Leukemia最新文献

{"title":"Mutations and translocations associated with venetoclax resistance in chronic lymphocytic leukemia","authors":"Kiyomi Mashima, Yanan Kuang, Stacey M. Fernandes, Shidong Xu, Benjamin Hanna, Samantha Shupe, Mariia Mikhaleva, Roberta Azevedo Santos, Paulina Predko, Rayan Fardoun, Ava Bidgoli, Stephen P. Martindale, Aishath Naeem, Matthew S. Davids, Cloud Paweletz, Jennifer R. Brown","doi":"10.1038/s41375-025-02611-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02611-9","url":null,"abstract":"<p>The mechanisms underlying acquired resistance to venetoclax (VEN) remain elusive. The BCL-2 family of proteins encompasses a complex network of anti-apoptotic and pro-apoptotic regulators that together govern cell fate decisions. While venetoclax selectively targets BCL2, resistance mechanisms often involve compensatory changes in other family members. For instance, <i>MCL1</i> amplification and increased expression of <i>BCL-XL</i> have been observed in both preclinical and clinical settings, contributing to treatment failure. Recent data from the CLL13 trial suggested that a highly complex karyotype (CK) with five or more abnormalities (CK ≥ 5) at baseline independently predicted worse progression-free survival following VEN-based treatment. Using whole exome sequencing, our group has found that clonal evolution during VEN treatment selects for 8p deletion +/− gain of <i>MCL1</i> in some resistant chronic lymphocytic leukemia (CLL) cases [1]. BCL2 G101V mutation is also associated with resistance but can appear before clinical progression at very low variant allele frequencies [2, 3]. The optimal threshold for significance and the clinical utility of measuring G101V remains to be established, and the extent to which <i>BCL2</i> mutations impact CLL progression during VEN treatment is not yet fully understood. In this study, we evaluated clinical next-generation sequencing (NGS) data, with BCL2 G101V mutation measured by droplet digital PCR (ddPCR), during continuous VEN treatment in CLL. In addition to the G101V mutation, we assessed a broader spectrum of <i>BCL2</i> mutations using targeted NGS (see Supplementary Methods for Amplicon-based Targeted NGS). Ethical approval was obtained from the Dana-Farber Cancer Institute Institutional Review Board, and all patients provided written informed consent prior to sample and data collection.</p><p>We retrospectively reviewed 2850 treatment periods in our database and extracted 234 VEN treatment periods for 207 patients (Supplementary Fig. S1). We ultimately collected 33 patients with available clinical NGS data during continuous VEN treatment; 19 patients with clinical NGS data at disease progression, designated as Group PD, and 14 patients with clinical NGS data during treatment without progression, designated as Group NP. All had banked DNA samples for ddPCR. We retrospectively evaluated a total of 69 sequential clinical NGS results, as well as 85 ddPCR results for BCL2 G101V mutation, from the 33 patients in our cohort. At baseline, before the initial period of VEN treatment, both deletion 17p (del(17p)) and <i>TP53</i> mutations were found to be enriched in the PD group (<i>P</i> = 0.02 and <i>P</i> = 0.046, respectively) (Supplementary Table S1). Other fluorescence in situ hybridization (FISH) abnormalities, such as del(11q), del(13q), and trisomy 12, as well as gender, age at diagnosis, and IGHV mutation status were not different between the two groups before the initial period of VEN treatm","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"25 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340809","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":"A molecular signature predicts hematologic evolution in polycythemia vera patients","authors":"Olivier Mansier, Eric Lippert, Lina Benajiba, Dana Ranta, François Girodon, Jean-Christophe Ianotto, Aurélie Chauveau, Lydia Roy, Françoise Boyer, Clémence Médiavilla, Suzanne Tavitian, Marion Divoux, Mélinda Fanet, Ivan Sloma, Véronique De Mas, Guillaume Denis, Christopher Nunes Gomes, Claire Calmettes, Fiorenza Barraco, Sarah Huet, Fabienne Vacheret, Mélanie Mercier, Anne Parry, Laurence Legros, Juliette Soret-Dulphy, Joris Argentin, Léa Sureau, Emmanuelle Verger, Corentin