HemaSphere最新文献

{"title":"Event-free survival in early polycythemia vera patients correlates with molecular response to ropeginterferon alfa-2b or hydroxyurea/best available therapy (PROUD-PV/CONTINUATION-PV)","authors":"Jean-Jacques Kiladjian, Christoph Klade, Pencho Georgiev, Dorota Krochmalczyk, Liana Gercheva-Kyuchukova, Miklos Egyed, Petr Dulicek, Arpad Illes, Halyna Pylypenko, Lylia Sivcheva, Jiří Mayer, Vera Yablokova, Kurt Krejcy, Victoria Empson, Hans C. Hasselbalch, Robert Kralovics, Heinz Gisslinger, for the PROUD-PV Study Group","doi":"10.1002/hem3.70137","DOIUrl":"https://doi.org/10.1002/hem3.70137","url":null,"abstract":"<p>Clonal expansion of <i>JAK2</i>V617F-mutated hematopoietic stem cells underlies almost all cases of PV, a rare myeloproliferative neoplasm.<span><sup>1</sup></span> Nevertheless, the clinical relevance of reducing the variant allele frequency (VAF) (i.e., achieving molecular response [MR] to treatment) has been disputed. Prospective trials in PV are challenging given the latent onset and low penetrance of major outcomes such as thrombotic events and progression to myelofibrosis or acute myeloid leukemia.<span><sup>2</sup></span> Therefore, recent analyses demonstrating a correlation of MR with prolonged EFS in high-risk PV patients resistant/intolerant to hydroxyurea generated strong interest.<span><sup>3, 4</sup></span> If confirmed in a wider PV population, these findings suggest MR could be a major treatment aim. We examined the relationship between MR and EFS in the PROUD-PV/CONTINUATION-PV studies (#NCT01949805; #NCT02218047) in an early-stage PV population and explored the clinical relevance of further depleting the <i>JAK2</i>V617F clone.</p><p>The phase 3 randomized PROUD-PV study and its extension CONTINUATION-PV enrolled low- and high-risk PV patients requiring cytoreduction who were treatment-naïve or hydroxyurea pre-treated for ≤3 years without resistance/intolerance. Design and methods have been published previously.<span><sup>5, 6</sup></span> Patients were randomized 1:1 to receive ropeginterferon alfa-2b or hydroxyurea for 12 months. Ropeginterferon alfa-2b (BESREMi®) was started at a dose of 50–100 μg every 2 weeks and escalated until blood counts normalized, with a maximum dose of 500 μg. Hydroxyurea was administered at 500–3000 mg daily. Patients who enrolled in CONTINUATION-PV remained in their allocated treatment arm. Control arm patients could switch from hydroxyurea to any standard treatment (i.e., best available therapy [BAT]); those receiving ropeginterferon alfa-2b could extend the administration interval to every 3 or 4 weeks.</p><p>The primary endpoint of both PROUD-PV and CONTINUATION-PV was the disease response rate; sample size calculations have been reported. Change in <i>JAK2</i>V617F VAF was a secondary endpoint assessed every 6 months; imputation of the last observation carried forward was utilized for missing values using an assay with a detection limit of 0.014% as previously described.<span><sup>6</sup></span> Adverse events were recorded at every visit. Clinical outcomes (events defined as thromboembolic events, progression to myelofibrosis or acute myeloid leukemia, or death, derived from safety data) were assessed over ≥6 years. EFS by treatment arm (intent-to-treat analysis) was assessed using Kaplan–Meier analysis of time to first event. The analysis was repeated whereby patients switching to any interferon therapy as BAT for ≥12 months were included in the experimental arm.