Blood最新文献

{"title":"GATA2 links stemness to chemotherapy resistance in acute myeloid leukemia.","authors":"Fatemeh Alikarami, Hongbo M Xie, Simone S Riedel, Haley T Goodrow, Declan R Barrett, Leila Mahdavi, Alexandra Lenard, Changya Chen, Taylor Yamauchi, Etienne Danis, Zhendong Cao, Vu L Tran, Mabel Minji Jung, Yapeng Li, Hua Huang, Junwei Shi, Kai Tan, David T Teachey, Emery H Bresnick, Tobias A Neff, Kathrin M Bernt","doi":"10.1182/blood.2024025761","DOIUrl":"10.1182/blood.2024025761","url":null,"abstract":"<p><strong>Abstract: </strong>Stemness-associated cell states are linked to chemotherapy resistance in acute myeloid leukemia (AML). We uncovered a direct mechanistic link between expression of the stem cell transcription factor GATA2 and drug resistance. The GATA-binding protein 2 (GATA2) plays a central role in blood stem cell generation and maintenance. We find substantial intrapatient and interpatient variability in GATA2 expression across samples from patients with AML. GATA2 expression varies by molecular subtype and has been linked to outcome. In a murine model, KMT2A-MLL3-driven AML originating from a stem cell or immature progenitor cell population has higher Gata2 expression and is more resistant to the standard AML chemotherapy agent doxorubicin. Deletion of Gata2 resulted in a more robust induction of p53 after exposure to doxorubicin. Chromatin immunoprecipitation sequencing, RNA sequencing, and functional studies revealed that GATA2 regulates the expression of RASSF4, a modulator of the p53 inhibitor MDM2 (mouse double minute 2). GATA2 and RASSF4 are anticorrelated in human cell lines and in bulk and single-cell expression data sets from patients with AML. Knockdown of Rassf4 in Gata2-low cells resulted in doxorubicin or nutlin-3 resistance. Conversely, overexpression of Rassf4 results in sensitization of cells expressing high levels of Gata2. Finally, doxorubicin and nutlin-3 are synergistic in Gata2-high murine AML and in samples from patients with AML. We discovered a previously unappreciated role for GATA2 in dampening p53-mediated apoptosis via transcriptional regulation of RASSF4, a modulator of MDM2. This role for GATA2 directly links the expression of a stemness-associated transcription factor to chemotherapy resistance.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2179-2195"},"PeriodicalIF":21.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EMZL at various sites: learning from each other.","authors":"Ming-Qing Du","doi":"10.1182/blood.2024025794","DOIUrl":"10.1182/blood.2024025794","url":null,"abstract":"<p><strong>Abstract: </strong>Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL) invariably develops from a background of chronic inflammatory disorder caused by a diverse chronic microbial infection and/or autoimmunity, depending on the site. These chronic inflammatory/autoimmunity disorders trigger innate and acquired immune responses, generating a unique microenvironment at each site that drives clonal evolution of B cells, their expansion, and eventual malignant transformation. At a molecular level, this involves temporal and spatial acquisition of cooperative oncogenic events by dysregulated immune responses and somatic genetic changes. Although these events are not yet fully characterized, EMZL at several sites shows distinct genetic profiles and molecular insights, bridging the pathologic process to lymphomagenesis. For example, gastric EMZL, particularly those lacking a BCL10 or MALT1 translocation, critically depends on T-helper cell signals produced by immune responses to Helicobacter pylori infection. Likewise, thyroid EMZL may also involve exaggerated T-cell help because of highly frequent inactivating mutations in TET2, CD274 (programmed cell death 1 ligand 1), and TNFRSF14, which impede the coinhibitory interactions between the neoplastic B- and T-helper cells, thus releasing T-cell help. Ocular adnexal EMZL shows frequent TNFAIP3 (A20) mutation/deletion that significantly associates with expression of autoreactive IGHV4-34 B-cell receptor, emphasizing its potential cooperation in NF-κB pathway activation. Finally, the genesis of salivary gland EMZL may be closely associated with GPR34 activation that is caused by mutation/t(X;14)(p11;q32) and/or paracrine stimulation mediated by ligand generated by lymphoepithelial lesions. This review will focus on these novel molecular insights and how these advances may provide a paradigm for future investigations.