Orvain, Jérémie Riou, Jean-Jacques Kiladjian, Bruno Cassinat, Valérie Ugo, Damien Luque Paz","doi":"10.1038/s41375-025-02660-0","DOIUrl":"https://doi.org/10.1038/s41375-025-02660-0","url":null,"abstract":"<p>Genetic analyses have been included in scoring systems to improve the prognostic stratification of hematologic malignancies. Until now, molecular risk scores have not been included into the practical management of patients with polycythemia vera (PV). In this work, we studied 439 PV patients recruited from 15 French centers and described their mutational landscape using high-throughput sequencing. We detected an additional mutation in 53.3% of patients, 22.7% of them having 2 or more mutations. A Bayesian approach identified preferential associations between mutations. Based on these associations, we identified high molecular risk abnormalities in PV (PV-HMR), consisting in mutations in <i>SRSF2</i>, <i>IDH1/2</i>, <i>EZH2</i> or <i>NFE2</i> genes, copy number variations (CNV) and carrying 2 or more non-driver mutations. These PV-HMR were associated with decreased overall survival (OS) and/or transformation-free survival (TFS). Notably, <i>ASXL1</i> mutations were not associated with a pejorative impact on OS or TFS when isolated. Based on these results, we developed a genomic 3-tier classification that efficiently predicted OS and more importantly TFS independently of age, sex, history of thrombosis and leukocyte and platelet counts. This model outperformed the IWG-PV and MIPSS-PV scoring systems in predicting the hematologic evolution of PV patients, which was confirmed in 2 external cohorts.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"12 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319679","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":"Measurement of Immunoglobulin Intraclonal diversification refines the clinical impact of IGHV mutational status in chronic lymphocytic leukemia","authors":"Filippo Vit, Tamara Bittolo, Antonella Zucchetto, Robel Papotti, Erika Tissino, Federico Pozzo, Annalisa Gaglio, Andrea Stacchetti, Eva Zaina, Ilaria Cattarossi, Paola Varaschin, Paola Nanni, Michele Berton, Alessandra Braida, Francesca Maria Rossi, Massimo Degan, Jerry Polesel, Roberta Laureana, Annalisa Chiarenza, Jacopo Olivieri, Annalisa Biagi, Giovanni D’Arena, Marco Rossi, Luca Laurenti, Agostino Tafuri, Pietro Bulian, Alberto Zamò, Ellen Leich, Andreas Rosenwald, Evgeny Arons, Robert Kreitman, Massimo Gentile, Massimiliano Postorino, Francesco Zaja, Francesco Di Raimondo, Maria Ilaria Del Principe, Valter Gattei, Riccardo Bomben","doi":"10.1038/s41375-025-02650-2","DOIUrl":"https://doi.org/10.1038/s41375-025-02650-2","url":null,"abstract":"<p>Chronic lymphocytic leukemia (CLL) cells may bear mutations in IGHV genes, the 2%-cutoff allowing to discriminate two subsets, unmutated (U)- or mutated (M)-CLL, with different clinical course. IGHV genes may also incorporate additional ongoing mutations, a phenomenon known as intraclonal diversification (ID). Here, through an original bioinformatic workflow for NGS data, we used the inverse Simpson Index (iSI) as diversity measure among IGHV sequences to dichotomize cases with different ID levels into ID_high (iSI ≥ 1.2) vs. ID_low (iSI &lt; 1.2) both in CLL (<i>n</i> = 983) and in other lymphoproliferative disorders (LPD; <i>n</i> = 127). In CLL, ID_high cases accounted for 14.6%, overrepresented in M-CLL (<i>P</i> = <i>0.0028</i>), while higher percentages were documented in GC-derived LPD. In M-CLL (<i>n</i> = 396), ID_high patients (<i>n</i> = 69) experienced longer time-to-first treatment than ID_low patients (<i>P</i> = 0.015), and multivariate analyses (<i>n </i>= 299) confirmed ID as independent variable. IGHV gene mutations of ID_high cases had molecular signatures indicating ongoing activity of the AID)/Polη-dependent machinery; consistently, ID_high M-CLL expressed higher levels of AID transcripts than ID_low M-CLL (<i>P</i> = 0.012). In conclusion, we propose a robust NGS protocol to quantitatively evaluate ID in CLL, demonstrating that: i) all CLL patients presented ID although at various degree; ii) high degree of ID has clinical relevance identifying a M-CLL subset with better outcome.