</p><p>EFS was assessed by Kaplan–Meier analysis by <i>JAK2</i>V617F MR (defined by European LeukemiaNet criteria<span><sup>7</su","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 5","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70137","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to Summary of Joint European Hematology Association (EHA) and EuroBloodNet recommendations on diagnosis and treatment of methemoglobinemia","authors":"","doi":"10.1002/hem3.70144","DOIUrl":"https://doi.org/10.1002/hem3.70144","url":null,"abstract":"<p>Iolascon A, Andolfo I, Russo R, et al. Summary of Joint European Hematology Association (EHA) and EuroBloodNet recommendations on diagnosis and treatment of methemoglobinemia. <i>HemaSphere</i>. 2021;5:e660. https://doi.org/10.1097/HS9.0000000000000660</p><p>The 8th co-author, incorrectly listed as first name Davis, has been updated. The correct name of this co-author is David Rees.</p><p>The online version of this article has been updated accordingly.</p><p>We apologize for this error.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 5","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70144","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901046","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":"Nivolumab plus ifosfamide, carboplatin, and etoposide are a highly effective first salvage regimen in high-risk relapsed/refractory Hodgkin lymphoma","authors":"Matthew Mei,&nbsp;Joycelynne Palmer,&nbsp;Hun Ju Lee,&nbsp;Iris Isufi,&nbsp;Robert Chen,&nbsp;Ni-Chun Tsai,&nbsp;Saro Armenian,&nbsp;James Godfrey,&nbsp;Joo Y. Song,&nbsp;John H. Baird,&nbsp;Swetha Thiruvengadam,&nbsp;Yazeed Samara,&nbsp;Jessica Flores,&nbsp;Lacolle Peters,&nbsp;Steven Rosen,&nbsp;Larry Kwak,&nbsp;Stephen J. Forman,&nbsp;Alex F. Herrera","doi":"10.1002/hem3.70126","DOIUrl":"https://doi.org/10.1002/hem3.70126","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 <p>Nivolumab is an anti-PD-1 antibody that is effective in patients with relapsed/refractory (RR) classic Hodgkin lymphoma (cHL). We previously showed PET-adapted sequential nivolumab ± ifosfamide, carboplatin, and etoposide (ICE) chemotherapy as the first salvage in RR cHL was a safe and effective bridge to autologous stem cell transplant (ASCT) (cohort A). We then tested a non-PET-adapted schema where all patients received nivolumab + ICE (cohort B). In this study, we present results from cohort B. Patients with high-risk RR cHL after frontline treatment received 240 mg nivolumab followed by 2–3 cycles of NICE (240 mg nivolumab day 1, standard doses of ICE). High-risk disease was defined as having one of the following: primary refractory cHL, relapse within 1 year of completing frontline therapy, B symptoms at relapse, extranodal disease at relapse, or frontline brentuximab vedotin use. PET/CT was performed after nivolumab × 1 and NICE × 2. Responding patients (complete response [CR] or partial response) were intended to proceed to ASCT. The primary endpoint was CR rate per 2014 Lugano classification. A total of 35 patients were enrolled, all of whom were evaluable for safety and efficacy. Overall response rate and CR were 100% and 86%, respectively; 2-year progression-free survival (PFS) and overall survival (OS) were 88% and 100%, respectively. Thirty-two patients proceeded to ASCT directly after NICE; 2-year post-ASCT PFS and OS were 94% and 100%, respectively. Immune-related toxicities were all grades 1–2, and no patient discontinued treatment for toxicity. Nivolumab/NICE is a highly effective salvage regimen and bridges patients effectively to ASCT.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 5","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70126","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143888830","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":"High-risk features of early relapse in newly-diagnosed multiple myeloma: The impact of cytogenetics and response to initial therapy","authors":"Andrea Manubens,&nbsp;Bruno Paiva,&nbsp;Norma C. Gutiérrez,&nbsp;Manuela Fernandez,&nbsp;Maria-José Calasanz,&nbsp;Laura Rosiñol,&nbsp;Albert Oriol,&nbsp;Ma Jesús Blanchard,&nbsp;Estrella Carrillo,&nbsp;Celina Benavente,&nbsp;Joaquín