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":"2117-2127"},"PeriodicalIF":21.0,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143254997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myelodysplastic neoplasm with biallelic TP53 inactivation in a patient with plasma cell myeloma after cytotoxic therapy.","authors":"Rong He,Dong Chen","doi":"10.1182/blood.2024028288","DOIUrl":"https://doi.org/10.1182/blood.2024028288","url":null,"abstract":"","PeriodicalId":9102,"journal":{"name":"Blood","volume":"68 1","pages":"2230"},"PeriodicalIF":20.3,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143921055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ANKRD26-related Thrombocytopenia 2 with a Baseline Increase in Blasts: Implications for Clinical Surveillance.","authors":"Lara Wahlster,Lucy A Godley,Jason X Cheng,Michael W Drazer,Christopher R Reilly,Geraldine S Pinkus,Jared H Rowe,Nina Weichert-Leahey,Robert Grant Rowe,Lev Gorfinkel,Karyn Jean Brundige,Franziska Wachter,Luana Miria Messa,Alan D Michelson,Alan B Cantor,Akiko Shimamura,Jacob R Bledsoe","doi":"10.1182/blood.2024027368","DOIUrl":"https://doi.org/10.1182/blood.2024027368","url":null,"abstract":"We report eight patients with ANKRD26-related thrombocytopenia-2 (ANKRD26-RT) with elevated bone marrow myeloblasts and dysmegakaryopoiesis, without somatic genetic abnormalities or progression to malignancy during long-term observation, findings which may constitute inherent ANKRD26-RT biology rather than progression to myeloid malignancy.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"1 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143914973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel, potent, and orally bioavailable LSD1 inhibitors induce fetal hemoglobin synthesis in a sickle cell disease mouse model.","authors":"Yu Wang,Lei Yu,Kaiwen Deng,Mathivanan Packiarajan,Angelo Aguilar,Sojin An,Greggory Myers,Hoon Oh,Sharon A Singh,Uhn-Soo Cho,Shaomeng Wang,Yuanfang Guan,Andrew White,Rami Khoriaty,James Douglas Engel","doi":"10.1182/blood.2024028006","DOIUrl":"https://doi.org/10.1182/blood.2024028006","url":null,"abstract":"Small molecules that inhibit LSD1 (lysine-specific demethylase 1, KDM1A) have been shown to induce abundant fetal hemoglobin (HbF) levels in red blood cells both in vitro and in vivo, therefore potentially serving as potent and cost-effective therapeutics to treat the β-globinopathies, sickle cell disease (SCD) and β-thalassaemia major (TM). However, most LSD1 inhibitors (LSD1i) that induce HbF in vivo are covalent and irreversible, which leads to adverse effects. In this study, we utilized structure-aided drug design to develop potent new reversible LSD1i's leading to robust γ-globin expression in vitro. Moreover, in a mouse model of SCD, oral administration of these novel inhibitors lead to significant HbF elevation and alleviation of multiple features of disease pathology that are the usual consequences of SCD. In addition, we discovered that combined treatment of an LSD1i with a BRD4 degrader (BD-9136) represses the induction of RUNX1 and PU.1, thereby rescuing the erythroid to myeloid lineage conversion that accompanies LSD1i in hematopoiesis. The data indicate that this new generation of LSD1i can effectively induce HbF levels, reduce SCD pathologies, and are well-tolerated by oral administration in SCD mice. We anticipate that the combination of these or related binary compounds offer exciting new therapeutic possibilities for treating SCD and TM.