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"30 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144319680","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":"Post-pandemic recommendations for the management of COVID-19 in patients with haematological malignancies or undergoing cellular therapy, from the European Conference on Infections in Leukaemia (ECIL-10)","authors":"Simone Cesaro, Per Ljungman, Malgorzata Mikulska, Hans H. Hirsch, David Navarro, Catherine Cordonnier, Varun Mehra, Jan Styczynski, Francesco Marchesi, Jose Luis Pinana, Gernot Beutel, Herman Einsele, Johan Maertens, Rafael de la Camara","doi":"10.1038/s41375-025-02649-9","DOIUrl":"https://doi.org/10.1038/s41375-025-02649-9","url":null,"abstract":"<p>In the post-pandemic years, SARS-CoV-2 morbidity and mortality declined due to less pathogenic variants, active and passive immunization, and antiviral therapies. However, patients with hematological malignancies and/or undergoing hematopoietic cell transplantation (HCT) remain at increased risk for poor outcomes. Therefore, adherence to contact and droplet precautions is essential to avoid transmission, especially during epidemic waves. Detection of viral RNA by nucleic acid testing of naso-oro-pharyngeal samples is the gold standard for diagnosis due to its high sensitivity and specificity. Direct antigen testing allows for rapid management decisions if positive, but has a low sensitivity, especially in asymptomatic patients. Active immunisation is the key to prevention and may require annual matching to circulating variants. Passive immunization with SARS-CoV-2 neutralizing anti-antibodies lost its indication due to the emergence of immune escape variants. Convalescent plasma has been proposed for passive immunization but is not readily available in most centres. For symptomatic patients, early antiviral treatment with nirmatrelvir/ritonavir or remdesivir may reduce the risk of progression to severe-critical COVID-19. Prolonged administration, repeated courses, and a combination of antivirals are considered for patients with clinical or virological failure to antiviral monotherapy. In severe-critical COVID-19, dexamethasone or drugs downregulating the inflammatory cytokine responses (anti-Il-6/anti-IL-2 agents, Janus kinase inhibitor) are recommended, together with the best supportive and intensive care, but care should be exercised in immunosuppressed patients. Deferral of intensive chemotherapy, HCT conditioning, T-cell-based immunotherapy, or T-cell engaging antibodies are considered for patients with COVID-19, whereas deferral decisions are taken on a case-by-case basis for asymptomatic patients with confirmed SARS-CoV-2 infection.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"47 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193039","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":"NOTCH1 signaling is dysregulated by loss of the deubiquitinase USP28 with del(11q), uncovering USP28 inhibition as novel therapeutic target in CLL","authors":"Alena Sophie Ehrmann, Miguel Quijada-Álamo, Viola Close, Min Guo, Valentina Carracoi, Claudia Pérez-Carretero, Luis Antonio Corchete, Tobias Friedrich, Benedetto Daniele Giaimo, Deyan Yordanov Yosifov, Johannes Bloehdorn, Alberto Rodríguez-Sánchez, Eugen Tausch, Christof Schneider, Hartmut Döhner, Thomas Kietzmann, Tilman Borggrefe, Stephan Stilgenbauer, Franz Oswald, Jesús-María Hernández-Rivas, Daniel Mertens","doi":"10.1038/s41375-025-02632-4","DOIUrl":"https://doi.org/10.1038/s41375-025-02632-4","url":null,"abstract":"<p>Aberrant active NOTCH1 signaling is a key pathogenic factor in chronic lymphocytic leukemia (CLL), detectable in half of patients and associated with disease progression. While some cases of active NOTCH1 signaling can be explained by mutations in <i>NOTCH1</i> or its regulators, like <i>FBXW7</i>, alternative mechanisms remain elusive. Here, we identified the deubiquitinase USP28 as regulator of NOTCH1 signaling in CLL. Notably, <i>USP28</i> is located within the frequently deleted chr11q23 region and is deleted in 90% of del(11q) patients, resulting in its decreased expression. USP28 interacts with the NOTCH1 intracellular domain (NICD) independently of FBXW7 and the NICD-PEST domain, stabilizing NICD and enhancing NOTCH1 