Martínez-López,&nbsp;Joan Bargay,&nbsp;Miguel Teodoro Hernández,&nbsp;Javier de la Rubia,&nbsp;Yolanda González,&nbsp;Miguel Paricio,&nbsp;Felipe de Arriba,&nbsp;Enrique M. Ocio,&nbsp;Ana Isabel Teruel,&nbsp;Ana López de la Guia,&nbsp;Maialen Sirvent,&nbsp;Mercedes Gironella,&nbsp;Antonia Sampol,&nbsp;José Ma Arguiñano,&nbsp;Carmen Cabrera,&nbsp;Adrián Alegre,&nbsp;Miquel Granell,&nbsp;Valentín Cabañas,&nbsp;Jorge M. Núñez-Córdoba,&nbsp;María Victoria Mateos,&nbsp;Juan José Lahuerta,&nbsp;Jesús F. San Miguel,&nbsp;Joan Bladé,&nbsp;Paula Rodriguez-Otero","doi":"10.1002/hem3.70127","DOIUrl":"https://doi.org/10.1002/hem3.70127","url":null,"abstract":"<p>Patients with newly-diagnosed multiple myeloma (MM) who experience early relapse (ER) have dismal overall survival (OS). Their prospective identification, either before or soon after treatment initiation, is paramount to use alternative approaches and prevent ER. In this study, we investigated the frequency and disease characteristics of ER during the first 18 months after treatment initiation (ER18), in a series of 1215 newly-diagnosed MM patients enrolled in four PETHEMA/GEM clinical trials for the transplant-eligible and transplant-ineligible populations. ER18 was observed in 266 of the 1215 patients (22%) and resulted in a median OS of 19 versus 114 months in cases without ER18. When compared to the ISS and the presence of ≥2 high-risk cytogenetic abnormalities, a modified version of the new high-risk definition from the International Myeloma Society (mHR-IMS) showed the most balanced negative and positive predictive values of ER18 (83.5% and 40%, respectively). In addition to the mHR-IMS, an ECOG = 2, ISS 3, and calcium levels ≥ 11 mg/dL were independently associated with ER18. These variables were modeled into a predictive score in which the rates of ER18 were 2%, 24.5%, and 59% in patients with low-, intermediate-, and high-risk score. The risk of ER18 and OS were modulated by the VGPR status at 6–9 months after treatment initiation. In conclusion, we present a risk model that predicts ER18 and can be readily applied in clinical trials and routine practice to identify treatment strategies empowered to prevent ER18 and improve survival outcomes of newly-diagnosed patients with functional high-risk MM.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 4","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70127","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143865687","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":"Comparing functional and genomic-based precision medicine in blood cancer patients","authors":"Lukas Kazianka,&nbsp;Alexander Pichler,&nbsp;Christiane Agreiter,&nbsp;Johannes Rohrbeck,&nbsp;Christoph Kornauth,&nbsp;Edit Porpaczy,&nbsp;Christian Sillaber,&nbsp;Wolfgang R. Sperr,&nbsp;Karoline V. Gleixner,&nbsp;Alexander Hauswirth,&nbsp;Ulrich Jäger,&nbsp;Peter Valent,&nbsp;Constanze Jonak,&nbsp;Stefanie Porkert,&nbsp;Ruth Exner,&nbsp;Wolfgang Willenbacher,&nbsp;Dominik Wolf,&nbsp;Peter Neumeister,&nbsp;Katharina Prochazka,&nbsp;Alexander Deutsch,&nbsp;Richard Greil,&nbsp;Clemens Schmitt,&nbsp;Robin Ristl,&nbsp;Marius Mayerhoefer,&nbsp;Ingrid Simonitsch-Klupp,&nbsp;Tea Pemovska,&nbsp;Philipp B. Staber","doi":"10.1002/hem3.70129","DOIUrl":"https://doi.org/10.1002/hem3.70129","url":null,"abstract":"<p>Tumor-agnostic precision medicine (PM) strategies promise to support treatment decisions in relapsed/refractory blood cancer patients. Genomic-based PM (gPM) and drug screening-based functional PM (fPM) currently represent the most prominent PM methodologies. In this study, we report the feasibility analysis of the first 55 patients enrolled in the multicentric, randomized controlled EXALT-2 trial (NCT04470947) comparing treatment recommendations of gPM, fPM, and physicians' choice (PC) head to head. In 54 patients (98%), the diagnostic workflow was successfully implemented, resulting in treatment recommendations for 42 patients (76%), of whom 29 (69%) received the suggested individualized treatments. Actionable targets were identified in 65% by gPM and 80% by fPM (64% microscopy-based, 86% flow cytometry-based fPM). The median time to report was shorter for fPM than for gPM testing. The two strategies revealed overlapping drug targets in 60% of cases. Both, gPM and fPM can efficiently be integrated into the clinical routine to guide therapy decisions for the majority of patients.