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"2 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Augmented CD47 expression impairs alloreactive T-cell clearance after allo-HCT.","authors":"Cindy Sheree Flamann,Haroon Shaikh,Carina Matos,Marina Kreutz,Hla Ali,Michael Ag Kern,Maike Büttner-Herold,Benedikt Jacobs,Simon Völkl,Christopher Lischer,Christian Kellner,Johannes Berges,Katrin Bitterer,Domenica Saul,Manisha Goel,Cornelia Link-Rachner,Alma Zernecke,Daniela Andrea Weber,Dimitrios Mougiakakos,Andreas Mackensen,Andreas Beilhack,Heiko Bruns","doi":"10.1182/blood.2023023056","DOIUrl":"https://doi.org/10.1182/blood.2023023056","url":null,"abstract":"Graft-versus-Host disease (GvHD) ensues as the most common non-relapse complication after allogeneic hematopoietic cell transplantation (allo-HCT). A pivotal goal in GvHD management revolves around quelling inflammation. Phagocytic clearance of inflammatory cells contributes substantially to termination of inflammatory processes. Nevertheless, the precise functions of phagocytosis in GvHD remain largely unclear. In this study, we identified the \"don't eat me\"-signal CD47 as a promising target for therapeutic interventions aimed at eradicating alloreactive T-cells subsequent to allo-HCT. Analysis of global data sets revealed a remarkable upregulation of CD47 expression on T-cells residing in the ileum of patients with inflamed intestine. Building on this finding, we examined CD47 levels in the gastrointestinal tract (GIT) following allo-HCT. Our work not only confirmed upregulated CD47 expression in the GIT of GvHD patients, but also identified CD47 on T-cells in the ileum of GvHD mice after allo-HCT. Additionally, we found that activated donor T-cells suppress antibody-dependent cellular phagocytosis (ADCP) via CD47 signaling in vitro. Application of anti-CD47 antibodies significantly invigorated the impaired ADCP of activated T-cells. Administering anti-CD47 antibodies to mice elevated phagocytosis of T-cells in the GIT, induced immunosuppressive responses and improved survival. Finally, transplantation of CD47 deficient donor T-cells significantly improved clinical GvHD score with improved survival after allo-HCT. Collectively, our findings illuminate CD47 upregulation as pivotal mechanism in GvHD patients, leading to impaired phagocytic clearance of alloreactive T-cells. This study proposes that anti-CD47 treatment could rectify the compromised phagocytosis of alloreactive T-cells, thereby aiding in the resolution of inflammation after allo-HCT.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"2675 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BLAST: A Globally Applicable and Molecularly Versatile Survival Model for Chronic Myelomonocytic Leukemia.","authors":"Ayalew Tefferi,Saubia Fathima,Maymona Abdelmagid,Ali Alsugair,Fnu Aperna,Mahsa Rezasoltani,Muhammad Yousuf,Anuya Natu,Clifford M Csizmar,Mark Gurney,Terra L Lasho,Christy M Finke,Rashmi Kanagal-Shamanna,Danielle Hammond,Kelly Sharon Chien,Alexandre Bazinet,Courtney D DiNardo,Tapan M Kadia,Abhishek A Mangaonkar,Naval G Daver,Animesh D Pardanani,Gautam Borthakur,Cinthya J Zepeda-Mendoza,Kaaren K Reichard,Rong He,Sanam Loghavi,Francesco Passamonti,Farhad Ravandi,Koji Sasaki,Dirk Larson,Guillermo Garcia-Manero,Francesco Onida,Naseema Gangat,Guillermo Montalban-Bravo,Mrinal M Patnaik","doi":"10.1182/blood.2024027170","DOIUrl":"https://doi.org/10.1182/blood.2024027170","url":null,"abstract":"We sought to develop a survival model in chronic myelomonocytic leukemia (CMML) that is primarily based on clinical variables and examine additional impact from mutations and karyotype. 