signaling. Integrating RBPJ-occupied genes in HG3 cells, RNA-Seq of <i>USP28</i>^{<i>WT</i>/<i>KO</i>} cells and gene expression from del(11q) CLL patients, we identified 15 NOTCH1 target genes specifically dysregulated by deletion of USP28 and del(11q) potentially influencing CLL pathogenesis. Pharmacological inhibition of USP28 with the small molecule AZ1 suppressed NOTCH1 activation in primary CLL cells. AZ1 combined with the BCL-2 inhibitor venetoclax reduced CLL cell viability, particularly in samples with high NOTCH1 activity. Our findings highlight USP28 as promising therapeutic target and provide a rationale for combined inhibition of USP28 and BCL-2 in CLL patients with active NOTCH1 signaling.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"47 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144193166","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":"Correction: Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody.","authors":"Marc S Raab, Yael C Cohen, Fredrik Schjesvold, Kimberly Aardalen, Adwait Oka, Andrew Spencer, Martin Wermke, Anita D Souza, Jonathan L Kaufman, Anna Maria Cafro, Enrique M Ocio, Noriko Doki, Kristin Henson, Gina Trabucco, Ana Carrion, Florent C Bender, Pierre-Eric Juif, Adonai Fessehatsion, Liqiong Fan, Jeffrey P Stonehouse, John W Blankenship, Brian Granda, Serena De Vita, Haihui Lu","doi":"10.1038/s41375-025-02516-7","DOIUrl":"10.1038/s41375-025-02516-7","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":"1545"},"PeriodicalIF":12.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144078573","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":"What is radiation-induced acute myeloid leukaemia/can it be accurately identified?","authors":"Christophe Badie, Robert Peter Gale","doi":"10.1038/s41375-025-02561-2","DOIUrl":"10.1038/s41375-025-02561-2","url":null,"abstract":"","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":" ","pages":"1334-1336"},"PeriodicalIF":12.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143730569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of ELN clinical signs and symptoms on the thrombotic risk in polycythemia vera patients treated with front-line hydroxyurea","authors":"Francesca Palandri, Massimo Breccia, Elena M. Elli, Roberto Latagliata, Giulia Benevolo, Erika Morsia, Mario Tiribelli, Francesco Cavazzini, Alessandra D’Addio, Alessia Tieghi, Mirko Farina, Fabrizio Cavalca, Alessandra Dedola, Florian H. Heidel, Giuseppe A. Palumbo, Elena Rossi, Filippo Branzanti, Valerio De Stefano","doi":"10.1038/s41375-025-02646-y","DOIUrl":"https://doi.org/10.1038/s41375-025-02646-y","url":null,"abstract":"<p>The European LeukemiaNet recently proposed specific Clinical Signs and Symptoms (CSSs) that may trigger cytoreduction in patients with polycythemia vera (PV) at low thrombotic risk (LR). To evaluate the impact of CSSs on the thrombotic risk of patients at LR, high risk by age only (HR-AGE) or by previous thrombosis (HR-THRO), we conducted a multicenter cooperative study (NCT06134102) involving 739 PV patients treated with first-line hydroxyurea. At hydroxyurea start, 443 patients had at least one CSS. In patients with and without CSSs, the incidence rate ratio of thrombosis was 2.2 and 0.7 per 100 patient-years, respectively (<i>p</i> &lt; 0.001), and the thrombosis-free survival (TFS) adjusted for delayed entry at 5 years was 88.7% and 96.1% (<i>p</i> &lt; 0.001). The best 5-years TFS was observed in LR and HR-AGE with no CSSs (LR, 100%; HR-AGE: 98.1%). LR, HR-AGE patients with CSSs and HR-THRO patients without CSSs had comparable TFS (89.2%, 92.1% and 88.8%, respectively). TFS of HR-THRO patients was 80.2%. In multivariate analysis including each CSS, inadequate hematocrit control (HR: 2.32, <i>p</i> &lt; 0.001), relevant CVRFs (HR: 2.87, <i>p</i> = 0.006), progressive splenomegaly (HR: 4.02, <i>p</i> = 0.03) and previous thrombosis (HR: 3.76, <i>p</i> &lt; 0.001) remained significantly associated with thrombotic risk. CSSs identify an increased thrombotic risk phenotype across all risk categories.