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 4","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143865688","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":"Cumulative review of cardiac failure with acalabrutinib in the treatment of chronic lymphocytic leukemia using data from clinical trials and postmarketing experience","authors":"Paolo Ghia,&nbsp;Naghmana Bajwa,&nbsp;Anthony J. Corry,&nbsp;Suman Jannuru,&nbsp;Georg Kreuzbauer,&nbsp;Manan Pareek","doi":"10.1002/hem3.70130","DOIUrl":"https://doi.org/10.1002/hem3.70130","url":null,"abstract":"&lt;p&gt;Bruton tyrosine kinase inhibitors (BTKis) have revolutionized the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). The first-generation BTKi, ibrutinib, has demonstrated efficacy in various CLL/SLL populations&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; but has been associated with cardiac toxicities, including atrial fibrillation, hypertension, and cardiac failure.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt; Acalabrutinib, a second-generation BTKi approved for CLL/SLL, has less off-target activity than ibrutinib,&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; with durable efficacy demonstrated in phase 3 trials of patients with treatment-naive (ELEVATE-TN)&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; and relapsed/refractory (ASCEND)&lt;span&gt;&lt;sup&gt;8&lt;/sup&gt;&lt;/span&gt; CLL/SLL. The head-to-head phase 3 ELEVATE-RR study in patients with relapsed/refractory CLL demonstrated noninferior efficacy and significantly lower incidences of any grade atrial fibrillation/flutter (9% vs. 16%) and hypertension (9% vs. 23%) with acalabrutinib versus ibrutinib,&lt;span&gt;&lt;sup&gt;9&lt;/sup&gt;&lt;/span&gt; consistent with findings from a pooled analysis of all sponsored clinical trials of acalabrutinib monotherapy in CLL (any grade atrial fibrillation/flutter, 5%; hypertension, 9%).&lt;span&gt;&lt;sup&gt;10&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Patients with CLL/SLL are typically older and therefore may have cardiovascular comorbidities that increase cardiac failure risk.&lt;span&gt;&lt;sup&gt;11, 12&lt;/sup&gt;&lt;/span&gt; Hence, characterization of the cardiovascular safety profiles of BTKis is warranted, including data from sources other than clinical trials, which may recruit patients with fewer comorbidities than those seen in routine clinical practice. In this study, we report results from a cumulative review of the cardiac failure safety profile of acalabrutinib based on (1) clinical trial data from ELEVATE-RR, ELEVATE-TN, and ASCEND, and (2) real-world postmarketing data from the Global AstraZeneca Patient Safety Database (GAPSD) (Figure 1A). The GAPSD includes acalabrutinib safety data from all sponsored and unsponsored clinical trials and real-world postmarketing sources; only the real-world postmarketing data were used in this analysis. The three clinical trials were conducted according to the ethical principles derived from international guidelines; all patients provided written informed consent. Real-world postmarketing safety data were collected and reported according to global and local rules and regulations.