457 molecularly-annotated patients were considered. Multivariable analysis identified circulating Blasts ≥2% (1 point), Leukocytes ≥13 x 109/L (1 point), and severe (2 points) or moderate (1 point) Anemia as preferred risk variables in developing a clinical risk Stratification Tool for overall survival (OS), acronymized to \"BLAST\": low-risk (0 points; median 63 months); intermediate-risk (1 point; median 28 months; HR 2.2, 95% CI 1.6-3.0), and high-risk (2-4 points; median 13 months; 5.4, 4.1-7.3); the corresponding 3/5 year OS rates were 68%/53%, 43%/18%, and 12%/1%. BLAST model performance (AUC 0.77/0.85 at 3/5-years) was shown to be comparable to that of the molecular CMML-specific prognostic scoring system (CMML-mol; AUC 0.73/0.75) and the international prognostic scoring system-molecular (IPSS-M; AUC 0.73/0.74). Multivariable analysis of mutations and karyotype identified PHF6MUT and TET2MUT as being \"favorable\" and DNMT3AMUT, U2AF1MUT, BCORMUT, SETBP1MUT, ASXL1MUT, NRASMUT, PTPN11MUT, RUNX1MUT, TP53MUT, and adverse karyotype, \"unfavorable\". Molecular information was subsequently encoded in a combined clinical-molecular risk model (BLAST-mol; AUC 0.80/0.86 at 3/5-years) that included the aforementioned BLAST clinical risk variables and a 3-tiered molecular risk score. BLAST and BLAST-mol were subsequently validated by two separate external cohorts. Independent risk factors for blast transformation included DNMT3AMUT, ASXL1MUT, PHF6WT, leukocytes ≥13 x 109/L, and ≥2% circulating or ≥10% bone marrow blasts. The current study proposes an easy to implement, globally applicable, and molecularly adaptive risk model for CMML.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"68 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase 1/2 Study of High-Dose Palifermin for GVHD Prophylaxis in Patients Undergoing HLA-Matched Unrelated Donor HCT.","authors":"Eduard Schulz,Lauren M Curtis,Noa G Holtzman,Jennifer Sponaugle,Kaska Wloka,Alen Ostojic,Alain Mina,Najla El Jurdi,Filip Pirsl,Ashley Carpenter,Mahshid Golagha,Arlene Sirajuddin,Theo Heller,Brian C Shaffer,Frances T Hakim,Jeffrey Steven Rubin,Ronald E Gress,Steven Z Pavletic","doi":"10.1182/blood.2024028303","DOIUrl":"https://doi.org/10.1182/blood.2024028303","url":null,"abstract":"Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT). Palifermin, a recombinant N-truncated keratinocyte growth factor (KGF), protects epithelial tissues, including the thymus and gut. While high-dose KGF prevents GVHD in preclinical models, lower doses of palifermin were ineffective in humans. We conducted a phase 1/2 trial evaluating high-dose palifermin for preventing severe chronic GVHD (GVHD) in matched unrelated donor T-cell replete peripheral-blood HCT following reduced-intensity conditioning (RIC). Using a 3+3 design, we determined the recommended phase 2 dose (RP2D), followed by an expansion phase. Palifermin (180-720 μg/kg) was given on day -7 before HCT. All 31 patients received fludarabine/cyclophosphamide RIC with tacrolimus, methotrexate, and sirolimus for GVHD prophylaxis. Palifermin was well tolerated, with self-limiting rash and pancreatic enzyme elevations as notable grade 3/4 adverse events. The RP2D was 720 μg/kg. Remarkably, no patients at this dose developed grade II-IV acute GVHD (0/19), though severe chronic GVHD rates (primary endpoint) remained unchanged compared to historical controls. Post-transplant lymphocyte phenotyping suggests palifermin modulates Treg and naïve CD4+ T-cell numbers. These findings indicate high-dose palifermin with RIC is safe and may prevent acute GVHD, though it did not impact chronic GVHD rates in this study. NCT02356159.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"19 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delineating Mpl-dependent and -independent phenotypes of Jak2 V617F- positive MPNs in vivo.","authors":"Nicolas Papadopoulos,Audrey Nédélec,Yacine Rahmani,Hosuk Ryou,Jean-Philippe Defour,Jens Rittscher,Daniel Royston,Stefan N Constantinescu","doi":"10.1182/blood.2024026711","DOIUrl":"https://doi.org/10.1182/blood.2024026711","url":null,"abstract":"The Jak2 V617F mutation stands as the main driver of myeloproliferative neoplasms (MPNs) by constitutively activating signaling of several type I cytokine receptors, namely those for erythropoietin (EpoR), thrombopoietin (TpoR), and Granulocyte Colony Stimulating Factor (G-CSFR). Among these, TpoR assumes a pivotal role in hematopoietic stem cell renewal and differentiation, being positioned as a key driver of MPNs alongside mutated