HemaSphere最新文献

{"title":"Biological relapse in multiple myeloma: Outcome and treatment strategies in a Spanish real-world setting","authors":"Adrián Alegre,&nbsp;Mercedes Gironella,&nbsp;Fernando Escalante,&nbsp;Juan M. Bergua,&nbsp;Carmen Martínez-Chamorro,&nbsp;Aurelio López,&nbsp;Esther González,&nbsp;Abelardo Bárez,&nbsp;Nieves Somolinos,&nbsp;Ernesto P. Persona,&nbsp;Alexia S. Cabrera,&nbsp;Alfons Soler,&nbsp;Belén I. Rodríguez,&nbsp;Joaquín M. López,&nbsp;Yolanda González,&nbsp;Verónica C. Giménez,&nbsp;Antonia Sampol,&nbsp;Carolina Muñoz,&nbsp;David Vilanova,&nbsp;Marta Durán,&nbsp;Carlos Fernández de Larrea,&nbsp;Spanish Myeloma Group (GEM_PETHEMA)","doi":"10.1002/hem3.81","DOIUrl":"https://doi.org/10.1002/hem3.81","url":null,"abstract":"<p>Recommendations regarding the best time to start treatment in patients with relapsed/refractory multiple myeloma (RRMM) after biological relapse/progression (BR) are unclear. This observational, prospective, multicenter registry aimed to evaluate the impact on time to progression (TTP) of treatment initiation at BR versus at symptomatic clinical relapse (ClinR) based on the Spanish routine practice in adult patients with RRMM. Patients had two or less previous treatment lines and at least one previous partial response. Baseline characteristics and treatment outcomes were recorded, and survival was analyzed. Of 225 patients, 110 were treated at BR (TxBR group) and 115 at ClinR (TxClinR group) according to the investigators' criteria. The proportion of patients with higher ECOG, previous noncomplete remission (CR), and second relapse were significantly higher in the TxBR group compared to the TxClinR group. TheTxClinR group showed improved outcomes, including TTP, compared to the TxBR group. Progression-free survival increased in the TxClinR group (56.2 months) compared to the TxBR group (32.5 months) (<i>p</i> = 0.0137), and median overall survival also increased (<i>p</i> = 0.0897). Median TTP was significantly longer in patients relapsing from a CR (50.4 months) and in their first relapse (38.7 months) compared to those relapsing from a non-CR response (32.9 months) and in their second relapse (25.2 months). Physicians seemed to start treatment earlier in RRMM patients with poor prognosis features. Previous responses to anti-MM treatment and the number of prior treatment lines were identified as prognosis factors, whereby relapse from CR and first relapse were associated with a longer time to progression.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.81","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141536952","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":"Assessing frailty in myeloma: The pursuit of simplicity may sacrifice precision of predicting clinical outcomes","authors":"Kazimierz Groen,&nbsp;Febe Smits,&nbsp;Kazem Nasserinejad,&nbsp;Mark-David Levin,&nbsp;Josien C. Regelink,&nbsp;Gert-Jan Timmers,&nbsp;Esther G. M. de Waal,&nbsp;Matthijs Westerman,&nbsp;Gerjo A. Velders,&nbsp;Koen de Heer,&nbsp;Rineke B. L. Leys,&nbsp;Roel J. W. van Kampen,&nbsp;Claudia A. M. Stege,&nbsp;Maarten R. Seefat,&nbsp;Inger S. Nijhof,&nbsp;Ellen van der Spek,&nbsp;Saskia K. Klein,&nbsp;Niels W. C. J. van de Donk,&nbsp;Paula F. Ypma,&nbsp;Sonja Zweegman","doi":"10.1002/hem3.85","DOIUrl":"10.1002/hem3.85","url":null,"abstract":"&lt;p&gt;In 2015, the International Myeloma Working Group (IMWG) introduced a frailty index (IMWG-FI), as a means to quantify fragility of patients with multiple myeloma (MM). This index categorizes patients into three groups: fit, intermediate-fit, or frail, based on age, comorbidities, and the level of assistance for (instrumental) daily activities ((i)ADL). Scores on the IMWG-FI range from zero to five points. A score of zero designates patients as fit, a score of one indicates intermediate-fit, and a score between two and five denotes frail. Three-year overall survival rates were 84% in fit patients, 76% in intermediate-fit patients (hazard ratio [HR]: 1.61; 95% confidence interval (CI): 1.02–2.56; &lt;i&gt;p&lt;/i&gt; = 0.042). and 57% in frail patients (HR: 3.57; 95% CI: 2.37–5.39; &lt;i&gt;p&lt;/i&gt; &lt; 0.001). In addition, frail patients had a significantly inferior progression-free survival (PFS), a higher tendency to discontinue treatment, and experienced more nonhematologic toxicity, compared to fit patients, which was found to be independent of ISS stage, chromosomal abnormalities, and type of therapy.