&lt;/p&gt;&lt;p&gt;Exposure-adjusted incidence rates (EAIR) were reported for “cardiac failure” using the broad Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ, v25.0). SMQs are validated, predetermined groups of MedDRA terms used to support drug safety monitoring and analysis. The “cardiac failure” SMQ consists of 107 cardiac failure-specific and cardiac failure-related terms (Table S1). In the clinical trials analysis, EAIRs for the “cardiac failure” broad SMQ and for the most common MedDRA preferred terms from the SMQ were compared between the a","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 4","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70130","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857181","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":"Phosphatidic acid phosphatase LPIN1 in phospholipid metabolism and stemness in hematopoiesis and AML","authors":"Karin Huber,&nbsp;Swati Garg,&nbsp;Lena Schlautmann,&nbsp;Rui Wang,&nbsp;Lixiazi He,&nbsp;Richard Huth,&nbsp;Alireza Pouya,&nbsp;Christian Rohde,&nbsp;Maike Janssen,&nbsp;Christian Lüchtenborg,&nbsp;Christian Arnold,&nbsp;Pilar M. Luque-Navarro,&nbsp;Judith B. Zaugg,&nbsp;Simon Raffel,&nbsp;Carsten Müller-Tidow,&nbsp;Irmela Jeremias,&nbsp;Luisa C. López-Cara,&nbsp;Britta Brügger,&nbsp;Caroline Pabst","doi":"10.1002/hem3.70118","DOIUrl":"https://doi.org/10.1002/hem3.70118","url":null,"abstract":"<p>Targeting metabolism represents a promising approach to eradicate leukemic stem cells (LSCs) that are considered critical drivers of relapse in acute myeloid leukemia (AML). In this study, we demonstrate that the phosphatidic acid phosphatase LPIN1, which regulates the synthesis of diacylglycerol, the key substrate for triacylglycerol, and phospholipid production, is crucial for the function of healthy and leukemic hematopoietic stem and progenitor cells (HSPC and LSC). <i>LPIN1</i> mRNA was highly expressed in the CD34+ compartment of primary human AML samples. <i>LPIN1</i> suppression inhibited the proliferation of primary leukemic cells and normal HSPCs in vitro and in xenotransplantation assays. Lipidomics analyses revealed a reduction of phosphatidylcholine (PC) and phosphatidylethanolamine and an upregulation of sphingomyelin upon <i>LPIN1</i> depletion. Distinct phospholipid composition was associated with genetic AML groups, and targeting PC production by choline kinase inhibitors showed strong anti-leukemic activity. In summary, our data establish a regulatory role of <i>LPIN1</i> in HSPC and LSC function and provide novel insights into the role of glycerophospholipid homeostasis in stemness and differentiation.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 4","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70118","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857180","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":"Orchestration of human multi-lineage hematopoietic cell development by humanized in vivo bone marrow models","authors":"Laurent Renou,&nbsp;Wenjie Sun,&nbsp;Chloe Friedrich,&nbsp;Klaudia Galant,&nbsp;Cecile Conrad,&nbsp;Anne Consalus,&nbsp;Evelia Plantier,&nbsp;Katharina Schallmoser,&nbsp;Linda Krisch,&nbsp;Vilma Barroca,&nbsp;Saryami Devanand,&nbsp;Nathalie Dechamps,&nbsp;Andreas Reinisch,&nbsp;Jelena Martinovic,&nbsp;Alessandra Magnani,&nbsp;Lionel Faivre,&nbsp;Daniel Lewandowski,&nbsp;Julien Calvo,&nbsp;Leila Perie,&nbsp;Olivier Kosmider,&nbsp;Françoise Pflumio","doi":"10.1002/hem3.70120","DOIUrl":"https://doi.org/10.1002/hem3.70120","url":null,"abstract":"<p>Hematopoiesis develops in the bone marrow (BM) where multiple interactions regulate the differentiation and preservation of hematopoietic stem and progenitor cells (HSPCs). Immune-deficient murine models have enabled the analysis of molecular and cellular regulation of human HSPCs, but the physiology of these models is questioned as human hematopoietic cells develop in xenogenic microenvironments. In this