Jak2. However, the impact of TpoR/MPL absence in the context of Jak2 V617F in vivo has been explored only through a transgenic Jak2 V617F mouse model, where regulation of Jak2 expression does not depend on its natural promoter. In this study, we use a novel mouse model expressing Jak2 V617F under its endogenous promoter at the heterozygous state within a Mpl knock-out background. Our findings indicate that erythrocytosis, leukocytosis and moderate splenomegaly with mild spleen peri-vascular fibrosis persist even in the absence of Mpl expression. Notably, the inherent growth-stimulating effect induced by Jak2 V617F remains consistent across diverse early hematopoietic progenitor populations in the absence of Mpl but is reduced at the stem cell level and does not allow clonal expansion in competitive transplantation. Our results delineate Mpl-dependent and -independent phenotypes induced by Jak2 V617F and confirm that inhibiting Mpl expression at the stem cell level negates the long-term advantage of the mutant clone. Consequently, while MPL emerges as a major player in Jak2 V617F positive MPNs, our study underscores that it is not the exclusive contributor, broadening the spectrum for therapeutic intervention.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"65 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Menin inhibition with revumenib for NPM1-mutated relapsed or refractory acute myeloid leukemia: the AUGMENT-101 study.","authors":"Martha L Arellano,Michael J Thirman,John F DiPersio,Mael Heiblig,Eytan M Stein,Andre C Schuh,Andrius Zucenka,Stéphane De Botton,Carolyn S Grove,Gabriel N Mannis,Cristina Papayannidis,Alexander E Perl,Ghayas C Issa,Ibrahim Aldoss,Ashish Bajel,David S Dickens,Michael W M Kühn,Ioannis Mantzaris,Emmanuel Raffoux,Elie Traer,Irina Amitai,Hartmut Döhner,Corinna Greco,Tibor J Kovacsovics,Christine M McMahon,Pau Montesinos,Arnaud Pigneux,Paul J Shami,Richard M Stone,Ofir Wolach,John G Harpel,Yakov Chudnovsky,Li Yu,Rebecca G Bagley,Angela R Smith,James S Blachly","doi":"10.1182/blood.2025028357","DOIUrl":"https://doi.org/10.1182/blood.2025028357","url":null,"abstract":"The prognosis for relapsed or refractory (R/R) nucleophosmin 1-mutated (NPM1m) acute myeloid leukemia (AML) is poor and represents an urgent unmet medical need. Revumenib, a potent, selective menin inhibitor, was recently approved for the treatment of R/R acute leukemia with a KMT2A translocation in patients aged ≥1 year based on results from the phase 1/2 AUGMENT-101 study. Here we present results from patients with R/R NPM1m AML enrolled in the phase 2 portion of AUGMENT-101. Enrolled patients received revumenib with or without a strong CYP3A4 inhibitor every 12 hours in 28-day cycles. Primary endpoints were rate of complete remission (CR) or CR with partial hematologic recovery (CRh; CR+CRh), and safety and tolerability. Secondary endpoints included overall response rate (ORR) and duration of response. As of September 18, 2024, 84 patients received ≥1 dose of revumenib. Median age was 63 years; 1 patient was aged <18 years. The protocol-defined efficacy-evaluable population for the primary analysis included 64 adult patients (≥3 prior lines of therapy, 35.9%; prior venetoclax, 75.0%). The CR+CRh rate was 23.4% (1-sided P=.0014); the ORR was 46.9%. Median duration of CR+CRh was 4.7 months. Five of 30 responders (16.7%) proceeded to hematopoietic stem cell transplant (HSCT); 3 resumed revumenib after HSCT. Treatment-related adverse events led to treatment discontinuation in 4 patients (4.8%). Revumenib demonstrated clinically meaningful responses in this heavily pretreated, older population with NPM1m AML, including remissions that enabled HSCT. The safety profile of revumenib was consistent with previously reported results. This trial was registered at www.clinicaltrials.gov as NCT04065399.","PeriodicalId":9102,"journal":{"name":"Blood","volume":"2 1","pages":""},"PeriodicalIF":20.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915085","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}