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;In response to the time-consuming nature and feasibility challenges of assessing the (i)ADL scales in clinical studies, the Simplified Frailty Index (Simplified-FI) emerged in 2020. It substitutes daily activities with the World Health Organization Performance Status (WHO-PS). Also the Simplified-FI underscored that frail patients faced an adverse outcome.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; Post hoc frailty subgroup analyses in the MAIA and the ALCYONE trials, utilizing the Simplified-FI showed that frail patients had an inferior OS (41.2 months) compared to non-frail (fit and intermediate-fit combined; 70.1 months) patients, particularly evident in the daratumumab-arm of both studies (HR: 1.86; 95% CI: 1.63–2.12; &lt;i&gt;p&lt;/i&gt; &lt; 0.0001).&lt;span&gt;&lt;sup&gt;3, 4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;While both the IMWG-FI and the Simplified-FI categorize patients as fit, intermediate-fit, or frail, the exact alignment of these groups remains uncertain. The question is whether physician-reported WHO-PS can actually replace patient-reported (i)ADL, which better reflects underlying physical, cognitive, or functional problems. There is reason to question concordance as variances in patient outcomes under the same treatment regimen have been noted, depending on which frailty index was employed. For example, intermediate-fit patients, as classified by the Simplified-FI, achieved a median PFS of over 36 months with continuous lenalidomide/dexamethasone in the MAIA study, while patients classified as intermediate-fit according to the IMWG-FI treated with the same regimen in an Italian study had a median PFS of only 18.3 months, suggesting that the Simplified-FI identifies a less vulnerable intermediate-fit patient population.&lt;span&gt;&lt;sup&gt;3, 5&lt;/sup&gt;&lt;/span&gt; Given expert recommendations advocating for treatment adjustments based on frailty, it is crucial to acknowledge potential dispa","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11223651/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534355","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":"Stage-adapted treatment of HIV-associated Hodgkin lymphoma: Long-term results of a prospective, multicenter study","authors":"Marcus Hentrich,&nbsp;Markus Müller,&nbsp;Christoph Wyen,&nbsp;Anna Pferschy,&nbsp;Vindi Jurinovic,&nbsp;Jan Siehl,&nbsp;Jürgen K. Rockstroh,&nbsp;Dirk Schürmann,&nbsp;Christian Hoffmann,&nbsp;for the German HIV-Related Lymphoma Study Group","doi":"10.1002/hem3.68","DOIUrl":"10.1002/hem3.68","url":null,"abstract":"<p>Results of a prospective study of stage-adapted treatment of human immunodeficiency virus (HIV)-associated Hodgkin lymphoma (HIV-HL) showed a 2-year overall survival (OS) of 90.7% with no significant difference between early favorable (EF), early unfavorable (EU), and advanced HL. Patients with EF HIV-HL received two to four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy involved field (IF) radiation, those with EU HIV-HL received four cycles of ABVD or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) baseline + 30 Gy IF, and six to eight cycles of BEACOPP baseline were administered in advanced disease. The objective of the present analysis is to determine long-term outcomes of HIV-HL. Of 108 patients, 23 (21%) had EF HL, 14 (13%) had EU HL, and 71 (66%) had advanced-stage HL. After a median follow-up of 9.14 (range, 0–12.9) years, there were five primary refractory HL patients (5%) and 11 relapses (10%), of which seven were late relapses (&gt;2 years). A