study, we thoroughly characterized a humanized (h) in vivo BM model, developed from fetal (F/) and post-natal (P-N/) mesenchymal stromal cell (MSC) differentiation (called hOssicles [hOss]), in which human hematopoietic cells are generated following the transplantation of CD34⁺ cells. Serial isolation and transplant experiments of hMSCs and HSPCs from hOss revealed the dynamic nature of these hBM niches. hOss modified human hematopoietic development by modulating myeloid/lymphoid cell production and HSPC levels, with no major transcriptional changes in HSPCs at the single-cell level. Clonal tracking using genetic barcodes highlighted hematopoietic cell cross-talks between the endogenous murine BM and hOss and differences in clonal myeloid/multipotent cell production between F/hOss and P-N/hOss, uncovering ontogeny-related impact of the BM on human hematopoietic cell production.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 4","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70120","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857179","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":"Spironolactone inhibits the NLRP1 inflammasome and alleviates defective erythropoiesis in Diamond-Blackfan anemia","authors":"Lola Rodríguez-Ruiz,&nbsp;Juan M. Lozano-Gil,&nbsp;María Ocaña-Esparza,&nbsp;Ana M. Conesa-Hernández,&nbsp;Ana B. Pérez-Oliva,&nbsp;José L. Fuster,&nbsp;Andrés Jérez,&nbsp;Laura Murillo-Sanjuán,&nbsp;Cristina Díaz-de-Heredia,&nbsp;Guzmán López-de-Hontanar,&nbsp;Julián Sevilla,&nbsp;Diana García-Moreno,&nbsp;María L. Cayuela,&nbsp;Alicia Martínez-López,&nbsp;Sylwia D. Tyrkalska,&nbsp;Victoriano Mulero","doi":"10.1002/hem3.70131","DOIUrl":"https://doi.org/10.1002/hem3.70131","url":null,"abstract":"&lt;p&gt;The relevance of the NLR family pyrin domain containing 1 (NLRP1) inflammasome was recently extended to the regulation of the erythroid-myeloid lineage decision in both zebrafish and human hematopoietic stem and progenitor cells (HSPCs), acting independently of dipeptidyl peptidase 9 (DPP9)&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; and being activated upon its phosphorylation by the ZAKα/P38 kinase axis following ribosomal stress.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; This novel function of the NLRP1 inflammasome may be of clinical relevance, since defects in ribosome biogenesis caused several ribosomopathies, such as Diamond-Blackfan anemia, in which reduced ribosome levels selectively impair translation of a subset of mRNAs, including &lt;i&gt;GATA1&lt;/i&gt; mRNA.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; For this reason, we performed a screening testing 768 compounds approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) using HEK293T cells transfected with NLRP1 and ASC-GFP plasmids (Supporting Information S1: Figure S1A). This approach enables the visualization and quantification of NLRP1 inflammasome activation by monitoring the oligomerization of the ASC adaptor protein fused to GFP. Upon inflammasome activation, ASC-GFP forms distinct cytosolic specks, whereas in the absence of activation, it remains evenly distributed throughout the cytoplasm. ASC specks were already visible at 6 h post-transfection (hpt) in cells transfected with both plasmids but not with ASC alone (Supporting Information S1: Figure S1B). However, no specks were observed at 4 hpt (Supporting Information S1: Figure S1B). Therefore, cells were treated at 4 hpt with the compounds at 10 µM and analyzed by fluorescence microscopy at 24 hpt (Supporting Information S1: Figure S1B). Among all the compounds analyzed, flufenamic acid, pantoprazole, spironolactone, and amlodipine decreased NLRP1-dependent ASC speck formation. These compounds were then tested at different concentrations (Supporting Information S1: Figure S2). Flufenamic acid at 100 µM and amlodipine