta-cel versus 47% and 77% ide-cel (<i>p</i> &lt; 0.001 and <i>p</i> = 0.06), and improved outcome for cilta-cel was confirmed after multivariable adjustment. Incidence of CRS and ICANS appeared similar (81% and 19% for cilta-cel versus 85% and 19% for ide-cel), while 10% and 7% in the cilta-cel group versus 4% and 2% in the ide-cel group showed severe CRS and ICANS grade 3–4, with CRS occurring significantly earlier for ide-cel (median, 2 days vs. 4 days; <i>p</i> &lt; 0.001). Nonrelapse mortality was 5% for cilta-cel versus 3% for ide-cel (<i>p</i> = 0.51). Cilta-cel showed later peak of CAR-T expansion at Day 14 versus Day 7 for ide-cel, while cilta-cel expansion was associated with ICANS. Our study provides real-world evidence that cilta-cel was associated with superior outcomes and distinct cellular dynamics versus ide-cel in triple-class exposed RRMM.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735948/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004501","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 results of a phase 1/1b study of ibrutinib plus umbralisib for relapsed/refractory chronic lymphocytic leukemia","authors":"Christine E. Ryan,&nbsp;Yue Ren,&nbsp;Svitlana Tyekucheva,&nbsp;Jon E. Arnason,&nbsp;Adam M. Boruchov,&nbsp;Caron A. Jacobson,&nbsp;David C. Fisher,&nbsp;Hari Miskin,&nbsp;Peter Sportelli,&nbsp;Jennifer R. Brown,&nbsp;Matthew S. Davids","doi":"10.1002/hem3.70067","DOIUrl":"10.1002/hem3.70067","url":null,"abstract":"&lt;p&gt;Given the fundamental importance of the B-cell receptor (BCR) pathway in chronic lymphocytic leukemia (CLL) pathophysiology,&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; we investigated dual BCR blockade in treating relapsed or refractory (R/R) disease. We hypothesized that combining the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, which is highly effective in R/R CLL,&lt;span&gt;&lt;sup&gt;2, 3&lt;/sup&gt;&lt;/span&gt; with the next-generation oral phosphoinositide-3-kinase-delta isoform inhibitor (PI3Kδi) umbralisib would be an effective, well-tolerated, and convenient therapeutic approach that could lead to more durable remissions than historical results with ibrutinib alone. Unlike the approved PI3Kis idelalisib and duvelisib, umbralisib also targets casein-kinase-1-epsilon,&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; which may spare regulatory T cell functioning through downregulation of WNT signaling,&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; and thereby lead to less immune-mediated toxicity. A large integrated safety analysis across four early-phase umbralisib monotherapy studies demonstrated favorable long-term tolerability.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Our initial results of this combination indeed found the combination achieved a high overall response rate (ORR; 90%) with a promising 2-year progression-free-survival (PFS) rate of 90%.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Here, we report long-term results with a median follow-up for survivors of just under 5 years.&lt;/p&gt;&lt;p&gt;The design of this multicenter, investigator-sponsored trial (NCT02268851) has been described previously.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Of note, the study also included patients with R/R mantle cell lymphoma (MCL), but here we report only on long-term follow-up for the patients with CLL, as nearly all of the patients with MCL had either progressed or died soon after the data cut for the prior publication. Briefly, key inclusion criteria were R/R CLL with progression after ≥1 prior therapy, indication for treatment per iwCLL guidelines,&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; and ECOG performance status ≤2. Key exclusion criteria were allogeneic transplantation within 12 months, active graft versus host disease, or central nervous system involvement. Patients received daily oral dosing of ibrutinib 420 mg and umbralisib at 3 dose levels. Study treatment was continued until progressive disease (PD) or unacceptable toxicity. Toxicity was by CTCAE 4.0 and iwCLL hematologic criteria, and response was by iwCLL criteria. Median duration on treatment was estimated by reverse Kaplan-Meier method. PFS and overall survival (OS) were estimated by Kaplan–Meier method. Statistical analyses used R version 4.3.1 (R Foundation for Statistical Computing).&lt;/p&gt;&lt;p&gt;Twenty-one patients with CLL were enrolled; median age was 67 years (range 48–85) with full characteristics previously described.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Patients had a median of 1 prior line of therapy (range 1–6), with 43% of patients having received ≥2 lines. Two patients had prior BTKi exposure (both treated with ibrutinib for &lt;","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 1","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143004527","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}