second primary malignancy (SPM) occurred in 10 patients after a median of 7.3 years (range, 1.5–10.7) from HL diagnosis. The 10-year OS for patients with EF, EU, and advanced HL was 95.7%, 84.6%, and 76.1%, respectively. By multivariate analysis, Center for Disease Control and Prevention category C (hazard ratio [HR] 3.00, 95% confidence interval [CI]: 1.16–7.74, <i>p</i> = 0.023) and achievement of complete remission were significant for OS (HR 0.03, 95% CI: 0.01–0.08, <i>p</i> = 2.45 × 10⁻⁹). In conclusion, a stage-adapted treatment approach for HIV-HL is highly effective with long-term survival rates similar to those reported in HIV-uninfected HL. However, the risk for late relapse and SPM is significant.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11221608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141497901","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":"NOTCH1 fusions in pediatric T-cell lymphoblastic lymphoma: A high-risk subgroup with CCL17 (TARC) levels as diagnostic biomarker","authors":"Emma Kroeze,&nbsp;Michelle M. Kleisman,&nbsp;Lennart A. Kester,&nbsp;Marijn A. Scheijde-Vermeulen,&nbsp;Edwin Sonneveld,&nbsp;Jessica G. C. Buijs-Gladdines,&nbsp;Melanie M. Hagleitner,&nbsp;Friederike A. G. Meyer-Wentrup,&nbsp;Margreet A. Veening,&nbsp;Auke Beishuizen,&nbsp;Jules P. P. Meijerink,&nbsp;Jan L. C. Loeffen,&nbsp;Roland P. Kuiper","doi":"10.1002/hem3.117","DOIUrl":"10.1002/hem3.117","url":null,"abstract":"<p>Twenty percent of children with T-cell lymphoblastic lymphoma (T-LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low-risk subgroup in pediatric T-LBL, yet these high-risk patients who need intensified or alternative treatment options remain undetected. Therefore, there is an urgent need to recognize these high-risk T-LBL patients through identification of molecular characteristics and biomarkers. By using RNA sequencing which was performed in 29/49 T-LBL patients who were diagnosed in the Princess Maxima Center for Pediatric Oncology between 2018 and 2023, we discovered a previously unknown high-risk biological subgroup of children with T-LBL. This subgroup is characterized by <i>NOTCH1</i> gene fusions, found in 21% of our T-LBL cohort (6/29). All patients presented with a large mediastinal mass, pleural/pericardial effusions, and absence of blasts in the bone marrow, blood, and central nervous system. Blood CCL17 (C-C Motif Chemokine Ligand 17, TARC) levels were measured at diagnosis in 26/29 patients, and all six patients with <i>NOTCH1</i> gene fusions patients exclusively expressed highly elevated blood CCL17 levels, defining a novel and previously not known clinically relevant biomarker for T-cell lymphoblastic lymphoma. Four out of these six patients relapsed during therapy, a fifth developed a therapy-related acute myeloid leukemia during maintenance therapy. These data indicate that T-LBL patients with a <i>NOTCH1</i> fusion have a high risk of relapse which can be easily identified using a blood CCL17 screening at diagnosis. Further molecular characterization through <i>NOTCH1</i> gene fusion analysis offers these patients the opportunity for treatment intensification or new treatment strategies.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141467599","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 bendamustine-containing bridging therapy in R/R LBCL patients receiving CD19 CAR T-cells","authors":"Gloria Iacoboni,&nbsp;Mario A. Sánchez-Salinas,&nbsp;Kai Rejeski,&nbsp;Ana Á. Martín-López,&nbsp;Mi Kwon,&nbsp;Víctor Navarro,&nbsp;Katarzyna A. Jalowiec,&nbsp;Rafael Hernani,&nbsp;Juan L. Reguera-Ortega,&nbsp;Laura Gallur,&nbsp;Viktoria Blumenberg,&nbsp;María Herrero-García,&nbsp;Claire Roddie,&nbsp;Ana Benzaquén,&nbsp;Javier Delgado-Serrano,&nbsp;Rebeca Bailén,&nbsp;Cecilia Carpio,&nbsp;Paula Amat,&nbsp;Lucia López-Corral,&nbsp;Lourdes Martín-Martín,&nbsp;Mariana Bastos,&nbsp;Marion Subklewe,&nbsp;Maeve O'Reilly,&nbsp;Pere Barba","doi":"10.1002/hem3.86","DOIUrl":"10.1002/hem3.86","url":null,"abstract":"<p>Bridging therapy (BT) after leukapheresis is required in most relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients receiving chimeric antigen receptor (CAR) T cells. Bendamustine-containing regimens are a potential BT option. We aimed to assess if this agent had a negative impact on CAR-T outcomes when it was administered as BT. We included R/R LBCL patients from six centers who received systemic BT after leukapheresis from February 2019 to September 2022; patients who only received steroids or had pre-apheresis bendamustine exposure were excluded. Patients were divided into two BT groups, with and without bendamustine. Separate safety and efficacy analyses were carried out for axi-cel and tisa-cel. Of 243 patients who received BT, bendamustine (benda) was included in 62 (26%). There was a higher rate of BT progressors in the non-benda group (62% vs. 45%, <i>p</i> = 0.02). Concerning CAR-T efficacy, complete responses were comparable for benda versus non-benda BT cohorts with axi-cel (70% vs. 53%, <i>p</i> = 0.12) and tisa-cel (44% vs. 36%, <i>p</i> = 0.70). Also, 12-month progression-free and overall survival were not significantly different between BT groups with axi-cel (56% vs. 43% and 71% vs. 63%) and tisa-cel (25% vs. 26% and 52% vs. 48%); there were no differences when BT response was considered. CAR T-cell expansion for each construct was similar between BT groups. Regarding safety, CRS G ≥3 (6% vs. 6%, <i>p</i> = 0.79), ICANS G ≥3 (15% vs. 17%, <i>p</i> = 0.68), severe infections, and neutropenia post-infusion were comparable among BT regimens. BT with bendamustine-containing regimens is safe for patients requiring disease control during CAR T-cell manufacturing.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 7","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208722/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141467598","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 “New approaches in gene therapy for sickle cell disease, moving in vivo”","authors":"","doi":"10.1002/hem3.107","DOIUrl":"https://doi.org/10.1002/hem3.107","url":null,"abstract":"<p>Kent DG. New approaches in gene therapy for sickle cell disease, moving in vivo. <i>HemaSphere</i>. 2024;8:e43.</p><p>In paragraph 2, the final sentence included the text “…involves large granulocyte-macrophage progenitor-level virus protection…”, which was incorrect. This should have read “Therapies that might remove the in vitro component, which involves substantial good manufacturing practice virus production and extensive quality control regimens, would therefore be of great utility and the field of in vivo therapies has understandably garnered intense interest”.</p><p>We apologize for this error.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 6","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.107","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141453601","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":"Metabolic blood profile and response to treatment with the pyruvate kinase activator mitapivat in patients with sickle cell disease","authors":"Myrthe J. van Dijk,&nbsp;Titine J. J. Ruiter,&nbsp;Sigrid van der Veen,&nbsp;Minke A. E. Rab,&nbsp;Brigitte A. van Oirschot,&nbsp;Jennifer Bos,&nbsp;Cleo Derichs,&nbsp;Anita W. Rijneveld,&nbsp;Marjon H. Cnossen,&nbsp;Erfan Nur,&nbsp;Bart J. Biemond,&nbsp;Marije Bartels,&nbsp;Roger E. G. Schutgens,&nbsp;Wouter W. van Solinge,&nbsp;Judith J. M. Jans,&nbsp;Eduard J. van Beers,&nbsp;Richard van Wijk","doi":"10.1002/hem3.109","DOIUrl":"10.1002/hem3.109","url":null,"abstract":"<p>Mitapivat is an investigational, oral, small-molecule allosteric activator of pyruvate kinase (PK). PK is a regulatory glycolytic enzyme that is key in providing the red blood cell (RBC) with sufficient amounts of adenosine triphosphate (ATP). In sickle cell disease (SCD), decreased 2,3-DPG levels increase the oxygen affinity of hemoglobin, thereby preventing deoxygenation and polymerization of sickle hemoglobin. The PK activator mitapivat has been shown to decrease levels