at 50 and 100 µM were toxic for the cells. In addition, although flufenamic acid, pantoprazole and amlodipine hardly decreased the number of specks at the different concentration tested, spironolactone was able to show a dose-dependent inhibitory effect (Supporting Information S1: Figure S2). Importantly, 50 µM spironolactone decreased the number of specks in HEK293T transfected with NLRP1 and NLRC4, while it did not affect the percentage of specks formed in the presence of NLRP3 (Supporting Information S1: Figure S3A,B). In addition, spironolactone failed to inhibit the self-oligomerization of ASC speck in the absence of NLRP1 (Supporting Information S1: Figure S3A,B). Notably, spironolactone was also able to inhibit the oligomerization of ASC promoted by the NLRP1 C-terminal fragment containing UPA and CARD subdomain, which form the platform to recruit ASC (Supporting Information S1: Figure S3C).&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; As spironolactone ","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 4","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70131","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143846111","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":"A German multicenter real-world analysis of talquetamab in 138 patients with relapsed/refractory multiple myeloma","authors":"Jan H. Frenking,&nbsp;Christine Riedhammer,&nbsp;Raphael Teipel,&nbsp;Florian Bassermann,&nbsp;Britta Besemer,&nbsp;Moritz Bewarder,&nbsp;Jan Braune,&nbsp;Annamaria Brioli,&nbsp;Franziska Brunner,&nbsp;Maria Dampmann,&nbsp;Roland Fenk,&nbsp;Deniz N. Gezer,&nbsp;Sarah Goldman-Mazur,&nbsp;Christine Hanoun,&nbsp;Marion Högner,&nbsp;Cyrus Khandanpour,&nbsp;Katja Kolditz,&nbsp;Igor Kos,&nbsp;Jan Krönke,&nbsp;Miriam Kull,&nbsp;Valentine Landrin,&nbsp;Theo Leitner,&nbsp;Maximilian Merz,&nbsp;Ivana von Metzler,&nbsp;Christian S. Michel,&nbsp;Carsten Müller-Tidow,&nbsp;Sebastian Theurich,&nbsp;Karolin Trautmann-Grill,&nbsp;Ralph Wäsch,&nbsp;Romans Zukovs,&nbsp;Mathias Hänel,&nbsp;Leo Rasche,&nbsp;Marc S. Raab","doi":"10.1002/hem3.70114","DOIUrl":"https://doi.org/10.1002/hem3.70114","url":null,"abstract":"<p>Bispecific T-cell engagers (BTCEs) represent a paradigm shift in the treatment of relapsed/refractory multiple myeloma (RRMM). Talquetamab, a GPRC5DxCD3 BTCE, has shown promising results in the MonumenTAL-1 trial and was recently approved by the Food and Drug Administration and the European Medicines Agency. However, treatment under real-world conditions may not represent patient characteristics in clinical trials with restricted enrollment criteria. We performed a retrospective real-world analysis including 138 RRMM patients treated with talquetamab at 21 German centers. Of evaluable patients, 43% had ISS stage III, 37% had extraosseous disease, and 48% had high-risk cytogenetics. After a median of six prior therapy lines, 58% of patients would not have been eligible for MonumenTAL-1. With a median follow-up of 8.2 months, we observed an overall response rate of 65% and a median progression-free survival of 6.4 months (95% confidence interval 5.1–9.0). Prior BTCE exposure, ISS stage III, extraosseous disease, and penta-drug refractory disease were associated with unfavorable outcomes. Grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 5.1% and 1.5% of patients, respectively. In summary, our real-world study confirms the efficacy and safety of talquetamab, despite a high proportion of patient- and disease-related risk factors. These results support its use as bridging or long-term treatment, even in advanced stages.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"9 4","pages":""},"PeriodicalIF":7.6,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.70114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143840668","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}