</p><figure></figure>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"98 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153323","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":"T cell receptor mimic CAR T cells targeting cathepsin G signal peptide","authors":"Jun Yan, Chunhua Shi, Guojun Yang, Ze Tian, Hiroki Torikai, Pariya Sukhumalchandra, Shaohua Peng, Edward Chang, Meng Cui, Celine Kerros, Anne Philips, Na Qiao, Mao Zhang, Timothy E. Lofton, Jason K. Allen, Michelle A. Gonzalez, Sathvik Patchametla, Anna Sergeeva, Lisa St. John, Helen He, Dongxing Zha, Jeffrey Molldrem, Gheath Alatrash","doi":"10.1038/s41375-025-02652-0","DOIUrl":"https://doi.org/10.1038/s41375-025-02652-0","url":null,"abstract":"<p>There has been a been a paucity of immunotherapy targets in myeloid malignancies. We identified the HLA-A2 (A2)-restricted, cathepsin G (CG)-derived signal peptide, CG1, as a promising immunotherapeutic target. CG1 is presented by HLA-A2 in acute (AML) and chronic (CML) myeloid leukemia. We previously developed a T cell receptor-mimic antibody (TCR-m) that targets CG1/A2, engineered it into a bispecific T cell engager antibody, and demonstrated its safety and efficacy in AML and CML. In this study, we provide data for the engineering, preclinical efficacy, and safety of CG1/A2-targeting chimeric antigen receptor (CAR) T cells (CG1/A2-CAR T), which utilize the CG1/A2 TCR-m constructs. We show that the CG1/A2 TCR-m has high affinity for CG1/A2 monomers and CG1/A2-expressing leukemia, including HLA-A2⁺ AML and CML. We demonstrate potent CG1/A2 CAR T killing of HLA-A2⁺ AML and CML both in vitro and in vivo. Importantly, we found that CG1/A2-CAR T cells did not affect normal bone marrow hematopoiesis. These results validate signal peptides as immunotherapeutic targets and provide a foundation for the continued clinical development of CG1/A2-CAR T cells in AML and CML.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"171 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144153324","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":"Cluster analysis reveals the clinical spectrum of Erdheim-Chester disease","authors":"Michelangelo Tesi, Francesco Pegoraro, Francesco Peyronel, Jean-François Emile, Francesco Catamerò, Matthew J. Koster, Gaurav Goyal, Matthew Collin, Paul Milne, Samia Boussouar, Fleur Cohen-Aubart, Matthias Papo, Zahir Amoura, Juvianee I. Estrada-Veras, Kevin O’Brien, Jerome Razanamahery, Radjiv Goulabchand, Ahmed Idbaih, Mathilde de Menthon, Noemie Gensous, Achille Aouba, Emmanuel Ledoult, Tanguy Le Scornet, Antoine Néel, Ronald S. Go, Roei D. Mazor, Corrado Campochiaro, Lorenzo Dagna, Eli L. Diamond, Augusto Vaglio, Julien Haroche","doi":"10.1038/s41375-025-02656-w","DOIUrl":"https://doi.org/10.1038/s41375-025-02656-w","url":null,"abstract":"<p>Erdheim-Chester disease (ECD) is a clonal-inflammatory neoplasm driven by mutations in MAPK pathway proto-oncogenes, such as <i>BRAF</i>. Clinical manifestations are protean, affecting virtually every system. This cohort study analyzed 661 patients with ECD to classify them based on clinical features and mutational profiles using unsupervised clustering. Nineteen clinical and mutational variables were subjected to hierarchical clustering combined with k-means. A three-cluster model emerged as the most stable. Most patients were classified according to key features, namely <i>BRAF</i>^<i>V600E</i> mutation, and large-vessel, heart, and perirenal involvement. The “Widespread Disease” (WID) cluster (320 patients, 49%) was associated with the presence of the key features and the “Limited Disease” (LIM) cluster (282 patients, 42%) was associated with their absence. The “<i>MAP2K1</i>-RDD” cluster (MAP) was assigned 59 patients (9%), based on <i>MAP2K1</i> mutation and/or overlapping Rosai-Dorfman-Destombes disease (RDD). Survival analysis revealed worse outcomes for WID compared to LIM (hazard ratio 1.54, 95% CI 1.09–2.17), while no significant survival difference was found for MAP. The identification of these clusters, based on mutational profiles, organ involvement and overlapping conditions, offers a data-driven validation of established clinical observations. These findings substantiate the role of the somatic mutation type in shaping the ECD phenotype.</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":"5 1","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144165411","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}