of 2,3-DPG and increase levels of ATP in RBCs in patients with SCD. In this phase 2, investigator-initiated, open-label study (https://www.clinicaltrialsregister.eu/ NL8517; EudraCT 2019-003438-18), untargeted metabolomics was used to explore the overall metabolic effects of 8-week treatment with mitapivat in the dose-finding period. In total, 1773 unique metabolites were identified in dried blood spots of whole blood from ten patients with SCD and 42 healthy controls (HCs). The metabolic phenotype of patients with SCD revealed alterations in 139/1773 (7.8%) metabolites at baseline when compared to HCs (false discovery rate-adjusted <i>p</i> &lt; 0.05), including increases of (derivatives of) polyamines, purines, and acyl carnitines. Eight-week treatment with mitapivat in nine patients with SCD altered 85/1773 (4.8%) of the total metabolites and 18/139 (12.9%) of the previously identified altered metabolites in SCD (unadjusted <i>p</i> &lt; 0.05). Effects were observed on a broad spectrum of metabolites and were not limited to glycolytic intermediates. Our results show the relevance of metabolic profiling in SCD, not only to unravel potential pathophysiological pathways and biomarkers in multisystem diseases but also to determine the effect of treatment.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 6","pages":""},"PeriodicalIF":7.6,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11196954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450365","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 ETO2 transcriptional cofactor maintains acute leukemia by driving a MYB/EP300-dependent stemness program","authors":"Alexandre Fagnan,&nbsp;Zakia Aid,&nbsp;Marie Baille,&nbsp;Aneta Drakul,&nbsp;Elie Robert,&nbsp;Cécile K. Lopez,&nbsp;Cécile Thirant,&nbsp;Yann Lecluse,&nbsp;Julie Rivière,&nbsp;Cathy Ignacimouttou,&nbsp;Silvia Salmoiraghi,&nbsp;Eduardo Anguita,&nbsp;Audrey Naimo,&nbsp;Christophe Marzac,&nbsp;Françoise Pflumio,&nbsp;Sébastien Malinge,&nbsp;Christian Wichmann,&nbsp;Yun Huang,&nbsp;Camille Lobry,&nbsp;Julie Chaumeil,&nbsp;Eric Soler,&nbsp;Jean-Pierre Bourquin,&nbsp;Claus Nerlov,&nbsp;Olivier A. Bernard,&nbsp;Juerg Schwaller,&nbsp;Thomas Mercher","doi":"10.1002/hem3.90","DOIUrl":"https://doi.org/10.1002/hem3.90","url":null,"abstract":"<p>Transcriptional cofactors of the ETO family are recurrent fusion partners in acute leukemia. We characterized the ETO2 regulome by integrating transcriptomic and chromatin binding analyses in human erythroleukemia xenografts and controlled ETO2 depletion models. We demonstrate that beyond its well-established repressive activity, ETO2 directly activates transcription of MYB, among other genes. The ETO2-activated signature is associated with a poorer prognosis in erythroleukemia but also in other acute myeloid and lymphoid leukemia subtypes. Mechanistically, ETO2 colocalizes with EP300 and MYB at enhancers supporting the existence of an ETO2/MYB feedforward transcription activation loop (e.g., on MYB itself). Both small-molecule and PROTAC-mediated inhibition of EP300 acetyltransferases strongly reduced ETO2 protein, chromatin binding, and ETO2-activated transcripts. Taken together, our data show that ETO2 positively enforces a leukemia maintenance program that is mediated in part by the MYB transcription factor and that relies on acetyltransferase cofactors to stabilize ETO2 scaffolding activity.</p>","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 6","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.90","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430255","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":"EHA2024 Hybrid Congress","authors":"","doi":"10.1002/hem3.104","DOIUrl":"https://doi.org/10.1002/hem3.104","url":null,"abstract":"","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 S1","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.104","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141326621","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":"Quantitative analysis of bone marrow fibrosis highlights heterogeneity in myelofibrosis and augments histological assessment: An Insight from a phase II clinical study of zinpentraxin alfa","authors":"Hosuk Ryou,&nbsp;Korsuk Sirinukunwattana,&nbsp;Ruby Wood,&nbsp;Alan Aberdeen,&nbsp;Jens Rittscher,&nbsp;Olga K. Weinberg,&nbsp;Robert Hasserjian,&nbsp;Olga Pozdnyakova,&nbsp;Frank Peale,&nbsp;Brian Higgins,&nbsp;Pontus Lundberg,&nbsp;Kerstin Trunzer,&nbsp;Claire N. Harrison,&nbsp;Daniel Royston","doi":"10.1002/hem3.105","DOIUrl":"https://doi.org/10.1002/hem3.105","url":null,"abstract":"&lt;p&gt;Accurate assessment of bone marrow fibrosis is central to the diagnosis and assessment of patients with myeloproliferative neoplasms (MPNs).&lt;span&gt;&lt;sup&gt;1-3&lt;/sup&gt;&lt;/span&gt; However, European consensus criteria for fibrosis are subjective, only semiquantitative, and cannot fully capture sample fibrosis heterogeneity.&lt;span&gt;&lt;sup&gt;4-6&lt;/sup&gt;&lt;/span&gt; In response, we have recently demonstrated the potential of machine learning to improve the detection and quantitation of marrow fibrosis in MPN using routinely prepared bone marrow trephine (BMT) samples.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Such approaches can support accurate MPN classification/risk stratification and provide quantitative analysis of fibrosis heterogeneity, with the potential to support clinical trial teams in the evaluation of current and novel antifibrotic therapies.&lt;span&gt;&lt;sup&gt;6&lt;/sup&gt;&lt;/span&gt; Here, we report evidence of such utility in the context of stage 2 of a phase II study of zinpentraxin alfa in patients diagnosed with primary or secondary myelofibrosis (MF) [ClinicalTrials.gov identifier: NCT01981850]. The primary trial endpoint was bone marrow response (≥1 grade reduction from baseline fibrosis at any timepoint). Secondary endpoints included effects on disease-related anemia, thrombocytopenia, and constitutional symptoms.&lt;/p&gt;&lt;p&gt;Zinpentraxin alfa (ZPN; previously PRM-151) is a recombinant form of human pentraxin-2 (PTX2; also known as serum amyloid P component or SAP), a circulating endogenous regulator of the inflammatory response to tissue damage and a natural inhibitor of fibrosis.&lt;span&gt;&lt;sup&gt;8-10&lt;/sup&gt;&lt;/span&gt; In the open-label stage 1 of this phase 2 study, ZPN showed evidence of clinical activity and tolerable safety as monotherapy or in combination with ruxolitinib in patients with primary MF, post-polycythemia vera (PV) MF, or post-essential thrombocythemia (ET) MF.&lt;span&gt;&lt;sup&gt;11&lt;/sup&gt;&lt;/span&gt; A subsequent randomized dose-ranging study (stage 2) evaluated the efficacy and safety of three different doses of ZPN as monotherapy in patients with IPSS intermediate-1, intermediate-2, and high-risk primary MF, post-PV MF, or post-ET MF who were anemic or thrombocytopenic and ineligible for, intolerant of, or had an inadequate prior response to ruxolitinib.&lt;span&gt;&lt;sup&gt;12&lt;/sup&gt;&lt;/span&gt; Patients were randomized to receive 0.3, 3.0, or 10.0 mg/kg ZPN on Days 1, 3, and 5 of cycle 1 and every 4 weeks thereafter for up to nine cycles. Reticulin-stained BMTs from three timepoints (screening, cycle 4 [C4D1], and cycle 9 [C9D29]) were analyzed for a subset of patients enrolled in the stage 2 study for whom digital scanned images were available at all three timepoints (50/97) (Figure 1A,B). Prior manual assessment of marrow fibrosis had been performed as part of a blinded, independent central review by three expert hematopathologists. Quantitative assessment of fibrosis using Continuous Indexing of Fibrosis (CIF) was performed by automated analyses as previously described.&lt;span&gt;&lt;sup&gt;7&lt;/sup&gt;&lt;/span&gt; Briefly, CIF","PeriodicalId":12982,"journal":{"name":"HemaSphere","volume":"8 6","pages":""},"PeriodicalIF":6.6,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/hem3.105","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141326447","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}